Schizophrenia

• one of the most complex and challenging of psychiatric disorders
• heterogeneous syndromes of disorganized and bizarre thoughts, delusions, hallucinations, inappropriate affect and impaired psychosocial functioning

Schizophrenia Symptoms

• positive symptoms: delusions, hallucinations, agitation
• negative symptoms: alogia, avolition, anhedonia, social isolation
• cognitive deficits: impaired atention and working memory

Schizophrenia

Dopamine hypothesis

• evidence suggests excessive limbic dopaminergic activity plays a role in psychosis
• drugs that increase dopaminergic activity such as levodopa, apomorphine, amphetamines and cocaine either aggravate schizophrenia or produce psychosis
• postmortem studies have reported increased dopamine levels and D2 receptor density in the nucleus accumbens, caudate and putamen
• imaging studies have reported increased baseline occupancy of striatal D2 receptors by extracellular dopamine

Dopaminergic pathways

• mesolimbic pathway: increased activation-positive symptoms
• mesocortical pathway: decreased activation - negative symptoms
• nigrostriatal pathway: movement disorders
• tuberoinfundibular pathway - hyperprolactinemia

Serotonin Hypothesis

Schizophrenia

• 5-HT2A receptors modulate the release of several NT such as dopamine, NE, glutamate, GABA and ACh-Cortex, striatum, limbic region
• 5-HT2C receptors modulate cortical and limbic dopamine release
• Atypical (2nd generation) antipsychotics are 5HT-2A and 5HT-2C antagonists

Glutamate Hypothesis

Schizophrenia

• Phencyclidine (PCP) and ketamine are noncompet inhibitors of the NMDA receptor that exacerbate bothy psychosis and cognitive impairments
• NMDA antagonists such as ketamine, PCP and dizocilpine (MK-801) increase locomotor activity and produce cognitive deficits in rodents and primates
• antipsychotics block the preclinical as well as the clinical effects of NMDA antagonists
• LY2140023, a glutamate receptor agonists, may be effective in schizophrenia

non NT regulation

Schizophrenia Factors

• anatomical/ structural abnormalities
• neurodevelopment factors
• infection-inflammation
• genetic factors
• environmental and social factors

Typical antipsychotics - 1st generation

• strong D2 antagonists
• effective in treating positive symptoms
• produce severe movement disorders
• causes hyperprolactinemia (high levels of prolactin)
• high and low potency
• prevents nausea and vomiting
• chlorpromazine, thioridazine, fluphenazine, haloperidol 

Atypical antipsychotics - 2nd generation

• posses D2 as well as 5HT-antagonist properties (High 5HT2/D2 ratio)
• effective treating both positive and negative symptoms
• does not produce severe moevement disorders
• produce adverse effects such as agranulocytosis, weight gain, cardiac arrhythmis
• improves cognition
• clozapine, olanzapine, risperidone, ziprasidone

Normal Anxiety

• a diffuse, unpleasant sense of apprehension often accompanied by autonomic symptoms (headach, dizziness, perspiration, increased heart rate, stomach pain)
• normal and adaptive respsonse, it is a defensive signal to recognize threat and take action to reduce danger to ourselves
• anxiety and fear are similar - anxiety is the anticipation of danger whereas fear is a more focused response to an obviously harmful treatment (anxiety of walking in a dark alley)
• both fear and anxiety activate cognitive, bodily and behavioral responses. both ivolve the limbic system. you learned about amygdala-centered fear circuitry during lectures on the limbic system. 

Anxiety Disorders

• anxiety becomes problematic when its: too intense, too persistent, inappropriately provoked 
• stimulus may be a minor threat, perceived threat or nonspecific
• maladaptie anxiety responses have cognitive, physiological and behavioral factors that are difficult to manage

Anxiety disorders Epidemiology

• roughly 40 million american adults in a given year have an anxiety disorder
• age of onset is earlier than other mental disorders: childhood, early adolescence
• not usually diagnosed/treated till adulthood
• 90% w/ anxiety disorders have some other psychiatric problem in lifetime
• 25-50% of anxiety disorders have substance abuse problems
• 50-60% with major depressive disorder have anxiety disorder
• anxiety disorders highly comorbid with each other

Amygdala in
fear/anxiety

• fear and some signs of anxiety are mediated through amygdala
• basolateral (BLA) amygdala's function is to establish emotional significance
• projects to central nucleus of the amygdala (main output nuc, producing responses to emotional stimuli
• projects to numerous other structures to produce fear/anxiety responses

