PSY 2007 Biological Psychology

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  • Created by: agloes
  • Created on: 05-02-18 10:18

Studying Sleep

polysomnogram: sleep study, a test used to diagnose sleep disorders. It records brain waves, the oxygen levels in blood, heart rate, and breathing, as well as eye and leg movements 

electroculography (EOG): a technique for measuring the corneoretinal standing potential that exists between the front and the back of the human eye. The signal is called the electroculogram

electromyopgraphy (EMG): a diagnostic technique that uses a machine to measure the electrical activity of skeletal muscles. The electrical measurements of muscles are used to detect muscular abnormalities and neuromuscular diseases

electrocardiogram (ECG/EKG): records the electrical activity of the heart over time. These waves pass through the body and can be measured at electrodes (electrical contacts) attached to the skin

electroencephalography (EEG): A recoding of the electrical waves of activity that occur in the brain, and across its surface. Electrodes are placed on differenct areas of a person's scalp, filled with a conductive gel, and then plugged into a recording device. Brain waves are then attracted by the electrodes, travel to the recording device and then amplified so that they can be more easily seen and examined

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Waves

Hertz: the SI unit of frequency, equal to one cycle per second, sine waves

Beta Wave (β): The frequency of the electrical activity in the brain that falls between 12 and 30 Hz and is the state that is associated with normal waking consciousness

Alpha Wave (α): 8-13 Hz. A type of brain wave that occurs when a person is relaxed, but still awake. α waves typically occur when you are falling asleep, as you pass from wakefulness into sleep

Theta Wave (θ): 3.5 - 7.5 Hz. A  frequency of electric wavelength that is produced by the brain. Cortical θ rhythms are lower frequency and have been recorded only in humans 

Delta Wave (δ): Less than 4 Hz. A type of brain wave that is large (high amplitude) and slow (low frequency) and is most often associated with slow wave sleep

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Stages of Sleep

Awake: alpha and beta wave activity 

Transitional Stages

  • Stage 1: Beta waves, lasts ~10 minutes
  • Stage 2: ~15 minutes, sleep spindles, K-complex

Slow Wave Sleep: deep sleep, non-REM sleep

  • Stage 3 & 4: delta waves 

Rapid Eye Movement (REM) sleep: A sleep period during which the brain is very active, and eyes move in a sharp, back and forth motion as opposed to a slower, more rolling fashion that occurs in other stages of sleep, also known as paradoxical sleep. Useful to diagnose causes of impotence.  

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Why do we sleep?

Most sleep on a circadian cycle, however some species sleep in very short bouts but they still get ~ 7 hours a day in total. Other species can sleep with one hemisphere at a time. This sort of happens in humans, however it is just the activity in the hemispheres that differ; it is not one at a time. 

Sleep deprivation: the condition of not having enough sleep; it can be either chronic or acute. Can cause fatigue, daytime sleepiness, cluminess, and weight loss or gain

  • Compensate by more sleep later (mostly SWS and REM)
  • No effect on exercise, but clear effect on concentration, cognitive abilities, and emotional control
  • rebound phenomenon: the increased frequency of intensity of a phenomenon after it has been temporarily suppressed; e.g. the increase in REM sleep seen after a period of REM sleep deprivation 
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Basic Features of the Nervous System

Nervous system consists of:

1. Central Nervous System: brain and spinal cord

  • Brain: encased in the skull and cerebrospinal fluid, a large mass of neurons, glia, and other supporting cells. Most protected organ, receiveds a large supply of blood and chemically guarded by the blood-brain barrier 

  • Spinal cord: consists of white matter, grey matter = cell bodies

2. Peripheral Nervous System: cranial nerves, spinal, nerves, and peripheral ganglia 

  • Spinal nerves: formed by junctions of the dorsal roots and ventral roots 
  • Autonomic Nervous System: 1) sympathetic 2) parasympathtic 
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Meninges

The three layers of tissue that encase the CNS, the dura mater, arachnoid membrane, and pia mater. 

dura mater: the outermost of the meninges; tough and flexible 

arachnoid membrane: the middle layer of the meninges, located between the outer dura mater and inner pia mater 

pia mater: the layer of the meninges that clings to the surface of the brain; thin and delicate 

subarachnoid space: the fluid-filled space that cushions tha brain; located between the arachnoid membrane and pia mater 

cerebralspinal fluid (CSF): A clear fluid, similar to blood plasma that fills the ventricular system of the brain and the subarachnoid  

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Ventricular System and Production of Cerebrospinal

Ventricle: One of the hollow spaces within the brain, filled with CSF

  • Lateral ventricle: One of the two ventricles located in the centre of the telecephalon
  • Third ventricle: The ventricle located in the centre of the diencephalon
  • Fourth ventricle: the ventricle located between the cerebellum and the dorsal pons, in the centre of the metecephalon 

Cerebral aqueduct: a narrow tube inerconnecting the third and fourth ventricles of the brain, locted in the centre of the mesencephalon 

choroid  plexus: the highly vascular tissue that protudes into the ventricles and produces CSF

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Forebrain

The most rostral of the three major divisions of the brain, including the telencephalon and diencephalon.

Telencephalon contains the cerebral cortex, limbic system, and basal ganglia. The main ventricle is the lateral ventricle.

The main ventricle for the diencephalon is the third ventricle and it contains the thalamus and hypothalamus. 

The primary visual cortex, primary auditory cortex, and the primary somatosensory cortex are three regions that receive sensory information. Primary motor cortex (movement control) is also included. 

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Midbrain

Or mesencephalon, the central of the three major divisons of the brain

Consists of:

  • tectum: involved in audition and the control of visual reflexes and reactions to moving stimuli
  • tegmentum: contains reticular formation (important in sleep, arousal, and movement), periaquductal grey matter, red nucleus, and substantia nigra. 

Major ventricle: cerebral aqueduct

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Hindbrain

The most caudal of the three major divisions or the brain; including the metencephalon and myelencephalon. It surrounds the fourth ventricle.

Contains the cerebellum, pons, and medulla. 

  • cerebellum: A major part of the brain located dorsal to the pons, containing the two cerebellar cortex; an important component of the motor system
  • pons: The region of the metencephalon rostral to the medulla, caudal to the midbrain, and ventral to the cerebellum
  • medulla: The most caudal portion of the brain; located in the myelencephalon, immediately rostral to the spinal cord. Involved in sleep and arousal and plays a role in control of movent and vital functions
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Spinal Nerves

spinal nerve: a peripheral nerve attached to the spinal cord, begins at the junction of the dorsal and ventral roots of the spinal cord

Part of the somatic nevous system, and from thoracic to lumbar regions and sacral regions are part of the autonomic nervous system. 

afferent axons: An axon directed toward the central nervous system, conveying sensory information; "bear toward" CNS

dorsal root ganglia: A nodule on a dorsal root that contains cell bodies of afferent spinal nerve neurons

efferent axons: An axon directed away from the central nervous system, conveying motor commands to muscles and glands; "bear away from" CNS

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Cranial Nerves

Attached to the ventral surface of the brain. A peripheral nerve attached directly to the brain. Most of these nerves serve sensory and motor fuctions of the head and neck region. 

vagus nerve: the largest of the cranial nerves, conveying efferent fibers of the parasympathetic division of the autonomic nervous system to organs of the thoracic and abdominal cavities

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Peripheral Nervous System

Includes the somatic nervous system with spinal nerves, crainal nerves, and the autonomic nervous system

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Functions of sleep

Evolutionary Theory

  • Sleep to conserve energy during the least productive parts of the day. However, this does not explain WHY we sleep. Explains more of why we sleep WHEN we do.
  • We sleep at night (or during the day) to save energy during that time when we are least likely to get anything done, either due to predation pressure or anyother reasons
    • If you keep someone in 24h light conditions they will still sleep. So, sleep is not just a reaction to light conditions and not being able to do anything
  • Species differences are conistent to this theory
    • large animals sleep more
      • large meal = less need for productivity (e.g. lions sleep a lot more compared to a zebra)
    • smaller animals sleep less
      • grazing animals, therefore more productive
  • Good theory to predict constraints on sleep, but not sleep itself
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Functions of sleep

Brain Revovery Theory

  • Brain recovery during slow wave sleep, resting and recovering the brain
  • STUDY: Overheating vs. cooling during exercise. Method - Hair dryer to hear head, hot vs. cold. Result - Overheating lead to more slow wave sleep. 
    • However, SWS is not affected by physical exercise. SWS is affected by brain temperature and by 'mental exercise'. 
  • Metabolic breakdown products are cleared during SWS (e.g. Amyloid β)
    • During this, the brain is in a different physical state to clear by-products
  • SWS is triggered by high metabolic rates. More mental stimulation = more SWS and more δ wave activity
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Functions of sleep

Memory Consolidation Theory

  • The brain needs to perform two mutually-exclusive fuctions: 1) be aware of its enviroment at all tiems 2) store memories for the longer term
  • Brain cannot do two processes at the same time with the same neurons
  • Storing long-term memories in existing circuitry is a slow process if one does not want to disrupt existing memories. So, the only way to store memories is to do it while the brain is NOT busy paying attention to its environment. Then, 'quick' memory traces (in the hippocampal circuitry) are replayed over and over into the cortex to put down new long-lasting memory traces.
  • If repetition is needed for memory consolidation, in order to store unique memories to LTM, the hippocampus must 'playback' which occurs during sleep.
  • REM sleep: consolidation of procedural memories and/or emotional memories 
    • Babies have more REM vs adults due to learning everything, therefore there is a correlation for procedural memories and REM
    • So, more learning = more REM. Less REM » worse memory retention
      • However, depends on kind of learning 
  • SWS: consolidation of explicit memories (hippocampus-dependent)
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Effect of REM on Learning

Study

  • Method: Trained in the morning on visual discrimination task. 90 minutes nap including SWS and REM, or just SWS, or no nap
  • Result:
    • SWS & REM: improvement with task
    • SWS only: stayed the same 
    • No nap: no improvement 
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Functions of sleep

Memory Consolidation Theory - SWS

  • Memory traces stored in the hippocampal circuitry are replayed during SWS
    • If occurs, should be able to record hippocampus activity in SWS
    • In mice, place cells » left hemisphere. Replays in SWS at a much quicker speed
    • Experiments with humans also confirm the importance of SWS for explicit memory consolidation.
      • however, only can be studied through behavioural observation
  • SWS in learning
    • with SWS, subjects on a declarative learning task (through a list of paired words) » task performance improved
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Rasch et al.

Procedure - Subjects learned a 2D object spatial location task (using the game 'Concentration') requiring memorization of the location of card-pairs showing the object. The set consisted of 15 card-pairs. Learning was followed by noctural sleep and recall was tested on the next day. 

  • EXP. 1 - An odor was presented repeatedly while subject learned the card-pair location, to form a context association. Same odor was presented again during subsequent SWS, memory for the spatial locations was distinctly enchanced at later retrieval, compared with a control night without odor re-expousre during SWS after learning.
  • EXP. 2 - Odor was not presented during learning, but only presented during SWS.
  • EXP. 3 - Odor presented during learning, re-exposed during REM
  • EXP. 4 - Odor presented during learning, re-exposed during waking. 

Results - To produce memory enchancement, association between odor and card-pair locations formed during learning was crucial because EXP. 2-4 proved to be uneffected. fMRI data showed that cuing memories thorugh odor re-exposure during SWS was associated with hippocampal activation. SO, hippocampal reactivation during SWS have a causative role for memory consolidation 

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Dreams

  • Everybody dreams during REM (but also some during nREM)
  • During REM, primary visual areas are very active, but inferior frontal is not. So inferior frontal is likely involved with memorizing event » hence why we forget dreams. This also relates to dreams being kind of "stream of consciousness" with no clear timeline; this same phenomenon happens in people with inferior frontal damage
  • Eye movements may be related to scanning visual scenes in dreams
  • SWS is sometimes accompanied by night terrors, but not narrative dreams 
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Why do we dream?

