Introduction to Neuroscience

Layers surround the brain

3 meninges (outside → in): dura mater → arachnoid mater → pia mater ∙dura mater: outer and inner layers, does not touch brain ∙arachnoid mater: does not touch brain ∙pia mater: attaches to brain 2 spaces ∙space b/w the two dura layers (2 sinuses) →superior/inerior sagittal sinus: contain blood from veins that will drain into jugular veins (remember superior sagittal sinus when we talk about spinal fluid) ∙subarachnoid space: b/w pia and arachnoid mater, contains blood vessels

Life Cycle of ACh

ACh is synthesized by choline acetyltransferase (ChAT) from choline and acetyl CoA ∙ChAT is synthesized in soma and transported to the axon terminal ∙only cholingeric neurons contain ChAT ACh is then pumped into vesicle, and released into synapse Synaptic acetylcholinesterase (AChE) causes degradation of ACh ∙AChE is secreted from neuron and is target of nerve gases (sarin), insectisides and drugs (physostigmine) Transport of choline is rate-limiting step: choline is low in extracellular fluids

Functional Classification of Neurons

Afferent → info TO CNS regarding external, internal stimuli Efferent → info FROM CNS to specialized target tissues Interneuron → processing, conveying info w/in CNS (local circuit)

Anatomical & Molecular Classification of Neurons

Anatomical ∙shape ∙location and projection ∙historical (cerebellar Purkinje neuron) Molecular ∙activity on target cell →excitatory = increased firing →inhibitory = decreased firing →modulatory = long lasting effect not directly related to firing rate ∙neurotransmitter system (glutamatergic, dopaminergic, cholingergic, peptidergic, etc.)

Pre and postsynaptic CNS connections vary in density and size

Asymmetrical synaptic differentiation: Gray's type I synapse, usually excitatory Symmetrical synaptic differentiation: Gray's type II synapse, usually inhibitory know that the typical depiction of a presynaptic and postsynaptic neuron is too simple for the CNS → there are many different ways the synapse can exist (i.e. presynaptic envelops postsynaptic, presynaptic can bifurcate and synapse many times, etc.)

Examples of various types of synaptic arrangements in the CNS

Axodendritic ∙axon of presynaptic neuron synapsing on dendrite ∙very common in CNS Axosomatic ∙axon of presynaptic neuron synapsing directly on cell body Axoaxonic ∙axon of presynaptic synapsing on another axon

Principles that apply to all NT receptors

Binding is determined by channel specificity specificity/selectivity determines whether or not the effects are stimulatory or inhibitory kinetics of the NT binding to the receptor determines the length of channel opening and effect a single NT can activate more than one receptor, and more than one type of receptor

Types of Glial Cells

CNS ∙astrocytes ∙ependymal cells ∙microglia ∙oligodendrocytes ∙NG2 cells PNS ∙satellite cells ∙Schwann cells

Noradrenergic Neurons

CNS Locus ceruleus NE neurons project to nearly every part of the brain and spinal cord and are involved in the regulation of sleep-wake cycles ∙may also play role in fear and stress responses NE system is important target of drugs that treat depression, anxiety and HTN

Intracellular Axon Guidance Pathways

Calcium ∙changes in calcium influence the activity of protein kinases and phosphatases ∙w/ regards to dendritic spines, rapid and high increases in calcium result in kinase activation and larger spines →slow changes stimulate phosphatase activity and spine shrinkage ∙kinase/phosphatase balance is critical to actin effectors (i.e. cofilin) that mediate polymerization ∙calcium also stimulates focal interlization of adhesions → localized changes in calcium affect adhesion molecule expression and localization Cyclic Nucleotides (i.e. cAMP) ∙there exists a complex interplay b/w calcium and cyclic nucleotide-dependent effects on growth cone guidance ∙distant calcium signaling can be modulated by cAMP, and this can influence an axon's bidirectional turning response Rho Signaling ∙Rho GTPase is an establish effector of actin dynamics in axonal and dendritic spine growth ∙calcium enters the cell to activate changes in Rho to affect actin polymerization

Major components of the nervous system

Central nervous system (CNS) = brain and spinal cord Peripheral nervous system (PNS) ∙spinal nerves (31 pairs) arise from spinal cord → sensory/motor ∙cranial nerves (12 pairs, all but first arise from brain) are largely concerned with motor and sensation of the head Visceral nervous system/autonomic nervous system = motor innervations of cardiac muscle, smooth muscle, glands, sensory innervations of viscera

Other designations for cell bodies in CNS

Columns ∙cortex: perpendicular to cortical plane ∙spinal cord: parallel to long axis layer, lamina, stratum ∙functionally related cells ∙parallel to larger structure

