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Sleep Physiology-basic mechanisms of sleep & arousal. In 1940’s Moruzzi & Magoun found that electrically + certain areas in the brain and brainstem produced cortical activation arousal states appear to be determined by an interaction among the brainstem, hypothalamus, thalamus & basal forebrain

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Sleep Physiology-basic mechanisms of sleep & arousal

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sleep physiology basic mechanisms of sleep arousal
Sleep Physiology-basic mechanisms of sleep & arousal
  • In 1940’s Moruzzi & Magoun found that electrically + certain areas in the brain and brainstem produced cortical activation
  • arousal states appear to be determined by an interaction among the brainstem, hypothalamus, thalamus & basal forebrain
  • Dampening of arousal systems with concomitant active inhibition by thalamo-cortical systems produces sleep
basic mechanisms of sleep cont
Basic mechanisms of sleep (cont)
  • Areas maintaining wakefulness include
    • oral pontine reticular formation
    • midbrain central tegmentum
    • posterior hypothalamus
  • Sleep promoting areas are located:
    • midline brainstem
    • dorsolateral medullary reticular formation
    • anterior hypothalamic preoptic region
interaction between sleep wakefulness areas
Interaction between sleep & wakefulness areas
  • Magnocellular nucleus basalis of Meynert located in the forebrain
    • intermingling of both sleep & arousal systems
    • sleep modulating center
      • both sleep and waking active sites
    • projections to neocortex and midbrain reticular formation
    • acetylcholine projections
  • Sleep is a behavioral state that differs from wakefulness by a readily reversible loss of reactivity to event’s in one’s environment.
  • Sleep is divided into stages based on:
    • electroencephalography (EEG)
    • electro-occulogram (EOG)
    • electromyogram (EMG)
sleep stages
Sleep Stages
  • Non Rem (NREM) or slow wave sleep
    • I (light) theta, delta (low amplitude) horizontal eye
    • II (light) theta, delta, sleep spindles, K complexes
    • III (deep) high amplitude delta (20-50%)
    • IV (deep) high amplitude delta (>50%)
  • Rapid eye movement (REM)
    • EEG resembles awake state or NREM stage I
    • dramatic decrease in EMG activity
  • Electrical stimulation of nucleus tractus solitarius (NTS) produces slow wave sleep
  • Lesions in NTS produces cortical desynchronization (waking pattern of EEG)
  • NTS appears to inhibit more rostrally situated neurons in the ascending reticular activating system
  • Direct connections between NTS & major areas of the limbic system exist (ant. thalamus, hypothalamus, amygdala)
sleep cont
Sleep (cont.)
  • Lesions in serotonin rich raphe nucleus produces insomnia
  • Parachlorophenylalanine (PCPA) a trytophan hydroxylase inhibitor also produces insomnia by blocking production of serotonin
  • SWS can be restored in PCPA induced insomnia by administration of 5 Hydroxytrytophan (5HTP)
sleep cont10
Sleep (cont)
  • Serotonin appears to modulate sleep through its effect on other hyponogenic factors in the anterior hypothalamus and suprachiasmatic nucleus
  • Serotonin is a melatonin precursor
  • Melatonin is synthesized and released by the pineal gland through sympathetic activation from the retino-hypothalamic tract
sleep cont11
Sleep (cont.)
  • Melatonin enhances sleep
  • prolonged bright light stimulation suppresses melatonin and sleep while subsequent melatonin injections can restore normal sleep patterns
  • Preoptic nucleus of ant. Hypothalamus appears to inhibit waking areas in the rostral midbrain and mesopontine reticular core
sleep cont12
Sleep (cont)
  • Prostaglandin D2 which is highly concentrated in the preoptic nucleus and induces both SWS and REM sleep
  • Prostaglandin inhibition by indomethacin can decrease diurnal sleep
  • The anterior hypothalamus may also promote sleep by inhibiting the waking area in the posterior hypothalamus
  • Factors such as triazolam, 5HTP, muramyl peptides, PGD2 have hypnogenic effects by acting on the anterior hypothalamus
slow wave sleep sws
Slow wave sleep (SWS)
  • Sleep spindles and delta waves are physiologic events involving GABAergic neurons via inhibition promote brain deafferentation
  • Sedatives (barbituates) and hypnotics (benzodiazepines) stimulate GABA receptors and facilitate sleep
  • Sleep spindles are rhythmic cortical waveforms generated by oscillatory activity in nucleus reticularis of the thalamus
slow wave sleep sws14
Slow wave sleep (SWS)
  • Slow waves (delta) are generated in neocortical circuits arising in all cortical layers
  • An increase in GABAergic anterior hypothalamic preoptic and basal forebrain neurons is associated with SWS
  • Afferent input to anterior hypothalamus, serotonin, muramyl peptides, interleukins, PG’s that produce temp increase resulting in heat loss may induce SWS
rem sleep
REM sleep
  • Cortical EEG is highly desynchronized (similar to waking)
  • Associated with pontine geniculate occipital spikes (PGO)
  • PGO spikes are associated with many phasic events such as rapid eye movements, changes in respiration, heart rate, muscle twitches, and dreaming
rem sleep cont
REM sleep (cont.)
