neuro 4.docx

7/30/2019 neuro 4.docx

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Autonomic Nervous System

Physiology ANS vs Endocrine Involuntary

Neuroanatomy Somatic nervous system: afferent & efferent Autonomic nervous system:

o Afferents from blood vessels ], heart and organs in body cavityo Efferents to smooth muscle, glands, cardiac muscleo Components

Sympathetic nervous system Parasympathetic nervous system Enteric nervous system

Viscerosensory System

Visceral Afferent Pathway:


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Referred Pain: Noxious stimuli that originate in a visceral structure are perceived as pain

arisng from a somatic portion of the body wall Mechanism: convergence of somatic and visceral afferents o to dorsal horn

neurons

Diagnostic tools

Comparison of Somatic and Visceral Motor (SNS, PSNS) Neurons

Somatic vs. Autonomic Similarities:

o Final common pathway ( motor neuron vs postganglion n.) Differences:

o Locationo 1 neuron vs 2 neuron chaino motor unit vs Boton en pasons

SNS vs. PSNS Similarities:

o 2 neuron chaino preganglionic fibers are myelinated , postganglionic fibers are

unmyelinated Differences:

o Location of preganglionic cell bodieso Location of postganglionic cell bodieso Length of preganglionic and postganglionic fibers


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Sympathetic System

Thoraco-lumbar system location of preganglionic cell bodies (T1-L2 intermediolateral cell column) Courses of SNS preganglionic fibers

Sympathetic ganglia (para vs pre) Adrenal medulla Targets

Horners Syndrome Miosis: constriction of the pupil Ptosis: drooping of the upper eyeid Anhidrosis: diminished or absent sweating

Internal Organization of Sympathetic Ganglia Divergence

o Axons will innervate multiple Convergence

o Receive info from many sources preganglionically and info from thetarget sources


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Parasympathetic System Craniosacral system

Enteric Nervous System Control

o Motility of the gut o Pancreaso Gall bladder

Two major interconnected plexuseso Myenteric (Auerbachs) Plexus

Control gut motilityo Submucosal (Meissners) Plexus

Control the secretory functions of the gut The ENS is autonomous

o Disrupt connection with CNs results in no change in small/largebowels

o The esophagus ad stomach is more dependent on the SNS and PSNS

Neurotransmission of the ANS Acetylcholine

o All SNS and PSNS preganglionic neuronso All PSNS postganglionic neuroeffector junctionso SNS postganglionic terminal innervation of sweat glands

Norepinephrineo Most SNS postganglionic neuroeffector junctions


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o Exceptions Epinephrine is secreted by the adrenal medulla DA is released by the postganglionic fibers innervating renal

vasculature

Cholinergic Receptors

Adrenergic Receptors


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Reticular Formation

Reticular Formation Neurons Raphe Neurons Large (magnocellular) neurons Small (parvicellular) neurons

Lateral Column (Receptor Unit) Small parvicellular neurons Receptor unit

o Inputs from Spinoreticular tract Other sensory tracts Higher brain centers

Relay to medial column

Medial Column (Effector Unit) Large magnocellular neurons Effector unit

o Caudal projection Reticulobulbar Reticulospinal tract

o Rostral projection Thalamus-cortex Limbic structure

Median Column Middle line location Raphe serotonergic neurons Projection

o Caudal to spinal cordo Cortex and limbic systemo Mesolimbic DA neurons

Brainstem Nuclei Nuclei in motor system

o Red nucleuso Inferior olivary nucleuso Precerebellar reticular nucleio PPRF (paraedian pontine reticular formation)

Periaqueductal gray


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ARAS (Ascending Reticular Activating System)& Behavioral Arousal

Functiono Asleepo Awakeo Alert o Attending

Clinical correlationso Comao Persistent vegetative stateo Anesthetics

Modulation of Pain Sensation Input from spinothalamic (DC-ML & ALS) and trigeminothalamic tracts