Astrocytes

Features ∙"star-shaped/stellate process bearing cells" ∙20-50% of brain volume ∙most abundant & largest glial cell ∙distributed in both gray and white matter ∙highly branched ∙derive from radial glial cells ∙astrocyte processes can contact neuronal cell bodies, dendrites & axonal surfaces, blood vessels and capillaries Functions ∙neuronal migration & guidance ∙produce & secrete growth factors that regulate morphology, proliferation, differentiation & survival of neurons ∙major source of extracellular matrix proteins & adhesion molecules ∙act as a physical barrier (protoplasmic) ∙respond to injury: reactive astrogliosis (fibrous) ∙maintain brain homeostasis →control blood flow, remove neurotransmitters/ions from synaptic cleft, provide energy and substrates for neurotransmission ∙glutamate-glutamine cycle (reuptake) ∙formation and modulation of synapse Structure ∙tripartite synapse (presynaptic, postsynaptic, and astrocyte) ∙gliotransmitters released from astrocytes ∙communicate in bidirectional manner with neurons via chemical/contact Disease associated with astrocytes ∙tumor caused by astrocyte = gliomas →common type of glial cancer ∙amyotrophic lateral sclerosis = astrocytes releasing toxic factors that kil motor neurons (ex. ALS, Lou Gehrig's) ∙Spinal injury cause glial scarring Types ∙Protoplasmic →found in gray matter →has thick, short, highly branched processes →serves to transport nutrients and oxygen from blood to neurons →projections with expansion are called end-feed, which can form perivascular-lining membrane by wrapping themselves around blood vessels →b/c of this, astrocytes can release vasoactive substances via perivascular-lining and control local blood flow →can also form glia limitans that protect the brain ∙Fibrous →found in white matter between nerve fibers →serves to respond to injury (reactive astrogliosis) →once activated, they undergo morphofunctional changes and proliferate and separate from the walls of the damaged area (anismorphic astrogliosis) →can communicate with neurons distally for neuronal remodeling (isomorphic astrogliosis) →processes are thin, smooth, long and less branched compared to protoplasmic astrocytes ∙Mueller cells →unique to retina

PNS Schwann Cells

Features ∙derived from the neural crest ∙provide myelin sheaths around peripheral axons ∙interrupted at regular intervals at the nodes of raniver (salutatory conduction) ∙as Schwann cell wraps around the axon, the cytoplasm progressively reduces → inner layers fuse ∙1 schwann cells = 1 internode/axon Functions ∙important during development and regeneration ∙phagocytose damaged axons ∙guide regeneration by forming a"tunnel" towards the target neuron ∙produce neurotrophins ∙essential for maintenance of healthy axons Disease associated with microglia ∙Guillain-Barre syndrome →acute inflammatory demyelinating polyneuropathy that blocks conduction leading to muscle paralysis →etiology is unknown but 50% of causes are triggered by acute infection →considered an autoimmune disease that targets SC membranes →first present with lower limb/face weakness but progresses rapidly ∙Chronic inflammatory demyelinating polyneuropathy ∙tumors (schwannoma) ∙Charcot-Marie-Tooth disease →most commonly inherited neuronal disorder that presents as an autosomal dominant demyelinating peripheral neuropathy →not fatal but can cause weakness of foot/lower leg muscles

Myelin

Features ∙layers of oligodendrocyte plasma membrane firmly pressed together ∙flattened sheet-like processes of plasma membrane produced by oligo's are wrapped repeatedly and tightly around the length of an axonal segment ∙myelin has high lipid/protein ratio (80/20) ∙not continuous along the axon ∙each myelinated segment = internode ∙each internode is followed by unmyelinated segment (node of Ranvier) ∙uninsulated regions have low resistance (rich in Na+ channels) Function ∙salutatory conduction (APs leap from node to node)

Oligodendrocytes

Features ∙much smaller than astrocytes ∙occupy both gray/white matter Functions ∙in gray matter = ? ∙in white matter = myelination of axons Disease associated with oligodendrocytes ∙Multiple sclerosis (MS) →inflammatory demyelinating disease →oligodendrocyte + myelin sheath degenerate ∙Progressive multifocal leukoencephalopathy (PML) and clinical depression →oligodendrocyte + myelin sheath degenerate ∙Oligodendrogliomas →slow growing oligodendrocyte tumor that develops from perineural oligodendrocytes Types ∙interfasicular →found in white matter →acts to myelinate axons →can create/maintain several myelin sheaths ∙perineural →found in gray matter close to neurons

Microglia

Features ∙smallest of glial cells ∙second most common glial cells (20% of total brain glia) ∙spread through CNS ∙derived from hematopoietic cells of monocyte-macrophage (mesoderm) Functions ∙resident immune cells of brain ∙becomes activated in response to pathological changes of brain caused by damage or infection ∙phagocytose debris and degenerating cells ∙CNS inflammatory response (produce/secrete cytokines, proinflammatory molecules, and chemokines) ∙important during CNS development Disease associated with microglia ∙bacterial meningitis can cause microglia to release excessive TNF-alpha/IL1-beta →causes blood brain barrier to be more susceptible, allowing leukocytes to enter brain and exacerbate the bacterial infection ∙HIV target microglia = pro-inflammation ∙following trauma, molecules secreted by activated microglia are neurotoxic - secondary cell death ∙neurodegenerative disease may be caused by increased microglial activation prior to the onset of cell death ∙MS, autism, environmental toxicants Types ∙resting = small rod-shaped soma with symmetrical or ramified processes ∙activated (reactive microglia) = thicker processes with larger cell bodies (non-phagocytic) →can take on more ameboid shape to allow for movement and phagocytosis

Types of tissues in the nervous system

Gray matter: neuronal cell bodies ∙in the brain = located on outer surfaces ∙in spinal cord = innermost tissue (what makes the butterfly) White matter: glial cells and neuronal processes (Tracts) ∙in brain = located on inner portions of brain ∙in spinal cord = outermost tissue (what surrounds the butterfly)

Axonal Transport

IMPORTANT: ∙maintaining function of axon/synapses ∙trophic support for neuron (back to cell body) bi-directional ∙anterograde/orthograde - from cell body towards synapse ∙retrograde - from terminals towards cell body