Other Major Structures involved in fear/anxiety

• insula: monitors arousal and aversive states
• dorsal anterior cingulate cortex (ACC) and medial prefrontal cortex: monitoring and expression of fear and responses to emotional conflict
• Ventral ACC/mPFC inhibits fear responses; regulates emtional conflict; involved with fear extinction
• hippocampus: dysfunction causes overgeneraliztion of fear to nonthreatening stimuli and problems with identifying safe vs threat contexts
• locus coeruleus: stress causes NE turnover in this structure which projects to limbic system structures and cortex. neurons in LC are activated in fear and anxiety states
• drugs that decrease NE firing in LC reduce anxiety

Brain regions in disordered anxiety

• each anxiety disorder does not allow for a one size fits all treatment
• pathophysiology of anxiety disorders is not well charactered or understood
• most thorough research has been done on PTSD, Generalized anxiety disorder (GAD) and OCD

Specific Phobia

• most common (6-12%) lifetime prevelance
• characterized by excessive fear triggered by a specific object or situation
• fear categories tend to involve: natural environment, bloold/injection/injury, animal or situational

Social Anxiety Disorder

• 10% lifetime prevelance
• persistant fear of performance/evaluative/social situations that person will be embarrassed or humiliated 
• specific(afraid of public speaking) or general (afraid to interact with others in a variety of situations)
• hyperactivation of amygdala and insula
• phobias are thought to be exaggerated responses of basic amygdala fear circuitry
• exaggerated amygdala and medial temporal lobe responses have been indicated in fMRI studies

Lifetime prevelance 

(LP)

• number of cases that present in a specific population over 1 year

Post traumatic stress disorder 

(PTSD)

• 6.8% LP, 15-19% in veterans
• must occur sometime after exposure to traumatic event that is a serious threat where person feels intese fear, helplessness
• reminders of exposure (intrusive thoughts, nighmares, flashbacks)
• activation (hypervigilence, insomnia, impulsivity, anger, exaggerated startle response)
• deactivation (numbeing, avoidance, derealization, depression)
• psychological distress with exposure to cues related to trauma
• physiological reactivity to cues related to trauma

Neurobiological dysfunction in PTSD

• complicated disorder that seems to involve multiple brain areas
• amygdala/insula hyperactivation has been shown and linked to exaggerated fear responses during cues that remind person of trauma
• reduced activation of mPFC
• mPFR normally inhibts stress responses and emotional activity in amygdala
• HPA axis dysregulation is a major problem resulting in what seems to be sustained autonomic nervous system (stress) responses
• hippocampus volume decreased from prolonge stress hormone (concentration, recurring memories, inability to

Generalized Anxiety Disorder

(GAD)

• 5.7 % of LP
• characterized by excessive worry and apprehension about a number of events/activities that is hard to control and associated with at least 3 of the following somatic symptoms:
• restlessness, fatigue, difficulty concentrating, irritability, muscle tension, sleep disturbance

Neurobiological dysfunction in GAD

• dysfunction in ACC/mPFC
• dysfunction in bed nucleus of the stria terminalis (BNST-part of amygdala)
• BNST may be involved in sustained worry and may regulate stress and anxiety responses
• amygdala may be involved in initial anxious/fearful reaction; BNST may maintain coninuous anxiety (anxiety disorder)

Panic Disorder

• 4.7 % LP
• recurrent unexpected panic attacks that involve at least 4 of the following factors: palpitations, sweating, trembling, choking, chest pain, nausea, dizzinesss, depersonalization, derealization, fear of losing control, fear of dying, numbness, hot flashes or chills
• people with this condition often avoid places where developing a panic attack could be embarassing
• 2/3 of those with panic disorders will go on to develop agoraphobia where they are fraid to leave the house

Neurobiological Dysfunction in PD

• some evidence has shown increased activation of the insular cortex and periaquiductal grey of the midbrain
• also corresponding decrease in ACC activity
• HPA dysfunction has not been shown to be involved in panic disorder it is involved in most of the other anxiety disorders
• ventromedial PFC, ACC, hypothalamus, anterior insula and PAG comrise a network thought to be involved in identifying and responding to threat stimuli

Obsessive compulsive disorder

(OCD)

• among the lowest LP at 1.6%
• recurrent thoughts/images that are intrusive/inappropriate and cause anxiety (obsessions) and repetitive behaviors (compulsions) that a person is driven to perform to alleviate anxiety caused by the obsessions
• Suicide rates high among people with OCD
• OCD occurs frequently along with tourettes sydnrome, suggesting common brain mechanisms

Neurobiological dysfunction in OCD

• orbitofrontal cortex (OFC), ACC, and basal ganglia (specifically caudate) are pricipally involved
• striatal pathology (caudate) causes insufficient gating at the level of the thalamus, results in the hyperactivity of the orbitofrontal cortex and ACC
• OFC hyperactivity = intrusive thoughts
• ACC hyperactivty = generalized anxiety
• tourettes syndrome, tics and OCD occure frequently together suggesting similar brain circuitry