  • PGO spikes originate from REM-ON cells in medial pontine reticular formation & adjacent reticular tegmental nucleus
  • In animals REM sleep has been eliminated by placing lesions ventral to locus ceruleus
  • REM sleep can be induced by cholinergic stimulation of the pons
  • REM-OFF cells are represented by noradrenergic cells of locus ceruleus which become silent during REM
rem sleep cont17
REM sleep (cont.)
  • Many antidepressants are REM suppressors; which increase activity of norepinephrine and/or serotonin
  • Progressive decrease in muscle tone associated with hyperpolarization of motor neurons
  • Rheobase 30% greater in REM sleep
rem behavior disorder
REM behavior disorder
  • Normally REM sleep is associated with a progressive decrease in muscle tone associated with hyperpolarization of motor neurons
  • In this disorder there is persistant muscular tone during REM
  • Characterized by bursts of excessive limb & body movements
  • Cause in humans unknown
    • In cats lesions of the pons that destroy area just ventral to the locus ceruleus
other changes in sleep
Other changes in sleep
  • Reduction in body and brain temperature at onset of sleep associated with vasodilation
  • general decrease in metabolism
  • reduced thermosensitivity of hypothalamic preoptic nucleus
  • Suprachiasmatic nucleus serves as an endogenous clock influencing both sleep and body temperature in a closely coupled fashion.
other changes in sleep cont
Other changes in sleep (cont)
  • Brain metabolism decreases 20-35% in SWS
  • Cerebral blood flow decreases during SWS
  • Adenosine appears to be a somnogenic neurotransmitter (caffeine blocks hypothalamic adenosine receptors)
  • Sleep onset is associated with inhibition of TSH, cortisol, & stimulation of GH & Prolactin
potential sleep promoting factors
Potential Sleep Promoting Factors
  • Many also have immune functions
      • Muramyl peptides
      • Lipopolysaccharides
      • Prostaglandin D2
      • Interleukin I
      • Interferon alpha2
      • Tumor necrosis factor
      • Delta sleep-inducing peptide
      • Vasoactive intestinal peptide
      • Serotonin/melatonin
      • Prolactin
function of sleep
Function of Sleep
  • Restores normal levels of brain activity and normal balance among different parts of CNS (restore natural balance)
  • Physiologic effects on the rest of the body
    • decreased SNS, increased Para effects in slow wave sleep
  • enhanced immune function
    • common factors
  • link
link between sleep weight loss
Link between sleep & weight loss
  • Sleep deprivation
    • can raise cortisol
      • Cortisol  insulin which promotes fat storage
    • Can contribute to insulin resistance
      • Linked to obesity, CV disease, type II diabetes
      • High fat, high sugar diet can lead to insulin resistance
    •  slow wave sleep (stage III and IV non REM)
      • Linked with  levels of growth hormone
        • Has an important role in fat loss and muscle growth
    • Individuals who sleep longer (>9 hr) less likely to be obese than individuals who sleep shorter (<6 hr) (I.J.Obesity&Metabolic Disorders 24; 1683, 2000.)
epilepsy seizures
Epilepsy (seizures)
  • Uncontrolled excessive activity of either part or all of the CNS “electrical storm”
  • Predisposition greater than incidence
  • Disrupts normal brain function
  • Epileptogenic circuitry
    • lowered threshold and/or facilitation
  • Causes
    • Trauma
    • Oxygen Deprivation
    • Tumors
    • Infections
    • Toxic States
    • (In1/2 of all cases the cause is unknown).
  • Incidence
    • .5-1% of population (2nd most common neurological disease)
  • Precipitating causes of a seizure
    • strong emotional stimuli
    • alkalosis (hyperventilation)
    • drugs
    • fever
    • loud noises or flashing lights
  • Termination of a seizure
    • neuronal fatigue
    • active inhibition (inhibitory NT)?
types of seizures
Types of Seizures
  • Grand Mal (Tonic-Clonic)
  • Petite Mal (Absence)
  • Psychomotor (Focal)
  • Jacksonian
  • Myoclonic
  • Atonic
  • Status Epilepticus
grand mal
Grand Mal
  • Aura
    • altered sensation prior to seizure, e.g. tingling
  • Tonic phase
    • rigid stiffening of body, loss of consciousness
  • Tonic-clonic phase
    • strong muscle contractions & convulsions, over within minutes
  • Post-ictal phase
    • return to consciousness; may be associated with confusion, stupor, slurred speech, weakness
  • Treatment
    • Drugs
      • phenobarbital
      • dilantin
      • tegratol
      • depekene (Valproic Acid)
    • Surgery
      • excision of epileptic foci
    • Vagal stimulator
    • Chiropractic adjustments
evoked potentials ep
Evoked Potentials (EP)
  • Sensory EP is a change in EEG resulting from stimulation of a sensory pathway
  • Sensory EP is extracted from EEG using computer averaging techniques
  • EEG is recorded during repetitive natural stimulation (eg. tap on skin or flash of light)
  • Computers samples the EEG before & after stimulation & sample data are averaged.
