MBB TOLO – Week 1

Lecture 2 – Introduction - Systematic approach

 History – Should have a very good guess already: Symptoms, Time course of onset and since onset
 Neurological Examination: Mental status, CN, Coordination, Motor, Somatosensory, Reflexes, Posture and gait, and
pertinent part of general physician exam
 Once you get symptoms and signs: Do lesion Localization
o Focal, multifocal, or diffuse
 Multifocal = more than one focal lesion, but probably because of same problem
 Diffuse = lesion of one or more systems that are dysfunctional with susceptible vulnerability – aka some
neurons are important for Vitamin B12 so if these all go bad, it would be diffuse lesion
o Intraparenchymal or extraparenchymal – in the nervous system, or outside of the nervous system pressing on the
nerve
o Negative and positive symptoms and signs
 Symptom = patient says this is happening
 Sign = you do physical exam and this is what you find
 Negative = muscle weaknesses – loss of sensation
 Positive = Rhythmical uncontrollable jerking, because NS is doing something not supposed to, neuropathic
pain
o Mass lesion – could result in headache because these lesions can press on pain sensitive receptors and maybe can
normal parts of brain can move to another compartment
o Neighborhood signs – weakness in left arm, you have to figure if its in the brain, is it in the plexus, or peripheral
nerve. So therefore, you look for the signs and tell you which region the lesion should be in in
o False Localizing signs – weakness in right arm, and says has double vision
 People with increased pressure in brain, because of mass lesions or otherwise, can sometimes affect the
lateral rectus muscle (Abducens nerve) so if weakness in right arm
 Approach to lesion localization
o Assume the lesion is focal
o Assume the lesion is diffuse
o Answer the question – where is the lesion?
o Consider symptoms and sign
o Construct one or more possible neurological syndromes (symptoms and signs are correlated)
 Time Course
o Acute, short subacute, long subacute, or chronic time course of onset is most important
 Subacute – up to many months
 Chronic = many years
o Time course since onset: Improved, stable, exacerbations (attacks) and remissions (improvements), still
experiencing chronic onset
 Categories of neurological diseases – VITAMNDEC
o Vascular (stroke) – acute, focal
o Infectious – fever, elevated WBC
o Traumatic – history or signs of trauma
o Autoimmune / Immunologic
o Metabolic / Toxic/ Endocrinological / Nutritional – diffuse, often subacute
 Hypothyrodism, Tay Sachs
o Neuroplasms – Focal – tumor that could be benign or malignant – abnormal growth
o Degenerative – Chronic, diffuse – MS, duchenne muscular dystrophy
o Episodic / Paraoxysmal – Each episode is acute and self limiting – most likely will have some underlying
disorder that belongs to other category
o Congenital / Development – could manifest later in life – some can belong in two categories but putting them
into another category, that is not congenital, can help with treatment
 Diagnosis and differential diagnosis
o It is fine if the patient does not end up with your diagnosis, but as long you are in the same category then it is
okay
 Tests
o History is most important, some can do EEG, Neuropsychological testing, neuroimaging, spinal fluid, biopsy
Lecture 3- Structural Neuroanatomy
 Terms of anatomical reference
o Dorsal – back, Ventral- forward,
 Major divisions of the NS
o CNS (brain, spinal cord, optic nerve) vs PNS (peripheral nerves, ganglia,
terminal processes)
 CNS = MS just affects the CNS
 PNS – ganglia = collections of nerve cells bodies outside the CNS
 Made up of most of cranial and from spinal nerves and what they make
o ANS – effector component of the visceral nervous system – partly in PNS and CNS
 Parasympathetic Nervous system – Cranial Sacral (this is where the ganglia are)
 Sympathetic Nervous system – thoracic lumbar – preganglic cell bodies are in lumbar part
o Muscular system – not part of NS but very relevant to neurological diseases
o CNS – made up of gray matter and white matter
 Gray matter – outside of cerebral and cerebellar hemispheres as cortex and deep down within the
brain and spinal cord as nuclei
 Nuclei = CNS, ganglia in the PNS
 White matter – bundles of nerve fibers, with myelin and no cell bodies- often organized into tracts
 Regional neuroanatomy of the CNS
o Central sulcus – divides the frontal lobe and parietal lobe?