Benzodiazepines

• diazepam(valium), alprazolam(xanax), clonazepam (klonopin)
• benzos have specific binding sites on GABAα receptors where they act as agonists
• when benzos and GABA bind to these receptors, benzos inc the freq of Cl- channel opening, increasing the inhibitory action of GABA
• anxiety has been asociated with low GABA action 
• work rapidly, and effectively; are a sedative (not great for daily use)
• can cause phys dependency, abuse potential, cross tolerance and synergistic effects with alcohol
• not good for long term or w/ indiv with substance abuse problems(comorbid with anxiety)
• prescribed for GAD, SAD, OCD, contraindicacted for PTSD (memory concerns that make extinction therapy difficult)

Serotonin-specific(SSRI) or

Serotin-NE specific (SNRI) 

reuptake inhibitors

• SSRI: Prozac, zoloft, lexapro
• SNRI: effexor, cymbalta, pristiq
• good efficacy and anxiolytic effects emerge as early as week 1
• tolerated fairly well and are safe (decreased libido and weight gain)
• block reuptke of 5HT by desensit somatodendritic 5HT1a autoreceptors. also block 5HT and NE transporters
• decrease NE turnover in locus coeruleus, reducing its firing rate (dec firing rate assoc with reduc anxiety)
• prescribed for GAD, panic (SSRI only), SAD, PTSD, OCD
• double duty: also treats comorbid mood disorders

Tricyclic Antidepressants

(TCAs)

• clomipramine(anafranil), amitriptyline(elavil), imipramine(tofranil)
• provides effective releif in patients who do not respond to SSRI/SNRI
• more side efects and less safe than those
• increases 5HT by blocking reuptake and causing postsynaptic 5HT2a receptor sensitization
• prescribed for panic, other disorders that dont respond to SSRI

Monoamine Oxidase Inhibitors

• examples: isocarboxazid(marplan)
• used when first line treatments dont
• potentially fatal interactions with tyramine-containing foods which limits their use (aged cheese, alcohol, chocolate, fermented products, aged meats)
• inhibts enzymes that break down 5HT and NE
• inhib effects on NE function reduces LC firing, NE turnover
• prescribed for panic, other disorders that dont respond to SSRI or TCAs

Psychosurgery for intractable

OCD

• capsulotomy: disconnect basal ganglia from frontal cortex by lesioning internal capsule
• cingulotomy: lesion anterior portion of cingulate gyrus tha disconnects cingulate gyrus and frontal lobes
• significant reduction in obsessions and compulsions

Deep Brain Stimulation

for treatment of intractable OCD

• when all pharmac therapies have been exhausted, an emerging technique is showing efficacy for helping these patients: Deep brain stimulation (DBS)
• neurosurgically-implanted electrodes that deliver coninuous electrical pulses to targeted brain structures using an implanted pacemaker
• patient is actually head-fixed and awake during procuedure so that electrode placement can be accurate and unwanted effects avoided
• suprisingly safe-few advers consequences resulting from neurosurgery
• targets for DBS in OCD are internal capsule/ventral striatum, nuc accumbens, BNST
• results promising-patient report relief of symptoms; targets are not often based on our knowledge of neurobiology of these disorders but what seem to work
• recently approved by FDA under humanitarian device exemption

Epidemiology of Mood Disorders

• roughly 20.9 million in a given year
• leading cause of disability in 15-44 year olds
• over 11 billion dollars spent on antidepressants a year in US
• it is highly comorbid with anxiety and substance abuse disorders
• suicide is a big problem

Major Depressive Disorder

(MDD)

• 16.6% LP
• depressed mood or a loss of interest or pleasure in daily activities for more than 2 weeks that results in impaired social, occupational or educational function
• symptoms include irritability, significant weight changes, insomnia or hypersomnia, change in activity levels, fatigue, feelings of worthlessness, guilt, inability to concentrate, suicidal ideation
• causes significant functional impairment
• depression must not be related to ilness or grief to be diagnosed as MDD

Neurobiology of MDD

• decreased volume of ACC in depressed patients, prolonged HPA axis/amygdala stress responses start mucking up information processing in the brain
• left dorsolateral PFC decreased function related to apathy, loss of attention, lethargy
• increased right ventromedial PFC related to depressive ruminations feelings of worthlessness
• loss of pleasure in activities may be associated with decrease in HC function; decreased activity in DA projections from ventral tegmental area to nuc accumbens

Bipolar Disorder I and II 

• 1-4% LP
• Bipolar I: manic episodes that last at least one week or are so severe the person needs hospitalization, usually accomp by 2 week depressive episodes
• Bipolar II: pattern of depress episod shifting backnforth w/ hypomanic(increased energy, productivity) episodes, nut no fullblown manic epis
• high suicide rates in these individuals

