Neurobiology

SG 27 Early Brain Development Development I

You should understand

  1. the stepwise development of the neural tube 

    1. Neurulation forms mesoderm, ectoderm, and endoderm → Mesoderm and ectoderm come in contact with each other to form neural plate → additional folding of the neural plate creates the tube

  2. that neurons are postmitotic cells which originate from neural precursor cells

  3.  that neural precursor cells are pluripotent

    1. pluripotent – stem cell

  4. that the development of neuronal identify is controlled by signal molecules and transcription factors

  1. Signal molecules form a network that coordinates and controls transcription factors for cell identity

  2. cellular identity of sensory,motor neurons and interneurons controlled by specific transcription factors that regulate gene expression

  3. the network of signals and their concentrations (RA,shh,BMP,Noggin, Chordin) controls the activation of certain transcription factors

  4. Examples: Nkx6.1 and NKx2.2 activation causes motor neuron formation in ventral spinal cord

  1. that local gene expression and chemical gradients of signal molecules determine the fate of developing neurons

  1. Development of cell identity and diversity results from the control of different sets of genes by endogenous/ local signaling molecules 

  2. These molecules are secreted by an embryonic cell class (floorplate/ roofplate)  or tissue and then diffuse through extracellular space to act on adjacent cell class or tissue 

  3. The signals can have graded effects based on the distance of target cells from the source 

    1. These effects may represent a diffusion gradient of the signal or graded activity 

  1. the early formation of neurons in the neural tube

Terms you should know

  • Prosencephalon

  • Mesencephalon

  • Rhombencephalon

  • Telencephalon

  • Diencephalon

  • Metencephalon

  • Myelencephalon

  • Neurulation

    • After gastrulation (the formation of the three germ layers; endoderm, mesoderm, ectoderm)

    • Phase in which the first structures of the embryonic nervous system form from the neuroectoderm 

  • neural plate

    • Forms after 18 days 

    • Formation is triggered by the mesoderm and ectoderm contact each other 

    • Earliest formation of the nervous system 

  • Neural groove 

    • 20 days 

    • Floor plate 

    • Neural crest 

  • neural tube

    • 22 days 

    • Forms when the neural plate folding causes closing of  the neural grooves 

    • Forms the roofplate 

  • neural crest 

    • cells of the neural crest region migrate away from the neural tube and go into lateral and ventral regions where they will form the autonomous nervous system, the enteric nervous system and certain glands

    • 4 distinct migratory paths lead to differentiation of neural crest cells into specific cell types and structures 

      • Paths 1,2: sensory and autonomic ganglia 

      • Path 3: enteric nervous system

      • Path 4: non-neuronal tissue 

  • Roofplate

    • Molecular (chemical) signals released lead to differentiation of precursor cells in the dorsal neural tube - giving rise to 

      • Spinal cord and hindbrain: Sensory neurons and interneurons in the dorsal regions

  • floor plate

    • Molecular (chemical) signals released lead to differentiation of cells in the ventral neural tube - giving rise to 

      • Spinal cord and hindbrain: motor neurons and interneurons (ventral) 

      • Basal forebrain structures and related interneurons (ventral) 

    • Floorplate cells are specialized glial cells 

  • retinoic acid (RA): inducer of early nervous system development 

  • Fibroblast Growth Factor (FGF): 

  • Bone Morphogenetic Proteins (BMPs) 

  • Wnt

  • sonic hedgehog (shh)

  • neural precursor cells

  • neural progenitor

  • Neuroblast

  • symmetric division 

  • asymmetric division

  • Delta Notch 


You should be able to

  1. describe the formation of the neural plate

Neurulation: when first structures of the embryonic nervous system form 

  1. the earliest formation of the nervous system is in form of the neural plate

  2. formation triggered when mesoderm and ectoderm contact

  3. 18 days 

  1. describe the formation of the neural groove

    1. forms when cell proliferation causes the neural plate to fold at the midline forming a groove