Activation-Synthesis Hypothesis (Hobson): dreaming results from the brain's attempt to make sense of neural activity that takes place during sleep; mechanistic, not functional explanation

External stimuli + internal stimuli (recent experiences, memories) = brain synthesizes a 'story' » dream

Possible that there is no function to dreaming. The function could be in replaying connections in the brain to move information to reinforce connections, and the "conscious experience" is a by-product. Given that inferior frontal cortex is not active, casuing us to forget really quickly, very possible that contents of dreams do not serve a conscious function. 

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Major Brain Subdivisions

Brain development: Forebrain » Midbrain » Hindbrain

Brainstem Reticular Formation: a group of dozens of nuclei running through medulla, pons, and tegmentum, part of this formation makes up the Reticular Activating System (RAS).

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Principle Cells of the Nervous System

Glia: The supporting cells of the central nervous system. They constitute approximately 85% of the cells of the brain. They surround neurons and hold them in place, control their supply of nutrients, insulate, neurons and remove dead neurons. 

neurons: the information-processing and information-transmitting element of the nervous system. Massive parallel procress, forms circuits. 

  • within-cell communication » electrical (e.g. action potential)
  • between-cell communication » chemical (e.g. neurotransmitters)

synapse: a junction between the nerve cells, consisting of a minute gap across which impulses pass by diffusion of a neurotransmitter

  • vesicles have neurotransmiter action potentials that release neurotransmitters into synaptic cleft, slower than electrical messages 
  • receptor molecules are located in the post-synaptic density 
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Mechanisms of Arousal

Reticular Activating System: consists of nuclei and tracts that are involved with regulating wakefulness, arousal, and some aspects of sleep

Acetylcholine (ACh): Two groups of ACh neurons: 1) in RAS in the pons (metencephalon) 2) basal forebrain (metencephalon). Small group with large axons, have synapes in almost every part of the brain. 

  • When active, brain = alert
  • stimulation of these neurons increases acetylcholine levels in the cortex and increases alertness
  • Cholinergic antagonists make EEG more sychronized, cholinergic agonists desynchronize

Noradrenaline (NAd)/ Norepinephrin (NorE): From Locus Coeruleus (in RAS in Pons). High activity during waking, lower during sleep. Related to Vigilance, induced by external stimuli.

  • amphetamines are agonists of the NAd system, they increase wakefulness and reduce sleepiness
  • activity of the LC related to unexpected stimuli or paying attention to presence or absence of stimuli; activated by type of stimuli that will induce behavioural changes 
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Mechanisms of Arousal

Serotonin (5HT): from Raphe Nuclei (RAS in Pons and Medulla); high during waking, low during sleep. Influences locomotion and cortical arousal, but not sensitive to external stimuli, more internal i.e 'I need to do the dishes'

  • more active while awake, less to nothing while asleep
  • electrical stimulation causes cortical arousal vs drug which influences 5HT production decreases arousal
  • more involved in keeping ongoing activity going, rather than reacting to stimuli
    • decrease firing when external stimulus (which would induce the noradrenergic system) arrives

Histamine: In the Tuberomammilary Nucleus (in the Hypothalamus); high during waking, low during sleep. Anti-histamines put you to sleep. Pharmacology » allergies

Hypocretin (=Orexin): In the lateral hypothalamus (like master controller). Has exictatory hypocretinergic connection to many brain areas. Active during active waking and exploration. Inactive during sleep. Injection of hypocretin promotes activity » wakefulness

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Mechanisms of Sleep Induction

  • Ventrolateral Preoptic Area (vlPOA)
    • in Hypothalamus
    • Connects through GABA-ergic (inhibitory) synapses to:
      • Acetylcholinergic area of basal forebrain
      • Tuberomammilary nucleus (histamine)
      • Raphe nuclei (serotonin)
      • Locus coeruleus (noradrenaline)
      • Lateral Hypothalamus (orexin)
    • Receives inhibitory input from most of these same brain areas
    • Inhibits arousal and neurotransmitters in 'alert' system, actively turns off
  • Destruction of VLPOA leads to insomnia and DEATH
  • Stimulation leads to drowsiness and sleep
  • Recording in VLPOA shows firing increases with drowsiness AND this is stronger when sleep deprived 
  • Hunger/orexinergic neurons keep you awake
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Mechanisms of Sleep Induction

Flip-flop is a system that is stable only in 2 mutually exclusive states. It can flip from one to the other state either spontaneously (system is unstable), or through outside influence. 

Feature of flip-flop systems is that state changes go quickly; that makes sense: we’re either awake or asleep transitions are fast (is adaptive too).

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Mechanisms of Sleep Induction

Adenosine: Produced by astrocytes which use up their glycogen stores. Increased levels of adenosine causes more δ-activity during SWS, increases IPSP. Has inhibitory effects on neurons. When glucose needs to be supplemented, glycogen stores in astrocytes are tapped, this causes the production of adenosine. Adenosine accumulates during the day, during night glycogen is restocked and adenosine goes down. 

  • matches brain recovery hypothesis
  • hypotheses for adenosine action
    • Disinhibition of vIPOA 
    • Inhibition of hypocretinergic neurons (these contain adenosine A1 receptors). Because hypocretinergic neurons are not involved in the mutual inhibition, they can bias the system to the "awake" state by activating the arousal system, hence suppressing the sleep-promoting system. 
  • more brain use = more glucose use. So, glucose breaks glycogen down which leads to more adenosine » more SWS
  • Adenosine repector blocked (i.e. caffiene) » stay awake
  • accumulation of adenosine indirecly leads to the activation of the vIPOA
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Mechanisms of Sleep Induction

Temperature of Brain and Skin: Sensed by another region in the basal forebrain. Higher temperature » inhibits ACh basal forebrain areas, inhibits tuberomammilary nucleus (which induces sleepiness)

  • this may explain the feeling of drowsiness when we have a fever, a hot summer day, or a hot lecture theatre

Dorsomedial Nucleus of the Hypothalamus: Input from Dorsomedial nucleus of the hypothalamus of the vIPOA and Laternal hypothalamus (orexinergic)

Which flip-flop state depends on the summation of the outputs. 

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REM Sleep

Brain is very active: θ and β activity

Loss of muscle tone = paralysis, penile erection, vaginal secretion

  • paralysis is produced by connections between neurons adjacent to the SLD that excite inhibitory interneurons in the spinal cord

Clear, narrative dreams

Rapid eye movements: produced by indirect connections between the SLD and the tectiom, through the medial pontine reticular formation and the AChnergic neurons in the pons

Pontine-Geniculate-Occipital (PGO) waves:

  • Seen at least in laboratory animals; hard to measure in humans because it needs intracranial electrodes
  • Related to the visual system because “occipital”. This maybe related to visual aspects of dreams
  • Waves start from the pons, then LGN, then visual cortex
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Onset of REM sleep

  • Mutual inhibition between:
    • Sublaterodorsal Nucleus (SLD) in dorsal pons » REM ON
      • SLD: Brain regions that control components of REM sleep. A region of the dorsal pons, just ventral to the locus coeruleus, that forms the REM-ON portion of the REM sleep flip-flop
    • Ventrolateral Peri-aqueductal Grey matter (vlPAG) in midbrain » REM OFF
      • vlPAG: A region of the dorsal midbrain that forms the REM-OFF portion of the REM sleep flip-flop.

This is another flip-flop! It is controlled by the sleep/waking flip-flop; only when the sleep flip-flop is in the 'sleeping' state can the REM flip-flop switch to the REM state. 

The lateral hypothalamus orexinergic neurons activates the vlPAG, then the vlPOA inhibits the vlPAG

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Sleep/Waking Flip-Flop

The major sleep-promoting region (the vlPOA) and the major wakefulness-promoting regions (basal forebrain and pontine regions that contain ACh neurons; the locus coeruleus, which contains NAd neurons; the raphe nuclei, which contains 5HT neurons; and the tubermammillary nucleus of the hypothalamus, which contains histaminergic neurons) are reciprocally connected by inhibitory GABAergic neurons.

When the flip-flop is in the "wake" state, the arousal systems are active, the vlPOA is inhibited, and the animal is awake.

When the flip-flop is in the "sleep" state, the vlPOA is active, the arousal systems are inhibited, and animal is asleep. 

When it switches from one state to the other, it is done so quickly. However, can be unstable. 

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REM Sleep onset triggers

Increase in activity in vlPOA » Decrease in activity in the lateral hypothalamus (orexin), nucleus coeruleus (NAd), raphe nuclei (5HT)

Temperature goes down during SWS and temperature does up during REM » may be the possible driver of the cycle

  • you fall asleep bettern when it's warm, but you don't get to REM as easy
  • However, the mechanism is not completely understood 
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Mechanisms of REM sleep

REM ON neurons (in SLD) (in)directly affect AChnergic basal forebrain and AChnergic pons which activates the lateral preoptic area, the LGN in the thalamus, neurons in the tectum, and causes muscle paralysis. 

Activation of the:

  • Lateral preoptic area » genital activity
  • LGN » PGO waves
  • Tectum (Mesencephalon) » Rapid eye movement

Some cholinergic agonists (like insecticdes) increase REM and antagonists decrease REM. Some of the synapses involved are nicotinic. The same neurons responsible for arousal, but now with low serotonin and NAd. 

These are all active during REM (REM-ON cells), and some during wakefulness as well. 

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Sleep Disorders

Insomnia: Difficulty falling asleep after doing to bed or after awakening during the night; affects approximately 25% of the population. Mostly self-reported; when actually measured time to fall asleep is often not much longer in self-proclaimed insomniacs. Sleeping pills can lead to drug-dependent insomnia because the body becomes physically dependent on the drug and cannot fall asleep with out it.

  • Sleep apnea: Cessation of breathing while sleeping. This wakes them up again. Often a physical problem with the airways that can be fixed surgically. 

REM sleep behaviour disorder (REM without Atonia): A neurological disorder in shich the person does not become paralyzed during REM sleep and thus acts out dreams. Caused by genetics or damage to brain stem. 

Problems during SWS: e.g. betwetting, sleepwalking, night terrors

  • sleep-related eating disorder: A disorder in which the person leaves their bed and seeks out and eats food while sleepwalking, usually without a memory for the episode the next day,
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Sleep Disorders

Narcolepsy: A sleep disorder characterised by periods of irresistible sleep, attacks of cataplexy, sleep paralysis, and hypnagogic hallucinations

    • sleep attack: a symptom of narcolepsy; an irresistible urger to sleep during the day, after which the person awakens feeling refreshed. People actually fall asleep.
    • cataplexy: a sympton of narcolepsy; complete paralysis that occurs during waking, often brought about by strong emotions
    • sleep paralysis: a sympton of narcolepsy; paralysis occurring just before a person falls asleep
    • hypnagogic hallucination: a sympton of narcolepsy; vivid dreams that occur just before a person falls asleep; accompanied by sleep paralysis 
  • Often genetic. The system responsible involved Orexin.
  • Shows degeneration of hypocretinergic neurons in humans; narcoleptic dogs show an inherited absence of hypocretin-2 receptors 
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Stimulants (& Alcohol)

Cocaine

Stimulant drug extracted from the coca plant which grows in regions of South America. Believed to reduce the fatiague associated whith the high altitude. Typically snorted in powder form or smoked in its free-base form (crack). Reaches peak in blood at 30-60 minutes if snorted (20-30% of drug makes it into circulation); much faster when smoked. Easily penetrates the blood-brain barrier. Biological half-life: 30-90 minutes. Can also be directly injected or ingested. 

Short term effects - Stimulant. Increases euphoria, energy, confidence, talkativieness, activity, alertness, attention.

Physiological action - Speeds up the CNS. When snorted, it enters the body through blood vessels in the nose and goes into the bloodstream where it travels throughout the body and crosses the blood-barin barrier. Monoamine (5HT, DA, NAd, Ad) transporter blocker; blocks DA reuptake thus it's an indirect agonist of DA repectors. This increases concentration of monoamines » more stimulation

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Stimulants (& Alcohol)

Cocaine 

Long term effects - The lack of reuptake results in depletion of monoamines. This leads to the "crash" into depression after several hours. This is usually remdied by takin gmore cocaine which leads to 2-3 day cocaine binges. It destroys the nasal septum because it is a vasoconstrictor; no blood to tissue, dies off. Schizophrenia-like symptoms occur (i.e. hallucinations, delusions or persecution, mood disturbances, repetitive behaviours). This leads mental health professionals having a hard time distinguishing between them. This leads to the theory that schizophrenia may be due to overactivation of some monoaminergic system in the brain. It can also lead to sexual dysfunction. Tolerance occurs for some 'desired' effects i.e. euphoria and sensitisation for other effects i.e. convulsiveness, addictiveness. Most users use more to couteract tolerance. Withdrawal symptoms are less bad compared to heroin, but they still exist. 