o Lateral fissure – divides temporal lobe and frontal lobe + parietal lobe
o Basal forebrain nuclei – Ach – projection system from here
o Diencephalon – thalamus, hypothalamus (homeostasis, biological clock, subthalamic nucleus, pineal gland)
o Midbrain = tectum (roof), Cerebral peduncle (tegmentum + substantia nigra + crus cerebri)
o Pons = temgumentum and basis points and Medulla
o Brainstem = midbrain, pons, medulla together aka BULBAR fibers
 Everything goes through the brain has to go through the brainstem
o Reticular formation – extends through brainstem and has 2 components
 1. Serotonergic raphe nuclei throughout brainstem
 2. Noradrenergic locus ceruleus (up brainstem and down) and
associated pontine nuclei
o The reticular activating system – partly within brainstem but extends
rostrally - Initiates and maintains arousal
o Cerebellum - connects to brainstem by 3 paired cerebellar peduncles (white
matter tracts), part of the motor system
o All the sensory information afferent information
comes on dorsal root, all the motor commands to
contract muscles come from the ventral root
 The ventral cell bodies are in the ventral
horn
 The dorsal root cell bodies are in the DRG

o Substantia gelatinosa – pain and temperature – where aspirin and opiates

work
o
 Cranial nerves – all of them are ipsilaterals!!!
o Parasympathetic are in 3, 7, 9, 10
o CN2 – PART OF THE CNS
o EYEs
 3 - Oculomoter nerve – medial, inferior, superior rectus, and inferior oblique
 Also has all the parasympathetics for the eye – ciliary ganglion – pupillary and cillary muscles
o Levator papillae – open eyelid
 4- Trochlear nerve – superior oblique
 6- Abducens nerve – lacteral rectus
 Sympathetics do not come from Brain, come from the spinal cord thorolumbar
 Ones that follow the internal carotid – make pupil bigger
 One that follow the external carotid - causes sweating on your face
 Smooth muscle – tarsal muscle – will open the eye a little more
o CN5 – somatosensation - comes out of the midpons! – where it is blending to the middle cerebellar peduncle
 Muscles of chewing
o CN7 –MOTOR NERVE Pontomedullary junction – cerebellarpontine angle
 Will contract muscle in middle ear to dampen sound waves (stapedius)
 Taste on ipsilateral side of the tongue
 Protect cornea by closing (orbicularis oculi)
o CN8 – also pontomedullary junction
o CN9 – Somatosensation from posterior pharynx – gag reflex (afferent limb) ??
o CN10 – soft palate goes up with swallowing - LVP , larynx (vocal cords)
o CN11 – spinal part – SCM and trapezius
 Cell bodies were probably in medulla there during the early development, and the cell bodies migrated
down so now it has to go up
 Right CN11 go to right SCM to rotate to the left ????
o CN12 – Pyramids and olive of the brainstem – tongue muscles
 Important related structures
o Skull and the CSF (in subarachnoid space) that will protect against contusion
o Meninges: pia, Arachnoid, Dura
o CSF – circulate out around the brain after the 4th ventricle and down to
spinal fluid
Lecture 4- Skull and Spine Cord anatomy
 Skull –
o Above
 Calvarium and skull base
 Calvarium = frontal, parietal, temporal squamous, sphenoid greater wing, occipital
 Face- hanging from the top of the neurocranium
 Suture – do not want these to close early on because your brain grows when you little. If it fuses early,
then the brain will protrude out from the back
o Skull base - Ptyergoid – where muscles of mastication attach
 Neurocranium
o Falx Cerebri – separates both cerebral hemispheres and falx cerebelli (posterior cranial fossa)
o Falx tentorium
 Brainstem, cerebellum, basilar artery – posterior fossa
 Temporal lobes – middle fossa, frontal lobes – anterior fossa
 Pituitary – sella turcica
o Page 53 – LEARN THE HOLES
 SCALP
o Loose connective tissue allows for your face to move – yay infections can move around in here
o Dense connective tissue keeps its arteries tightly so they cannot retract so they stay open and bleed to death so
you have to apply pressure
o Nerves – trigeminal nerves go to forehead and upper part of scalp, back of head and left side ( have to consider
nerves that are coming out of spine and going down but also wrapping around head) – more likely a sensory
lesion
 Face
o Muscles originate on bone/fascia and insert on skin (for facial expression)
 Orbicularis oculi – close eye, Buccinator – chewing, Orbicularis oris – close mouth, kissing
o Facial sensation = V1, V2, V3
o Blood supply – facial artery and veins, lots of interconnections but infection can spread 
 Orbit
o Blowout fracture specifically in the medial wall (lacrimal, ethmoid, palatine bone)
 Go into and interfere nasolacrimal duct
 Lots of infection maybe can get through thin ethmoid which come from nose
 Lacrimation
o Blinking helps drain it laterally to medially and into inferior nasal cavity
o Lacrimal punctum  lacrimal canaliculi  lacrimal sac
o CN 7 – parasympathetic – greater petrosal nerve so will not have tears
 Problem with this, will affect blinking and so no tears and no closing eyes
 Eye
o Eyelid
 Levator palpebrae superioris – opens the eye (3)
 Superior tarsal muscle – sympathetic supply – will open the eye even more, problem with this
(dysfunction will lead to dropping)
 Tarsal muscles and gland
 Conjunctive – outer surface of the eye – pink eye (inner
side of eyelid)
o Extraocular muscles – Do the H
 Eyes are organized strangely so it can rotate around if you move your head
o Orbital Contents
 Superior optic fissure – CN3, 4, 6, sympathetic fibers, Opthalamic branch of trigeminal nerve
(nasociliary, etc)
o Eyeball
 Cornea – Reflecting and focus light (this is the surgery of Lasix ) – and is not vascularized
 Uveal tract – highly vascularized
 Ciliary body – suspension of the lens – small focusing – last little adjustment for things that are closer or
farther.