(VTTT & DTTT) Output

o Reticulobulbar tractso Reticulospinal tractso Raphespinal tracts

Mechanism of pain modulationo PAG projects to raphe 5-HT neuronso At dorsal horn, 5-HT activates inhibitory, enkephalinergic

interneurons

Regulation of Muscle Movements Neuroanatomy

o Reciprocal connections with motor nuclei, cerebellum and motorcortex

Functiono Segmental stretch reflexo Muscle tone


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Control Eye Movements Horizontal conjugated eye movement PPRF

o Receive input from Superior colliculus

Vestibular nuclei Frontal eye field

Autonomic Control of Cardiovascular Function Preganglionic neurons not intrinsically active SNS: IML (T-L)

o Target Ganglionic neurons that innervate heart and vessel Adrenal medulla

o Activation: vasoconstriction and cardiac stimulationo Result: increased arterial pressure and tachycardia

PSNS: (nucleus amiguus)o Target: heart via vagus nerveo Activation: cardiac depressiono

Result: decreased heart rate and BP

Sympathetic Premotor Neurons These neurons are intrinsically active Location: rostral ventrolateral medulla (RVLM) Targets: sympathetic preganglionic neurons Activation: excitation of SNS preganglionic neurons Result: increased heart rate and arterial BP

Brainstem Inhibitory Center Location: caudal ventrolateral medulla (CVLM) Target: SNS premotor neurons in RVLM Activation: inhibition of RVLM Result: decreased arterial BP and heart rate Function: inhibit spontaneous activity of sympathetic premotor neurons in

RVLM Not intrinsically active


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Nucleus of Solitary Tract Location: dorsal medulla Target: CVLM and NA Activation: excite CVLM (=inhibit RVLM), excite NA Result: decreased arterial BP and heart rate

Function: relay visceral afferent (including input from baroreceptor) toprovide tonic inhibition of RVLM and excitation of cardiac vagal neurons

Baroreceptor Reflex Circuit

Autonomic Control of Respiration Location: respiratory center overlap the cardiovascular center Targets: SNS preganglionic neurons, PSNS nuclei, motor neurons Activation: decrease in blood pO2 will activate chemoreceptor reflex Result: increased heart rate, vascular tone and respiration

Hypothalamus Location: multiple hypothalamic nuclei, including PVN Targets: descending autonomic pathway

Activation: o Excitation of SNSo Inhibition of PSNS (vagus) o Suppress baroreflex

Function: mobilize cardiovascular reserve in the fight or flight or defenseresponse, therefore executive override of homeostatic mechanisms


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Central Autonomic Network (CAN) Location:

o Hypothalamuso Insular and medial prefrontal cortexo Extended amygdalao PAG Function:o Coordinate local autonomic reflexeso Coordinate autonomic and somatic motor activityo Provide information on planning and execution

Regulation of Homeostasis


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Cortex & Cortical Function

Forebrain

Controls lower centerso Brain stemo Spinal cord

Telencephalon Components

DIENCEPHALON TELENCEPHALON

FOREBRAINPROSENCEPHALON


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Rhinencephalon

Rhinencephalon Derivatives

Cerebral Cortex: Developmentally, Morphologically & Functionally

BASAL NUCLEI

BASAL GANGLIA

RHINENCEPHALONSMELL BRAIN

CEREBRAL CORTEXPALLIUM

TELENCEPHALON

ALLOCORTEX

CORTICAL

REGIONS

BASALFOREBRAIN

STRUCTURES

SUBCORTICAL

STRUCTURES

RHINENCEPHALONDEVELOPMENTALLY

PRIMITIVE

ANTERIOR

PERFORATED

SUBSTANCE

N. BASALIS

MEYNERT

N. ACCUMBENS

V. STRIATUM

SEPTAL N.

MED. & LAT.