Addictiveness - Direct effect on dopamine released in the N. Accumbens and prefrontal cortex. Therefore, it directly activates the "seeking" or "reward" pathway. Strong 'psychlogical' addictiveness, much less physical addictiveness. 

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Stimulants (& Alcohol)

Amphetamines

Uptake speed and half-life depend on the drug and the method of taking it. All cross the blood brain barrier with ease. Different forms are taken as drugs of abuse:

  • Speed (d-amphetamine): often taken orally
  • Crystal meth (methamphetamine): often smoked
  • Ecstasy (MDMA): usually taken orally
  • Mephedrone, methadrone, methylone (cathinone derivatives): snorted or orally

Short term effects - Increases euphoria, energy, confidence, talkativeness, activity, alertness, attention. MDMA is often used in raves. Methylone is similar to MDMA. Increased confidence and feelings of energy lead to an increase in dehydration, exhaustion, muscle breakdown, overheating, convulsions. 

Physiological action - Enhances monamines i.e. serotonin, dopamine, and noradrenalin, but influences dopamine the most.  

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Stimulants (& Alcohol)

Amphetamines

Long term effects - Similar to cocaine. Tolerance and sensitisation to some effects. Extended use of MDMA can kill dopaminergic and serotonergic neurons in teh brain. Decrease in serotonin can lead to depression symptoms. 

Addictiveness - Similar to cocaine. Strong potential for "psychological" addiction. Lower potential for "physical" addiction. 

Ritalin (Methylphenidate) - Acts similary to cocaine by blocking the monoamine reuptake transporter. The release is much more gradual and it does not have the same immediate effects as cocaine, therefore there is no high. It is an effective treatment for ADHD possibly because the increase at noradrenaline synapses increases attention, while the increase at serotonergic synapses serve to calm. Ritalin has been being taken more and more as a study drug. 

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Stimulants (& Alcohol)

Caffeine

Typically ingested in coffee or soft drinks. Concentration peaks after ~40 minutes. Easily passes through the blood-brain barrier. Biological Half-life: 3.5-5 hours (longer in chlidren). Lethal does: 100 cups of coffee (10g of caffeine). 

Short term effects - Increases alertness and wakefulness, induces clear thinking and restlessness, difficulty with fine movements, increases cardiac contractions, constricts blood vessels. Side effects are anxiety, insomnia, change in mood, hypertension

Physiological Action - Blocks adenosine receptors. Adenosine is involved in inducing sleep and vasodilation (dilation of blood vessels that decreases blood pressure). Stimulates adrenaline release from adrenal gland. Headaches are often due to vasodilation, so caffeine helps by vasoconstriction. 

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Stimulants (& Alcohol)

Caffeine

Long term effects - Mostly sleep deprivation (especially SWS). Some of its effects can be countered by using more caffeine to wake up in the morning. 

Addictiveness - Clear physical dependence, withdrawal includes: headaches (vasodilation), sleepiness, irritability, difficulty concentrating. Psychological dependence: increases dopamine release in the n. Accumbens. Dopamine release is stimulated by blocking Adenosine A1 receptors (but not A2A). 

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Stimulants (& Alcohol)

Nicotine

From the tobacco leaf, typically smoked and sometimes chewed. Within 7 seconds of a puff, 25% of the nicotine in the smoke has already croosed the blood-brain barrier. Biological half-life: 2 hours in the chronic smoker 

Short term effects - Induces vomiting by stimulating receptors in the brain stem region which induces vomiting (aslo stimulates receptors in the stomach), reduces muscle tone (relaxes) and weight gain, increases heart rate and blood pressure. The body gains tolerance very quickly, so smokers do not have issues with vomiting, mostly onaly at first time smoking. The feeing of relaxation is not more relaxed than non-smoker, but when not smoking stress levels are higher because of tolerance mechanism. So smoking just brings the balance back. 

Physiological action - Binds to nicotinic ACh repeptors. Nicotinic receptors are involved in stimulation of sympathetic nervous system, including the release of adrenaline from the adrenal gland. Nicotinic receptors are also found in the brain. 

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Stimulants (& Alcohol)

Nicotine

Long term effects - Body easily develops tolerance. Possibly wears out the heart more quickly. Major problems are from other components of tobacco (and cigarette smoke), which can cause cancer, cardiovascular disease, etc. 

Addictiveness - A large component of physical dependence, withdrawal symptoms: craving, irritability, increased appetite, imsomnia. It is possibly the most addictive drug from a psychological point of view. The effect is most in the VTA because the nicotinic blocker here countered the effects of nicotine on dopamine release in the N Acc, whereas the same blocker in the N Acc does not. 

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Stimulants (& Alcohol)

Alcohol

Usually ingested (mostly as drinks). Reaches max blood concentration in 30-90 minutes. Easily crosses the blood-brain barrier due to is solublity in both water and lipids. Mostly eliminated through the liver, which breaks it down at a steady rate. It can be taken up directly from the stomach if it is empty; if full, it takes longer. 

Short term effects - Low dose » mild euphoria, anxiolytic effect. Higher does: intoxication » slower reflexes, incoordination, sedation, memory problems. Bilation of blood vessels » heat loss. Diuretic » more urination. 

Phsyiological Action - Agonist of GABA-A receptors which increases inhibitory processes. Antagonist of NMDA receptors which suppresses excitatory processes. GABA-A repectors are targeted by anxiolytic drugs such as BZs. This is probably what is responsible for the anxiolytic properties of alcohol. NMDA recpetors are involved in memory formation, so this explains memory problems. NMDA antagonists also have anxiolytic, sedative, and cognitive effects. 

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Stimulants (& Alcohol)

Alcohol

Long-term effects - Cirrhosis of the liver » liver failure. Brain damage, especially hippocampus » Korsakoff's syndrome. Foetal alcohol syndrome. 

Addictiveness -

  • Physical dependence: Tolerance is induced even from one night drinking and results in mild withdrawal symptoms (hangover). After chronic use, there are very strong withdrawal symptoms (Delirium Tremens); this can be fatal. Part of the hangover symptoms are from dehydration as well. Seizures are caused by sensitization of the NMDA receptors by tolerance (upregulation), which are then overstimulated upon withdrawal. 
  • Psychological dependence: It increases dopamine release in the N. Acc (as do other NMDA receptor antagonists). Strong hertable component to alcoholism. Opiod antagonists can reduce the rewarding properties of alcohol. 
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Reward in the brain

Classical Conditioning: A learning procedure; when a stimulus that initially produces no particular response is followed several times by an unconditional stimulus that produces a defensive or appetitive response (the unconditional response), the first stimulus (now called a conditional stimulus) itself evokes the response (now called a conditional response)
 

Operant Conditioning: A learning procedure whereby the effects of instrumental conditioning a particular behavior in a particular situation increase (reinforce) or decrease (punish) the probability of the behavior; also known as instrumental conditioning. In which we or animals profit from experience

  • reinforcing stimulusAn appetitive stimulus that follows a particular behavior and thus makes the behavior become more frequent.
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Operant Conditioning - Reinforcement

Olds and Milner discovered that rats would perform a response that caused electrical current to be delivered through an electrode placed in their brain; thus, the stimulation was reinforcing. Although several neurotransmitters may play a role in reinforcement, one is particularly important: dopamine. The cell bodies of the most important system of dopaminergic neurons are located in the ventral tegmental area, and their axons project to the nucleus accumbens, prefrontal cortex, limbic cortex, and hippocampus.

Intracranial self-stimulation research is what lead to the discovery of several brain areas in which stimulation is rewarding: i.e. it increases lever pressing rates. There is a very strong effect in the medial forebrain bundle. This caries a lot of dopaminergic axons from the mesencephalon to the telencephalon; especially from the substantia nigra to dorsal straitum (basal ganglia) » motor coordination, and from the ventral tegmental area to the nucleus accumbens. 

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Mesotelencephalic Dopamine System

It is a system that has cell bodies in the mesocephalon, specifically the ventral tegmental area and the substantia nigra, that has axons that make synapses in the telencephalon. The nuclei in the mesocephalon use dopamine as their main neurotransmitter. 

The main target of the VTA is the nucleus accumbens, where it releases DA. The medial forebrain bundle connects the VTA and the nucleus accumbens that releases DA. With stimulation, DA is released and a strong reinforcement effect occurs. This is a crucial step in the reward system. 

However, dopamine is released with punishing stimuli as well. So, reinforcement ≠ pleasure. Overtrained rats do not release dopamine upon reward. DA blockers make rats work less hard for food, but they still enjoy it. Therefore, the system doesn't say "this is good!!!" rather is seems to say "this is important, pay attention and change behaviour."

You can think of addiction as a reinforcement of the behaviour of taking a drug. 

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Seeking hypothesis of dopamine

The release of DA triggers seeking or exploration for stimuli. The exploration and the drive to explore in itself is pleasurable. 

Male rat is placed in a new environment (does not know it is a sex chamber), and DA levels increase even before a female is introduced. 

However, the feeling of seeking or searching is also reinforcing. 

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Drugs

Drugs: Chemical substances which interact with the biochemistry of the body. It inhibits or reinforces enzyme activity, blocks or activate receptors, interacts with neurotransmitters or hormones in other ways, and it attacks "invaders" (e.g. antibiotics).

Psychoactive drugs: Any chemicals that influence the way we feel or act. Usually they interact with the nervous system and/or the endocrine system. Mostly, they act at synapses (among other places).

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Agonist vs. Antagonist

agonist: A drug that facilitates the effects of a particular neurotransmitter on the postsynaptic cell.

antagonist: A drug that opposes or inhibits the effects of a particular neurotransmitter on the postsynaptic cell.

At the receptor level, if the receptor is in the post-synaptic terminal, then the agonist on the receptor is the same as the agonist on the synapse. Same concept goes for antagonists. 

However, there are also receptors in the pre-synaptic terminal. Usually, these have negative-type feedback effects. They prevent too much NT from being released into the cleft. So, when a NT binds to a pre-synaptic terminal, it causes less NT to be released. A drug that is an agonist on the pre-synaptic terminal is an antagonist on the synapse because it stops NT from being released.

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Pharmacokinetics

pharmacokinetics: The process by which drugs are absorbed, distributed within the body, metabolized, and excreted.

Intake Many routes such as the digestive tract, respiratory tract, through skin or mucous membranes, intravenous injection (directly into the blood), intramuscular injection (into the muscles), subcutaneous injection (under the skin). All of these routes eventually result in drugs in the bloodstream, and hence going to everywhere in the body. 

Distribution - Bloodstream goes all across the body. Water-soluble molecules can be directly dissolved in the blood, but do not pass through cell membranes. Lipid-soluble molecules need carriers to transport them through the blood, but can pass directly through cell membranes. 

Elimination - All drugs are eventually eliminated from the body by chemical breakdown (by enzymes) or by excretion (in urine). Some drugs can be stored in the body for a long time (e.g. lipod-soluble drugs in fat tissue. Biological Half-Life can vary from minutes to weeks. 

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Blood-Brain Barrier

A semipermeable barrier between the blood and the brain produced by the cells in the walls of the brain’s capillaries.

The cells that form the walls of the capillaries in the body outside the brain have gaps that permit the free passage of substances into and out of the blood and  the cells that form the walls of the capillaries in the brain are tightly joined.

Drugs can be designed to enter the brain or not. Many drugs do enter the brain, as do many hormones. Lipid-soluble molecules go straight through cell membranes and therfore through the blood-brain barrier but they need to get around in the blood (water-based).