evoked potentials cont
Evoked Potentials (cont)
  • Sensory EP consist of multiple components related to various aspects of subcortical & cortical processing (scalp electrodes)
  • Clinically useful for assessing the function of sensory systems or evaluating demyelinating diseases (eg. M.S.)
    • Destruction of myelin causes conduction velocity to decrease which increase latencies
mental illness
Mental Illness
  • Affect core elements that define humanity
    • personality, goal directed behavior, language, creativity, abstract thinking, emotion, mood, social organization
  • Neural disruptions are probably complex, multiple, not readily observable
    • occur at biochemical or molecular level
  • range from mild to severe
mental illness33
Mental Illness
  • Mild
    • obsessive-compulsive personality
    • antisocial personality
  • Severe
    • dementias
    • schizophrenia
    • bipolar disorder
    • major depression
    • anxiety disorders (e.g. panic attacks)
schizophrenia shattered mind
Schizophrenia (shattered mind)
  • Characterized by a mixture of S/S of which no single one is necessarily present
    • significant deterioration in functioning
    • relatively chronic course
    • very incapacitating (60% morbidity)
    • onset early in life (late teens-early twenties)
  • Is a disease of neural connectivity caused by multiple factors that affect brain development
    • Multiple hits
      • Some combination of genetic and non genetic factors
schizophrenia symptoms
Schizophrenia - symptoms
  • Positive symptoms
    • most prominent during psychotic episodes
    • Unable to interpret reality correctly
    • distortions or exaggerations of normal cognitive or emotional functions
schizophrenic symptoms
Schizophrenic symptoms
  • Positive symptoms (cont.)
    • Delusions
      • Abnormal beliefs that are not supported by facts & not changed by evidence
    • Hallucinations
      • Perception occuring without an external stimulus
    • Bizarre behavior
    • Illogical thinking
      • Loss of normal connections or associations btw. ideas (derailment) resulting in incoherent thoughts & speech
    • Exaggerated mesolimbic activity (dopaminergic)
      • ventral tegmental area to many areas of limbic system
schizophrenia symptoms37
  • Negative symptoms
    • loss or decrease of normal functions
      • alogoria -poverty of speech or empty content
      • flat affect-decrease in ability to express emotion
      • anhedonia-inability to experience pleasure
      • avolition -inability to initiate or persist in goal directed behavior
      • attentional impairment
    • tend to impair the persons ability to function in daily life more so than positive symptoms
    • Exaggerated mesocortical activity
      • ventral tegmental area to neocortex (dopaminergic)
schizophrenia symptoms38
  • Cognitive symptoms
    • Poor attention
    • Deficits in working memory
      • A form of explicit short term memory critical for executive functions
        • Organizing one’s day
        • Planning and carrying out a sequence of events
      • Involves the prefrontal cortex
    • Chronic and persistent
    • Most difficult aspect of the disease to manage
  • Various symptoms suggest possible involvement of a variety of cortical & sub-cortical areas
  • Metabolic activity in prefrontal cortex is subnormal at rest & with any specific mental activity ( is less)
  • Anatomical abnormalities
    • enlargement of ventricles
    • prominent sulci due to abnormal brain development
  • Mix of genes & environment as causative factors
  • Strikes 1% of population worldwide
    • 2-3% of pop. has schizotypal personality disorder
      • Milder form without psychotic behavior
schizophrenia causes
  • Genetics
    • Concordance in monozygotic twins- 40%
    • Concordance in dizygotic twins- 10%
  • Non genetic factors
    • poor nutrition
    • infections during pregnancy or childhood
    • toxins-damage neurons or affect NT systems
    • radiation-mutations
schizophrenia dopamine
  • Exaggerated Dopamine activity (working hypothesis but is oversimplified)
    • at key sites-limbic areas, language areas
    • dopamine receptor blockers (type 2)
    • increased dopamine receptors
    • L-dopa causing schizophrenic symptoms
    • increased levels of dopamine metabolites
disorders of mood
Disorders of Mood
  • Depression
  • Mania
  • Anxiety Disorders
  • Mood
    • sustained emotional state
  • Affect is a sign- what can be observed
    • Normal affective responses
      • Euphoria, elation, pleasure, surprise, anger, anxiety, disappointment, sadness, grief, despair, depression
unipolar depresssion
Unipolar Depresssion
  • First described in Hippocratic writings in 5th century B.C.