Characteristics of Specific Neurotransmitters

Life Cycle Characteristics: ∙Synthesis and rate-limiting step ∙Metabolism (if there is an enzyme that inactivates it) ∙Termination of action Central pathways ∙localization and projections ∙physiological/pathological role

Degradative Pathways of Catecholamines

MAO: monoamine oxidase COMT: catechol-O-methyl transferase dopamine can be metabolized by both enzymes, sequentially, to make HVA ∙NE has the same thing, but to make both VMA and MHPG metabolites can distinguish activity of neurons

Differentiating b/w Terms

Nerve = axons/support cells (macrostructure) neuron = nerve cell nerve fiber = axon neurites = neuron projections (development, in vitro) neuropil = collection of projections, support cells within CNS gray matter

Functional divison of neurotransmitters

Neural signaling ∙mediate communication b/w neurons ∙Amino acids: Glutamate, GABA and glycine Trans-system modulators ∙Modulate large populations of target neurons in multiple systems ∙Biogenic amines ∙have very long projections Within-systems modulators ∙modulate info by neurons w/in systems ∙neuropeptides ∙have very short projections

Peptide Neurotransmitters

Peptide NTs = neuropeptides make up over 20 different types of NTs (i.e. opioids, enkephalins, endorphins) Major differences b/w small molecule NTs and peptide NTs: ∙site of synthesis and packaging ∙termination of action ∙stimulus magnitude required for release ∙localization stimulation

Major Chemical Categories of Neurotransmitters

Small Molecule ∙Amino acids (Glutamate, GABA, Glycine) -->glutamate and GABA predominate by weight (~99%) ∙Biogenic Amines (ACh, serotonin, histamine, catecholamines) Peptides ∙3-36 amino acids ∙opioid peptide used in this class another category like gaseous agents, but we won't go there

Dopaminergic neurons

Substantia nigra par compact ∙with prjections to striatum forms nigrostriatal system that is involved in movement ∙individuals w/ Parkinsons have low striatal L-dopa levels due to degeneration of this system (can be decrease as great as 80% before tremors are seen) Ventral tegmental area (VTA) ∙with projections to nucleus accumbens, prefrontal cortex and cingulated cortex forms the mesolimbocortical DA system ∙found to be involved in drug reward pathways Arcuate nucleus of hypothalamus ∙projections to pituitary that affect glandular secretions

Terms of cerebrum/cortex

Sulcus/Fissues: allows or increased area to hold more neurons/pathways (sulcus means "ditch") ∙longitudinal fissure = separates left and right hemisphere ∙central sulcus (Fissure of Rolando) = separates frontal lobe from parietal lobe ∙lateral fissure = (Fissure of Sylvius) = separates temporal lobe from frontal/parietal lobe Gyri (pl.): wave-like curves of cortex, each gurus (singular) has a particular function ∙precentral = motility → if stroke occurs here, movements will be impaired but on contralateral side ∙postcentral Commissure: connecting fiber tracts for communication in the brain ∙major commissure (corpus callosum): connects left and right →stroke here will result in problems w/ communication of left and right hemispheres ∙don't confuse w/ tracts, which are tract and not usually able to visualize Lobes: putting gyri together, each lobe has a different function ∙Frontal lobe →anterior portion = planning, reasoning →posterior portion = motor control ∙Temporal lobe →anterior portion = higher order visual and auditory processing, semantic processing →medial portion = memory processing →dorsal/posterior portion = hearing (injury can cause impaired hearing/deafness) ∙Parietal lobe →primary sensory area - nerve impulses related to pain, temperature, touch and pressure →attention, spatial processing ∙Occipital Lobe →processing of visual information

PNS Satellite Cells

Surround cell bodies of sensory and autonomic ganglia regulate external environment, respond to ATP connected by gap junction responds to injury and produces pro-inflammatory molecules

Neurotransmitters are involved in synaptic transmission b/w neurons

Synaptic transmission - signal transduction process that begins with an action potential-dependent release of neurotransmitter from a presynaptic terminal ∙presynaptic neuron gets an electrical stimulus (AP that changes electrical properties) and converting it into a chemical signal neurotransmitters then binds and activates postsynaptic receptors that modify the electrical and biochemical properties of the postsynaptic cell ∙receiving chemical signal, depolarizing/hyperpolarizing cell (based on the signal) and signal is converted to an electrical signal and propagated to the next neuron in the relay

Life cycle of a neurotransmitter in the regulation of synaptic activity

Synthesis → storage → release → reception → reuptake/catabolism/diffusion

Neurotransmitter processing is a target for many CNS drugs and neurotoxins

To target synthesis: ∙either decrease precursor or inhibiting specific enzyme activity ∙will decrease concentration of NT in neuron and decrease its activity To target storage: ∙inhibit vesicular uptake pumps ∙depletes NT in presynaptic neurons To target release: ∙facilitate release → more NT is released than normal, eventually causing depletion To inactivate re-uptake or degradation: ∙block reuptake or inhibit enzymatic degradation ∙result in an increased transmitter concentration in the synapse To target receptor binding: ∙block transmitter binding ∙if you want a specific modulation of NT effect, this is best way to get it