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Physical Dependence

tolerance: The fact that increasingly large doses of drugs must be taken to achieve a particular effect; caused by compensatory mechanisms that oppose the effect of the drug.

  • However, it does not necessarily develop for all symptoms evenly. Some effects sensitize, whilst others develop tolerance.
  • Tolerance leads to increasing usage of higher doses, stronger drugs, and faster ways of intake.
  • This may be necessary to get the desired effect, but can exacerbate the sensitized effects.
  • Tolerance is a way for the body to try and reestablish homeostasis, activating mechanism (i.e. metabolic tolerance, functional tolerance) that counteract the drug actions. 
  • Leads to withdrawal effects
  • Tolerance is context dependent. Overdosing is easier in new surroundings and withdrawal symptoms also occur in familiar settings. This is possibly a reason for relapsing.  

withdrawal symptoms: The appearance of symptoms opposite to those produced by a drug when the drug is suddenly no longer taken; caused by the presence of compensatory mechanisms.

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Psychological dependence

When drugs directly interact with the brain's reward system, addicts will crave the drugs even while disliking their effects. 

This works through the mesotelencephalic dopamine pathway. Drugs bypass the system that signals "this was good/bad". So there is no evaluation of whether it was good or bad. Drugs directly stimulate the reward system. This leads to craving and compulsion to do it again = psychological dependence. 

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Pain

pain: An unpleasant feeling that is conveyed to the brain by sensory neurons. Pain is more than a sensation or the physical awareness of pain; it also includes perception. Perception gives information on the pain's location, intensity, and something about its nature. 

prostaglandins: One of a number of hormone-like substances that participate in a wide range of body functions such as the contaction and relaxation of smooth muscles, the dilation and constriction of blood vessels, control of blood pressure and modulation of inflammation. Derived from a chemical called arachidonic acid. 

  • Prostaglandins are released by the response of many noxious stimuli (inflammation response) and sensitize the nociceptors. 

nociceptors: Pain receptor cells. Comes in three types: cutaneous (skin), somatic (bones and joints), and visceral (body organs). Can process pain that is mechanical, chemical, or thermal in nature and transmits the information to the brain. 

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Types of Nociceptors

Highly myelinated axons (Aδ fibres) convey mechanical pain very quickly and precisely » early pain. This is informative about location. 

Unmyelinated axons (C fibres) convey different kinds of pain moreslowly and less precisely » late pain. This is vague about location. 

Sensitive to extremes of mechanical stimulation, extremes of temperature, acid, capsaicin, and pungent irritants. 

capsaicin: A colourless irritant phenolic amide C18H27NO3 found in various capsicums that gives hot peppers their hotness and that is used in topical creams for its analgesic properites. 

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Somatosensory Pathways

Somatosenses provide information about what is happening on the surface of our body and inside it.

Somatosensory axons from the skin, muscles, or internal organs enter the central nervous system via spinal nerves.

Aδ and C fibres are located in the dorsal root ganglion near the spinal cord. In the dorsal horn of the spinal cord, the first synapse between the Aδ or C fibre and a central neuron in the spinal cord. The central neuron axon crosses to the other side of the spinal cord; the signal goes up the cord through the medulla and midbrain and hits the thalamus. The thalamus is the station where all the senses go through before going to the primary somatosensory cortex. The primary somatosensory cortex maps where on the body something happens. Pain goes through here, so we can map where the pain occurs. 

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Substance P as a co-transmitter

Glutamate is the major neurotransmitter, as many neurons in the CNS use this. But they also use a co-transmitter. 

When enough action potential goes through the fibre, the co-transmitter Substance P is also released. This only occurs when there is enough action potentials fired. To the post-synaptic neuron, substance P signals that there is a lot of pain (i.e. a lot of action potentials firing). Substance P makes the pain signal stronger, therefore we perceive stronger pain. 

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Pain perception

phantom limb: Sensations that appear to originate in a limb that has been amputated.

Therefore, pain perception can be independent of input. 

Dual brain mechanism:

  • Pain sensation (physical) » Primary somatosensory cortex
  • Unpleasantness perception » Anterior cingulate cortex — can use hypnosis to diminish the unpleasantness of pain
  • Emotional consequences of chronic pain » prefrontal cortex

Activation of the primary somatosensory cortex by a painful stimulus was not affected by a hypnotically suggested reduction in unpleasantness of a painful stimulus, indicating that this region responded to the sensory component of pain. The anterior cingulate cortex showed much less activation when the unpleasantness of the painful stimulus was reduced by hypnotic suggestion. 

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Descending Analgesia Circuit

Pain is important. The body has a system of suppressing pain because sometimes we don't want to feel pain (i.e. prey animals like mice hide their pain from predators).

  • Descending - Starts in the midbrain/brainstem, then decends along the spinal cord
  • Analgesia - pain suppression
  • Circuit - different neurons that are connected

The periaqueductal grey controls the descending analgesia circuit. It has neurons that have axons that connect to the Raphé magnus. The neurons in the Raphé magnus has axons running all long the spinal cord and makes synapses in the dorsal horn of the spinal cord. They make synapses on local interneurons (neurons that have axons that don't go very far and only make synapses on local neurons). These stimulate inhibitory local interneurons that inhibit the synapse where the pain signal first comes into the spinal cord. It inhibits both pre and post-synaptically. The pain fibres are also inhibited by the local interneurons. Therefore, any pain signals coming from the periphery don't make it pass the first synapse becasue it cannot cross due to the inhibition of the pain signal. So, it will not lead to the release of Glu and substance P.

enkephalin: One of the endogenous opioids.

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Non-drug approaches for pain suppression

  • Direct stimulation of the PAG
  • Stressful situations suppress pain (i.e. soldiers who go off into battle don't realise they are missing a limb)
  • Placebo effect - the brain will make predictions about what should happen and makes some of it happen; only if you believe it is an analgesic. The brain can activate the desending analgesia circuit when it believes it should.
  • Acupuncture - nerve stimulation causes release of endorphins in the brain; measured using microdialysis

Naloxone: A drug that blocks opiate receptors, clinically used to reverse opiate intoxication 

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Capsaicin

capsaicin: A colourless irritant phenolic amide C18H27NO3 found in various capsicums that gives hot peppers their hotness and that is used in topical creams for its analgesic properites. 

  • Used topically on the skin for muscle pain (feels hot)
  • Depletes sensory neuron terminals of Substance P, providing local analgesia

Can induce and suppress pain

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NSAIDs

Non-Steroidal Anti-Inflammatory Drugs: A drug class that reduce pain, decrease fever, prevent blood clots and, in higher doses, decrease inflammation; e.g. Aspirin, Ibuprofen, COX-2 inhibitors 

  • Acts peripherally; poor blood-brain barrier penetration because of binding proteins in the blood

Mechanism of action - Inhibits Cyclo-Oxygenase 1 and 2 (COX-1 and COX-2), reduces the production of prostaglandins

Side effects - COX-1 involved in blood clotting and the protection of stomach lining from acid; aspirin prevents blood clotting, NSAIDs bad for the stomach

cyclooxygenase (COX): An enzyme that is responsible for formation of prostanoids, including thromboxane and prostaglandins such as prostacyclin. Both enzymes produce prostaglandins that promote inflammation, pain, and fever; however, only COX-1produces prostaglandins that activate platelets and protect the stomach and intestinal lining.

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Paracetamol

paracetamol: Also known as acetaminophen, is a medicine used to treat pain and fever. It is typically used for mild to moderate pain relief. The mechanism is still under investigation. 

Latest theory - Paracetamol reacts with endogenous molecules to form an agoist of the TRPV1 and CB-1 cannabinoid receptors.

Transient Receptor Potential Vanilloid 1 (TRPV1) receptor: A capsaicin receptor. A protein that is encoded by the TRPV1 gene and it's function is detection and regulation of body temperature. It also provides a sensation of scalding heat and pain. 

Cannabinoid (CB1) receptorCB1 receptors are found in the brain, especially in the frontal cor- tex, anterior cingulate cortex, basal ganglia, cerebellum, hypothalamus, and hippocampus. It is widely distributed in the brain and peripheral organs where it regulates cellular functions and metabolism. Found in many central and peripheral pain-related circults.

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Opiates

Derived from the opium poppy. Used for a long-time and a very powerful analgesics, and it's well-known for their abuse-potential.

Taken in different forms: 

  • Opium - mostly smoked or eaten
  • Morphine - many different ways; only 20% crosses blood-brain barrier, half-life is ~3-4 hours
  • Codeine - typically oral, as cough suppressant 
  • Heroin, diamorphine - typically injected; lipid soluble, so more crosses the blood-brain barrier

Short term effects - Relieves pain, cough, diarrhoea. Induces hypothermia, sleep. Stimulate pleasure. 

Physiological Action - Opiate drugs mimic the action of endogenous opioids » endorphins. They bind to endogenous opioid receptors, which can be found in many places in the body and the brain. 

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Opiates

Long term effects - Surprising mild, as long as the drug is taken: constipation, pupil constriction, menstrual irregularity, reduced libido. But there are withdrawal symptoms. Typical bad effects of heroin addiction on with the poverty and not taking care of oneself. Also, unknown quality of street drugs can have bad effects (e.g. overdose when it's purer than expected). Secondary problems include cutting with dangerous chemicals, poverty, crime, AIDS and Hepatitis B (dirty needles)

Withdrawal effects - Begin 6-12 hours after last dose and disappear after 7 days or so. Effects include restlessness, watering eyes, chills, nausea, tremor, runny nose, sweating, gooseflesh, diarrhoea, muscle spasms. Despite these severe physical symptoms, the physical effects of opiate addiction are not too bad (except when overdosing). So, well off people can often live normal lives with the addiction. 

  • Counteracting the effects - more heroin, methadone, accupuncture, avoiding drug-related contexts

In the locus coeruleus, opiates suppress firing. It compensates at withdrawal, it increases firing. It has to do with wakeness and suppressing REM sleep. 

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Opiates

Addictiveness - Mesotelencephalic Dopamine System:

  • In the VTA, opiates inhibit GABAergic interneurons. This releases inhibition frmo neurons which project to nucleus accumbens. This leads to more dopamine release. 
  • In the N. Acc, effects are independent from but similar to dopamine from VTA.
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Opioid Receptors

Discovered in 1973. These finding have taught us a lot about how we naturally experience the emotions that opiate drugs induce, as well as pain perception. Receptors don't exist just to accommodate drugs. 

  • Present in the brain
    • Preoptic area (hypothermia)
    • Mesencephalic Reticular Formation (sedation)
    • Locus Coeruleus (sedation)
    • Ventral Tegmental Area and N. Accumbens (rewarding)
    • Peri-Aqueductal Grey area (pain relief, pleasure)
    • Brainstem (coughing centre, breathing regulation)
  • And in the periphery » diarrhoea relief

ligands: A protein that binds to the receptor, (i.e. neurotransmitter). Receptor proteins have specific sites into which the ligands fit like keys into locks. Endogenous ligands are produced in the body and it is not those introduced into the body. 

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Cannabis

  • Smoked (as joints or in a pipe, often mixed with tobacco) or eaten (often in baked goods)
  • Different parts of the plant used: resin (hash), leaves (grass/weed)
  • 20-50% of active compound (THC) is taken up from smoke, less from ingested (6%)
  • THC is very lipid soluble and easily crosses the blood-brain barrier
  • It is easily stored in fat tissue, and has a half-life of 7 days (still detectable after 30 days)

(delta-9) tetrahydrocannabinol (THC): Active ingredient of marijuana. Delta-9-THC and Delta-8-THC are the only compounds in the marijuana plant that produce all the psychoactive effects of marijuana. Because Delta-9-THC is much more abundant than Delta-8-THC, the psychoactivity of marijuana has been attributed largely to the effects of Delta-9-THC. 

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Cannabis

Short term effects - Recreational use: reduction in anxiety, dissociation of ideas, heightened sensation, distorted sense of time, intense emotional experiences, hallucinations. Intoxication is similar to alcohol. Attention and short-term memory problem (very distractable), panic attacks, paranoia. No realistic lethal overdose. 