DIAGONAL BAND

BROCA

BED NUCLEUS

STRIA TERMINALIS

BASAL

FOREBRAIN

STRUCTURES


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Cerebral Cortex: Neocortex (Isocortex) Parietal, occipital, temporal lobes

o Reception and elaboration of conceptual data (by association ytakesinto consideration our experiences and compares them to come upwith things such as a new novel)

Frontal lobeso Complex motor responses

o Judgment o Foresight

Make judgments or look into future based on past experienceso Mood & behavior

Has 6 morphological layers

Cortical Histology Cortical Mantle Superficial gray matter (consists mostly of cell bodies) Variable thickness

o 1.5-4.5mmo cytoarchitecture

2:1 ratio of glial cells to nerve cells four cell types predominate

Cortical Cell Types

SURVIVAL

PRIMITIVE

ALLOCORTEX

NON 6 LAYERED

REASONING

HIGHER FUNCTIONS

NEOCORTEX

6 LAYERED

CEREBRAL

CORTEX

ALLOCORTEX

ARCHICORTEXMAXIMUN3 LAYERS

PALEOCORTEXMAXIMUM5 LAYERS

PARAOLFACTORYAREA

SUBCALLOSALGYRUS

CINGULATEGYRUS

HIPPOCAMPALFORMATION

UNCUSPIRIFORM

PARAHIPPOCAMPALGYRUS

LIMBIC LOBE


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Pyramidal Cellso Most predominant o Axons oriented to deeper layers of cortexo Dendrites oriented to superficial layerso Come in 3 sizes: s 10, m 50, l 100 micrometers = betz cells of

motor cortex Granule (Stellate) Cellso Interneurons, usually inhibitoryo Small (8 micrometer) star shapedo Short axon & dendriteso Form short association fibers

Fusiform Cellso Spindle shapedo Located in the deepest cortical layerso Dendrites oriented toward superficial layerso Axons oriented toward deep cortical layers

Horizontal Cells of Cajalo Limited to superficial layer of cortexo Spindle shaped cell body with dendrites at both ends

Laminar Organization of Neocortex Layer I: Molecular Layer

o Thin layer near the piao Large synaptic fieldo Horizontal cells of Cajal

Layer II: External Granular Layero Granule cells most abundant o Small pyramidal cells that terminate in the deeper layers of cortex

Layer III: External Pyramidal Layero Pyramidal cells (medium to medium large)o Axons from:

Commissural (callosal) fibers Cortical association fibers (interact with other areas of the

cortex within the same hemisphere)o Important projection layer

Layer IV: Internal Granular Layero Mostly granule cellso

Input from specific thalamic nuclei (VPL, VPM)o Communicates with layers V. VI Layer V: Internal Pyramidal Layer

o Mostly medium & large Pyramidal (Betz cells)o Cells give rise mostly to projection (corticofugal) fibers

Influence lower motor neurons Layer VI: Fusiform Layer

o Deepest layer or cortex


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o Mostly fusiform cells some pyramidal cellso Corticofugal, Association, & Commissural Connections

Functional/Morphological Relationship in Neocortex Homotypical

o 6 distinct morphological layerso most prominent in association areaso 75% human neocortex association cortex

amount unique to humans Heterotypical

o Six ill defined morphological layerso Phylogenetically early cortical areaso Seen in primary cortical areaso 25% total human cortex

Brodmanns Cytoarchitectural Map: Primary Areas (Heterotypical)

Visual (Striate): BA 17 Somatosensory(S-I): BA 3,1,2 Motor (M-I): BA 4 Auditory (Transverse Gyrus of Heshel): BA 41,42 Vestibular: BA 40 Taste (S-II): BA 43

Brodmanns Cytoarchitectural Map: Association Areas (Homotypical) Visual: BA 18,19

Somatosensory: BA 5,7 Motor (M-2): BA 6,8,8a Language (Wernicke): BA 39, 40,22 Motor Speech (Broca): BA 44,45 Prefrontal (Reasoning): BA 9,10,11,12

Cortical Laminar Connections: Overview of Efferent Connections Neurons in deeper layers (V,VI) project to subcortical CNS areas (brainstem,

spinal cord, thalamus, basal ganglia) Corticofugal Neurons in layers III & VI project to other cortical areas Cortico- cortical

projectionso Association Project on same sideo Commissural

Cross neuraxis (midline)