Symptoms of Bipolar I and II

• can occur during mood disturbance include inflated self esteem, grandiosity, decreased need for sleep, inc talkativeness, racing thoughts, distractibility, psychomotor agitation, increase in risky behavior
• during depressive episode are same as for MDD, causes sign functional impairment or results in hospitilization or psychotic symptoms
• depression is often more profound, disabling symptom than mania

Neurobiology of bipolar disorder

• connections btw prefrontal cortexes and amygdala are thought to be dysfunctional in bipolar disorder
• reduction in dorsolateral PFC activity with concomitant increase in amygdala activity may account for problems w/ emotional regulation
• cortex (in charge of cognitive control) is failing to keep amygdala activity in check, thus resulting in failure to regulate emotion

Treatment for MDD

• recall all clases of antidepressants used for anxiety (SSRI, SNRI, TCAs, MAO-I, atypicals)
• drugs that increase activity of 5HT and NE treat depression
• despite immediate inc in these monoamines, time lag until therapeutic effects seen( 2-4 weeks)
• suggets downstream mechanisms related to monoamine deficiency might be underlying cause of depression (desensitization of 5HT autoreceptors; decreased brain derived neurotropin factor; BDNF) and could explain lag of treatment

Treatment of Bipolar Disorder

• goal: mood stabilization of both manic and depressive symptoms
• decrease overexcitment of CNS while not causing depression
• lithium: sedative inc reuptake of NE but inc 5HT release (toxic, first line treatment)
• anticonvulsants: lamotrigine and carbamazepine
• antipsychotics quetiapine and olanzapine block dopamine and 5HT2 receptors
• bupropion, SSRIs target depression with some success but do not adress mania
• best practice is combination therapy; olanzapine and fluoxetine (SSRI) combo

Electroconvulsive Therapy (ECT)

• treatment resistant MDD and Bipolard
• done under anesthesia, seizure is induced with electrical current applied to scalp
• unilateral just as effect as bilateral with less memory loss
• series of ECT is needed; often repeated months later
• still need to take antidepressants but shock seems to make brain more responsive to them

Deep Brain Stimulation (DBS)

for MDD and bipolar disorder

• DBS of subcallosal cingulate significantly has been shown to reduce depression and increase function
• equally effective with MDD and bipolar
• effects take a while to actualize but seem to last long time with coninued active stimulation

Neurogenesis in adults

• generation of new cells through multipotent neural stem cells to replace old or damaged ones
• this rarely occurs in mammalian nervous system 
• in the few places where adult neurogenesis occurs, functional significance is unclear and the mechanisms are controversial

Dr Henry Head

• neurologist in early 1900s
• cut his radial nerve and they  re-appositioned the two cut ends (important)
• first genral sensation to pressure and touch recovered, than sensation to light touch, temperature recovered more slowly 
• motor function recovered last and not fully (even after 2 years not complete)

Epineurium in PNS

• outermost, dense, thick CT covering entire peripheral nerve
• consists of type I collagen fibrils and fibroblasts (least specialized cells in CT) 
• is important in protecting the nerve and anchoring the nerve to adjacent tissues and is useful for surgical reposition of severed nerves

Perineurium in PNS

• CT
• compact layer, epithelial-like and acts as a blood-nerve barrier surrounding each gorup (fascicle) of axons
• consists of several layers of flattened fibroblasts; function like other barriers, eg blood brain
• protects the nerve from toxins, drugs and other materials that could negatively influence the function of the nerve

Endoneurium in PNS

• innermost fine CT around axons
• consists of type II collagen fibrils and fibroblasts
• aids in regeneration of axons in PNS

Neuropraxia

• temporary blockade of axoplasm flow (axonal transport) and cease of action potential propagation
• no obvious physical damage of the axon, nor degeneration of surrounding myelin and the connective tissues are intact
• complete recovery of functions is expected
• causes: light nerve crush/compression

Axonotmesis

• damage of axons and myelin, but the connective tissues are intact (good continuity of connective tissues, forming a guidance sheath for the regenerating axon)
• a growth cone forms at the proximal end of the cut
• regenration occurs but functional recovery may not be complete
• causes: nerve crush or cut with good reapposition

Neurotmesis

• damage of axons, myelin and connective tissue
• regenration is unlikely
• example is nerve cut without good re-apposition of the cut ends

Wallerian Degenration

• also called anterograde degen or orthograde degen
• when the axon terminal distal to the injury degenrate/die-axon skeleton disintegrates and axonal membrane breaks apart and dies
• due to lack of protein supply transported from the cell body
• schwann cells also degenerate(lose myelin but aintain basal lamina)
• dead tissue cleared by macrophages and schwaan cells proliferate which produce many singals in axon guidance during development, promoting regeneration