  • Medicinal use:
    • Increase in appetite is one of the reasons why it is used to suppress some of the symptoms of chemotherapy, which often leaves people nauseated and without appetite. Also reduces nausea, increases appetitie, dilation of bronchioles, blocks seizures, decreases severity of glaucoma. 
    • Reduces pain, is as effective as opiates for acute pain. Greate potency and efficacy than opiates for chronic pain (but side effects).
    • Sites of action include the peripheral nerves, direct spinal cord activity, descending analgesia circuit, anterior cingulate cortex
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Cannabis

Physiological Action - Active ingredient is Δ9-tetrahydrocannabinol. This binds to cannabinoid receptors in the brain. The endogenous ligands are anandamide and 2-AG which are lipids. The highest concentration of cannabinoid receptors exists in the hippocampus. 

Cannabinoid receptors are always presynaptic endogenous cannabinoids work as negative feedback systems to the pre-synaptic neurons, reducing their transmitter release. These can be glutamatergic or GABAergic, so not specifically inhibitory or excitatory, but has effects on both.

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Function of Endocannabinoids

endocannabinoids: A lipid; an endogenous ligand for receptors that bind with THC, the active ingredient of marijuana. 

Released from the post-synaptic side of a stimulated synapse that works in the close vicinity on other synapses. It suppresses the pre-synaptic release of GABA, hence suppressing inhibition » Depolarization-induced Suppression of Inhibition (DSI)

The discovery that DSI is mediated by endocannabinoids finally explained why both the CB1 receptor and the endocannabinoids are both so widely distributed in the brain. DSI is a very common form of short-term plasticity and thus needs to be mediated by a commonly found neurotransmitter. The use of endocannabinoids in this method of signalling is quite logical, since both molecules can be synthesized relatively easily from lipids in the plasma membrane. DSI is therefore the primary cortical process mediated by the endocannabinoids, and may contribute to many forms of cortical plasticity and synaptic strengthening.

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Distribution of Cannabinoid Receptors

  • Cerebral Cortex (psycho-active effects)
  • Hippocampus (memory effects)
  • Movement control centres (motor dysfunction)
  • Brain stem (analgesia, vomiting control, sleep)
  • Spinal cord (analgesia)
  • Hypothalamus (appetite, sleep)
  • Amygdala (emotions)
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Cannabis

Long term effects - Problems associated with smoking (not related to THC), impairments in memory recall and attention, slower decision making, decline in IQ with persistent use, especially vulnerable if starting during adolescence. All cognitive effects suggested are real, but subtle. 

Addicitveness -

Physical dependence: Tolerance develops during extended use, but withdrawal symptoms are rare. Withdrawl symptoms are rate because of the fat-stores of THC being released very slowly. Long-term users may experience sensitization of the desired effects. Injection of THC into the VTA does not affect dopamine release, so there may be a heterosynaptic effect on the dopamine synapses. 

Psychological dependece: THC acts directly on the N Acc to increase dopamine release from VTA terminals. Yet, people who typically smoked only occasionally could drop the habit fairly easily. More recent versions (e.g. skunk) have higher levels of addiction. 

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Stress Response

stress: A general, imprecise term that can refer either to a stress response or to a stressor (stressful situation). Has effects throughout the body.

fight-or-flight response: A species-typical response preparatory to fighting or fleeing; thought to be responsible for some of the deleterious effects of stressful situations on health. 

General to many "stress-full" conditions such as being attacked, attacking somebody, hunger, being cold, overheating, etc.

The stress reponse is adaptive, however chronic activation can be maladaptive. 

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Logic of the Stress Response

Stress prepares the body for fast and strong action by: 

  • mobilizing energy stores
  • increasing blood flow to brain and muscles
  • decreasing blood flow to digestive and reproductive systems
  • not wasting energy on growth, reproduction, or healing
  • ignoring pain

"If a hurricane is coming, you don't start painting the garden fence."

Stress stimulates the sympathetic and inhibits the parasympathetic nervous system. 

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Problems with the stress response

It evolved for short-term responses to external stressors.

Long-term activation can have devastating effects.

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Metabolic stress response

Stress stops energy storage by insulin. It accesses previously stored energy such as glucagon, catecholamines, and glucocorticoids. Insulin promotes fat storage in fat cells, glycogen storage, and production in liver and muscles. Its aim is to keep the circulating energy supples (glucose, fats, etc.) in the bloodstream ready for use. It also aims to mobilize previously stored energy from all possible sources. This includes breaking down proteins into amino acids which can cause some weakness in the long term. Also, the process uses up a lot of energy so it very inefficient. 

glucocorticoid: One of a group of hormones of the adrenal cortex that are important in protein and carbohydrate metabolism, secreted especially in times of stress.

corticotropin-releasing hormone (CRH): A hypothalamic hormone that stimulates the anterior pituitary gland to secrete ACTH (adrenocorticotropic hormone).

adrenocorticotropic hormone (ACTH): A hormone released by the anterior pituitary gland in response to CRH; stimulates the adrenal cortex to produce glucocorticoids.

Long-term stress problems: weakness and fatigue

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Metabolic stress response

The adrenal hormones are stimulated during this stress response. Because the speed of transmission of hormones is through the blood, as opposed to neural transmission through the sympathetic nervous system, the glucocorticoid response is delayed by 30-60 minutes. 

The secretion of glucocorticoids is controlled by neurons in the para-ventricular nucleus (PVN) of the hypothalamus. The neurons of the PVN secrete a peptide called corticotropin-releasing hormone (CRH), which stimulates the anterior pituitary gland to secrete adrenocorticotropic hormone (ACTH). ACTH enters the general circulation and stimulates the adrenal cortex to secrete glucocorticoids.

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Cardiovascular Stress Response

The sympathetic nervous system causes increased heart rate and vasoconstriction.

Vasopressin recovers more water in the kidneys which increase blood volume which increases blood pressure. The goal is to deliver the released energy and oxygen to the muscles and brain. 

Long-term stress problems: weak heart and blood bessels, atherosclerosis, coronary heart disease 

Pituitary hormones are released during this stress response. Vasopressin is released from the posterior pituitary gland and β-endorphins are released from the anterior pituitary gland. β-endorphins reduce pain during stressful situations. 

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Gastro-intestinal stress response

The gastro-intestinal stress response inhibits of all digestive activity through activation of the sympathetic nervous system and suppression of the parasympathetic nervous system. For example, when we are stressed we get dry mouths. This happens because saliva secretion is under the parasympathetic control and is blocked by the sympathetic nervous system. 

Long term stress problem: gastro-intestinal pathologies, including gastric ulcers

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Reproductive stress response

Reproduction is not very important when you're getting attacked, so stress can shutdown the reproduction system. It decreases the release of GnRH, FSH, LH, gonadal sensitivity to LH, and probability of erection in males. 

However, reproductive mechanisms are robust. 50% of women in Nazi concentration camps continued to ovulate despite high chronic stress. 

Long term effects: Infertility due to reduced ovulation, reduced chances of implantation (females), reduced erection, reduced sperm production (males)

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Growth and repair during stress

Growth hormone release is increased in the short-term, but inhibited in the long-term. So, the repair of wounds and damage postponed.  

Long-term effects:

  • Children » stress dwarfism
  • Adults » slow healing. decalcification 
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Stress and the Immune System

Early effects of stress stimulate immune fuction. This could lead to auto-immune disease. Glucocorticoids suppress this increase back to normal levels. 

Long-term effects: chronic stress leads to increased susceptibility to disease and infection

psychoneuroimmunology: the study of the effect of the mind on health and resistance to disease

Glucocorticoids (cortisol) are used as immunosuppressants (autoimmune disease, transplant rejection) and also used to suppress inflammatory response (swelling, etc.) 

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Control of the stress response

The psychogenic stress response is tightly regulated. The amygdala stimulates the stress response while the hippocampus inhibits the stress response. The central nucleus of the amygdala activates many processes such as sympathetic nervous system (via the lateral hypothalamus) and the HPA axis (via the paraventricular nucleus). The hippocampus contains many receptors for glucocorticoids. In response to an increase in glucocorticoids, the hippocampus becomes more active and indirectly inhibits the HPA axis (PVN).

However, this is not the only way to activate the stress response, but it is definitely a major one. 

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Affective disorders

Chronic and repeated activation of the stress response can lead to affective disorders, such as Major Depressive Disorder and Anxiety Disorders. Different people have different levels of sensitivity to chronic stressors

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Chronic Stress: Positive Feedback

When you have a stressor,  the amygdala stimulates hypothalamic pituitary adrenal (HPA) axis. Then, the glucocorticoids (i.e. cortisol) enters the bloodstream and activates the locus coeruleus. Remember, the locus coeruleus is on the awake side of the sleep flip-flop system. The locus coeruleus activates the amygdala, among other brain areas, which then increases activity in the HPA axis. 

Normally, the hippocampus brings the cortisol levels down. But in chronic stress, the positive feedback loop brings the HOS axis out of regulation; cortisol levels stay higher and the HPA axis stays more stimulated. 

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Chronic Stress: Reduced negative Feedback

When stress happens chronically, the hippocampus gets damaged which leads to less negative feedback. Repeated stimulation by glucocorticoids reduces the sensitivity of receptors in the hippocampus. 

Chronically high glucocorticoids also damage hippocampal neurons, leading to a furter reduction of negative feedback (in the long term). 

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Glucocorticoids damage the hippocampus

Glucocorticoids damage the hippocampus because they reduce adult hippocampal neurongenesis, shrink dendritic arbors, and reduce glucose uptake. In the long run, this can kill hippocampal neurons. All of this can lead to smaller hippocampal volume. 

Glucocorticoids partially block glucose uptake into all cells. Normally this is to prevent storage, and the increase in the blood stream makes sure that neurons still get their fair share of glucose in normal conditions. 

However in chronic stress, this is not compensated for. This leads neurons to be a bit starved. So this increases the effects of other things, such as oxygen deprivation. Hippocampal neurons are very sensitive to this. This leads to a positive feedback loop, because those hippocampal neurons suppress Corticotropin-releasing hormone (CRH) in the hypothalamus, and when they are gone, you get more CRH and more glucocorticoids. 

This may also contribute to ageing related damage to hippocampus and hence leads to decline of learning and memory due to cumulative damage over a life time. 

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Endocrinology of Depression

A dysregulated HPA axis is common in affective disorders. Borth pathological increases and decreases in cortisol (due to other causes) can lead to depressive symptoms. 

It unclear whether the overactivity or underreactivity is to blame. Decreased reactivity can lead to decreased negative feedback, and therefore it leads to increased release. It is possible that decreased reactivity only happens in some parts of the body, but not others. 

  • Cushing's disease » increased cortisol
  • Addison's disease » decreased cortisol
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Other effects of chronic stress

Chronic stress leads to the depletion of noradrenaline from the locus coeruleus, depletion of serotonin from raphe nuclei, and depletion of dopamine from the VTA to the N ACC and the PFC. 

Corticotropin-releasing hormone (CRH) is also used as a neurotransmitter, among other places in the connection from the amygdala to the locus coeruleus. Depletion of its transmitter results in less vigilance and inactivity. Serotonin is also involved in alertness. In addition, it stimultes the LC so it leads to additional decrease in NAd release. 

Because these play a role in awakness, this also affects sleeping behaviour as well. 

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Role of monoamines in depression

Reserpine: A strong antagonist of vesicle loading for dopamine, Noradreneline, and serotonin; a monoamine antagonist; induces depression. 

5-Hydroxyindoleacetic Acid (5-HIAA): A breakdown product of serotonon when destroyed by MAO. Low levels in the cerebrospinal fluid can lead to depression.

Tryptophan: An α-amino acid that is used in the biosynthesis of proteins, a precursor to serotonin and other monoamines. When you give someone a diet low in trypotophan, then the next day you give them a lot of amino acids but no tryptophan, the amino acids compete with the trypto for transporter into the brain. Tryptophan deletion (i.e. no precursors for monoamines) leads to depression. 

  • tryptophan depletion procedure: A procedure involving a low-tryptophan diet and a tryptophan-free amino acid “cocktail” that lowers brain tryptophan and consequently decreases the synthesis of 5-HT. 
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MOA targeting treatment

MAOIs block the enzyme MAO. This prevents it from breaking transmitters into inactive metabolites. 