Cortical Laminar Connections: Overview of Afferent Connections Specific Thalamic N. project to a specific cortical layer: IV


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Non specific Thalamic N. (CM) project to all cortical layers: I through VI Forebrain & midbrain Subnuclei (N. Basalis of Meynert, Raphe) project to all

cortical layers: I through VI Association tracts synapse in layers I & III Callosal fibers synapse in layers I, III & IV

Corticofugal Neurons Cell bodies in layers V & VI form subcortical projections Layer V pyramidal cells project to brainstem (corticobulbar), spinal cord

(corticospinal tract)& basal ganglia (corticostriate) Pyramidal cells from layer V of BA 4 form a portion of corona radiata,

internal capsule to form the CST Layer VI pyramidal and fusiform cells send axons to thalamus

(corticothalamic projections)

Cortical Laminar Connections Review Corticofugal Neurons

o Subcortical distribution Layer V pyramidal cells

Spinal cord (corticospinal) Brainstem (corticobulbar) Basal ganglia (corticostriate)

Layer VI pyramidl & fusiform cells Thalamus (corticothalamic)

Cortico-Cortical Neurons: Association

Axons from layers III & VI synapse in adjacent gyrus or in same hemisphere Cingulum bundleo Interconnects cingulate, parahippocampal g. frontal, parietal,

occipital, temporal cortexo Limbic gateway to neocortex

Superior Longitudinal Fasciculus (Arcuate Fasciculus)o Interconnects Brocas motor speech area (BA 44,45) with Wernickes

sensory speech area (BA 22, 39, 40)o Interconnects frontal, parietal, occipital, and temporal lobes

Uncinate Fasciculuso Interconnects anterior temporal area with orbitofrontal cortexo Seizure progressiono Uncinate fits

Cortical Laminar Connections: Review Corico-cortical Neurons

o Association tracts interconnect same hemisphereo Layers III & VI pyramidal cells

Cingulum bundle


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Superior Longitudinal Fasciculus Uncinate fasciculus

Cortico-cortical Neurons: Commissural Corpus callosum

o Interconnects all lobes between hemispheres Genu (forceps minor) interconnects frontal lobes Body interconnects frontal parietal and temporal lobes

Does not interconnect hand & foot BA 3,1,2 Splenium (forceps major) occipital lobes

Not BA 17 (visual) Anterior commissure

o Interconnects inferior temporal gyrus and olfactory cortices Posterior commissure

o Pupillary light reflex

Cortical Laminar Connections: Review Cortico-cortical Neurons

o Commissural neurons interconnect similar gyri in oppositehemispheres

o Layers III & VI Corpus Callosum

Genu (forceps minor): frontal lobes Body: frontal, parietal, temporal lobes Splenium (forceps major): occipital lobes

Anterior Commissure: inferior temporal gyri Posterior Commissure: light reflex

Cortical Neurochemistry Glutamate/aspartate & GABA rapid signaling Gluatamate/aspartate Corticofugal, Association, & Commissural fibers

o Co-transmitter with neuropeptide GABA Interneurons

o GABA aloneo GABA + Neuropeptide

Neuropeptideso Slow signalingo Peptide only neuronso Co-transmitter w/ Corticofugal and ascending monoamine neurons

Transmitters Intrinsic to cerebral cortexo Glutamate/aspartate (projection)o GABA (interneurons)o Neuropeptides (interneurons, projection)

Synthetic sources of ACh, NE, DA & histamine is subcorticalo ACh N. Basalis (Basal forebrain)


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o NE Locus Ceruleus (Brainstem)o 5-HT Raphe (Brainstem)o DA Substantia Nigra (A9), VTA (A10) (Mesocortical System)o Histamine hypothalamus