  • Moods were thought to depend upon the balance of the four humors
    • blood, phlegm, yellow bile, black bile
  • An excess of black bile was thought to cause depression
    • melancholia means black bile
unipolar depression
Unipolar Depression
  • Most likely several disorders
  • Untreated, typically lasts 4-12 months
  • Characterized by pervasive unpleasant mood that is present most of the day
  • inability to experience pleasure (anhedonia)
  • generalized loss of interest
unipolar depression46
Unipolar Depression
  • Additional symptoms (3 to make Dx)
      • disturbed sleep
      • diminished appetite (sometimes overeating)
      • loss of E
      • decreased sex drive
      • restlessness
      • retardation of thoughts/actions
      • difficultly in concentrating
      • indecisiveness
      • low self esteem
      • guilt/pessimistic thoughts
      • thoughts about dying & suicide
unipolar depression47
Unipolar depression
  • Additionally symptoms may show a diurnal variation usually worse in mornings
  • schizophrenia & other neurological diseases need to be excluded
  • Incidence-5% of population (U.S.= 8 mil)
  • Average age 30
  • Subtypes
    • (endogenous) melacholic
    • reactive
bipolar manic depressive
Bipolar (Manic-Depressive)
  • Gives rise to Euphoria (Manic phase)
  • Similar to unipolar depression with mania
  • Mania
    • elevated expansive or irritable mood which lasts at least a week
      • overactivity (including speech)
      • social intrusiveness
      • increased energy & libido
      • decreased need for sleep
      • reckless involvements
depression in general
Depression (in general)
  • Strong genetic predisposition
    • concordance in monozygotic twins =50% (even when reared apart)
  • Incidence of suicide in biologic relatives of depressed adoptees 6-10 X higher than biologic relatives of normal adoptees
  • stress can play a role
    • average age of onset has declined over last 60 years




Chronic low

Back pain

link btw chronic low back pain depression brain shrinkage
Link btw. Chronic low back pain, depression & brain shrinkage
  • Chronic low back pain sufferers have a high rate of depression
    • Depression is by far the most common emotion associated with chronic low back pain
  • In addition chronic low back pain is associated with increased rates of brain shrinkage
    • Loss of gray matter
    • Brain may age up to 20X faster than normal
      • Overstimulation of nociceptor pathways
treatment of depression
Treatment of Depression
  • Electroconvulsive therapy (ECT)- 90%
  • Drugs-70%
    • MAO inhibitors
    • Tricyclic
    • Specific Serotonin uptake blockers
    • Lithium Salts
  • Alternatives-?%
    • St. John’s Wort
    • Chiropractic
    • Omega 3 Fatty Acids
  • In use for over 50 years
  • full remission or marked improvement in about 90% of patients with well defined major depression
  • 6-8 trts at 2 day intervals over 2-4 wks.
  • Anesthesia with complete muscle relaxation
  • therapeutic change in aminergic receptor sensitivity
  • Side effects included memory loss (link)
mao inhibitors
MAO inhibitors
  • Decrease breakdown of biogenic amines (norepinephrine & serotonin)
  • 70% response rate
  • lag of 1-3 weeks; 4-6 weeks for full effect
tricyclic compounds
Tricyclic Compounds
  • Biogenic amine uptake blockers
  • 70% response rate
  • Also 1-3 week lag; 4-6 weeks for full effect
serotonin uptake blockers
Serotonin uptake blockers
  • fluoxetine (Prozac)
  • 85% effective
  • Specifically block the re-uptake of serotonin
  • lag of 1-3 weeks; full effect in 4-6 weeks
lithium salts
Lithium Salts
  • Effective at terminating manic episodes
  • have inhibitory effects on neuronal signal transduction systems (characteristic of mood stabilizers
  • Omega 3 Fatty acids have similar damping effects on signal transduction associated with phosphatidylinositol & arachidonic acid
anxiety disorders
Anxiety Disorders
  • Key feature- frequent occurance of symptoms of fear (SNS)
    • arousal
    • restlessness
    • heightened responsiveness
    • sweating
    • racing heart
    • increased BP
  • Anxiety is adaptive
    • signals potential danger & can contribute to mastery of difficult situation
  • Excessive anxiety is maladaptive
    • too intense
    • inappropriately provoked by events that present no real danger
  • Subjective manifestations
    • heightened sense of awareness
    • deep fear of impending disaster & death
panic attacks
Panic Attacks
  • Brief episodes of terror
  • Recurrent & unexpected
  • Last  15-30 minutes 1-3 X/week
  • intense overactivity of SNS
    • heart races, shortness of breath, chest pain, dizziness, trembling, flushes, chills
  • average age of onset- late 20’s
  • induced by:
    • infusion of sodium lactate into blood
    • inhalation of CO2
generalized anxiety disorder
Generalized Anxiety Disorder
  • Long lasting
    • unrealistic or excessive worry > 6 months
    • increased motor tension
      • trembling, twitching muscle aches, restlessness
    • increased SNS
      • palpitations,  HR, sweating, cold hands
      • feeling on edge
    • exaggerated startle response
    • difficulty in concentrating
drug treatment anxiety
Drug Treatment- Anxiety
  • Benzodiazepines (Valium, Librium)
    • enhance activity of GABA receptors
    • Stimulation of GABA receptor
      • opens Cl- channel, increasing Cl- influx, hyperpolarizing cell
  • Progressive decline in mental function
  • age related but does not have to occur
  • rare between 45-65
  • In U.S. 11% of population older than 65 show mild to severe mental impairment
    • from 75 on there is 2% increase/yr.