  Ciliary muscles are parasympathetically innervated and when they contract, there is less tension on
the fibers that connect to the lens. Then the lens can relax and become wide again and so you can see
closer
 When you age, your lens no longer wants to move anymore, so you cannot see things that are close
 Also ciliary body secrets the aqueous humor – behind the cornea (gives oxygen to the cornea) and
also fills the posterior chamber which is in front of the lens but behind the iris
o Anterior chamber is in front of the iris but behind the cornea
o This is different than the vitreous humor which fills the eyeballs
 Iris is also automatically innervated – and sphincter pupillae can contract with sympathetic innervation for
dilation. And other muscles close for parasympathetic innervation
 Opthalmologic topical drugs
o Mydriatic – dilates the pupil
 mACHR antagonists (block constriction) or alpha 1 agonist
o Cycloplegic – prevents accommodation – prevents ciliary muscles from contracting – parasympathetic system
 mACHR antagonist – stop lens from moving back and forth (important if you want to look behind the
cornea and lens to look at the retina)
o Tropicamide (Mydriacyl) – probably used for mACHR antagonist
 blocks mACHR on papillary sphincter muscles and on ciliary muscles so also no accommodation
o Phenyleprine – alpha 1 agonist – when you do not need to block accommodation
 MOA – radial dilator muscles - Can cause glaucoma
o Benoxinate – topical anaesthetic – fluorescein dye to see any imperfections in the cornea
 So no pain or discomfort when examining pressing eye to see intraocular pressure, blocks VG Na
channels
 Ear – external, middle, and internal ear - vestibular / auditory functions
o External ear = has external acoustic meatus for air pathway
o Tympanic membrane – reflection of the cone of light is
caused by the protruding
o In the petrous part of the body labriynth – cochlea and
vestibular system
 Endolymph- K+ rich – inner fluid
 Perilymph – CSF similar- cushioning – outer fluid
 Intracranial Pressure
o 1400 cc of volume (1250 is brain, rest is CSF and blood)
o IF you trap CSF, or brain swollen, or more blood
o Can measure the LP for pressure (should be less than 20)
o Problems – can lead to herniation into the cingulate (other side which hurts with falx celebri which is sharp),
uncal (go posterior), trastentorial (type of uncal), tonsilar (to brainstem)
o Medications for intracranial pressure:
 Dexamethasone and other corticosteroids
 For vasogenic edema (leak BBB) – stabilizes BBB
 Edema clears after hours – days
 Glucosteroids will increase glucose release and will decrease
immune response, increase neutrophils so WBC overall should
increase- can lead to steroid psychosis so could get super hyper
 GCs are part of the feedback mechanism in the immune system which reduces
certain aspects of immune function, such as reduction of inflammation and when they
bind to GC receptor, they induce anti-inflammatory
 Mannitol
 Osmotic diuretic – rapidly pulls water from brain
 Sad- rebound intracranial pressure
 Can lead to pulmonary edema and electrolyte imbalances
 Used for emergencies to get patient to OR. Put IV and works very quickly
 Shift from interstitial and intracellular to plasma
 Vasogenic edema occurs due to a breakdown of the tight endothelial junctions that make up the blood–brain barrier. This allows
intravascular proteins and fluid to penetrate into the parenchymal extracellular space.