Lateralization of Language Dominant hemisphere: controls speech Brocas Area: determines dominant hemisphere Wernickes Area: Language comprehension Handedness vs. Dominance

o All right-handed people have left dominant hemisphereo Majority of left-handed people have left dominant hemisphereo Ambidextrous people have mixed dominance

Repetition

Info comes in from auditory apparatus and up through the brainstem,through the MGB and to primary auditory cortex (BA 44,42)

Then the iformation goes into Wernickes area Then using the Arcuate Fasci culus the information is transferred to Brocas

motor speech area to set up the program for what will be spoken Then the info travels to the motor cortex

Reading Aloud


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Information comes in from visual system (BA 17) into language

comprehension center (BA 18,19) from there it goes to Wernickes ar ea andvia the Arcuate fasciculus the info travels to Brocas area; finally it travels tothe motor cortex

Hemispheric Asymmetries

Cerebral Localization of Cortical Function: Hemispheric Independence Left Hemisphere

o Intellectualo Rationalo Verbalo analytical

Right Hemisphereo Perceptiveo Emotionalo Non-verbalo Intuitive

Cerebral Localization of Language

DOES

NOT

TALK

PERCEIVES

LEARNS

REMEMBERS

PERFORMS

MOTOR

TASKS

LIMITED

LANGUAGE

COMPREHENSION

SOLVES

SPATIAL-PERCEPTUAL

PROBLEMS

NON-DOMINANT

HEMISPHERE

SPEECH PRODUCTION

LANGUAGE

COMPRHENSION

ANALYTICAL

MATH SKILLS

DOMINANT

HEMISPHERE

COMMISSUROTOMYSPLIT-BRAIN

PATIENTS


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Aphasia

o Partial of complete loss of language abilities

Wernickes Aphasia Theory Specific cortical area with UMNs that control & coordinate vocalization

muscles = (Brocas) o Face (VII normal)o Tongue (XII normal)o Jaw (V normal)o Throat (normal)

Sensory component o Angular gyruso Auditory &/or visual perception brought to Wernickes area

Arcuate Fasciculuso Transfers heard or read word to Brocas Area o Transection of Arcuate fasciculus

Loss of ability to speak Conduction aphasia

Wernickes : receptive or fluent aphasia o Unable to comprehend spoken wordso Unable to read (alexia)o Unable to write (agraphia)o Fluent paraphasic speech (clear, fluent, melodic) but unintelligible

(word salad)

Agnosia Inability to recognize objects

Intact somatosensory systemApraxia Inability to carry out purposeful motor movements Disconnect between planning & execution Absence of paralysis

o Intact UMN systemso Intact LMN systems

BRODMANN44,45

CANNOTSPEAK

BROCA'S(MOTOR)

EXPRESSIVE

BRODMANN39,40

POST. 22

CANNOTCOMPREHEND

WERNICKE'S(SENSORY)RECEPTIVE

APHASIA


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Neglect Syndrome Right posterior lobe lesion Lesion of non-dominant hemisphere

Neglect of extra-personal space on left side of external worldo Constructional (drawing) apraxiao Dressing apraxia

Multiple Long Term Memory Systems

Declarative Memory (explicit) knowing what; know that Conscious awareness (focus, bring to our attention) Requires hippocampal formation/ medial temporal lobe

Non-declarative Memory (implicit) knowing how to independent of conscious awareness Medial Temporal Hippocampal formation not necessary

o Habits cortico-striate loopso Sensorimotor cerebellar loopso Emotional amygdalao Priming cortical

Memory

Short term memoryo Limited capacityo No permanent storage

Long term memory (Secondary/Tertiary)o Very large capacityo Permanent storage

Declarative: through conscious experience Procedural: through conditioning

VISUAL

AUDITORY

TACTILE

CONTRALATERALSIDE

PARIETAL-LOBE

LESION

LACKS APPRECIATION FOR

CONTRALATERAL

SIDE OF BODY

CONSTRUCTIONAL

APRAXIA

ASSOC. RIGHT

HEMISPHERIC

LESIONS

NEGLECT

SYNDROME

AGNOSIA


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Sleep

Sleep Stages A normal nights sleep runs in ~90 minute cycles with the proportion of REM

sleep increasing during the night The older an individual, the less time is spent sleeping REM sleep declines more with age than non-REM sleep