  • Alzheimer’s - most common form (70%)
alzheimer s disease
Alzheimer’s Disease
  • Findings on CT or MRI are non specific
    • thining of coritical gyri
    • enlarged ventricles
  • Early manifestations
      • forgetfulness
      • untidiness
      • transient confusion
      • periods of restlessness
      • lethargy
      • errors in judgement
alzheimer s disease65
Alzheimer’s Disease
  • Genetic component to certain forms (early onset type)
  • DNA marker on long arm of C21
  • Alzheimer’s is present in almost all people with Down’s syndrome who live past age 35 (Trisomy of C21)
  • In addition to C21, C1, C14, C19 may also be involved
  • Video clip
alzheimer s disease66
Alzheimer’s Disease
  • Extracellular plaques containing amyloid
    • amyloid-variety of different proteins that accumulate as extracellular fibrils
    • concentrated in neocortex, hippocampus
    • amyloid gene-on long arm of C21
  • Neurofibrillary Tangles- intracellular
    • bundles of abnormal filaments
      • Abnormal Tao protein
  • Video clip-Merzenich –Plasticity and Alzheimer’s
alzheimer s disease cont
Alzheimer’s Disease (cont.)
  • Decreased neuropeptides
    • somatostatin, NPY, Corticotropin RF, Substance P & VIP
  • Neuronal cell loss
    • hippocampus, N. basalis of Meynert (ACH)
cerebral blood flow
Cerebral Blood Flow
  • Lack of cerebral blood flow results in loss of consciousness within 5-10 seconds
  • normal blood flow 50-65 ml/100 gms/min
  • 750-900 ml/min (1500 gms of brain tissue)
  • represents about 15% of resting cardiac output
  • metabolic control- CO2, H+ (pH),  O2 will cause vasodilatation
cerebral blood flow69
Cerebral blood flow
  • Lack of cerebral blood flow-”stroke”
    • occlusive- 75%
    • hemorrhagic- 25%
  • Neurologic effects
    • depend on area of brain affected
blood brain barrier bbb
Blood Brain Barrier (BBB)
  • Most substances that must cross BBB are not lipid soluble and use specific carrier mediated transport systems
  • Brain uses glucose exclusively which gains entrance via a specific transporter (Glut1)
    • Glut1
      • facilitative, saturable, stereospecific
      • non energy dependent (only with concentration grad)
areas without bbb
Areas without BBB
  • BBB not found in all areas of brain
    • posterior pituitary & circumventricular organs (e.g. area postrema & median eminence)
    • consistant with physiologic function
      • secretory products that must pass
    • leaky areas isolated from the rest of the brain by specialized ependymal cells (tanycytes) which prevent free exchange with CSF
blood brain barrier cont
Blood Brain Barrier (cont)
  • Amino acids (AA) transported across via 1 of 3 carrier systems
    • L system (energy & Na+ independent)
      • large neutral AA with branched or ring side chains
        • leucine, valine
    • A system (energy & Na+ dependent)
      • neutral AA with short linear or polar sidechains
        • alanine, serine
      • may limit accumulation of - NT glycine in cord and + NT glutamate in the brain
    • ACS system (energy & Na+ dependent)
      • alanine, serine, cysteine
metabolic considerations of bbb
Metabolic considerations of BBB
  • Certain enzyme systems in endothelium
    • DOPA Decarboxylase and monoamine oxidase
      • change L-dopa into dihydroxyphenylacetic acid
    • -glutamyl transpeptidase
      • detoxifies glutathione-bound compounds & vasoactive leukotrienes
cerebral spinal fluid
Cerebral Spinal Fluid
  • Secreted by Choroid Plexus
    • 500 ml/day
  • Total CSF volume of 150 ml
    • turns over about 3X per day
  • secretory product related to plasma
    • < protein, glucose, K+, Ca++, Mg++, pH
    • > Cl- water
    • = osmolarity, Na+,
functions of csf
Functions of CSF
  • Communicates with brain ISF
    • important in maintaining a constant external environment for neurons and glia
  • removal of potentially harmful brain metabolites-(modified lymphatic system)
  • mechanical cushion
  • reduces weight of brain
  • transport of peptides to distant sites
  • pH affects both ventilation & blood flow
  • Study of secreted immune cell products (cytokines, lymphokines, monokines) actions in CNS and PNS
  • Nerve supply and regulation of lymphoid organs (e.g. spleen & thymus)
  • neuroendocrine (e.g. hypothalamic-pituitary axis) regulation of the proliferation and activities of monocytes, macrophages, lymphocytes, and glial cells
sns control of immune funtion
SNS Control of Immune Funtion
  • SNS innervation of the thymus, spleen, lymph nodes, and Peyer’s Patches
  • noradrenergic fibers in contact with thymocytes, B lymphocytes, macrophages
  • these immune cells possess both alpha and beta adrenergic receptors
  • activation of SNS inhibits proliferation of lymphocytes and results in suppressed immune response
ans immune interactions
ANS-immune interactions
  • Several peptides found in autonomic nerves innervating thymus, spleen and lymph nodes are also regulators of the immune system & lymphocytes possess receptors for these products.