Lecture 5 – Neurocytology and Neurhistology
 Overview
o Two types of cells: Neurons and Glial cells
o Classification by shape and circuit type
 Shape: monopolar (DRG), bipolar(sensory), multipolar (most neurons)
 Circuits:
 Principal neurons= long axons that project out of brain regions in which the cell body resides
(cortex send out into the spinal cord)
 Local Circuit neurons = Short axons that ramify in the same brain region
(inhibitory/interneurons)
 Anaxonic = no axon at all
o Imaging:
 Electron micrographs – look at membranes
 Nissl stain = stains acidic structures, mostly RER in the cell body
 Parts of neuron
o Cell body, dendrites, axon, and synaptic terminals
o Cell body
 around the nucleus = perikaryon, prominent nucleolus
 Same organnels as other cells- very prominent golgi apparatus, polyribosomes, RER
 Protein synthesis and organelles are in the cell body – gene transcription and protein synthesis
 Typically if the axon is separated, it will not be able to survive on their own
o Cytoskeleton – 3 main components
 1. Microtubules (25 nm) – Microtubules associated proteins (MAP’s) – different in axons and dendrites
 2. Intermediate Filaments (10 nm) – cell type specific and in neurons, it is neurofilaments
 3. Microfilaments (5-7 nm) – actin (important for plasticity of Nervous system
 Cytoskeleton is important for establishing and maintaining polarity and shape, for growth and
development, plasticity and for axonal transport
o Dendrites vs axons
 Neurons can have multiple dendrites but only one axon
 Organelles
 Dendrites have similar organelles as cell soma proximally (near soma), but the RER and Golgi
decrease distally (far from soma)
 Axons – no ribosomes and Golgi, axon without cell soma cannot survive
 Cytoskeleton – have different microtubule associated proteins
 Dendrite spines
o Specialized extensions (fuzz) are on some dendrites and each receives a single excitatory synaptic contact
(glutamate)
o The number of spines can change their size, shape and number in response to environmental and pathological
events- enriched in actin
 Important for synaptic plasticity
 Axonal transport
o Anterograde - stuff is made in cell soma and transported into axon
 Fast component organelles, synaptic vesicles – microtubule based motors
 Slow component – cytoskeletal components and other proteins
o Retrograde - Substances also transported back to cell soma (retrograde transport)
 Returns materials from the nerve terminal to the nerve cell body for degradation or reuse
 Growth factors or viruses taken up from postsynaptic side
 Relies on microtubules and motors
o Neuropril - a dense network of interwoven nerve fibers and their branches and synapses, together with glial
filaments.
 The glia – in CNS and PNS- COPS
o Types of glia: Oligodendrocyte, Schwann cell, Astrocyte, Microglial, glial progenitor cells
o Functions:
 development (neuronal migration, growth factors, synaptogenesis)
 physiological (myelin, trophic support, synaptic signaling regulation, CSF – choroid epithelial cells,
uptake of NT)
  Pathological – formation of glial scar after injury, phagocytosis (microglial), regeneration (PNS)
o Astrocyte – one of the more numerous cells
 surround neuronal surfaces, blood vessels, and surface of brain, and have NT receptors- probably to take
the NT away
 React to injury (gliosis) and contribute to the formation of the glial scar
o Myelin Sheath – large axons (>1 um) in both CNS and PNS are wrapped in insulating sheath = myelin –
facilitates axonal conduction while conserving space
 To form, glial cell wraps around it its cytoplasm is squeezed out so it is mostly fat, which does not
conduct electricity)
 All cells in PNS are ensheathed, but not all in CNS
 Nodes of Ranvier – myelin gaps – site of AP propagation
 CNS – oligodendrocytes – one oligo to many aoxns, no basal lamina, astrocytes ensheath the node
 50% CNS myelin is made up of PLP (proteolipid protein)
 PNS – Schwann cell – one schwann cell to one axon – basal lamina surrounds node
 50% PNS myelin are PO?
o Oligodendrocyte Progenitor Cells (OPCs) – small population of precursor cells in adult brain that can make
more oligodendrocytes – a lso know as polydendrocytes – NG2 cells
 Maybe can contribute to remyelination in adult brain
 Express PDGF and is more commonly found in white matter
Lecture 6- Anesthetic drugs
 Anesthetic – produce loss of sensation by blocking impulse conduction in axons of sensory system
 Use knowledge of electrophysiology, voltage-gated sodium channels, and the effect of pH on the distribution of weak
bases to describe the mechanism of action of the local anesthetics
o The resting membrane potential- around -70
 Made by NaK ATPase, K+ leak channels, not many Na+ leak channels
 K+ equilibrium potential is around -90
o Action potential
 Threshold is around -55 and VG Na channel opens
o Propagation – neighboring positive charges activate more VG Na channels so it can propagate
 In unmyelinated neurons, there is equally expressed VGNa channel so it gets activated normally
 Myelinated neurons – VG Na only at the nodes so the signal is jumping down
o Conduction is faster in axons with larger diameter and with myelination
 Various Anesthetic drugs and MOA
o Block VGNa channel from the outside – stop breathing and you die
 Saxitoxin, tetrodotoxin
o Local anthestetics – block VGNa from the inside
 They are weak base, It gets in as B, then when it comes inside, because intracellular is slightly acidic, it
becomes HB+ and binds the channel on the inside when it is in the open state
 Factors influencing the action of Las. Compare the sensitivity of different types of nerve fibers to local anesthetics
o 1. Membrane depolarization / axon activation
 More depolarization  more time the channel is in the open state, so then more anesthetic can get in
o 2. pH
 if you have inflammation, you get an acidic environment and this decreases efficacy because then
the drug will be able to get in through the membrane
 IF you add Bicarborb with the drug, then you decrease time of the onset??