    2. causes formation of the flooplate and neural crest

    3. 20 days 

  2. describe the formation of the neural tube

    1. additional folding of the neural plate causes closure of the neural groove and formation of the neural tube

    2. formation of roofplate

    3. 22 days 

  3. describe the progression of regional specification of brain areas during embryonic development

early development (primitive brain) 

  • Prosencephalon - gives rise to the forebrain 

  • Mesencephalon - midbrain 

  • Rhombencephalon - hindbrain 

  • Spinal cord (from the neural tube) 

Middle development 

  • Prosencephalon → Telencephalon and Diencephalon 

  • Mesencephalon

  • Rhombencephalon → Metencephalon and Myelencephalon 

Origin of brain regions

Prosencephalon

  • Telencephalon 

    • Olfactory bulb 

    • Cerebral hemispheres 

    • Hippocampus

    • Lateral ventricles 

    • Basal ganglia (putamen, caudate nucleus) 

    • Corpus striatum 

    • Corpus callosum 

  • Diencephalon 

    • Thalamus 

    • Hypothalamus 

    • Epithalamus 

    • Retina (from optic vesicles) 

    • Habenula 

    • Pituitary gland 

Mesencephalon 

  • superior and inferior colliculus

  • substantia nigra

  • periaqueductal gray

  • red nucleus

  • (optic tectum in fish)

Metencephalon 

  • Pons 

  • Cerebellum 

Myelencephalon  

  • Medulla oblongata

  • Reticular formation 

  1. explain the concept that causes formation of neuronal identity in the spinal cord

    1. During development the neural tube adjacent to the somites (precursors of skeleton) becomes the rudimentary spinal cord

  2. list growth factors that participate in regulating the early development of neuronal tissue

    1. Retinoic acid: inducer of early nervous system development 

    2. FGF: cell differentiation and proliferation 

    3. Wnt: signal molecules that regulate nervous system morphogenesis (organ and tissue)

    4. Shh: inducer of nervous system development 

  3. describe the role of neural crest cells in the development of the peripheral nervous system

    1. Path 1 and 2: migrate away from neural tube and interact with different kinds of cellular environments from which they receive inductive signals 

    2. Cells in the peripheral nervous system originate from neural crest cells (these are outside of the neural tube) 

      1. autonomic ganglia - neurons of the autonomic nervous system (adrenergic and cholinergic neurons)

      2. sensory neurons (dorsal root) ganglia

  4. describe the mechanism of signal molecules such as FGF and wnt

  • growth factors are molecules that stimulate or regulate cell division and differentiation

    • Retinoic acid (RA) FGF (fibroblast growth factor)

    • Sonic hedgehog (Shh) Wnt

    • bHLH

  • Roofplate and floorplate secrete inductive signals

    • Different receptors on neuroectoderm transduce these signals to drive cellular differentiation

  • Results of these signaling molecules 

    • Gene expression, shape, motility of target cells 

Retinoic acid (RA) 

  • released from floor and roof

  • Inducer of early nervous system development 

  • RA activates receptors that are transcription factors 

    • These transcription factors/ receptors modulate the expression of several target genes 

FGF (fibroblast growth factor) 

  • Peptide hormone 

  • 22 different kinds 

  • modulate cell proliferation and differentiation

  • Binds to the same receptor tyrosine kinase that initiates a phosphorylation-based signaling cascade via the RAS-MAP kinase pathway 

  • Mechanism: FGF binds to receptor tyrosine kinase (RTK)

    • RTK signaling activates ras-MAP kinase pathway 

    • MAP kinase activation can lead to altered gene expression for several target genes 

  • Function 

    • FGFs regulate the development of the brain 

    • FGFs in mesoderm (somites) regulate spinal cord neurogenesis 

    • FGF8: important regulator for forebrain and midbrain 

Wnt

  • signal molecules that regulate nervous system morphogenesis (development of tissue and organs) and neuronal differentiation (regulation of some gene expression)

