Brain Stem_ Sleep and Hypothalamus

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					NS SNN: Brain Stem, Sleep and Hypothalamus

Brain Stem – Lecture 33 - Hen:
• Cranial nerves: Some Say Marry Money, But My Brother Says Big Boobs Matter More
        (CN I, II are Sensory, III, IV are Motor, V is Both, etc…)

• Organization and Development
        • Sensory pathways and nuclei: more lateral, develop from dorsal alar plate
        • Motor pathways and nuclei: more medial; develop from the ventral basal plate
        • Brainstem Reticular Formation: ventral to sensory/motor nuclei in brainstem
                - coordinate reflexes & simple behaviors mediated by cranial nerves (eg. swallowing),
                important in arousal of other brain systems

• Cell groups in brain stem with long projections are defined by their neurotransmitters
         • Neuromodulatory systems: norepinephrine, dopamine, serotonin, acetylcholine, histamine

• Noradrenergic System:
        • Main nucleus is Locus Ceruleus.
        • Projections to cerebral cx, cerebellum, brain stem, spinal cord.

• Dopaminergic System:
       • tyrosine → dopamine (rate limiting step involves tyrosine hydroxylase).
       • Projections to brain stem, spinal cord, pituitary gland, and retina.
       • Dopaminergic synapses:
                • Monoamine Oxidase (MAO) breaks down dopamine in pre-synaptic cell
                • Dopamine reuptake transporter: blocked by ritalin and cocaine
                • D2 receptor on post-synaptic cell: inhibited by anti-psychotic/schizophrenic drugs
                • Amphetamines stimulate large vesicular release of dopamine.
       • 2 important dopaminergic areas:
                • Ventral Tegmental Area & projections to cx
                        • mesocortical system: involved in negative symptoms of schizophrenia
                        • mesolimbic system: involved in positive symptoms of schizophrenia
                • Substantia Nigra & projections: motor control
                        • defective in motor deficits and Parkinson’s

• Serotinergic System:
         • tryptophan → serotonin (5-HT) (rate limiting enzyme: tryptophan hydroxylase).
         • Main nucleus: raphe nucleus.
         • Projections to the forebrain, cerebellum and spinal cord.
         • Serotonergic synapses:
                  • 5-HT removed from synapse by serotonin transporters
                  • Selective serotonin reuptake inhibitors (SSRIs) (e.g. Prozac) block reuptake
                           • serotonin stays in synaptic cleft longer
                  • MAO breaks 5-HT down
                           • MAO inhibitors: delay breakdown of 5-HT, used at anti-depressants
                  • LSD: stimulates 5-HT2a receptor on post-synaptic cell

• Cholinergic System:
        • Main sites of ACh production: basal forebrain (especially nucleus basalis of Meynert) and
        pontine nuclei.
        • Projections to entire brain (except cerebellum).
• Histaminergic System:
        • Main site of production: tuberomamillary nucleus.
        • Projects widely, but fewer projections than other systems

• Ascending Arousal System:
       • increase wakefulness & response to sensory stimuli (arousal)
       • ascending pathway from brain stem and hypothalamus → cerebral cx & thalamus
       • Main contributors to ascending arousal system:
                locus ceruleus, dorsal/lateral raphe nuclei, tuberomamillary nucleus, nucleus basalis of
                Meynert, melanin-concentrating area

• Sleep vs. Wakefulness
        • awake state:
                 • EEG desynchronized
                 • spike mode in thalamus: more depolarized state
                          • much sensory info transmitted
        • sleep state/coma:
                 • EEG synchronized
                 • bursts of activity in thalamus: result from hyperpolarized state
                          • little signal transfer occurring in thalamus

• nucleus of solitary tract coordinates autonomic functions
• amygdala and brain steam nuclei coordinate fear response
        • lesion central nuc. of amygdala = fear response effected (can’t interpret scary face)