Tricyclic drugs and SSRIs block reuptake.

Monoamine oxidase inhibitos (MOAIs): A class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A and monoamine oxidase B.

Tricyclic antidepressantsA class of drugs used to treat depression; inhibits the reuptake of norepinephrine and serotonin but also affects other neurotransmitters; named for the molecular structure. 

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SSRIs

Selective serotonin reuptake inhibitor (SSRI): An antidepressant drug that specifically inhibits the reuptake of serotonin without affecting the reuptake of other neurotransmitters. Usually ingested through pills and is very lipophilic. 

Different pharmacokinetics for different drugs:

  • Fluoxetine (Prozac): slow uptake, half-life » 1 - 4 days
  • Fluvoxamine (Faverin): bit faster, half life » 8 - 28 hours 
  • Citalopram (Cipramil): bit faster, half-life ~36 hours
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HPA Axis targeting treatments

These target HPA activity becasue normalizing activing can aid in the recovery of depression. 

Anti-coricosteroids (e.g. RU486): A drug that blocks the action of cortisol itself.

CRH-receptor blockers: A drug that blocks CRH receptors. 

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Drug treatments

Antidepressants only work after several weeks. The first two weeks is for adaptation of auto-receptors. The early effects of antidepressants are often the same as a placebo. 

Increase in monoamine activity could down-regulate sensitivy (through post-synaptic receptors) or even release (via auto-receptors).

In depression, the volume of the cortex and the hippocampus decreases. One of the long-term effects of antidepressants is the up-regulation of Brain-derived neurotrophic factor (BDNF), which may have something to do with the repair of the brain and maybe of the depression.

  • Brain-derived neurotrophic factor (BDNF): A protein released by either a nerve cell or a support cell, such as an astrocyte, and then binds to a receptor on a nearby nerve cell. There, it prompts the increased production of proteins associated with nerve cell survival and function.

There is evidence that reuptake inhibitors initially stimulate the HPA axis but over time, they normalize the reactive and feedback loop. 

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Adult hippocampal neurogenesis

Neurogenesis can take place in the dentate gyrus—a region of the hippocampal formation—in the adult brain. Several studies with laboratory animals have shown that stressful experiences that pro- duce the symptoms of depression suppress hippocampal neurogenesis, and the administration of antidepressant treatments, including MAO inhibitors, tricyclic antidepressants, SSRIs, ECT, and lithium, increases neurogenesis

Time course of increase = time course of effectiveness 

Destroying adult neurogenesis prevents antidepressant effects. Exercise increases adult neurogenesis and improves depression symptoms. 

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Other uses of SSRIs

SSRIs are also prescribed in many other conditions, such as anxiety disorders, panic disorder, OCD, eating disorders, etc.

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Benzodiazepines

Usually ingested through pills. Reaches max blood concentration in about 60 minutes (however different drugs have different kinetics). Lipid solubility varies from drug to drug. Depending on the exact chemical, half-lifes can be 90 minutes to 6 days. 

OTC sleeping aids are usually anti-histamines. Some BZs are broken down into long-lasting pharamcologically active intermediates, which extend the active half-life up to 60 hours. Others (i.e. short-acting ones) are broken down immediately into inactive compounds. 

Rohypnol (flunitrazepam): is used as a ********* drug

Short term effects - Sleepiness, reduction of anxiety, anterograde amnesia, muscle relaxation, mental confusion. Overdose can be lethal if taken with alcohol. Clinically, used as sleeping pills (against insomnia), anxiolytics (against anxiety and panic disorders), recovery from alcohol withdrawal, and anticonvulsant (in combination with other drugs). 

  • Sleeping pills should work quickly and only last for the night, so a quick uptake and short half-life is needed.
  • Anxiolytics should work slowly and for a long time so different kinetics are needed.
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Benzodiazepines

Physiological Action - There are no direct agonists, but rather they facilitate the effects of GABA binding on GABA-A receptors, increasing the inhibitory effects. GABA-A receptors exist throughout the brain i.e.

  • cerebral cortex (amnesia and confusion), 
  • Hippocampus (amnesia and anti-epileptic),
  • spinal cord and brain stem (muscle relaxant),
  • cerebellum (muscle relaxant, anti-epileptic), 
  • Amygdala, orbitofrontal cortex and insula (anxiolytic), 
  • tuberomammillary nucleus, etc. (hypnotic).

Long term effects - Mental confusion, induction or extension of dementia, learning problems. However, these can improve after cessation of the medication. 

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Benzodiazepines

Addictiveness - 

  • Physical dependence will develop even with therapeutic doses. Withdrawal symptoms include anxiety, insomnia, restlessness, agitation, and irritability. 
  • Due to psychological dependence, alcoholics can be sensitive to BZs addiction as well. There are GABA-A receptors in the VTA and the N Acc as well. 
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Behaviour and rhythms

  • Years » earth around the sun
  • Months » moon around the earth

Because we evolved on an environment with rhythms, those rhythms effect us (and other organisms).

  • Earth axis + moon = tides » mussel and fish
  • Earth axis + sum = day and night 
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Circadian Rhythms

Circadian rhythms: A daily rhythmical change in behavior or physiological process. Can effect drug absorpsion, pain thresholds, and hormones. Memory is better in the morning compared to nighttime. However theres are not causes, it just shows circadian rhythms. 

Regulation of CR: It may be a direct response to external stimuli (e.g. light/dark), the feedback loop (activity » tired » sleep), or endogenous rhythms.

Free-running CR - When an animal is maintained in constant dim illumination, it displays a free-running activity cycle of approximately twenty-five hours, which means that its period of waking begins about one hour later each day.

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Biological Clocks

suprachiasmatic nucleus (SCN): A nucleus situated atop the optic chiasm in the hypothalamus. It contains a biological clock that is responsible for organizing many of the body’s circadian rhythms.

Evidence: 

  • Lesions: not organised, inactive/active, chaotic
  • Recording: neurons fire more during subjective daytime 
  • In-vitro slice: the CR can't be driven by other parts of the brain because it is on its own; therefore it is evidence of endogenous rhythms. However, single neurons will start to drift apart so when the SCN is intact the neurons communicate with each to keep in sync (not through synapses!!!)
  • Transplantation: Hamster mutation and makes hamster have 20 hr CR. Transplant 20 hr SCN to a hamster without muation, restores CR and becomes 20 hr.

Therefore, the SCN is the master of endogenous time. 

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Molecular mechanisms

period genes (Per1-3): the main targets within the core molecular oscillator for stimuli that phase shift the clock

  • PER1: important to the maintenance of circadian rhythms in cells, and may also play a role in the development of cancer
  • PER2: involved human sleep disorder and cancer formation
  • PER3: found to be important for endogenous timekeeping in specific tissues and those tissue-specific changes in endogenous periods result in internal misalignment of circadian clocks in Per3 double knockout (-/-) mice. PER3 may have a stabilizing effect on PER1 and PER2

cryptochrome genes (Cry1-2): A class of flavoproteins that are sensitive to blue light. Involved in the circadian rhythms of plants and animals, and possibly also in the sensing of magnetic fields in a number of species.

clock (Circadian Locomotor Output Cycles Kaput) gene: components of the circadian clock comparable to the cogwheels of a mechanical watch. They interact with each other in an intricate manner generating oscillations of gene expression.

Bmal1 (Brain and Muscle ARNT-like 1) gene: gene involved in circadian clock mechanisms

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Molecular mechanisms

Basic biology: Genes are transcribed into mRNA. When the mRNA is made, it exits the nucleus into the cytoplasm where the mRNA is translated into protein. They is a cyclical process. The more mRNA is made, the more proteins are made. When proteins are made, they form hetrodimers. 

CRY+PER1 & CRY+PER1+PER3 (these are hetrodimers) are brought back into the nucleus. Their main function is to inhibit the CLOCK and Bmal1 genes, which are the genes that stimulate transcription of the CRY and PER genes. The more protein, the more inhibition to the point where CLOCK and Bmal1 have stopped transcription. Over time, CRY and PER proteins will breakdown and disappear. When the levels are low enough, they will stop inhibitng CLOCK and Bmal1. So CLOCK and Bmal1 will start to stimulate transcription. The peaks in protein concentration is roughly slightly longer than 24 hours. This is a self-inhibiting process (like a thermostat). May be the driver of endogenous rhythms of the SCN.

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Molecular mechanisms

CRY+PER2 exits and enters the nucleus. These increase the Bmal1 production of mRNA. Note: CLOCK is made continously. There is no cycle of production. So Bmal1 protein is made in the cytoplasm and then binds to CLOCK (which will always be avaliable) and together they go back into the nucleus and stimulate production of CRY and PER1-3 genes. 

Due to this extra cycle, this happpens offset from the other cycle When Bmal1 and CLOCK is being inhibited, most of the stimulation occurs to produce more Bmal1. So, Bmal1+CLOCK are at its highests concentration when CRY+PER1 and CRY+PER3 are at it's lowest concentrations. 

SO, inhibition and stimulation is cyclical. BUT they are offset from each other. 

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Molecular clock

molecular clock: Measures the number of changes, or mutations, which accumulate in the gene sequences of different species overtime

SCN activity peaks at the middle of subjective day. Gene expression cycles must somehow interact with the excitability of the membrane. There is evidence for feedback loops between membrane potential and gene expression. 

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Molecular clock

Possible mechanisms—

Synthesis and degradation:  Ion channels and other membrane proteins are made and then transported to the membrane through the rough endoplasmic reticulum (ER) to the Golgi. The membrane proteins are transported to the membrane and removed for degradation through vesicles. There is evidence of the rhythmic transcription of several ion channels. However, we do not know the half-life of these channels in the SCN.

Trafficking: AMPA receptors and potassium channels have been shown to be rapidly inserted and removed from the membrane in response to physiological stimulation. Therefore, the daily trafficking of ion channels and associated proteins is another possible mechanism that may be responsible for the firing rate rhythms.

Distribution The distribution of ion channels within the plasma membrane can change from day to night, and this may also contribute to changes in firing rate rhythms between day and night. 

Phosphorylation state: Circadian regulation in the phosphorylation state of ion channels through the balance between kinase and phosphotase activities is a likely mechanism that underlies the rhythm in spontaneous neural activity in SCN neurons.

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Outputs of the SCN

There are unknown sychronizing chemical signals that influence activity rhythms.

Neural signals: GnRH producing cells (direct and indirect), pineal gland (indirect)

Transplants do not affect circadian rhythms of several hormones, such as melatonin and GnRH; those connections are neural only.

Connection to the pineal gland (located on the dorsal surface of the diencephalon) happens as follows: 

  • SCN sends projections to PVN (paraventricular nucleus). This in turn sends projections to the spinal cord (intermediolateral column). IML sends projections to the sympathetic Superior Cervical Ganglion. This in turn innervates the pineal gland with Norepinephrin as the NT
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Melatonin

melatonin: A hormone secreted during the night by the pineal body; plays a role in circadian and seasonal rhythms. It feeds back to the SCN. It affects the entrainment of circadian rhythms. In higher doses, it has sleep-inducing effects (but only in diurnal animals). 

NOTE, the data are still a bit controversial on whether melatonin works or not. It does seem to facilitate reentrainment to a new cycle. Congenitally, retinally blind people can synchronise their circadian rhythms by taking melatonin at the same time each day. The mechanisms linking high melatonin to sleep induction are still unknown. 

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Outputs of the SCN

  • SCN influences the Ventral Subparaventricular zone (vSPZ) through synapses and chemical signals
  • vSPZ affects activity in the Dorsomedial nucleus of the Hypothalamus (DMH)

DMH: 

  • Inhibits vlPOA
  • Excites the lateral Hypothalamus (hypocretinergic)

The ventral SPZ gets both neural and local hormonal input from the SCN. It sends axons into the VLPA, hence probably affecting sleep-wake cycle by biasing the flip-flop mechanism one way or the other. Given that some animal would be active during the day, and others during the night, it would be expected that this link is different in different animals (inhibitory or excitatory). 