  • 19 human Wnt ligands can activate 2 distinct signal transduction cascades

Sonic hedgehog Shh

  • peptide hormone needed for induction of nervous system development

  • Important for closing the neural tube and establishing the identity of neurons (esp. motor)

  • Ventral portion of spinal cord and hindbrain 

  • Binds to receptor that disinhibits translocation 

bHLH (basic Helix-Loop-Helix proteins)

  • family of a transcription factor proteins in neural development


  1. describe the mechanism and function of delta-notch

  • Delta notch signaling causes neuronal differentiation 

  • Key regulators of neural stem cell decisions to generate either additional stem cells or postmitotic neurons 

  • Delta and notch are membrane bound proteins 

    • Delta is the ligand on the cell surface 

    • Notch is the receptor on neural progenitor cells 

  • Delta binds to notch 

  • Notch is cleaved and released from NCID (notch intracellular domain) 

  • NCID is transported into the nucleus and binds to a transcriptional complex that includes RPB-J

  • Binding of NCID stops RBP-J mediated repression of HES gene expression 

  • Results in the transcription of several genes

  • Activation of gene expression influences the expression of transcriptional factors involved in the differentiation of neural cells 

  • Overall function 

    • Causes the development of precursor cells into postmitotic neurons 

    • Causes differentiation of adjacent cells into neurons 

  1. describe the steps from neural precursor to neuroblast development

  2. explain the function of asymmetric and symmetric cell division in neural development

  3. describe the migration and development of neural crest cells

  • Migration brings different classes of neurons together so they can interact 

  • It ensures the final position of postmitotic neurons 

  • The migration of a neural precursor is essential for its differentiation 

  • The final location of a postmitotic neuron is critical since the neural function depends on the connections made by these cells and their targets 

  • Migratory paths of neural crest cells from the neural tube ate influenced by the initial positions of the neural crest cells at distinct anterior and posterior locations in the neural tube 

  • Neural crest cells are guided along different migratory pathways by signals (hormones, cell surface ligand receptors / adhesion molecules, or ECM molecules) 

  • Specific peptide hormone growth factors available cause neural crest cells to differentiate into specific phenotypes 

    • These cues modulate the bHLH genes expression in the neural crest cells during the transition from migratory precursor to postmitotic neuroblast 

  1. explain the concept of integrated networks of signal molecules and transcription factors that control the development of neurons


SG 28 Formation of Neural Circuits - Axon // Growth Development II

You should understand

  1. that growth cones guide axon

    1. Growth cones– specialized, at tip of developing axons

      1. Probe the environment for signals, direct axons growth, construct neural units, become presynaptic ending if synapse is formed

  2. that growth cones are attracted by chemicals (chemoattraction)

  3. that growth cone are repelled by chemicals (chemorepulsion)

  4. that the movement of growth cones is controlled by diffusible and non-diffusible molecules

    1. Specific cues cause the growth cone to move in a particular direction

    2. Cues are related to cell adhesion and cell-cell recognition 

    3. Long range signals tend to be diffusible molecules secreted by cells whereas short range signals are non-diffusible and bound to cell surfaces or the extracellular matrix (ECM)

  5. that cell signaling plays a major role in the shaping of the growth cone and axon growth

 Terms you should know

  • growth cone

  • Lamellipodium

  • Filopodium

  • Polymerization

  • Depolymerization

  • Cell adhesion

  • cell recognition 

  • Chemoattraction

  • chemorepulsion 

  • ECM

  • Integrin

  • Netrin

  • Semaphorin

  • robo&slit

  • Tropic

  • Trophic

  • Topographic map

  • Chemoaffinity

  • ephrin

You should be able to

  1. describe the function of a growth cone in development

  • properties of growth cones

    • a specialized structure

    • at the tip of developing axons

    • transient structure

  • Function

    • probe the environment for signals

    • direct the direction of axon extension/growth

    • used for construction of neuronal circuits

    • becomes presynaptic ending if a synapse is formed

  • anatomy 

    • Lamellipodium-  is large flat extension of axon

    • filopodia - are fine extensions of the lamellipodium

  • Growth cone - explores extracellular environment, determines the direction of growth, guides the extension of the axon in that direction via drives axon elongation