o 3. Differential sensitivity
 unmyelinated and smaller fibers are more
sensitive to anesthetics because you get
more Na channels in a particular amount of
space in smaller fibers, and unmyelinated
have more exposed VGNa
 Adelta and C sensory pain fibers fire faster
when there is pain and so that’s why pain is
blocked before all of the other sensations
 Describe, compare, and contrast the major local
anesthetics – are all “caines”
o The duration of the anesthetic depends on how
fastly it is metabolized
o Esters are metabolized more quickly in the liver by
esterases so they last less
o Amides are metabolized in liver by CUPs and have to be
conjugated so they last longer
o Duration also increased if co-adminstered with
vasoconstrictor
 EPI – increased alpha
vasoconstriction which prolongs
effect and you should not use it with
EPI if you are cutting anywhere
terminal that would have its blood
flow already compromised
 Benefits: less bleeding so
you can see better
 Describe the sequence of toxicities that occur as the dose of a local anesthetic is increased
o Start with CNS effect, and then lead to Cardio effects
o Can get methemoglobinemia – drug oxides Fe2+  Fe3+ so it can no longer carry O2 (often seen with
prilocaine)
o Allergies – lots to ester, which is metabolized into PABA, which a lot of people are allergic to
o Local toxicity – can get neural injury in spinal anesthesia – by injecting LA into subarachnoid space ( very rare)
 Mostly get transient neurological symptom following spinal anesthesia
 These two things are common with lidocaine so you do not use it with spine anesthesia
o If you see adverse effect of toxicity: give Intralipid formulation – binds to L.A and gets rid of it

 Describe, compare, and contrast the common routes of administration of local anesthetics and the clinical situations in
which each is appropriate).
 Other drugs that prolonged inactivated VGNa
o A lot of anti-seizure medications, and
neuropathic pain so these do have the same
target but they do it differently – they just hold
the inactivated state so this just decreases the
frequency of the AP
 Drugs that block VG K+ channel
o Dalfampridine – Can improve gait in patients
with MS
o This would prolong the AP and can improve
conduction in demyelinated fibers
 However, prone to getting more
seizures
Lecture 7 – CNS Neurotransmitters
 Introduction
o Synaptic Transmission – each presynaptic typically release one NT, but some can release more
 Postsynaptic – lots of different receptors
o AP comes and opens VG Ca channel, which fuse synaptic vesicles and cause NT release
o Two types of postsynaptic response
 1. Postsynaptic excitation (EPSP) – depolarization opening of Na channels
 2. Postsynaptic inhibition: (IPSP) hyperpolarization opening of Cl- channels
 If EPSP and IPSP depolarize past threshold, then you get synaptic transmissions
o Presynaptic neuromodulation:
 1. Presynaptic inhibition – reduce Ca influx or increase Cl-
 2. Presynaptic facilitation – prolong Ca influx by closing K+ channels
o Introduction: CNS pharmacology – most drugs act on CNS transmissions 1.
Lidocaine – block AP
o 2/3. Reserpine (antipsychotic), Tetrabenazine – inhibit VMAT which affects
storage and synthesis of NT
o 4. Mao inhibitors – inhibit metabolism of NE, DA, 5-HT
o 5. Botulinum toxin (block excotysosis of ACH), amphetamine (stimulates release
of NE, DA, serotonin)
o 6. Tricyclic antidepresents – inhibit NET, SERT for NE, serotonin
 SSRI – inhibit SERT for serotonin
o 7. Cholinesterase inhibitors – AchE
o 8. Dihenhydramine (parkinson’s disease) – mAChR antagonist
o 9. Caffeine (stimulant) – antagonizes adenosine receptors
o 10. Retrograde signaling – cannabinoids, NO - retrograde messengers
 Classes of receptors
o Ligand gated ion channels vs metabotropic G protein ion channels
 CNS Neurotransmitters


 Monoamines – Catecholamines (NE/EPI and Dopamine)

o Cell bodies are localized and act very wide
 NE – in locus ceruleus and lateral tegmental area and go
everywhere
 Important for regulation of lots of homeostasis, and
decrease NE is associated with depression and decreased
concentration to go for goals
 Dopamine – Substantia Nigra (pars compacta), ventral tegmental
area, arcuate
 SN  Striatum
 Ventral tegmental area  limbic forebrains, cerebral
cortex
 Arcuate nucleus – median emminance
 Synthesis:
 Tyrosine  Dopa  Dopamine
 VMAT then transports dopamine into synaptic vessels
 Tetrabenazine inhibits VMAT2 depleting monoamines
 NE is made from dopamine in the vesicles
o Metabolism
 All metabolism by MAO and COMT (dopamine only)
o Termination – reuptake by NET, and DAT
 Tricyclics antidepressents and SSRIS
o Role in disease
 Parkinson’s loss of dopaminergic neurons  motor deficits (substantia nigra)