Catecholamine Synthesis Pathways

Tyrosine hydroxylase (TH) is the first step in catecholamine synthesis ∙tyrosine → L-dihydroxyphenylalanine (dopa) ∙rate limiting step ∙highly regulated by transcriptional, translational and post-translational (phosphorylation) mechanisms and product feedback inhibition Dopa decarboxylase converts dopa to dopamine ∙decarboxylates other enzymes too, not specific to this rxn ∙found in all catecholamine neurons ∙cytoplasmic enzyme requiring pyridoxal phosphate as a cofactor Dopamine beta-hydroxylase (DBH) converts dopamine to NE ∙identifies NE neurons ∙vesicle-associated enzyme (only one that is in there with NT) that requires Cu++ and ascorbic acid as cofactors ∙released with NE Phentolamine N-methyltransferase (PNMT) converts NE to Epi ∙found in epinephrinergic neurons and adrenals ∙requires SAM as cofactor

Serotonin

aka 5-hydroxytryptamine, 5-HT only 1% of serotonin is found in CNS (rest in mast cells/platelets) made in a 2 step process beginning w/ conversion of tryptophan to 5-hydroxy tryptophan 5-hydroxylase (rate limiting step) ∙final conversion to serontonin utilizes same decarboxylase as in DA synthesis serotonin is taken up and stored in vesicles until release termination occurs by re-uptake or degradation by MAO

Microtubules are dynamic

allows neurons/axons to grow and change Tau protein stabilizies microtubules ∙depending on phosphorylation state of Tau, microstubules can disassemble and reassemble ∙in some neurodegenerative diseases, there is a hyperphosphorylation of Tau → more phosphorylation = less Tau binding = destabilized microtubules when microtubules are destabilized and they fall apart, the form perihelical filaments ∙seen in a number of diseases, i.e. Alzheimers

Axon

arises from cell body at the axon hillock transmits information (action potential) ∙to other neurons ∙to effector cells (i.e. muscle) cytoplasm/axoplasm ∙contains dense bundles of microtubules & neurofilaments ∙play a key role in transport of metabolites & organelees typically devoid of ribosomes ∙distinguishes axons from dendrites ∙developing, regenerating & mature neuron axons support protein translation generally single axon ∙range from short (few mm) to long (>1.5m) ∙accounts for ~99.8% of total neuron volume smooth surface often end in fine branches: terminal arbors ∙in most neurons, axon terminal is capped with a small terminal bouton axons end at synapses large axons are myelinated ∙CNS = oligodendrocyte ∙PNS - Schwann cell smaller axons are less myelinated, while the smallest axons are unmyelinated ∙all axons still have intimate contact with oligodendrocytes or Schwann cell myelin serves to increase AP conduction ∙salutatory conduction ∙nodes of Ranvier

Axonal Growth Cone

axon grows by extending its growth cone growth cone is a long process (amorphous & hand shaped) that grows outward to detect factors affecting directionality and growth growth cone elongation is a very dynamic process in which changes occur distally such that microtubules are added at the growing (distal) end

Synapse

axons branch extensively near target regions axons end as terminal boutons synaptic contacts may also form along axon length composed of pre- and post-synaptic elements, synaptic cleft variety of types

Catecholamine Structure

benzoic acid with two hydroxl groups, with ethylamine substitution at 1 position

Neurotransmitter Receptors

both pre-synaptic and post-synaptic NT receptors do exist, but we only discuss post-synaptic NT receptors 2 major types: ionotropic and metabotropic receptors can act through 2 major mechanisms: ∙direct gating = characteristic of ionotropic receptors →faster, involves 2 NTs binding directly to an ion channel, channel opening, and then ion flow ∙indirect gating = characteristic of metabotropic receptors →slower, NT binds to the receptor which subsequently activates G proteins, which then act intracellularly to activate nearby ion channel, and then ions can flow

Tracts in CNS vs. PNS

bundle of parallel axons CNS ∙tract, fasciculus, lemniscus, commisure ∙funiculus (group of several parallel tracts) PNS ∙root, ramus, nerve ∙plexus (complex network of nerves)

Axonal transport: Clinical relevance

can be important clinically (i.e. rabies virus, tetanus toxin are retrogradely transported)

Ventricular System

cerebrospinal fluid (CSF) formed by choroid plexuses of lateral ventricle, third and fourth ventricles CSF flows into third ventricle via intraventricular formane and drains into fourth ventricle and central canal of spinal cord via cerebral aqueduct Functions of CSF ∙shock absorber of brain ∙deliver nutrients and remove waste ∙flow b/w brain and spine and compensate for changes in intracranial blood volume Other facts: ∙volume = 700mL/day ∙exists through venous/sinus system ∙obstruction to flow results in enlarging ventricle → hydrocephalus

Axonal Guidance

chemoattraction and chemorepulsion are both modulated by substrate-bound molecules and diffusible (soluble) factors ∙4 classes of molecules that control axonal guidance when thinking about cell migration, think about a climber climbing a wall ∙associated substrate-bound molecules w/ pseudo-rocks that stick out to hold on ∙upon making grasp/adhesion, you must de-adhese from previous hold, allowing you to move up wall ∙axon guidance is more like Gumby → can continually stretch arms, continually make new contacts without losing adhesions at distal end soluble molecules bind to receptors expressed on the filopodial surface ∙these molecules mediate attraction by stimulating actin polymerization or repulsion by actin depolymerization stable or cell-attached molecules also regulate axon guidance ∙cell-surface receptor is important for signaling → cell-adhesion molecules (CAMs) cadherins, and integrins play a role in cell migration & axon guidance by affecting activity of intracellular protein kinases/phosphatases that ultimately regulate actin dynamics REMEMBER: contact interactions affect actin dynamics