  • guides the axon by transducing positive and negative cues into signals that regulate the cytoskeleton, thereby determining the course and rate of axonal growth toward its targets, where it will form synapses

  • Growth cones sense environmental signals through their filopodia

  • Once a growth cone reaches and recognizes and appropriate target (relying on cues) it is transformed into a presynaptic ending for an axon

  1. describe the dynamic changes of growth cone structure during axon growth

  • Growth cone - place of dynamic polymerization/depolymerization of actin/tubulin proteins

  • force to move axon is generated by modification of actin and microtubule cytoskeletons 

    • Actin cytoskeleton regulates changes in lamellipodia and filopodia for directed growth

      • Actin filaments form the filopodia and the very tips of the growth cone 

    • Microtubule cytoskeleton is responsible for the elongation of the axon itself 

      • Microtubules extend from the axon into the growth cone 

  • Polymerization/depolymerization of actin at membrane of lamellipodium and within filopodium sets the direction of growth cone movement to or away from substrates

  • Polymerization/depolarization of tubulin into microtubules consolidate the direction of movement of the growth cone by stabilizing the axon shaft 

  • Balance of active growth and stability 

  • calcium ions represent a major intracellular messenger that regulates polymerization and depolymerization

    • regulation of intracellular calcium levels

      • voltage-gated ion channels

      • TRP channels (transient receptor potential) activated by second messengers

      • release from intracellular Ca2+ strores


  1. explain the concept of chemoattraction

  • Signals (likely released from the target) selectively attract growth cones to useful destinations  

  • Tropic signals 

  1. explain the concept of chemorepulsion

  • Signals that discourage axon growth toward inappropriate targets 

  1. describe the function of the non-diffusible factor integrin

  • Extracellular matrix cell adhesion molecules 

    • Lamins, collagens → adhesion molecules found in the extracellular matrix (ECM)

    • ECM = adhesive macromolecular complex outside the cell 

    • ECM’s serve as ligands for integrin receptors 

    • Integrins transduce ECM signals by interacting with cytoplasmic kinases and activating Ca2+ channels 

    • This can stimulate axon growth and elongation 

  • Integrin receptors couple to actin in growth cones when they bind molecules associated with the surface of adjoining cells or the extracellular matrix, thereby influencing motility.

  1. describe the mechanism of netrin function

    1. Netrin = attractive secreted signals

    2. Acts through DCC receptors which bind Netrin 

      1. UNC5 - mediates netrin-dependent chemorepulsion 

    3. netrin is released and binds to UNC/DCC to stimulate extension of the growth cone via a Rho/ GAP signaling pathway

    4. focal adhesion kinase (FAK)

    5. Netrins chemotropically regulate pathway formation in commissures

      1. Works with slit /robo = stops growth 

    6. Found in midline of nervous systems - crossing midline and not crossing back 

  2. describe the mechanism of semaphorin function

    1. Repulsive cues that can either be bound to cell surfaces or ECM and secreted 

    2. Prevent extensions of nearby axons 

    3. Receptors for semaphorins = plexins and neuropilin 

      1. These receptors are found on growth cones 

    4. Semaphorin signaling leads to Ca2+ concentration changes 

    5. Activate intracellular kinases and other signaling molecules to modify the growth cone cytoskeleton  = Cause growth cones to collapse and stop axon extension 


  1. explain the difference between tropic and trophic molecules

  • Tropic molecules: guide axons toward a source 

    •  a tropic molecule regulates the physical path that a growth cone follows or a growing axon takes

  • Trophic molecules: support the survival and growth of neurons and their processes 

    • a trophic factor supports gene expression for the extension of neurites and the health of neurons

    • a trophic factor acts locally

  1. describe mechanisms of topographic map formation

    1. Chemoaffinity theory - how topographic maps arise during development 

    2. axons from regions with a low concentration of a tropic factor end in the region of a high concentration of a chemoattractant