 Schizophrenia – block dopamine receptors decreases symptoms – mesolimbic and mesocortical
 Addiction – dopamine reinforce effects of abused drugs – mesolimbic
 Monoamine – Serotonin
o Synthesis: Made in Raphe (median and dorsal) , pons, and medulla
 Tryptophan  5-Hydroxy trptophan  5-HT
 Uses same dopa decarboxylase as dopamine
 VMAT-2 transmits 5-Ht into synaptic vessels
o Metabolism
 In pineal gland, can be made into melatonin
 MAO  5-HIAA
 Termination of action is by reuptake with SERT so SSRIs, which target
SERT, increase serotonin
o Role in disease:
 Important for Mood, anxiety, sleep, sexual function, pain perception,
appetite and its vascular effects
o Drugs
 SSRI – only affect SERT so only serotonin
 SNRI – affect SERT and NET – both NE and serotonin
 MAO- breakdown the serotonin, dopamine, NE/EPI
o Peripheral effects of serotonin
 GI motility – stimulation increases GI motility, cramps and diarrhea
 Also stimulates platelet aggregation
o SSRI – often cause adverse GI effects and block reuptake of serotonin by platelets and can also get GI bleeding
 Monoamine – Histamine
o Synthesis – posterior hypothalamus / tuberomammillary nucleus – very widespread
o Regulates: arousal, attention, learning, memory, appetite, energy balance
o Drugs:
 Vertigo, motion sickness, nausea, vomiting – H1 antihistamines – diphenhydramine
 Insomnia – H1 antihitamines and tricyclic antidepressents – diphenhydramine
 Overall general monoamine disease states
o Transporters are SERT, DAT, NET for serotonin, dopamine, and NE
o Depression – caused by decreased synaptic availability of amines
 VMAT inhibitor depletes vesicular stores of NE and 5HT causes depression
 Antidepressants – increase synaptic ability of NE and 5HT
 Cocaine blocks NET but does not help with depression
o Parkinson’s
 Nigrostriatal dopaminergic pathways involved in control of voluntary movement
 Symptoms of parkinson’s helped by L-dopa and can cause Parkinson’s like symptoms using antipsychotic
drugs that block D2 receptors
 MPTP (contaminent of designer heroin) – destroys dopaminergic neurons
 Taken up in astrocytes and turned into MPP , goes into dopamine neurons and kill the
mitochondria
 Acetylcholine
o Synthesis: Rate limiting  transport in choline through CHT, which is made
into Ach through choline acetyltransferase
 Vat brings into vesicles
 Termination by acetylcholinesterase
o mAChRs are important as drug targets, and nAChRs are usually
presynaptic which regulate NT release
o Locations:
 Basal nuclear complex of forebrain (nucleus basalis, medial septal
nucleus)  cortex, limbic system (amygdala, hippocampus)
 This pathway degenerates in Alzheimer’s disease
 Striatum  striatum interneurons
 Balance between Cholinergic and dopaminergic regulation of GABAergic
striatal neurons is off in Parkinson’s disease
 Amino Acids (GABA, Glycine, Glutamate)
o GABA
 Synthesis: Glutamate  GABA by GAD
 GABA comes back into neuron by GAT or taken up by astrocytes and converted
to glutamine (which won’t excite anything)
 GABAergic neurons – 2 types:
 1. short local inhibitory neurons – in cortex and cerebellum
 2. Project neurons out of striatum (voluntary movement)  decreased GABAergic function in
important in Huntington’s disease
 Receptors:
 A – Ligand gated that regulates Cl- to come in , looks like nicotinic Ach Receptors and
hyperpolarizes cells - postsynaptic
 B- GPCR – most are presynaptic
o Opens K+ channel and hyperpolarize nerve terminal and decrease NT exocytosis
 Drugs:
 Can target GABA for epilepsy
 Benzodiazepines and non-benzos act on GABA receptors and increases potentiation
o Glycine
 When you activate glycine ligand gated receptor, you get increased Cl- conductance
 Strychinine (glycine receptor antagonist)  violent contraction of SKM
o Glutamate
 Glutamine  (glutaminase)  glutamate  (transaminases)  alpha-ketoglutarate
 Reuptake by glial cells , which turns it into glutamine to make transfer it back to the cell
 Four different receptors: NMDAR, AMPAR, Kainate – all ligand gated, and GPCR
 AMPA is on all neurons to create EPSP
 Kainate – only in cerebellum, spinal cord,
hippocampus but like AMPA
 NMDA – does EPSP with Na but also has Ca for
2nd messenger function
o Normally, Magnesium blocks NMDA at
Resting membrane potential, and depolarization and
glutamate binding will remove the Mg. Glycine or serine is
required as co-agonist
o In disease states:
 Seizures: Decreased GABA will increase glutamate and DEPOLARIZATION
so the NMDA receptors are activated and you get more and more seizure
activation. NMDA antagonists have lots of side effects tho  so most drugs just increase GABA
 Excitotoxic neuronal denegeration  Increased AMP