Chromatolysis

• reaction of the cell body of a neuron to injury of axon
• visible as swelling of soma, nuc becomes eccentrice and dissolution of the nissl substance
• these are signals that neuron is injured and there is preparation of the neuron for protein syn, regeneration and recovery
• genes associated with axon growth are activated producing growth assoc protein 43, Trk and p75 needed for repair

Apoptosis of Injured 

CNS neurons

• signaling molec seen during development are lacking to support growth of injured parts
• in some cases(stroke, seizure) excessive release of glutamate causes excitotoxicity
• inflammotry cytokines can activate cytokine receptors on cell membrane
• these and others cause inhibition of the protective anti apoptotic protein called Bcl-2 leading to release of cytochrome c, activated caspases
• caspase 3 is the death gene

Glial responses to brain injury

• all glial types respond (astrocytes, oligodendro, microglia)
• death of glial cells is rare, proliferate in response
• excessive growth forms scars, occupying space and preventing neuronal regen, barrier
• many signals are secreted by function is complicated
• could promote apoptosis, or protect remaining neurons; some growth inhibitory (NOgoA) supressing regen of axons

Axon growth after CNS injury

• proximal end of injured axon forms bulbous axonal abnormalities, instead of a growing growth cone like the pns
• both peripheral and central envioronments contain growth-promoting elements, but central nerves also contain inhibitory components
• central myelin is a potent inhibitor of axon outgrowth
• central axon may be intrinsically incapable of regenration because of lack of proteins critical for axon elongation (assoc protein 43)
• plays major role in preventing recovery

Locations of adult neurogenesis

• olfactory bulbs, hippocampus and olfactory receptor cells
• olfactory bulb: new cells born at lateral wall of lateral ventric and migrate to position along rostral migratory stream(RSM) formed by glial cells; some of them form primarily interneurons within bulb
• hippocampus: newborn cells at the subgranular zone (SGZ) of the lateral ventricles, exhibit charact of developing neurons, they can travel a short distance, some of them may join the local existing circuitry as GABAergic interneurons (most die w/o differentiation

Cellular and molec Mechanisms

of Adult Neurogenesis

• subventricular zones are where new cells are bron in adult brain
• some cells in these zones function as neuronal stem cells
• girve rise to an intermediate cell class, transit ampllifying cell
• an asymmetrical division of a transit amplyfing cell produces a transit amplyifying cell and one neuroblast
• neuroblast can migrate to form new neurons

Stem Cells

• somatic stem cells: in various tissues, can form all classes of cells within the relevant tissue
• neural stem cells: in NS can give rise to neurons or glial cells
• embryonic stem cells: derived from pre-gastrula embryos, can give rise to all tissue and cell types
• injection of embryonic stem cells into a specific location in the NS where there is damage might lead to recovery of functions, promising results in animal experiments

General Development of the Brain

• NS develops in 1st trimester
• by end of 1st (13 week), the primary sulci (longitudinal cerebral fissue, lateral fissure) are recognizable
• secondary sulci are completed by 32 weeks (8months), with tertiary sulci during last month
• myelination starts in spinal cord at about 4 months and in the brain at about 6 months gestation
• fully grown, brain 3% of body weight, female brains lighter but have higher ratio of brain weight over body weight

Gastrulation

• starts in early third week (16 days of gestation) and ends on day 28
• gastrulation is the process that transforms the bilaminar embryonic disc into a trilaminar structure comprised of the three primary germ layers of the embryo: ectoderm (future NS, epidermis), mesoderm (future muscle, skeleton), and endoderm (future gut, liver etc)

Neural Tube Formation

• gastrulation starts with the formation of primitive streak, a narrow groove in the midline (at future caudal end) with slightly bulging regions on either side
• primitive streak establishes a visible longitudinal axis of bilateral symmetry around which all embryonic structures will organize and align
• epiblast cells divide and migrate toward the primitive streak and move beneath the epiblast layer (invagination); cells that replace the hypoblast layer form endoderm, cells btw the two layers form mesoderm and cells remain in the epiblast and ectoderm

Induction

• organs formed btw cells and tissues
• induction is where one group of cells or tissues causes another set of cells or tissues to change their fate

Neurulation

• process by which neural plate is converted into the neural tube
• starts on day 20, ends by end of 4th week, day 28
• induced by notochord
• lateral edges of plate rise to form neural folds with central depression (neural groove), than fuse forming tube
• fusion first occurs in the cervical region and proceeds rostrally and caudally
• rostal and caudal neuropores close by end of 4th week 
• complete fusion of neural folds is necessary for mesodermal components to migrate and form meninges, bone, muscle and skin that overlie the spinal cord
• failure in fusion results in developmental defects