Consciousness and the EEG How do you objectively measure consciousness? Development of the electroencephalogram (EEG)

o Hans Berger first recorded mirovolt signalso Summed electrical output of large cortical pyramidal neuronso Large synchronous slow wave EEG = drowsy stateo Small, high frequency waves = alert, active subject o Many abnormal firing patterns (e.g epilepsies) can be detected and

localized with EEG Until the 1940s the default state of consciousness was assumed to be sleep

o Wakefulness was thought to only occur with sensory input o However, sensory input is neither necessary nor sufficient to maintain

consciousness Destruction of the pontine and medullary reticular formation results in coma The RF serves as a central pattern generator for

o Primitive functions such as respiratory and cardiovascular rhythmso Maintaining wakefulnesso Regulating sleep patterns

Phenomenological Comparison of the Sleep Cycle States


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Sleep Cycle in the EEG Stage 1- falling asleep

o Theta waves of low amplitude. Lightest sleep, easy to arouse Stage 2 deeper sleep

o More theta waves, but interspersed with rapid sleep spindles

Stage 3 deep sleepo Appearance of slow delta waves of high amplitude and low frequency

Stage 4 deep sleep (subject difficult to arouse)o Strong delta wave activityo Sleep walking and talking, bedwetting occur in Stage 4

Rapid Eye Movement (REM) Sleep resembles Stage 1 EEG

Sleep Cycles: Brain Circuitry

Diurnal rhythmicity originates in the hypothalamus (SCN) Thalamocortical connections regulate NREM sleep ad EEG Midbrain pontine RF regulates NREM-REM cyclic oscillations

Mammalian Clock Genes Regulate Diurnal Rhythms Mammalian clock genes include Per1, Per2, Per3, Cry, Clock, Bmall Genes expressed in ~20,000 SCN neurons Protein products are transcription factors Cyclic, mutual feedback regulates their expression Mutant mice (null) for these genes have disturbed or shifted sleep/wake

cycles


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REM Sleep: Phenomenology Termed rapid eye movement sleep due to occulomotor activity Most dreaming occurs during REM sleep REM sleep increases following days of new experiences Muscles are relaxed and inactive (termed REM paralysis)

REM sleep percentage increases during sleep cycle

REM Sleep: Mechanisms Pontine RF is cortical integration site for REM Inhibitory connections to spinal cord reduces muscle tone inhibitory connections to cortex leads to EEG desynchronization most inhibitory connections are aminergic (dopamine, 5-HT)

Sleep Disorders Insomnia

o Most common sleep disordero Often related to auxiliary problem (depression, anxiety)o Hypnotics used therapeuticallyo Current therapies involve agonists for the benzodiazepine site on

GABA-A receptor with short half life

Sleep apneao Cessation of breathing during sleep, awakening to begin breathingo Associated wth obesity, compression of the windpipeo Bariatric surgery can assist in resolving sleep apnea

Narcolepsyo Excessive sleepiness during the day

Sudden breakthrough of REM sleep activating mechanism inypactive, awake domain

Cataplexy, loss of motor tone and controlo Genetics

First discovered in a colony of Doberman Pinchers at StanfordUniversity

Mutation in a gene encoding hypocretin Hypocretin null mice exhibit narcolepsy

o 90% of human narcoleptics associated with reduced hypocretin

(orexin) levelso may be degenerate loss of hypocretin neurons

REM Sleep Disordero Muscles may not become paralyzed as is normal for REM sleepo Subject may consequently physically act out dreams o Different from sleep walking


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Night Terrorso Occurs most often during Stage 4 NREM Sleepo Not a nightmare, rather its a panic attack o Subject may remain intensely afraid following arousal