 More ischemia affects ion gradients so you will get more NMDA receptor activation  lead to
more membrane depolarization , increase Ca and will affect mitochondria release of badstuff
  Learning and memory – increased stimulation will open NMDA which will eventually add on more
AMPA so you will have increased baseline AMPA through CaM kinase long term potentiation
 Neuropeptides
o Small peptides are made and associated with specific NT, neuromodulatory role
o Typically found in same synaptic vesicles as NT or different vesicles and can be released by same / different
stimulant
 Cannabinoids
o Receptors:
 CB1 – neurons throughout CNS
 CB2 – immune cells
o Endogneous cannabinoids are made in cells
 Anandamide and 2-arachidonyl glycerol – work in neuromodulation
o Action: sleepiness, increase appetite, decrease spasms, impair cognition, euphoria, slow motor function
Lecture 8 – Macroscopic development of NS, development of ear and eye
 Development of embryo
o Start with fertilization of embryo, plants on endometrium in the uterus
o Week 1
o Week 2 – epiblasts and hypoblast and trophoblasts
 Epiblast becomes endoderm, mesoderm and ectoderm
o Week 3- Gastrulation – create Tri-laminar germ
 Endoderm – gut
 Mesoderm – muscle, bone, blood, notochord
 Ectoderm – NS, and skin
 Notochord creates primitive streak which terms into NS
o Week 4-
 Cranial Neuropore closes – failure to close produces anencephaly (no head)
 Caudal neuropore closes – failure to do so can range from spina bifida to myelomeningocele
 If it mainly closes except for a little, you get spina bifida occulta which could be perfectly
fine, however, if there is complications with neurons growing there so the spinal cord is
outside in fluid sac
 Folate – for closure of the tube

 Development of brain- week 5

o Prosencephalon
 Telecephalone (cortex, basal ganglia)
 Dicencephalon (thalamus, hypothalamus, subthalamic nucleus)
o Mesencephalon – midbrain
o Rhombencephalon
 Metencephalon (cerebellum, pons)
 Myelencephalon (medulla)
o Radial glial cells (neuro genital cells are in the grooves of germinal matrix!!! lay out paths for neurons to
crawl to where they are supposed to go
 Neurogenesis is by day 103 and spontaneously make connections, which eventually causes the brain
to fold itself
 Development of spinal cord and PNS
o Spinal cord
  Neuroepithelial cells line ventricles, migrate through radial glial cells and lead them to the middle of
the spinal cord
 Sulcus limitans in the middle are fluid filled column of fluid in the middle which eventually close
o PNS – next to neural crest cells are the somites that are made
 The Somite becomes bone and muscles – which is from mesoderm
 Neural crest cell becomes sensory and autonomic ganglia (DRG), which was from ecoderm to begin
with
 Myelin has to add on with motor roots first, then goes over the rest of body until age of 5
 Because of this, some diseases of myelin show up when they get older
 Development of eye- Fourth week
o Part of Neural tube is optic groove which make pouches, which induce ectoderm to form lenses
 Development of ear
o Hearing – need to create system to change sound wave into electrical signals
 Needs membrane to transmit sound waves, system to control membrane, and vibrating transducing to
move hair cell differently with different frequencies
o Balance – sense acceleration – fluid filled tube with little rocks to create current flow based on movement
o Internal ear – otic placode (from the hindbrain) – induces tissue around it to make the necessary structures
o Middle ear – create malleus, incus, and stapes – 1st pharyngeal pouch
o External ear – Tymphanic membrane – made from endoderm, ectoderk, and mesoderm
 Ecoderm  External auditory meatus
 Pinna made from 1st and 2nd pharyngeal arches
o Problems
 Septo-optic dysplasia – septum and optic nerve
 If there are no optic nerves, you would think about the pituitary gland or septum because all
these things occur at the same time

 Lecture 9 – NS development, Plasticity and aging of NS
 Development is through growth events and retraction events
 1. Cellular proliferation (neurogenesis and gliogenesis)
o Neuroepithelial line thickness of the neural tube and undergo cellular division – mainly
o Glial cells are made from same progenitor cells as neural cells but later in time (except radial glial cells)
o First neurons that are made are large projection neurons, then afterwards is interneurons
o Growth is driven by FGF, growth factors and mitogens
o Notch is very important in preventing neurons from predifferentiating so theres enough to make all the
neurons
 2. Migration and aggregation
o use the radial glial cells to create lamina
o Reelin is important for proper migration
o N-CAM (neural cell adhesion molecule) – important for aggregation