    • VIP
    • NPY
    • Substance P
other neuropeptides in both brain and immune system
Other Neuropeptides in both Brain and Immune System
  • Corticotropic Releasing Factor (CRF)
  • ACTH
  • enkephalins
  • beta endorphin
  • vasopressin
  • oxytocin
  • neurotensin
effects of stress
Effects of Stress
  • During physical or psychological stress many of these neuropeptides are released, along with activation of SNS
  • They may mediate the suppression of the immune system and increased susceptibility to disease and infection that often follows periods of prolonged stress
  • Soluble mediators that are produced by immune cells
  • modify the proliferation and activity of other cells of the immune system
  • activated immune cells can cross BBB & release cytokines into brain
  • microglia & astrocytes (lesser degree) secrete IL-1, IL-2, IL-4, IL-6 & TNF
  • IL-1, IL-2, IL-6 receptors exsist in the brain
interleukin i
  • Formerly known as lymphocyte activating factor
  • endogenous pyrogen is actually IL-I
  • produced by macrophages, as well as hypothalamic & hippocampal neurons
  • Involved in immune cell proliferation & fever production
  • Alpha MSH (Pit) & endogenous IL-1 receptor antagonist negates fever producing response of IL-I
il 1 cont
IL-1 (cont)
  • Physical(trauma, infection, inflammation) & psychologic stressors of brain tissue stimulate production of cytokines
    • IL-1 produced by glial cells & neurons
      • Prolonged production of IL-1 and other cytokines (IL-6, TNF) in the brain during pathologic states can produce fever, sleep induction, anorexia, dementia & neuronal death
      • elevated in Alzheimer’s & Aids
      • contribute to behaviorial disturbances
  • Negative effects of elevated IL-l offset by endogenous IL-1 receptor antagonist
  • IL-1, IL-2, IL-6 in physiologic concentrations appear to help regulate the neuroendocrine axis
    • IL-1 stimulates the synthesis & release of CRF which + ACTH which + glucocorticoids (cortisol)
    • Cortisol down- regulates IL-1, IL-2, IL-6 & CRF (classic negative feedback)
    • After injury IL-1 + synthesis & secretion of nerve growth factor
    • IL-1 + release of somatostatin, & - GHRH, GnRH, TRH
  • Tumor Necrosis Factor (TNF-)
    • can supresses thyroid function directly and indirectly via - TRH which  BMR
    • contribute to fatigue & lethargy
neuroendocrine peptides in immune cells
Neuroendocrine peptides in Immune Cells
  • Neuroendocrine (NE) peptides have been shown to be produced by immune cells
    • B lymphocytes contain ACTH and enkephalins & its secretion can be + by CRF & - by glucocorticorticoids
    • T cells synthesize GH, TSH, LH, FSH
    • Monocytes synthesize Prl, VIP, somatostatin
    • These secretory products primarily act locally
  • Immune cells posess receptors for NE products (eg. NT, peptides, hormones)
neuroimmune interactions
Neuroimmune interactions
  • ACTH suppresses macrophage activation & synthesis of antibodies by B cells
  • Gonadotropins decrease the activity of T cells and natural killer cells
  • Somatostatin and VIP inhibit I cell proliferation & the inflammatory cascade
  • GH & Prl can + lymphocycte proliferation & antibody synthesis (oppose glucocorticoids)
neuroimmune interactions cont
Neuroimmune interactions (cont)
  • GH also functions to activate macrophages
  • Prl enhances the tumoricidal activity of macrophages & synthesis of interferon
  • TSH enhances antibody synthesis
  • -endorphin + activity of T, B, and NK cells
bidirectional communication
Bidirectional Communication
  • Bidirectional communication between cells of the nervous & immune systems directly or indirectly (via endocrine messengers)
  • Stress can + IL-1 release from activated monocysts, glial cells or hypothalamic neurons  hypothalmic release of CRF  + ACTH release from the anterior pituitary