The SCN controls circadian rhythms in sleep and waking. During the day cycle, the DMH inhibits the vlPOA and excites the brain stem and forebrain arousal systems, thus stimulating wakefulness.

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Outputs of the SCN

Many other processes show circadiam rhythms. Most are controlled from nuclei in the hypothalamus, close to and controlled by the SCN (e.g. activity, temperature, cortisol, thyroid, and parathyroid, growth hormone, prolactin).

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Zeitgebers

zeitgebers: "Time Givers" (German). A stimulus (light, food, sounds) that resets the biological clock that is responsible for circadian rhythms. They entrain the internal rhythm with the external rhythms. 

Short light pulses can reset the clock and light early in the night cycle sets the clock back. Light late in the night cycle sets the clock forward. 

Phase-Response Curve (PRC): A curve describing the relationship between a stimulus, such as light exposure, and a response, in this case a shift in circadian rhythm (phase shift). A phase shift in your circadian rhythms means that your bedtime and wake-up time will move earlier in the day (phase advance) or later in the day (phase delay). The PRC is important because it can determine when to time light and melatonin correctly in order to advance (or delay) your circadian phase.

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Resetting the Clock

Direct projection from the retina (i.e. the influence of light) to the SCN (retino-hypothalamic tract) can reset the clock. Indirect projection from the retina (i.e. partial effect of light or other zeitgeber effects) to the SCN via the LGN also can reset clock. 

Ganglion cells perceive light with the light-sensitive molecule, melanopsin. Rods and cones have nothing to do with it. 

melanospin: A photopigment present in ganglion cells in the retina whose axons transmit information to the SCN, the thalamus, and the olivary pretectal nuclei.

RHT axons synapse onto SCN using glutamate onto NMDA receptors. There is an increase in intracellular calcium and induction of second messenger casades. Transcription regulation of clock genes also reset the clock. Inducing more Per and Cry at subjective dusk would keep the subjective day going for longer, leading to a phase delay (as expected at that time).

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Jet lag

A temporary phenomenon; after several days people who have crossed several time zones find it easier to fall asleep at the appropriate time, and their daytime alertness improves.

It is a disparity between internal and external rhythms. Different rhythms in the body are out of sync with each other. It disappears slowly over time by entrainment to the new environment. 

Can be treated with melatonin. 

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Shift work

A disparity between internal and external rhythms. However, there are no cues to resynchronise the clock. 

People who always do night shift don’t entrain to it well because of the light conditions: too dim inside to properly reset the clock, and having to travel through outside to get home.

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Major Depression

In a patient with major depression, there is reduced sleep latency, reduced REM latency, reduction in SWS, and general fragmentation of sleep. 

Sleep pattern changes: REM sleep is entered too early and REM sleep deprivation has long-term effects. Many anti-depressants (but not all) suppress REM sleep. Depending on the patient, one night of SWS or total sleep deprivation can have immediate effects. 

Phase shift between endogenous circadian rhythm and externally imposed sleep-wake cycle can lead to lower mood or depression. The circadian cycle is often advanced in major depression paitents. Going to sleep with the circadian clock will slowly shift the clock which may help.

Bright Light Treatment seems to have positive effects for non-seasonal depression. This could be related to the advanced circadian clock and the treatment could set it back. There is evidence of connection between melanopsin-containing RGCs and v1POA.  

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Seasonal Rhythms

Animals in temperate climates have to deal with large changes in temperature, day length, and in food availability. This affects seasonal reproduction, migration, and hibernation.

Seasonal reproduction —

  • For some animals, shortening days (sheep, deer) or lengthening days (birds, rodents) effects the time from impregation to delivery (or hatching). 
  • There are also patterns in human production, however it is much more subtle. In particular, there are more conception in early spring. 

Changes in day length —

The SCN influences melatonin release from the pineal gland during the night. Longer nights mean more melatonin release. So, more melatonin signals winter conditions. The duration of exposure of melatonin is what makes animals perceive changes in day length. The length of the night can change, when the oscillator in SCN seems to be a single cycle thing that can be shifted only in its entirety. 

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Seasonal Rhythms

Animals in temperate climates have to deal with large changes in temperature, day length, and in food availability. This affects seasonal reproduction, migration, and hibernation.

Seasonal reproduction —

  • For some animals, shortening days (sheep, deer) or lengthening days (birds, rodents) effects the time from impregation to delivery (or hatching). 
  • There are also patterns in human production, however it is much more subtle. In particular, there are more conception in early spring. 

Changes in day length —

The SCN influences melatonin release from the pineal gland during the night. Longer nights mean more melatonin release. So, more melatonin signals winter conditions. The duration of exposure of melatonin is what makes animals perceive changes in day length. The length of the night can change, when the oscillator in SCN seems to be a single cycle thing that can be shifted only in its entirety. 

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Seasonal Affective Disorder

Seasonal Affective Disorder (SAD): A mood disorder characterized by depression, lethargy, sleep disturbances, and craving for carbohydrates during the winter season when days are short.

Symptoms include depressed mood, loss of libido, trouble focusing, carbohydrate cravings, lethargy, anxiety, weight gain, and hypersomnia. 

It is more prevalent in women and higher latitudes. It responds to chaning the sleep-wake cycle and bright light therapy. SAD patients have a very hard time waking up in winter. 

This could be caused due to the endogenous rhythm being delayed relative to the sleep-wake rhythm, different endogenous rhythms are desynchronised or scrambled, long melatonin exposure, or low serotonin levels especially in winter. 

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Neurochemical Messengers

neurotransmitter: A chemical that is released by a terminal button; has an excitatory or inhibitory effect on another neuron. Communicates from one neuron to the next through local action. Effects can be through activation or inhibition, depending on the transmitter/receptor combination. 

hormone: A chemical substance that is released by an endocrine gland and that has effects on target cells in other organs. Communications through the bloodstream and has global action. Effects can be varied, depending on the hormone/receptor combination.

Note, the same substance can be a neurotransmitter or a hormone depending on context: e.g. noradrenaline 

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Gender vs Sex

Gender: In modern use, a euphemism for the sex of a human being, often intending to emphasize the social and cultural, as opped to the biological, distintions between the sexes. 

Sex: Either of the two divisions of organic beings deistinguished as male and female respectively; the males or the females (of a species, etc. especially of the human race) viewed collectively.

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Sex Determination in Mammals

Chromosomes

A person’s chromosomal sex is determined at the time of fertilization. All cells of the human body (other than sperms or ova) contain twenty-three pairs of chromosomes. A person’s genetic sex is determined at the time of fertilization of the ovum by the father’s sperm. Twenty-two of the twenty-three pairs of chromosomes determine the organism’s physi- cal development independent of its sex. The last pair consists of two sex chromosomes. 

  • gamete: A mature reproductive cell; a sperm or ovum 
  • sex chromosome: The X and Y chromosomes, which determine an organism’s gender. Normally, ** individuals are female, and XY individuals are male. 
  • gonad: An ovary or testis

Turner's syndrome: Results when one normal X chromosome is present in a female's cells and the other sex chromosome is missing or structurally altered. Characterized by lack of ovaries but otherwise normal female sex organs and genitalia.

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Sex Determination in Mammals

SRY: The gene on the Y chromosome whose product instructs the undifferentiated fetal gonads to develop into testes.

  • Turns the fetal gonad into a testis » Testis-Determining Factor 
  • In its absence, the gonal becomes an ovary

Early testis produces 2 types of hormones:

  • Anti-Mullerian Hormone: A peptide secreted by the fetal testes that inhibits the development of the Müllerian system, which would otherwise become the female internal sex organs.
    • defeminising effect: An effect of a hormone present early in development that reduces or prevents the later development of anatomical or behavioral characteristics typical of females. 
  • Androgens: A male sex steroid hormone. Testosterone is the principal mammalian androgen.
    • masculinising effect: An effect of a hormone present early in development that promotes the later development of anatomical or behavioral characteristics typical of males. 

In the absence of these hormones, female sex organs develop. This is the general mammalian pattern. 

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Sex Determination in Mammals

androgen insensitivity syndrome: A condition caused by a congenital lack of functioning androgen receptors; in a person with XY sex chromosomes, it causes the development of a female with testes but no internal sex organs.

persistent Müllerian duct syndrome: A condition caused by a congenital lack of anti-Müllerian hormone or receptors for this hormone; in a male, it causes development of both male and female internal sex organs. 

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Internal Sex Organs

Early in embryonic development, the internal sex organs are bisexual; that is, all embryos contain the precursors for both female and male sex organs.

However, during the third month of gestation, only one of these precursors develops; the other withers away.

The precursor of the internal female sex organs, which develops into the fimbriae and Fallopian tubes, the uterus, and the inner two-thirds of the vagina, is called the Müllerian system.

The precursor of the internal male sex organs, which develops into the epididymis, vas deferens, and seminal vesicles, is called the Wolffian system.

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External Sex Organs

The external genitalia are the visible sex organs, including the penis and scrotum in males and the labia, ********, and outer part of the vagina in females.

The external genitalia do not need to be stimulated by female sex hormones to become female; they just naturally develop that way. In the presence of dihydrotestosterone the external genitalia will become male. Thus, the gender of a person’s external genitalia is determined by the presence or absence of an androgen.

dihydrotestosterone: An androgen produced from testosterone through the action of an enzyme.
 

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Hormonal controls of development of sex organs

XY - MALES → Testis-determining factor → Primodial gonads develop into testes. 

  • Defeminization through Anti-Müllerian hormone = Müllerian system withers away.
  • Masculinization through Androgens = Wolffian system develops into vas deferens, seminal vesicles, prostate. Primordial external genitalia develops into penis and scrotum. 

** - FEMALES → Primodial gonads develop into ovaries 

  • No hormones = Wolffian system without androgens withers away
  • Müllerian system develops into fimbriae, fallopian tubes, uterus, inner vagina. Primordial external gentalia develop into ********, labia, outer vagina

Prenatal testosterone and the face - For both males and females, levels of prenatal testosterone correlates with how masculine the face is in later life. 

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Sex Determination in Mammals

The developing brain is also sensitive to circulating androgens (through conversion to estrogen): masculinisation and defeminisation. Often, testosterone is converted into estrogen in the cell before acting in its masculinzing role. Free estrogen in the bloodstream (like in girls) do not have this effect because α-feto-protein binds estrogen and prevents it from acting in a masculinizing role. 

The preoptic area of the hypothalamus is sensitive to early androgens. Sex-chromosone specific genes may also play a role. In rats, this determines later the susceptibility to different hormones and ditermines which effects the hormones have on behaviour. 

Masculinization and defiminization are separate processes, and sometimes one could happen without the other. This may suggests a mechanism for a range of sexual orientations. 

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Genetic vs hormonal effects on sex differentiation

Done in rats.

Move SRY off of the Y chromosome, thus independently effecting whether the rat is genetically male or female and whether it has testosterone or not. 

  • X XSry → Female genes, but Male hormone ∴ testes 
  • XY-  → Male genes, no SRY ∴ ovaries 
  • X X → normal female control
  • XY(-)SRY → normal male control

Gonadal effects: sex behaviour, LH secretion, agression, nociception 

Sex chromosome effects: habit formation, alcohol preference, aggression, nociception 

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Actions of hormones

Organizational: effect remains after the hormone has been removed. Often occurs during a sensitive period

Activational: effect is reversible, depending on presence or absence of hormone

Activational hormones can still imply structural changes, as long as they are reversible or continue to be flexible. One particular hormone can have BOTH actions, depending on what it is acting. 

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Puberty

Puberty: The development/start of the adult pattern of sexual physiology and behaviour.