Restless Leg Syndromeo Varying intensity involuntary leg movementso A primary cause of insomniao Linked to several genes, but treated with dopaminergic drugs

The Function of Sleep: NREM In humans, a neurodegenerative disorder (fatal familial insomnia) leads to

death after several months Studies have shown that seven hours of sleep correlates with longer life span

in humans Striking inverse correlation between sleep time and body mass Though to reflect metabolic repair requirements

The Function of Sleep: REM In humans and other mammals, a profound inhibition of motor activity

(excepting postural muscles) occurs during REM sleep Destruction of pontine adrenergic neurons removes hibition, leading to

thrashing behavior (acting out dreams) Motor inhibition may thus be protective aspect Selective deprivation of REM sleep leads to REM rebound, i.e. more REM

sleep

REM rebound also follows dugs use (alcohol, LSD, amphetamines) suggestinga need for REM sleep REM sleep appears important for consolidation of short term to long

term memory

REM Sleep & Memory Although evidence is mounting, if its still a highly debated concept Conflicting data in humans

o Dreams in humans do not consistently reflect recent eventso REM sleep deprivation does not always alter non-declarative memoryo MAO-inhibitors suppress REM sleep, but do not consistently alter

memory What are dreams?o Significant but undefined reflections of our experiences


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Alzheimers Disease & Dementia

I. Introduction AD is the most common from of dementia, a progressive

neurodegenerative disease with multiple neurochemical abnormalities

AD is also a degenerative metabolic disordero Rate of energy metabolism is decreased, density of glucose

transport sites in microvessels is also diminished Reduction of NT like ACh, 5-HT, NE Neuorpathological features: presence of neuritic plaques &

neurofibrillary tangles I several cortical & subcortical areas,hippocampus, basal forebrain including the cholinergic nucleus basalis

II. Genetics Mutations in APP detected in members of AD families

III. Environment, early-life exposure, epigenetic the LEARn (Latent Early-LifeAssociated Regulation) model

IV. Neurobiological Interactions of the key protein molecules: APP, PSI/II, ApoE Amyloid B protein: neurodegeneration B-amyloid precursor protein: neurotic outgrowth, synaptogenesis,

developmental role Alpha-antichymotrypisn: neuronal growth BACE: APP processing enzyme Presenilins: protein trafficking

V. The major early hallmark is the deposition of extracellular amyloid Amyloid deposits consist of aggregates of 39 to 43 aa peptide termed as

amyloid B peptide (AB) or A4 Various forms of AB Only part of the AB peptide is buried inside the membrane, ~2/3 is

extracellular and is inside the membrane AB is an abnormal cleavage of a larger B-amyloid precursor protein (APP)

VI. Beta amyloid precursor protein: structure and function APP is an integral type I membrane glycoprotein

APP has sites for phosphorlaytion, glycosylation, and sulfation APP is a secretory protein which is secreted in the conditioned mediumas a carboxyl truncated form of APP

Functions of APP: synapyogenesis, cell adhesion

VII. Amyloid Cascade Theory : Processing of APP Generation of AB peptide by abnormal cleavage of APP Amyloid pathway or normal pathway


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o Amyloid pathway sAPPB, ABo Normal pathway sAPPa

Role of enzymes: secretase, a secretase, B-secretase (BACE), y-secretase(PSI)

VIII. Gene Expression of APP: structure and function of the regulatory protein of the gene APP exists in several distinct foms which are derived by alternative

mRNA splicing Encoded on chromosome 21, the gene itself is large The promoter region of APP has a complex transcriptional unit

IX. Participation of APOE: different isoforms: E2,E3,E4a. E4 is a risk factor for AD while E3 acts as a neuroprotective factorb. E4 acts as a chaperone molecule and may participate in B-amyloid

formationX. APP-related proteins: similar to APP but lacking AB domain

XI. Treatment strategy:a. Anticholinesteraseb. Protease inhibitors (BACE inhibitors)c. Anti-inflammatory drugsd. Anti-oxidants

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neuro 4.docx