Neural Crest Cells

• neural crest cells are derived from neuroectoderm
• break free from lateral boundaries of the neural plate during neurulation to migrate throught the embryo
• contribute to the peripheral nervous system (PNS): form neurons of peripheral ganglia, both sensory and autonomic, give rise to schwann cells and satellite cells, become chromaffin cells of adrenal medulla, form enteric nervous system, become some of the mesenchyme (neuromesenchyme) of head and neck

Brain Development: differentiation of

component parts

• after neural tube formation, three primary brain vesicles appear at its cranial end during the 4th week
• during week 5, five secondary vessicles form

Secondary Brain Vessicles

• prosencephalon (forebrain)-forms 2 brain vesicles; telen- and diencephalon
• mesecephalon (midbrain)
• rhombencephalon (hindbrain) forms 2 brain vesicles; metencephalon (pons and cerebellum), and myelencephalon (medulla and 4th vent)
• a central cavity extends from the cord area. this cavity expands and forms the future ventricular system (brain ventricles)

Development of CNS Polarity

• organization of neural tube is marked by a longitudinal groove called the sulcus limitans, this seperates the regions into dorsal alar plate and ventral basal plate
• inductive signals from the roof plate lead to fomratino of alar plates/lamina; precursor cells have become sensory or secondary sensory relay neurons located in gray matter of alar plate(future dorsal horn of spinal cord) and sensory neurons of brainstem
• basic organization exists throughout future spinal cord and brain (except in forebrain there is no basal plate)

Rhombic Lips

• dorsal enlargements of the alar plates in the pons area
• these form the cerebellum
• cerebellum becomes roof of 4th vent
• note that though cerebellum is a alar plate derivate, its main fucntion is motor, neurons in cerebellum do not innervate and activate mescles directly

Hypothalamic sulcus

• equivalent and continuous structure to the sulcus limitans in lower brain structure
• divides the diencephalon into dorsal part of alar plate (thalamus) and ventral part of alar plate (hypothalamus)

Somatic Motor Neurons

• motor neurons develop from neurectoderm in the intermediate or mantle layer of the basal plate
• development and distribution of their efferent nerves is tied with developing skeletal muscle
• myogenic cells migrate from their origin and motor axons from neurons in the mantle layer follow
• they exit ventrolaterally from neural tube to form the ventral root

Somatic Sensory Neurons

• primary sensory neurons are derived from neural crest
• they form dorsal root ganglia of spinal nerves
• central processes of developing primary sensory neurons grow into the neural tube and form conections to CNS neurons of the alar; 
• peripheral processes of the developing primary sensory neurons form the dorsal root in spinal nerves and grow to peripheral targets (dermatomes, myotomes and viscera

Cauda Equina 

• bundle of spinal nerves from lumbar, sacral and coccygeal levels
• result of outgrowth of vertebral column compared to spinal cord during development

Sympathetic NS Development

• preganlgionic sympathetic neurons are intrinsic to the cord and develop from cells of the mantle layer at 14 segments of neural tube (T1-L2/L3)
• their axons exit the ventral horn, forming the preganglionic aons growing to peripheral ganglia
• postganglionic neurons are derived from neural crest cells

Parasympathetic NS Development

• preganglionic parasymp neurons are intrinsic to the cord and develop from cells of the mantle layer at sacral (S2-4) and cranieal segment of neural tube
• their axons exit ventrolaterally, forming the preganglionic axons growling to peripheral ganglia 
• postganglionic neurons are derived from neural crest cells

Spina Bifida

• occulta: vertebral body fails to completely form, but the defect is not open and the spinal cord is normal
• cystica: include meningocele (meninges protrude through the defect), and meningomyelocele (meninges and some spinal cord protrudes through the defect)

Anencephaly

• more severe failure of fusion of neural folds at the anterior neuropore
• this is incompatible wiht life because the brainstem is affected and breathing and blood pressure fails
• neural tube defects can be diagnosed in uterus with ultrasound
• open neural tube defects are detectable by analyzing amniotic fluid for alpha-fetoprotein
• levels of this protein in amniotic fluid are elevated with defects
• folic acid (folate) reduces neural tube defects by as much as 70% if 400 ug is taken daily prior to and during pregnancy 

Hierarchical-chain Circuits

• most common type
• typical sensory systems are organized as ascending hierarchies
• typical motor systems are organized as descending hierarchies 
• chain circuits are vulnerable to interference by injury, disease, stroke or tumor which leaves the whole ciruit/pathway inoperative
• interneurons are interposed in these chians; short axons and operate in a spatially restricted area, forming local circuits (excitatory, inh, or modulatory)
• effects of lesion of the circuit are specific (loss of sens, or paralysis of certain muscles in a motor pathway)