  • Organizational and activational role of sex hormones
  • Development of secondary sexual characters
  • Pubic and axillary hair are adrogen sensitive in both males and females
  • Developmental timing mechanism
  • Permissive factors:
    • metabolic cues: fat reserves, insulin, leptin, glucose
    • social cues: presence of opposite sex, dominance relationships
    • environmental cues: seasonal cues in seasonal breeders (melatonin receptors in thalamus and hypothalamus convey the signal to GnRH neurons
  • Sex differences in mechanisms and timing. These are probably set up during early development and/or due to genetics. 
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Puberty

Puberty starts in the hypothalamus with pulses of GnRH at night. There are only 2000-3000 GnRH neurons and they are spread out throughout the hypothalamus. Prepuberal release of GnRH from these neurons is very low and very sensitive to steroid feedback. Puberty is a combination of increased excitation and decreased inhibition on the GnRH neurons. These also life of the negative feedback (lower sensitivity to steroids), allowing more release and the maturation of the gonads. These two do not have to happen simultaneously, but they do reinforce each other's effects. 

Puberty is initiated when the hypothalamus secretes gonadotropin-releasing hormones (GnRH), which stimulate the release of gonadotropic hormones by the anterior pituitary gland. In males, the GnRH releasing neurons fire in a 2-hour cycle. 

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Pituitary Hormones

Anterior Pituitary Gland — gonadotropic hormone:  A hormone of the anterior pituitary gland that has a stimulating effect on cells of the gonads.

  • follicle-stimulating hormone (FSH): The hormone of the anterior pituitary gland that causes development of an ovarian follicle and the maturation of an ovum. Males - sperm production. Females - follicles ripen
  • luteinizing hormone (LH): A hormone of the anterior pituitary gland that causes ovulation and development of the ovarian follicle into a corpus luteum. Males - testosterone production. Females - induce ovulation and formation of corpus lutem. 

Posterior Pituitary Gland

  • vasopressin: a pituitary hormone which acts to promote the retention of water by the kidneys and increase blood pressure.
  • oxytocin: a hormone released by the pituitary gland that causes increased contraction of the uterus during labour and stimulates the ejection of milk into the ducts of the breasts.

Vasopressin and oxytocin, peptides that serve as hormones and as neurotransmitters in the brain, appear to facilitate pair bonding. Vasopressin plays the most important role in males, and oxytocin plays the most important role in females

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Hypothalamus-Pituitary-Gonadal Axis

The hypothalamus releases gonadotropin releasing factors through the hypothalamic portal system. This leads the anterior pituitary gland to release gonadotropin into general circulation. The gonads then release estrogens, androgens, and progestins into the body tissues. 

Behaviour is influenced by gonadal hormones acting on the brain. Positive or negative feedback influences the subsequenct release of hormones. 

The hypothalamus senses levels of circulating sex hormones which affects GnRH production. Feedback happens at the level of the pituitary. In males, at the pituitary, the feedback is only negative. At the hypothalamus, it can be positive as well in the sense that it increases sexual motivation. In females, this is a 28-day cycle. 

In rats, males do not respond to estrogens, but in primates they do a little bit. 

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Menstrual Cycle

menstrual cycle: The female reproductive cycle of most primates, including humans; characterized by growth of the lining of the uterus, ovulation, development of a corpus luteum, and (if pregnancy does not occur) menstruation.

A cycle begins with the secretion of gonadotropins by the anterior pituitary gland. These hormones (especially FSH) stimulate the growth of ovarian follicles, small spheres of epithelial cells surrounding each ovum.

Women normally produce one ovarian follicle each month; if two are produced and fertilized, dizygotic (fraternal) twins will develop.

As ovarian follicles mature, they secrete estradiol, which causes the lining of the uterus to grow in preparation for implantation of the ovum, should it be fertilized by a sperm.

Feedback from the increasing level of estradiol eventually triggers the release of a surge of LH by the anterior pituitary gland.

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Menstrual Cycle

  • The LH surge causes ovulation. The ovarian follicle ruptures, releasing the ovum. Under the continued influence of LH, the ruptured ovarian follicle becomes a corpus luteum (“yellow body”), which produces estradiol and progesterone.
  • The ovum enters one of the Fallopian tubes and begins its progress toward the uterus. If it meets sperm cells during its travel down the Fallopian tube and becomes fertilized, it begins to divide, and several days later it attaches itself to the uterine wall
  • If the ovum is not fertilized or if it is fertilized too late to develop sufficiently by the time it gets to the uterus, the corpus luteum will stop producing estradiol and progesterone, and then the lining of the walls of the uterus will slough off. At this point, menstruation will commence.

ovarian follicle: A cluster of epithelial cells surrounding an oocyte, which develops into an ovum.

corpus luteum: A cluster of cells that develops from the ovarian follicle after ovulation; secretes estradiol and progesterone.

progesterone: A steroid hormone produced by the ovary that maintains the endometrial lining
of the uterus during the later part of the menstrual cycle and during pregnancy; along with estradiol, it promotes receptivity in female mammals with estrous cycles.

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Premenstrual syndrome (PMS)

premenstrual syndrome (PMS): Physical and emotional symptoms that occur in the one to two weeks before a woman's period. Symptoms include mood swings, anxiety, breast pain/swelling, irritability, weight gain, and bloating. 

  • Extreme form: Late Luteal Dysphoric Disorder

There are no obvious differences in hormone levels. It may be due to hormone withdrawal. Suppressing just the luteal phase (i.e. progesterone) does not work. However, suppressing the entire cycle does. But then, reintroducint hormones on top of that reinstates some of the symptoms. This suggeusts it is an inappropriate response to normal hormone levles. 

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Post-partum depression

Mild form is called baby blues. Baby blues occurs 24-48 hours after birth. Symptoms include uncontrolled emotions and crying.

The moderate form includes symptoms of depression. This can last up to 4-8 weeks with symptoms of depressed mood, insomnia, crying, irritability, feelings of inadequacy, reduced coping ability, and fatigue.

Baby blues may be due to the drop in hormones, especially β-endorphins.

Longer term effects are more likely enviromental. Evidence for environmental influences include the fact that fathers have similar symptoms and symptoms are worse in stay at home mothers and with unwanted pregnancies.   

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Sex differences in cognitive skills

Female Advantage:

  • Verbal Abilities
  • Perceptual Speed & Accuracy

Male Advantage:

  • Visuo-Spatial Abilities
  • Quantitative Abilities

However, the effect sizes are very small. 

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Sexual orientation

One of the most extreme sex differences. 

90-95% of men are attracted to women exclusively whilst 85-90% of women are attracted to men exclusively. 

Think about orientation as a continuum from preferring male sexual partners to preferring female sexual partners. The extremes would be female-oriented vs male-oriented. 

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Origin of sex differences in sexual orientation

Experience/cultural effects

  • Most people feel their sexual orientation has always been this way
  • No good evidence to support effects of parenting, learning, etc.
  • Evidence from other species
    • Sexual orientation in sheep
      • 8% of male sheep are exclusively interested in other males
      • The sexually dimorphic nucleus (SDN) of the preoptic area is smaller in these males. The size of the SDN is influenced by developmental T levels.

Activational Hormonal effects

  • No differences detected in adulthood between different sexual orientations
  • Hormone manipulations or treatments affect sexual motivation, but not orientation
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Origin of sex differences in sexual orientation

Organizational Hormonal effects

  • Clinical cases
    • Congenital Adrenal Hyperplasia (CAH): A condition characterized by hypersecretion of androgens by the adrenal cortex; in females, causes masculinization of the external genitalia. These women are more likely to identify as non-heterosexual. 
    • Women exposed to Diethylstilbestrol (DES) in utero are more likely to identify as non heterosexual.
  • Adult correlates of early hormone exposure
    • Childhood play styles: There is no positive correlation between prenatal testosterone levels and how 'boylike' play styles are 
    • Cognitive performanceIn gay men, verbal abilites ae better while visuo-spatial performance is worse. Mental rotation is faster in lesbians. 
    • Digit ratio lengths: Sex differences in digit ratios; early testosterone dependent. Butch lesbians have more masculine 2D:4D, however there is no consistent finding in gay men
    • Oto-acoustic emmisions: When stimulated with a click, ears make a sound back. This is louder and more frequent in women. Gay women's OAEs are closer to males. 

Most evidence points towards a role of prenatal testosterone in developing as a female-oriented adult. However, this is not the only factor. 

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Origin of sex differences in sexual orientation

Genetic Effects

  • Sex Chromosomes are sexually dimorphic
  • Genes on Y-chromosome only exist in males, genes on X-chromosome exist in 1 copy (1 allele) in males, but 2 copies in females
  • Certain genetic abnormalities allow us to distinguish between X and Y chromosome contributions. (E.g. Turner's syndrome)
  • Sex-linked characteristics » Red-green colour blindness
    • Genes for red and green photoreceptors are located on the X-chromosome. One good copy is enough to have "normal" colour vision. Males are 8 times as likely to be red-green colour blind. This characteristic skips a generation from grandfather to grandson.
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Origin of sex differences in sexual orientation

Genetic effects

  • Twin studies: Higher concordance in MZ than DZ twins. Estimates from 30-100%. Possibly higher concordance for women than men
  • Genetic mapping: Gay men often have gay maternal uncles. This suggests an X-chromosome inheritance pattern. 
  • Concerns from an evolutionary angle: Heterozygote advantage, different effects in males vs females, and kin selection are possible mechanisms for maintaining such genes. 
  • Fraternal birth order effect: Only works for real brothers from the some mother. More likely to be homosexual if you have more older brothers if you are male.
    • Maternal immunization hypothesis - indicates the existence of proteins (and hence genes) in brain development that are involved in sexual orientation 

There are clear biological development influences, however there is no absolute influence. Sexual orientation can be influenced by a number of different factors. 

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Sexual Behaviour

Appetitive behaviour: behaviour aimed at finding and obtaining a sexual partner 

  • External stimuli: usually related to opposite-sex conspecifics, often learned, can be of different sensory modalities (can lead to strange stimuli eliciting sexual motivation e.g. fetishism)
  • Internal motivation: hormones 
    • pheromones: A chemical released by one animal that affects the behavior or physiology of another animal; usually smelled or tasted.

Men » testosterone is involved in sexual interest

  • the developmental processes have made certain parts of the brain more or less sensitive to different hormone types and more or less likely to engage in certain behaviours. T sensitizes some of the brain areas involved in sexual motivation

Women » both androgens and estrogens are involved in sexual interest 

  • T seems to act in similar ways: give T and libido increases, take it away and it decreases. 

Prolactin reduces sexual desire in both sexes. 

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Sexual Behaviour

Consummatory behaviour: behaviour of the actual sexual act

Four stages of arousal: Excitement, plateau, /o r g a s m/, resolution

Excitement and plateau - Parasymphathetic stimulation relaxes smooth muscle in blood vessels. More blood enters the genitals. This leads to penile/clitoral erection. This leads to engorgement of labia and vaginal lubrication. Nitric Oxide (NO) plays a role in the relaxation of the smooth muscle. Viagra increases the effect of NO, so it helps cause and maintain erection. There is a feedback mechanism between “psychological” sexual arousal and physical arousal, where the one probably increases the other (positive feedback). So sexual motivation may start as a purely mental process, or as a purely physical process. But after a while, they cannot be really separated. 

/o r g a s m/ - Triggered by combination of local stimulation and central input. Sympathetic stimulation and pulsatile release of oxytocin results in series of smooth muscle contractions. Pain thresholds are increased.  Cervical stimulation in women increases pain threshold, even in women with spinal cord injury. Seems to work through the vagus nerve. 

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Sexual Behaviour

Resolution: Satiety - Active inhibition of sexual motivation. During /o r g a s m/, blood oxytocin levels peak. Oxytocin is also involved in pair-bond formation. During /o r g a s m/, prolactin is also released. High prolactin levels suppress sexual motivation

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Erectile dysfunction

Erectile dysfunction: also known as impotence, is a type of sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual activity. Erectile dysfunction can have psychological consequences as it can be tied to relationship difficulties and self-image.

A physical problem can lead to psychological problems (once cannot get it up, worries about it next time, stress, etc) then when physical problem (e.g. blood vessel problem) is fixed, still a problem of confidence.

Stress leads to increased sympathetic activity, which causes vasoconstriction. Learned aversions can have effects. 

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Menstrual Cycle

The estrogen has a negative feedback on FSH, which causes it to stop being secreted. This increased amount of estrogen causes a positive feedback to occur on the LH cells in the pituitary. LH secretion will rise, and ovulation occurs.

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