One Step Acetylcholine Synthesis

comes from choline acetyl coenzyme A through choline acetyltransferase acetylcholinesterase is major enzyme for metabolizing it, breaking it down to choline and acetate ∙choline recycled to make ACh again

Structure of Neurons

continuous plasma membrane extensive, complex cytoskeleton composed of: ∙dendrites ∙cell body/soma ∙axon ∙synapses

Spinal Cord

continuous with the brain in an area called medulla receives information from all other parts of body (except face) and sends commands for motor activity Pathways: ∙ascending: generally sensation, toward brain ∙descending: generally motor, away from brain

Glutamate

created from glutamine by the enzyme glutaminase ∙rate-limiting step ∙there are high levels of glutamine available for glutamate synthesis from Krebs cycle synthesis or glial cell synthesis once made, it is packed into vesicle and exocytosed into synapse terminated by re-uptake by BOTH the neuron and glial cells ∙glutamate taken up by glial cell is converted back into glutamine by glutamine synthetase, then released back into presynaptic neuron Glutamate regulation is very important to maintain neurons ∙excessive glutamate can lead to pathological conditions such as epilepsy, anxiety, and neuronal damage Physiologically, glutamate is intimately involved in neuroplasticity, neuronal development, and learning/memory

Characteristics of Glia

do not directly propagate action potentials can divide derived from mesoderm or neuroectoderm majority of central nervous system cells are glia fraction of glia is proportional according to the size of the animal separated into classes based on morphology, function and location

Neurons

do not divide (mature, differentiated) receive, process and send information ∙changes in biochemical and bioelectrical properties ∙high metabolic demand ∙large surface area ∙use a lot of oxygen and glucose different types

Initial segment of axon (AIS)

earliest site of action potential initiation first ~50-100 μm of axon

Peripheral Nerve Components

epineurium = outermost connective tissue ∙vasculature blends with surrounding tissues perineurium = connective tissues around fascicles endoneurium = innermoust connective tissue ∙Schwann cells, fibroblasts, etc. fascicle (fasciculus) ∙bundle of parallel axons

Anterograde: toward synapse

fast (100-400mm/day) ∙kinesin: moves vesicles & mitochondria along microtubules slow (~1mm/day) ∙less well understood ∙moves cytoskeletal & cytosolic components

Retrograde: toward cell body

fast (50-400mm/day) dynein: moves trophic support molecules (growth factors), axon recycling growth factors are taken up near the axon terminal by vesicle-mediated pinocytosis, receptor-mediated endocytosis

Components of axonal growth cone

filopodia (think fingers) ∙contain actin-rich protrusions and dynamic microtubules lamellipodia (think webbing b/w fingers) long arm ∙contains stable microtubules and cytoskelton-associated proteins that carry cargo bidirectionally

Histamine

found in low amounts in CNS (majority in mast cells) made in 1 step process w/ histadine decarboxylase ∙rate limiting step termination occurs metabolically by diamine oxidase and histamine methyltransferase histamine antagonists are used to treat nausea, and cause sedation

Serotonergic neurons

found predominantly in Raphe nuclei of brainstem have projections into nearly every part of brain

Glycine

glycine neurons are restricted to the spinal cord and brain stem also inhibitory glycine is formed from serine, which is present at relatively high levels in mammalian tissues and fluids ∙Serine is converted to glycine by the enzyme serine transhydroxymethylase Glycine can be terminated by neurons and glial cells

Naming Conventions in CNS/PNS

gray vs. white matter nucleus = CNS ganglion = PNS

AMPA glutamate receptors

have fast kinetics are permeable to Na and K but not Ca desensitize rapidly

Histamine neurons

histamine cell bodies are localized in tuberomammillary nucleus of the hypothalamus projections are sparse but widespread

Representative Axon Guidance in vitro Experiments

if neurons are grown on collagen media with stripes of laminin, processes tend to grow out along the laminin stripes ∙experiment highlights importance of ECM molecule laminin in forming a scaffold on which axons may readily grow and extend Netrin elicits axon outgrowth ∙floor plate expresses netrin, which attracts processes to the midline ∙placement of a spinal cord explant adjacent to floor plate laeds to growth of axonal processes towards floor plate Sema-3A (repelleant molecule which depolymierzes actin) expression results in axonal growth away from gradient ∙use of blocking antibody against Sema-3A receptor in increasing concentrations results in gradually decreasing amounts of repulsion as less and less Sema-3A receptors are active

Metabotropic Receptors

indirectly activate ion channels through interactions with G proteins also activate intracellular activity through second messenger systems slows than ionotropic receptors have 7 membrane-spanning helices in one protein unit actual receptor is fixed in the membrane, and G proteins that can be activated move along intracellular face of membrane ∙when ligand binding occurs, conformational change occurs in the receptor, the G proteins are activated and exchanged GDP for GTP ∙then, G protein dissociates from receptor to go activate second messenger system/ion channel, however, receptor is still activated and can activate other G proteins →activation of single receptor can lead to both signal amplification (if many of the same G proteins are activated) and diverse long term effects (if many different G proteins are activated) activation of a G protein can lead to several different effector processes ∙an activated G protein can directly activate an ion channel ∙an activation G protein can activate a membrane-bound enzyme to initiate a cascade of effects within the post-synaptic enzymes →specifically, downstream cascade can activate a number of second messenger systems involving Ca, cAMP, cGMP, IP3, DAG and NO NE → increase protein phosphorylation Glutamate → increase protein phosphorylation and activates Ca-binding proteins Dopamine → decrease protein phosphorylation