Single-source Divergent Circuits

• neurons send axons to many recipient cells and their effects are extremely divergent
• participate in volume (extrasynaptic) vs wired (synaptic) neurotransmission; dump NT into extracellular space
• effects produced by these circuits are nonspecific (mood, arousal) compared to specific hierarchical effects
• effects of NT are conditional; depend on existing conditions in the area of release and influence global behavioral states 
• lesion of such circuits produce nonspecific effects(changes in mood, pleasure, reward, personality, depression, sleep) rather than a speficif loss of function like in hierarchical

Embryological Development of 

Circuits

• neurogenesis: cell proliferation, birth of neurons and glia
• migration: newly formed cells relocate
• aggregation and differentiation
• synaptogenesis and circuit formation: 
• apoptosis: programmed cell death of overproduction
• synapse rearrangement: maturation of synapses via strengthening some synapses and weakening others

Cell proliferation in brain vesicles

• cellular membrane of cells in ventricular zone forms a process that extends towards the pial surface
• nuc of the cell migrates toward the pial surface along this process, during which the cells DNA is copied
• nucleus moves back to the ventricular surface 
• extended process is retracted from the pial surface
• cell divides, producing two daughter cells
• vertical proliferation produces same, horizontal produces 2 different cells, one that stays and one that goes

Neuroepithelial layer 

(ventricular zone)

• these cells are mitoticallya ctive throughout intrauterine development and are the sources of all neurons and astrocytes (maybe oligod) of the CNS
• neuroepithelial cells divide and form neuroblasts (primitave/immature nerve cells) and giablasts (primitive/immature glial)
• after all cells enter a postmitotic state, the remaining cells form the ependyma lining of the ventricular system

Mantle Layer

(intermediate zone)

• neural tube wall
• consists of neuroblasts and gliablasts
• neuroblasts differentiate into neurons and gliablasts differentiate into astrocytes
• as neurons develop they extend axons to the evolving white matter zone(marginal)
• cells in mantle layer will form grey matter for spinal cord
• the layer thickens by differentiation of oligodendrocytes and production of myelin

Marginal Layer

• consists of axons orginating from neurons in the mantle layer, and axons that pass through from lower and/or higher centers, forminig white matter for spinal cord

Migration

• neurons migrate along raidal glial cells
• occurs for neurons destined to form a laminated or smilaminated structure
• cell bodies of radial glial cells located in ventricular zone and into marginal zone
• migrating neurons form close associations with glial cells (crawl along)
• leading processes of migrating cells are highly active, extending numerous flopodia which move along the process of the radial glial cells

Giloblasts

• primitive glial cells that are also formed by neuroepithelium
• migrate to the mantle and marginal layers and differentiate into astrocytes
• in marginal layer they also possibly become oligodendrocytes (also derive from mesenchyme)
• microglia develop from mesoderm or neuroectoderm; appearance coincides with vascularization of CNS

Axonal Growths

• the tip of an elongating axon expands as a growth cone with filopodia
• growth cone is a sensory-motor structure that recognizes and respons to guidance cues
• filopodia adheres to tissue substrates and directs the path of axonal extension
• axon growth also guided by chemical and morphological cues
• growth cone guides the axon by transducing positive and negative cues into signals that cytoskeleton responds to

Chemoattractants

• diffusible molecules that attract growth cones toward their targets (netrin), which are secreted by ectodermal cells and are important guides for axons that must cross the midline (commissural)
• examples are spinothalamic axons, majority of corticospinal axons and half of the retinal axons

Chemorepellents 

• diffusible molecules that chase growth cones away (slit, semaphorin)
• note that the determination of such a diffusible molecule depends on its action loci
• some molecules can act as a chemoattractant in some region and as a chemorepplent in other region 

Synaptogenesis

• target recognition: formation of selective connetions btw the eveloping axon and its target, growth cones guide them to their appropriate target by combinations of signaling molec in the extracellular space
• presynaptic differentiation: transformation of axons growth cone into a nerve terminal; transmitter release machinery is concentrated at the future active zone of the axons terminal 
• for many neurons in brain the choice of NT is part of cells intrinsic neurogenetic program
• the motor neuron axon terminal secretes protein agrin, which binds w/ MuSK on the muscle cell membrane
• interaction in turn triggers the clustering of AChRs in the muscle membrane via the actions of another protein rapsyn 