  • ACTH + release of cortisol from adrenals  suppresses proliferation & cytokine secretion from monocytes lymphocytes & glial cells
specific example of nim
Specific example of NIM
  • Several peptides in autonomic nerves innervating thymus, spleen, and lymph nodes are also regulators of cells of the immune system
    • VIP
      • Inhibit proliferation of lymphocycts, NK cells, alter production
    • NPY
    • Substance P
  • Medical definition
    • Rate of wear & tear in the body
  • Hans Seyle
    • Father of stress
  • G.A.S (General Adaptation Syndrome)
    • Alarm reaction
    • Stage of resistance
    • Stage of exhaustion
  • Role of the Neuroendocrine system
    • Maintain homeostasis
  • Prolonged stress characterized by 3 major changes
    • Hypertrophy of the adrenal cortex
    • Atrophy of the thymus, spleen & lymph node
    • Ulceration of the GI tract
immune system
Immune system
  • Regulated to a large extent by intrinsic cellular & humoral events
  • Sensitive to signals generated by the neuroendocrine system
    • Receptors on immune cells to neuroendocrine peptides, NT, hormones
    • Alterations in the neuroendocrine system may cause functional modifications of immune reactivity
  • Immune organ that induces proliferation & differentiation of stem cells to mature T-cells
  • Synthesizes and secretes various hormone like peptides with effects on T cells
  • Plays a key role in neuroendocrine-immune interactions
  • Progressive decline in function as one ages
    • Is not irreversible
  • In neonatal mice thymectomy causes degeneration of the anterior pituitary gland
    • Progressive in # of degranulated acidophilic cells over 1 month
restoration of thymic function
Restoration of Thymic function
  • Neuroendocrinological manipulation may restore thymic function comparable to young levels
    • In old mice, treatment with L-thyroxine, restores thymic capacity to produce thymulin
      • Histological morphology reverts back to young-like
  • Thymic grafts in old mice reverses non-immunological parameters associated with aging
    • IPR-induced DNA synthesis in submand. G. 
    • Beta receptor density in brain tissue
    • Plasma T3 levels 
    • Plasma insulin levels 
    • % tetraploid cells in liver 
  • Neuroendocrine (NE) system influences immune functions & I0 thymus efficiency by modulating its hormonal activity
  • The thymus interacts with other endocrine glands and may influence body homeostatic mechanisms
  • Thymus-NE interactions work during the entire life of the organism
  • NE manipulations are able in old age to rejuvenate the thymus, fully recovering its endocrine activity
spinal cord injury
Spinal cord injury
  • Spinal cord injury patients have decreased:
    • NK cell function
    • T cell (adaptive) function
    • CAM’s (cellular adhesion molecules)
  • The above function in immune function and wound healing
spinal cord injury98
Spinal cord injury
  • negative effect on immune cells & responsiveness in SCI patients may be due to:
    • disrupting the outflow of signals from the SNS to lymphoid tissues & their blood vessels
    • immunosuppression caused by stressors
    • interrupting returning signals to the CNS reducing facilitation of immunoregulatory CNS neurons
      • (Immunologic Res 15(4):306-14, 1996)
chronic stress
Chronic Stress
  • Associated with immunosuppression
    • corticosteriods
    • catacholamines
    • endorphins
    • met-enkephalin
  • Coordinates the response to stress through the release of soluble products from the SNS & HPA axis.
  • NS & ES are not concerned with immunological specificity
    • NS & ES do influence the intensity, kinetics & localization of immune responses
immune cells
Immune Cells
  • Can produce neurologically active peptides including ACTH, CRF, GH, thyrotropin, PRL, hCG, endorphin, enkephalins, substance P, somatostatin, VIP.