Sleep – Lecture 33 - Kavey
• Sleep is an active physiologic process.
• Circadian rhythms: inherent biological, 24-hour cycle
         • regulatory centers for circadian rhythms:
                  • Suprachiasmatic Nucleus of hypothalamus (SCN)
                  • Retinohypothalamic tract (light signals directly from retina to SCN)
                          • light is major organizer of sleep-wake rhythm
                          • Light/outside stimulus  retinohypothalamic tract  SCN of hypothalamus 
                          regions of brain stem  nuclei on or off
         • Evening: activating systems decrease action & sleep systems inc. action
                  • 4:30 am: activsting systems inc. action & sleep systems decrease action
                          • body temperature: higher in the morning, lower in evening, lowest at 3:30am
                          then increase 4:30am to prep for waking
                  • Problem with rhythm = jet lag (when body rhythm is no longer sync’d to society and
                  environment), takes 1-2 weeks to adjust
• Sleep centers
         • 1940s Moruzzi and Morgan
                  • Ascending Reticular Activating System: midbrain into posterior hypothalamus
                          • active in awake state
         • Jouvet et al
                  • REM sleep promoters: cholinergic neurons of roof of pons
                          • ACh released from laterodorsal tegmentum (LDT) & pedunculopontine
                          tegmentum (PPT)
                  • REM sleep suppressors: monoaminergic neurons in locus ceruleus (noradrenergic) &
                  raphe nuclei (serotonergic)
• Nerves involved in regulation of sleep/wake and REM/non-REM: adrenergic, cholinergic, serotonergic,
glutamatergic, dopaminergic
                      Wake                                              Sleep
Neurotransmitters     • Histamine: wake promoting (released by          • GABA: inhibitory; bringing sleep; in
                      tuberomammillary nuc.)                            hypothalamus, basal forebrain, thalamus
                      • Hypocretin/Orexin: wake promoting; in           • Adenosine: accumulates in basal
                      hypothalamus                                      forebrain during awake periods = buildup
                      • Glutamate: wake promoting                       of sleepiness; triggers sleep at proper
Neurophysiology       • From retina  Lateral hypothalamus              • Ventral and lateral pre-optic area of
                      (suprachiasmatic nuc.)  projections use          hypothalamus stimulate sleep
                      hypocretin to stimulate wakefulness nuclei       • GABA is inhibitory output → inhibition
                      causes release of:                                of nuclei in brainstem that stimulate
                      - ACh: from basal forebrain, pedunculopontine     wakefulness
                      tegmentum nuc., laterodorsal tegmental nuc.
                      - Norepinephrine: from locus ceruleus
                      - Serotonin: from raphe nuclei
                      - Histamine: from tuberomammillary nuc.
                      - Dopamine: from ventral tegmental area (VTA)

                     REM                                              non-REM
Neurophysiology      • Cholinergic neurons of PPT & LDT release       • Neurons of locus ceruleus release norepi =
                     ACh = stimulate REM sleep                        turn off REM sleep
                     • release of glycine causes muscle paralysis
                     during dreams (REM) (protective mechanism,
                     don’t act out dreams)

• Cycles of Sleep and Wake:
                  Wake             Non-REM sleep, 75%                                                 REM, 25%
                                   Stage 1       Stage 2            Stage 3          Stage 4          Stage 5
% of sleep                         5%            45%                12%              13%              25%
Type of sleep                      light sleep   moderate           deep sleep       deepest sleep    dream sleep
EEG               Alpha            mixed (most   theta activity     slow delta       more slow        mixed
frequencies                        theta, some   K-complexes        waves            delta waves      frequency
                                   alpha)        & spindles
EMG muscle        high submental   high          high tonic          slightly        slightly         low tonic
tone                               submental     submental           reduced         reduced          submental
                                                                     submental       submental
Characteristics                    Classical quiet sleep, even breathing                              Rapid eye
                                                                                                      mvts, variable
                                                                                                      hearth &
                                                                                                      rates, muscle

  • regular sleep cycles for young person:
        • REM sleep occurs in 90 minute cycles (ultradian rhythm)
        • longer REM periods as night goes on
        • mostly Stages 3,4 in early part of night
        • stage 2,5 occur later in night
        • With age, less Stage 3,4 sleep, REM the same, more awake periods
• Sleep deprivation:
        • cognitive, emotional, personality, physical performance decrements
        • physiological changes: increased cortisol, increased sympathetic tone, decreased immune
        function, increased cardiac risk, changes in glucose metabolism/insulin response
• REM deprivation  REM pressure and REM rebound (build-up of REM when you REM-deprive
someone) (inc. amt REM when REM sleep re-occurs = more nightmares)

• Sleep Disorders:
        • Insomnia: difficulty falling asleep and staying asleep
        • Hypersomnia: excessive daytime sleepiness
        • Narcolepsy: adrenergic centers don’t shut down REM sleep, so get REM during daytime
                • Narcolepsy tetrad:
                         1) excessive daytime sleepiness
                         2) cataplexy: sudden loss of muscle tone
                         3) sleep paralysis: unable to move when initially wake up
                         4) hypnagogic hallucinations: visual and auditory; associated with dream
        • Parasomnia: neurophysiological disorders during sleep that are normally observed during
                • Somnambulism (sleep-walking) and Sleep Terror: in Stage 4 (NOT REM, so NOT
                while dreaming), typically in children
                • REM sleep behavior disorder: failure of suppressing muscle tone, act out the dream,
                more in elderly and Parkinson’s patients
                         • locus ceruleus deteriorates = no paralysis during dreams
        • Snoring & Sleep Apnea: decreased muscle tone in upper airway (not nose) during sleep;
        obstructed = increased air turbulence = vibrate muscles = snore; worse in REM sleep