Neurotrophic Factors 

• secreted by target cells of motor neurons
• bind to receptors of axon terminals, internalized and retrogradely transported to the cell bodies
• Nerve growth factor(NGF), Brain derived nerve factor (BDNF), NT3, NT4/5
• expressed in different tissues and bind to tyrosine kinase and P75NTR
• while survival of PNS neuron depends on neurotrophins, the role of neurotrophic factors in the CNS remain unclear
• supress endogenous cell death

Neurological disorders

and apoptosis

• apoptosis may be involved in parkinson's disease and amyotrophic lateral sclerosis (ALS)
• research on neurotrophic factor signaling and the biochemistry of cell death mechanisms is beginning to be applied to search for treatment of neurodegenerative disorders 

Hebbian Rule

• synaptic rearrangement 
• thought to be modulated by patterns of electrical activity in the pre- and postsynaptic partners
• neurons that fire together wire together
• this competition extends into postnatal life and is influenced by experiences

Postnatal Changes

• most changes occur in the cerebral cortex
• about 70% of CNS neurons are in the cerebral cortex; cortical development differentiates humans from animals
• learning and behavioral demands and sensorimotor training increase dendritic extensions and synapses of cortical pyramidal cells

Experinece
(circuitry)  

• changes in connectivity that affect behavior can happen at sensory input levels, internal levels of processing (assess information, retrieve memory, make decisions), and motor output levels
• abnormal experience (blindness, deafness) will alter neural circuitry to be maximally adapted to an altered environment or ability
• for example, in an individual blind from early in life, the territory of visual cortex thatis not activated by visual experience will eventually respond to sensory stimuli from other modalities (auditory or somatosensory)

Critical Periods

• time course during development 
• where experience early in life is most important for acquiring sensory, cognitive and motor abilities
• critical periods and the underlying mechanisms are elaborated below
• critical periods exist for many types of behavior but vary in duration
• after end of critical period, the behavior is largely unaffected by subsequent experience
• involves changes at the level of cortex

Hebb's Theorem

• simultaneous activity of a presynaptic and postsynaptic neuron will strengthen the synaptic connection btw them (cells that fire together wire together_
• synapses with persistant correlated activity will be retained and/or strengthen and processes from the presynaptic cell may sprout new branches
• synapses with persistent uncorrelated activity will vanish and/or weaken, and the presynaptic cell may lose branches
• cellular basis of learning and memory, applies to long term modifications of synaptic strength, including during development

Opening Critical Period

• inhibitory circuits must reach a certain level of maturity 
• more excitatory than inhibitory in the cortex, and as inhibitory cirucits mature, there is a gradualshift toards balance
• eperimental treatments that accelerate inhibitory (GABA) function can open a critical period
• conversely, experimental treatments that slow down GABA circuit function can delay the onset of a critical period

During Critical Periods

• correlated or uncorrelated neural activity strengthens or weakens synaptic connections
• LTP and LTD are involved in synaptic strength changes
• to make these changes permanent,  correlated activity increases Ca flow into the cell, which initiates biochemical cascades at both the cell body and distal dendrites
• these cascades can promote synaptic growth and stabilize synapses, alter dendritic structure, alter neurotransmitter receptors

Closing Critical periods

• structural changes that limit new connectivity
• proteins that inhibit axonal sprouting
• proteins that form tight "perineuronal nets" around GABA cells, thus restraining synaptic inputs

Amblyopia

• vision is prevented in one eye early on in critical period (misalignment called strabismus)
• ocular dominance columns are much smaller for the deprived eye
• indicates that more of the cortex recieves LGN inputs from the nondeprived eye than from the deprived eye
• result in that these animals are functionally blind in the deprived eye
• neural responses of visual cortex are shifted to respond only to one eye
• called cortical blindness and is permanent
• in adulthood, after a 10 day period of complete visual deprivation, neural responses of visual cortex are shifted toward the unoccluded eye

Strabismus

• condition when the two eyes are not aligned, which can induce amblyopia
• objects in the same part of visual space do not activate corresponding spos on the two retinas at the same time
• unlike monocular deprivation, there is an equal LEVEL of activity in both eyes but patterns are different
• anatomical rearrangement: ocular dominance columns are much SHARPER than normal
• binocular responses are reduced and impaired vision
• estropia (crossed eyes), and exotropia (divergent)

Children Isolated from language

• children isolated till their early 
• they never learn the grammatical and syntactic complexities of language, and the left hemisphere language regions are not involved in their speech production

Native Vs Non-native Phonemes

• adults cannot distinguish speech sounds (phonemes such as ra and la) that do no exist in their own language but do exist in other languages
• for example, japanese speakers cannot distinguish btween the r and l sounds english 
• babies can distinguish amongst native and non-native sounds but lose this ability by ~1 year 
• indicates critical period not only for language, but particularly for the acquisition of phoneme pereption and production
• until age of 7 or 8 children can acquire a second language with equivalent fluency