Action Potential

inputs to neuron (receptor or synaptic) alter membrane potential summation reaches critical point = action potential ∙occurs at axon hillock (or 1st node of Ranvier for sensory neurons) AP propagation ∙unidirectional (anterograde) ∙small, unmyelinated axons = aided by general distribution of ion channels ∙myelinated axons = aided by nodes of Ranvier at synapse, AP results in activation of voltage gated Ca+ channels, which results in vesicular release of neurotransmitter

How are intracellular events initiated?

ion channels play an important role in intracellular calcium concentration cell adhesion molecules affect kinase/phosphatase activity that regulate actin polymerization G protein coupled receptors (GPCR) ∙GPCR function in cell shape and migration as well as axon outgrowth ∙GPCRs are most abundant receptor cell type in brain, are target of many pharmaceuticals ∙belong to receptor family that contains 7 transmembrane domains ∙activation involves binding of a solbuel agonist to its external domain, leading to dissociation of the βγ-subunit →has important effect on overall calcium levels and ultimately actin dynamics ∙GPCRs are also linked intracellularly to an α-subunit →different GPCRs have different α-subunit functions and effects, but the cell and axon migration signal is usually transmitted to Rho GTPase through the α-subunit

Identification Criteria for a Neurotransmitter

it is synthesized in the neuron ∙need synthetic enzymes in the neuron to make that neurotransmitter it is found in the presynaptic terminal in high enough concentrations to exert an effect it is released in response to presynaptic depolarization and release is Ca++ dependent specific receptors exist on the post-synaptic cell when applied exogenously it mimics the action of endogenously released transmitter specific mechanisms exist which terminate its actions

Axon hillock

last site in soma where graded membrane potentials are summated before being transmitted to the axon

Injury, Repair and Loss of Neurons

limited repair mechanisms, especially CNS destruction of cell body (or site distal to injury) → Wallerian (anterograde) degeneration of axon loss of cell body = loss of neuron less severe damage to neuron or injury to axon = central chromatolysis ∙cell body sweels ∙eccentric nucleus ∙Nissl substance disperses ∙cell body attempts repair

Node of Ranvier

lower membrane resistance node rich in Na+ channels (juxtaparanode rich in K+ channels) salutatory conduction: the AP traveling along the length of the axon jumps from one node to another

nAChR

made up of 5 transmembrane subunits, each with 4 membrane spanning helices ∙creates negatively charged ion channel receptor is only activated when 2 ACh molecules bind, 1 to each alpha subunit of the receptor ∙when binding of ligands occur, pore opens almost instantaneously ∙highly permeable to Na+, but can also be permeable to Ca++ neuronal AChR desensitizes rapidly (on the order of msec) and is highly influenced by structural diversity, such that the specific composition of the receptors subunits affects the rate of desensitization and Ca++ permeability

Glutamate Receptors

major mediator of excitatory synaptic transmission in brain have 5 transmembrane domains ∙each domain has 3 membrane-spanning helices and 1 pore loop ∙each domain is composed of 2 repeating subunits → structure differs slight for nAChR and GABA receptors 3 major glutamate receptors are AMPA, NMDA and Kainate receptors

GABA Receptors

major mediator of inhibitory synaptic transmission in the brain same overall structure of nAChR, but instead require 2 GABA molecules to be activated ∙when 2 GABAs bind, pore opens and is highly selective for Cl- molecules ∙causes hyperpolarization of membrane inner core of GABA receptors is positive to attract Cl- many pharmacological interventions produce allosteric potentiation of GABA receptors → CNS depressants ∙i.e. benzodiazepines, barbiturates, steroids) picrotoxin is a GABA receptor antagonist ∙leads to buildup of glutamate ∙can induce seizures

Selective Serotonin Reuptake Inhibitors (SSRIs)

major pharmacologic agents involved in 5-HT modulation highly selective for serotonin (unlike cocaine) ∙use for everything

Pharmacological modulation of norepinephrine neurons

many drugs affect both NE and DA neurons selective modulation can occur at the level of postsynaptic receptor Reserpine will decrease uptake of NE w/in vesicle leading to NE/dopamine depletion Amphetamine promotes release of NE w/in synapse and increases synapse concentrations Desipramine (anti-depressant) will block re-uptake of NE once its released Pargyline is an MAO inhibitor

Brainstem

midbrain: relay b/w cerebral cortex and spinal cord, visual and auditory reflex patterns pons: relay b/w cerebral hemispheres and cerebellum medulla: lowerst parti - contiguous with spinal cord → respiration, heart rate

Classification of Neurons

multiple ways to classify structural ∙unipolar ∙pseudounipolar ∙bipolar ∙multipolar ∙multipolar ∙amacrine functional ∙sensory vs motor vs interneuron ∙afferent vs. efferent anatomical molecular properties

Cerebellum

muscle coordination, balance, writing and walking if you need to figure out anterior and posterior parts of the brain, locate cerebellum ∙will be posterior (longitudinal axis of forebrain)/dorsal (longitudinal axis of brainstem/spinal cord)