Hypothalamus - Lecture 34 - Salzman
• Goal is to maintain homeostasis
• Hypothalamus controls the “four F’s: Fighting, Fleeing, Feeding, Mating
• Hypothalamic Nuclei:
         • Arcuate Nucleus: controls feeding
         • Medial/Lateral preoptic nuclei: involved in temperature regulation
         • Paraventricular Nucleus: controls endocrine & autonomic processes
                  • contains 2 types of cells:
                           • Parvocelluar
                                   • Medially: parvocellular neurons secrete hypothalamic releasing
                                   hormones (like CRH)
                                   • Dorsally & Ventrally: neurons project to medulla & spinal cord for
                                   autonomic control
                                            • some secrete oxytocin & vasopressin
                           • Magnocellular
                                   • control endocrine function directly by releasing oxytocin & vasopressin
                                   into posterior pituitary
• Hypothalamus controls endocrine system:
         • directly: magnocellular neurons secrete neuroendocrine products (oxytocin & vasopressin) into
         general circulation from posterior pituitary gland
         • indirectly: parvocellular neurons secrete regulatory hormones into local portal circulation,
         which drains into anterior pituitary
        • some hypothalamic neurons synapse at peptidergic neurons (link btw peptidergic neurons and
•Visceral info. to hypothalamus:
        • visceral info from CN VII, IX, X → Nucleus of the solitary tract → parabrachial nucleus →
        hypothalamus & other limbic structures (eg. amygdala)
• Hypothalamus: inputs and outputs
                      Neural Output                             Hormonal Output
Neural Input          Controls the ANS (eg. emotion)            Controls release of oxytocin for milk
Hormonal Input        Used for drives & motivated behavior      Controls release of vasopressin for fluid
                      (eg. sex hormones)                        regulation

• Maintains homeostasis through a servo-control system
                                                                 - Like a thermostat in the house!
                                                                 - Hypothalamus compares temperature in the
                                                                 room to a set point. It computes the
                                                                 difference, which is the error signal.
                                                                 - The set point can change, mainly in times
                                                                 of fever.
                                                                 - ANTERIOR hypo (pre-optic area):
                                                                 mediates heat dissipation
                                                                 - POSTERIOR hypo: mediates heat
                                                                 - This temperature change can be mediated
                                                                 by ANS, endocrine responses, and behavioral
• Feeding Behavior
        • Biological set point for weight: variable in humans (many factors play a role)
            • Short-term satiety signals (regulates meal size): CCK, mechanical from stomach,
            • Adiposity signals (long-term control): leptin and insulin
                • Leptin secreted by fat cells; insulin secreted by pancreas
                • leptin & insulin → arcuate nucleus → PVN & LHA
                         • NPY (neuropeptide Y) & AgRP (agouti-related protein): released by neurons in
                         arcuate nucleus; inhibited by adiposity signals
                                  • anabolic peptides – encourage tissue growth
                         • a-MSH (a-melanocyte-stimulating hormone) & CART (cocaine-amphetamine-
                         related transcript): released by neurons in arcuate nucleus; stimulated by
                         adiposity signals
                                  • catabolic peptides – metabolic breakdown, release energy

                                                                           NYP and AgRP: INHIBITED by
                                                                           adiposity signals, ANABOLIC
                                                                           α-MSH and CART: STIMULATED
                                                                           by adiposity signals, CATABOLIC

                                                                           PVN (paraventricular nucleus):
                                                                           CATABOLIC (break down)
                                                                           releases CRH & oxytocin
                                                                           LHA (lateral hypothalamic area):
                                                                           ANABOLIC (build up)
                                                                           releases orexin A & melanin-
                                                                           concentrating hormone (MCH)
• Caloric Homeostasis:
        • Leptin inhibits NPY/AgRP neurons  ↓ inhibition to catabolic pathway and
             ↓ excitation to anabolic pathway  net catabolic
        • Leptin stimulates α-MSH/CART neurons  ↑ excitation of catabolic pathway and
         ↑ inhibition of anabolic pathway  net catabolic
        • Leptin thus increases energy expenditure and decreases caloric consumption!
                     • May play a role in obesity. Leptin treatments work only early in development (can
                     rescue projections from the arcuate nucleus to paraventricular nucleus)

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