  • Cytokines are likely important mediators of the HPA response to immune stimuli
  • Antistress effects in mice
    • immobilization stress (IS)
      • mortality < 10%
    • innoculated with vaccinia virus (VV)
      • mortality < 10%
    • IS + VV
      • mortality > 90%
    • IS + VV + PM melatonin injection
      • mortality < 10%
    • IS + VV + PM melatonin inj + naltrexone
    • mortality > 90%
  • A PM injection of melatonin (AM injection ineffective) abrogated effects of IS + VV
  • This effect of melatonin is mediated by the EOS (endogenous opioid system) as naltrexone (an opioid receptor blocker) negates the melatonin effect
  • regular melatonin administration (10 ug/ml) in mice prolonged lifespan (931  80 days vs 752  81 days p < .01)
neural plasticity
Neural Plasticity
  • Damage to the nervous system can induce remodeling of neural pathways
  • Such remodeling reflects plasticity
  • CNS is much more plastic than once believed
    • Plasticity greatest in the developing brain
      • Young child
    • some degree of plasticity remains in the adult brain
  • Critical period
  • Alteration of connections in visual cortex in visually deprived neonates
  • Amblyopia (reduced visual capacity)
  • Sprouting of new axons does occur in the damaged CNS
neurotrophic factors
Neurotrophic factors
  • Target tissues play a critical role in regulating the # of surviving neurons by secreting a variety of neurotrophic factors
  • Neurotrophin class
    • nerve growth factor (first one discovered)
      • protein with 3 subunits (MW 130,000)
      • beta subunit is biologically active
    • bind to specific receptors
    • promote neuronal survival
neurotrophic factors107
Neurotrophic factors
  • Elimination of neurotrophic factors & their receptors lead to neuronal death
  • sensory and sympathetic neurons require trophic support from neurotrophins secreted by their targets
  • target cells secrete limited amounts of neurotrophic factors
  • deprivation of neurotrophic factors activates a cell death program in neurons
    • apoptosis
  • Cell death characterised by 4 features
    • cell shrinkage
    • condensation of chromatin
    • cellular fragmentation
    • phagocytosis of cellular remnants
  • Process prevented by neurotrophins
  • The cell death program is the cause of neuronal cell loss that normally occurs in the first year of life
    • Caspase- enzyme that cleaves COOH (protein)
damage in the nervous system
Damage in the nervous system
  • Most injuries involve damage to axons
    • axotomy- transection of the axon
      • dooms the distal segment
      • glial cells degenerate (Wallerian degeneration)
      • proximal portion also affected probably due to lack of trophic factors from target cell
      • postsynaptic neurons can also atrophy and die
      • inputs to injured neuron can withdraw “synaptic stripping” & replaced with Schwann cells (PNS) or Microglia or Astrocytes (CNS)
      • neuronal degeneration can propagate through a circuit in both antro and retrograde directions
regeneration in the nervous system
Regeneration in the nervous system
  • New neural connections can reform following injury
  • Regenerative capacity is
    • > PNS
    • < CNS
  • Axonal Sprouting
  • Chemotropic factors secreted by Schwann cells attract axons to distal stump
pns regeneration
PNS regeneration
  • Once they return to their targets regenerated axons can form functional nerve endings
    • regeneration of neuromuscular junctions
    • re-innervation of glands, blood vessels, & viscera by ANS
    • sensory axons can re-innervate muscle spindles
  • In all three divisions of PNS (motor, sensory & autonomic the effects of axotomy are reversible (but not necessarily perfect)
cns regeneration
CNS regeneration
  • Little regeneration occurs in CNS after injury (short stumps)
  • long distance regeneration of axons is rare
  • may have a latent regenerative capacity that can be exploited via therapeutic interventions
    • environment
    • growth promoting factors (laminin, cell adhesion molecules)
    • central myelin is an inhibitor of axon outgrowth
regeneration cont
Regeneration (cont)
  • Restoration of function requires synaptic regeneration
    • Central axons may retain capacity to form synapses even in adult
minimizing damage in nerve trauma
Minimizing damage in nerve trauma
  • Antioxidants
    • methylprednisone
      • lipid peroxidation
  • Preventing excitotoxicity
    • NMDA receptor antagonists
      • MD 801
focal hand dystonia
Focal hand dystonia
  • Pt. is unable to independently control digits of the hand.
    • Happens when fingers are moving together at a high rate of activity for long periods of time.
      • Pianists practicing certain pieces for up to 8 hours/day
  • Somatosensory representation in cortex of affected digits are fused
    • In monkeys when two adjacent digits sewn together (sydactyly) the cortical representations of both digits become one
the newborn brain
The newborn brain
  • Contains about 100 billion nerve cells
  • Each neuron connects to anywhere from a few thousand to 100,000 other neurons
  • At birth each neuron averages about 2500 synapses
  • By age 3-4 this has risen to about 15,000 synapses and then you start to lose synapses
    • Process called “pruning”
  • Adult brain 100-1000 trillion synapes
    • Humans have about 35,000 genes
    • So what governs the connections in the brain?
plasticity in brain development
Plasticity in Brain Development
  • The final wiring of the brain occurs after birth & is governed by early experience
    • Neurons that fire together wire together
  • A protein called MAP2 ( microtubule-associated protein 2)
    • Map2 molecules form bridges between neurofilaments and microtubules
      • Part of internal skeleton that affects neurons growth and structure
      • May mediate the formation of new neural pathways
      • (Scientific Am, Dec 1988, p56-64.)
  • Even in adults the sensory cortex is constantly remodeling
  • The existence and importance of brain plasticity are no longer in doubt
  • “Some of the most remarkable observations made in recent neuroscience history have been on the capacity of the cerebral cortex to reorganize itself in the face of reduced or enhanced afferent input.” (Edward Jones UCD, center for neuroscience, 2000)
the wiring of the brain
The wiring of the brain
  • Is governed by the neuronal activity
    • Synaptogenesis governed by activity
  • Patterns of stimulation
    • Neurons that wire together fire together
  • Its survival of the busiest