Selective Vulnerability

neurons are post-mitotic ∙limited stem cell pools (sub-ventricular zone → olfactory bulb, sub-granular zone → hippocampus high energy demands ∙20% of O2, 15% CO, only 2% of body complexity of nervous system ∙anatomically very complex ∙many different cells, phenotypes ∙very integrated b/w cells and systems limited repair mechanisms ∙difficult for axons and dendrites to re-grow, especially CNS variety of insults ∙trauma, toxins (environmental, biological, cardiovascular), metabolic changes, age-related damage, developmental, genetic

Ionotropic Receptors

post-synpatic NT receptors have ligand-gated ion channels made up of 5 transmembrane proteins, which fold in and out of membrane to form ion channel major ionotropic receptors can be divided into 2 families based on structural make up: ∙Family #1) nicotinic ACh receptor (nAChR) and GABAA →5 transmembrane domains w/ 4 membrane-spanning helices, and both N and C terminus is extracellular ∙Family #2) AMPA, NMDA, Kainate →5 transmembrane domains w/ 3 membrane-spanning domains and 1 pore loop, extracellular N terminus, intracellular C terminus composition of subunits (domains) determines specificity and kinetics of each individual NT receptors

GABA

primary inhibitory neurotransmitter in the CNS ∙found in relatively high concentrations (mM) ∙only trace amounts found in PNS GABA is formed from glutamate through rate-limiting decarboxylation by the enzyme glutamic acid decarboxylase (GAD) ∙GAD only found in GABA neurons, not in glutamate neurons similar to glutamate, GABA is terminated through re-uptake performed by pre-synaptic neuron or by glial cell activity ∙however, GABA is metabolized in neurons and glial only when alpha-ketoglutarate is present by the enzyme GABA-T ∙when alpha-KG is present, GABA can be deaminated to form succinic semialdehyde and eventually succinic acid that can be utilized in Krebs cycle GABA regulation is important since it provides tonic control over gluamate levels in the CNS ∙excess GABA can act as a CNS depressant ∙lack of GABA can lead to glutamate excess-like situations → seizures, anxiety, etc.

Cholinergic Systems in the Brain

projecting cholinergic neurons arise from 8 nuclei in the basal forebrain and upper brain stem ∙medial septal nucleus (Ch1), diagonal band (Ch2, 3) ∙nucleus basalis of Meynert (Ch 4) ∙Brain stem nuclei (Ch5-8) ACh is synthesized in local circuit interneurons and long projection neurons Alzheimer's disease is characterized by degeneration in cholingeric neurons and reduced ACh in hippocampus and cortex

Structural Classification of Neurons

pseudounipolar ∙bifurcated single process ∙central and peripheral branch bipolar ∙single dendrite & axon ∙found in structures associated with special senses multipolar ∙many dendrites, single axon ∙majority of neurons (~9%) ∙variety of shapes (fusiform, flask, triangular, polygonal, stellate) amacrine ∙"axonless" ∙specialized retinal neurons

Dendrites

receive, transmit signals from receptor, other neurons information travels from distal to proximal & converges at the cell body extension of the cell body usually branch extensively ∙primary, secondary dendrites can possess dendritic spines ∙spines have various shapes & sizes dendrites are the site of synaptic contact numerous dendrites per cell & expansive arborization increase in thickness as they near the cell body not myelinated contain neurofilaments, microtubules (both distal and proximal) thicker dendrites contain a number of organelles (especially primary dendrites) ∙cytoskeletal components, mitochondria, ER, polyribosomes

Subcortical structures

remove this structure and you can still do what the cortex wants to do, but not well ∙remove cortex, and you can't think/do higher level functions basal ganglia: motor control/reward/drug abuse ∙putamen (lateral): looks like "big knots" ∙caudate nucleus (caudal = tail): "c-shaped structure" ∙globus pallidus (medial): darker region within the "big knots" ∙thalamus: all the senses except smell stop here before proceeding into hemispheres Limbic system: motivation, memory, emotion ∙Hippocampus →memory →controls visceral nervous system (which stimulates contraction of muscle fibers and glandular secretions of internal organs, regulates appetite, thirst and temperature) →controls hormonal secretions via pituitary ∙Amygdala pineal gland = biological clock

Axon Guidance in the Mature CNS

same molecules governing axon guidance are important in regeneration after injury and learning & memory changes regeneration is inhibited by repulsive adhesion molecules → harder to get regeneration in mature NS due to much higher expression of repulsive & axon inhibitory molecules compared to mature PNS actin polymerization and dendritic protrusions can affect both the number of synapses and the number of dendritic spines, which are key to learning and memory changes

NMDA Receptors

slows permeable to Na, K and Ca require co-agonist glycine to be activated also require initial depolarizarion to remove Mg++ blockage NMDA receptor is unique b/c it is both ligand gated and voltage gated ∙basically, in neuron, both glutamate and glycine can bind to NMDA receptor, but if there is no initial depolarization, Mg will still be bound and block ion flow ∙under conditions of membrane depolarization (generally by AMPA receptors that are nearby) Mg is removed, and ion flow can occur through NMDA receptor →in most glutamate synapses, AMPA and NMDA receptors co-exist responsible for development, learning & memory, and neurotoxicity