 3. Determination and cytodifferentiation
o Start as cuboid but convert to lots of shapes
o Initially only Calcium channels for prolonged depolarization exist, but eventually Na comes in
o NT for the neuron is determined by interacting with nearby cells
 Sweat glands initially produce NE but switch to ACH because of cholinergic differentiation factor
 4. Process outgrowth and axon pathfinding
o Growth is guided by growth cone, which has actin and can sense environment
 Factors like Semaphorins, slits, sign posts, and adhesive molecules can create gradients or connect to
neurons to guide their growth
 Many proteases are secreted to provide space to grow and create bridges
o Pioneer axons that grow need to use these cues to find the right way, others follow in process called
fasciculation
o Connect to multiple things and later on, there is selective pruning
 5. Synapse formation (synaptogenesis)
o Presynaptic region has lots of active zone stuff and vesicles – 3 main proteins: Neuroligins, synCAM, and
netrin-G-ligand
o Receptor aggregation – receptors are randomly placed but start to localize around a presynaptic neuron when
it contacts the cell
o Synapse formation – basement membrane of marker proteins are thick and can guide synapse formation
 6. Programmed cell death (apoptosis)
o 30-75% neuronal death during development = usually the ones who have differentiated and made synapses
are the ones to die
o Maybe competition for target space and growth factors determine who survives and who doesn’t
 7. Process elimination
o Elimination of many synaptic connections and this happens when electrical activity starts
o Proteases could also be helping
 8. Functional validation
o Behavior and environmental stimuli further fine tunes everything
o Visual cortex – gets input initially from two overlapping eye so visual experience is necessary to sort out
these experience
 If during the critical period, the eye is not open, then the vision will be lost in that eye
o Myelination – begins in the middle of fetal life but typically after birth until age 20.
 Adult neurogenesis – neurons in adult are post-mitotic and will not divide
o Brain has some neural stem cells that can produce neurons – specifically in: dentate gyrus (hippocampus)
and olfactory bulb
 CNS Plasticity – ability of CNS to undergo modification or rearrangement
o Can happen by creating new synaptic connections, strengthening current synapses,
o Can modify silent synapse – unmask systems that are not normally active, but will turn on if there is some
injury
 Also can have sprouting – intact axons can grow new axon processes to create synapses
o Mechanisms of recovery after injury:
 1. Diaschiasis / neural shock – transient loss of electrical function after injury – no death of neuron –
typically gets previous function – such as in spinal cord injury aka spinal shock
  Could also explain loss of consciousness in concussions
 2. Compensation – remaining system can increase function to compensate for something lost
 3. Substitute – alternative system can replace lost one – lesion in occipital cortex – can maybe see a
little by neurons in superior colliculus
 Language destruction in left brain – will develop in right brain
 4. Supersensitivity – increase in postsynaptic receptors after loss of normal input – in Parkinson’s
disease and schizophrenia – lead to greater reactivity of remaining input
 Neurologic signs of normal aging
o Cognitive changes
 Less accidental learning and timed task performance
 Will keep verbal intellect, immediate memory and Long term storage, and semantic memory
 Better at judgment, perception, well being
o Neuro-opthalmologic signs
 Smaller pupils and decreased response to light and accommodation
 Cannot look up, or look together at close objects (convergence), and more sensitivity to glare and
cannot deal well with dark
o Hearing – decreased high frequency because loss of hair cells
o Smell – decreased smell, a little bit in loss of taste
o Motor – progressive loss of anterior horn cells – reduced coordination, motor, strength in dorsal interossei,
thenar, and tibialis anterior
o Reflex – decreased reflex at ankles after 70, gone after 80
 Increased snouth and palmomental reflex ( brush thenar, get twitching chin) after 60
o Somatosensory – los of sensory axons so impaired vibration sense in toe and ankle
 Proprioception should still be good
o Posture and gait – shorter step, slownesss, and tend to steep
 Aging and neurodegeneration
o Superagers – elderly who have preserved cognitive abilities despite aging are super agers
o Neurodegeneration
 Different than normal aging
 Proteins are altered in neurodegenerative diseases – play role in normal development