Differences b/w Small Molecule NTs and Peptide NTs

small molecule NTs are synthesized in nerve terminal, and packaged into vesicles ∙peptide NTs are formed as pre-propeptides in rough ER (cell body) and activated & packaged in Golgi (cell body) ∙packaged vesicles then transported to nerve terminal →at times, peptide NTs are packaged w/ small molecule NTs small molecule NTs are terminated by re-uptake mechanisms ∙peptide NTs are degraded ocne they are released, not recycled ∙new synthesis and axonal transport must be occurring in order to provide continuous peptide NT transmission release of small molecule NTs versus peptide dependent ∙low-frequency stimulation (low frequency APs) lead to localized increase in calcium (at the terminal) and will stimulate small molecule NT release ∙high-frequency stimulation will lead to diffuse increase in Ca, and thus lead to peptide NT release localization of stimulation refers to projections that are made onto the rest of brain, or where each specific type of NT will have an effect ∙small molecule NTs are trans-system or multi-system modulators →project into many areas of brain ∙peptide NTs are within-system modulators

Cell Body

soma, perikaryon support and metabolic center for neuron highly active ∙transcription/translation ∙euchromatic nucleus ∙prominent nucleolus ∙extensive Golgi complex ∙extensive rough ER, polyribosomes (basophilic Nissl substance) ∙high energy metabolism ∙large numbers of mitochondria varies in size/shape due to function

Neuron Cytoskeleton

structure/shape of neurons microtubules ∙helical cylinders made up of 13 protofilaments, α-/β-tubulin ∙development and maintenance of neuron's processes ∙damaged in neurodegenerative diseases (e.g., Alzeimers) Neurofilaments ∙composed of fibers ∙abundant in axon Microfilaments ∙globular actin monomers ∙motility of growth cones

Life cycle of norepinephrine

synthesis → vesicular packaging → release termination of signal: primarily reuptake by plasma membrane transporters ∙have the ability to metabolize, but not primary mechanism

Lumbar Puncture to Remove CSF

test to check status of brain Procedure ∙pt lies on one side, curled forward to open interspinous spaces of lumbar region ∙spine of vertebra L4 is identified in the intercristal (spracristal) plane at the level of the tops of the iliac crests ∙under aseptic conditions, lumbar puncture needle is introduced obliquely above the spine of vertebra L4, parallel to plane of the spine ∙needle is passed through the interspinous ligament, slight give is perceived when needle pierces the dura-arachnoid mater and enters the subarachnoid space

Terms of direction

the axis of direction shifts at an imaginary point w/in skull, so we use different terms Longitudinal axis of the forebrain ∙rostral = anterior ∙caudal = posterior ∙dorsal = superior ∙ventral = inferior Longitudinal axis of the brainstem and spinal cord ∙use normal terms of directions Planes of section ∙Sagittal plane: divides body into two along vertical line →median plane: specific type of sagittal plane that divides the body into equal halves ∙coronal/transverse plane :divides anterior portion of body from posterior portion along a vertical line ∙horizontal plane: cuts body along horizontal line

Functional Classification of Neurons by Discharge Patterns

tonic or regular spiking ∙interneurons or neostriatum fast spiking ∙cortical inhibitory neurons, retinal ganglion cells phasic or bursting ∙dopaminergic neurons in VTA

Synthesis & Trafficking of Axonal Proteins

translated primarily in cell body and proximal dendrites proteins translocated across rER during synthesis ∙membrane, lumenal, transmembrane proteins synthesized as pre-propeptides large dense core vesicles and synaptic vesicles

CNS Catecholamine Neurons

tyrosine is the precursor to all the catecholamines and is found in high concentration in brain ∙only 2% of total tyrosine is used for catecholamine synthesis TH activity is the rate limiting step in synthesis CNS contains distinct dopamine, norepinephrine and epinephrine containing neurons transmitter of a catecholamine neuron is the last one formed development of specific antibodies against synthetic enzymes help to localize neurons using immunohistochemical techniques

Growth cone elongation

very dynamic process changes occur distally such that microtubules are added at the growing (distal) end ∙same distal changes occur in actin treadmilling, which takes place in the actin protrusions in filopodia ∙actin polymerization takes place in the leading or distal edge of the finger, while actin depolymerization occurs proximally, and this results in the movement and/or extension of the filopodia actin polymerization and microtubule stabilization occur in the direction of turning

Synthesis of small molecule neurotransmitters

vesicles and synthetic enzymes are transported from the cell body to the nerve terminal ∙formed in cell body, separately transported through axon to terminal small molecule NTs are synthesized in nerve terminal ∙enzymes form NT when they unite with precursors

Pharmacological modulation of dopamine neurons

we have DA receptor blockers, enzyme inhibitors and re-uptake inhibitors cocaine affects re-uptake of all catecholamines and serotonin

Netrin & Robo/Slit

well studied example of axon guidance during development, our neurons must get to the midline and cross w/o recrossing Netrin (soluble molecule) guides axons to midline Robo and Slit determine whether neurons cross midline or not ∙Robo is repulsive receptor ∙Slit (expressed particularly in midline) is ligand that stimulates repulsion axons either cross or don't cross midline ∙crossing axons have very low Robo levels and thus do not respond to Slit that is present in high levels at the midline ∙it is thought that the expression of Comm maintains low Robo levels ∙upon crossing the midline, Robo levels are increased such that axons do not recross the midline neuron growing in a direction parallel to the midline has high Robo expression to ensure constant repulsion from midline ∙neuron expressing Comm and low Robo may cross the midline, after which it will increase expression of Robo to ensure no recrossing of midline

Brain facts

~100 billion neurons in human brain ~1 billion neurons in human spinal cord ~186 million more neurons in left vs. right hemisphere Rate of neuron growth ~250,000 neurons/min Rate of neocortical neuron loss = 85,000 per day (~1 per second, ~31 million per year)