    3. axon from regions with high concentration of a tropic factor end in the region of a low concentration of a chemoattractant

    4. Cells have identification tags (cell adhesion or cell recognition molecules) and the growing terminals seek these out 

    5. Behavior of growing axons suggested there are gradients of cells surface molecules to which growing axons respond = gradients of affinities 

  2. explain the concept of integrated networks of signal molecules and transcription factors that control the development of neurons



SG 29  Neural Circuit Formation II - Synapse // Formation Development III

You should understand

  1. that synapses formed stepwise

  2. that synapse formation requires cell adhesion molecules and trophic factors

  3. that neurotrophins are secreted from target tissue to regulate synapse formation

  4. that synapse formation is a competitive process

  5. that neurotrophins act locally via activation of Tyrosine Kinase Receptors

  6. that Trk signaling regulates synapse growth and elimination

Terms you should know

  • cadherin/protocadherin

  • Neuregulin

  • Neurexin

  • Neurolignin

  • DSCAM

  • NGF

  • BDNF

  • TrkA

  • TrkB

  • TrkC

  • P75 receptor

  • apoptosis/cell death

You should be able to

  1. explain the concept of initiation of synapse formation

  • Once an axon reaches its target region, additional cell-cell interactions dictate which target cells to innervate from a variety of potential synaptic partners 

  • Initial contact and attachment of pre and post synaptic sites 

  • Initiation of a synapse depends in local recognition between the pre-and postsynaptic membranes

  • Adhesive factors: family of Ca2+ - dependent adhesion molecules 

    • Cadherin 

    • Protocadherin 

  • After cell-cell contacts have formed differentiation of the presynaptic and postsynaptic occurs 

  • Once synapses are formed - they either grow and are strengthened or eliminated 

  1. explain the concept of development of synapse identity

  • Adhesive factors: family of Ca2+ - dependent adhesion molecules 

    • Cadherin 

    • Protocadherin 

  • Once initial specialization is established/ initial step of synapse formation, you can have additional adhesion molecules recruited

    • stabilize and specialize initial contacts between presynaptic and postsynaptic membranes

      • via cell adhesion and cell signaling

    • Once you recruit them, you have signaling results in differentiation of active zones and postsynaptic density

  • inductive factors include (adhesion molecules) 

    • SynCAM, EphrinB/EphBR, neurexin, neuroligin

      • Neurexin and neuroligin stimulate the formation of synapses 

        • They are shared by all developing synapses 

  • Neurexin: found on presynaptic membrane 

    • Binding partner = neuroligin on the postsynaptic membrane 

    • Neurexin and neuroligin bind to one another and promote adhesion between pre-and post synapse 

    • Neurexin → has a specialized transmembrane protein that helps localize synaptic vesicles, docking proteins, and fusion molecules 

  • Neuroligin: postsynaptic membrane 

    • Promote clustering of neurotransmitter receptors 

  • Neuregulin 1 

    • influences expression and clustering of postsynaptic receptors

    • released from the postsynaptic cell 

      • binds to ErB receptors, a TrK receptor, in postsynaptic membrane 

  1. list factors that regulate initiation of synapse formation

    1. Initiation of a synapse depends on local recognition between pre and post membranes

    2. Adhesive factors: family of Ca2+ - dependent adhesion molecules 

      1. Cadherin 

      2. Protocadherin 

    3. Thought to influence recognition of any suitable postsynaptic positions on dendrites, cell bodies, or other targets by a process of conversion of the growth cone to a presynaptic terminal 

  2. list the main neurotrophic factors

    1. Neurotrophic factors = neurotrophins 

    2. They regulate differentiation, growth, and survival in nearby cells.

    3. Nerve growth factor (NGF)

      1. stimulates outgrowth of neurites and survival of neurons

      2. Cells in a culture dish develop growth of numerous neurites

      3. supports survival of neurons of the sympathetic nervous system

    4. Brain derived neurotrophic factor (BDNF)

      1. Stimulates number of dendrites on neurons such as pyramidal cells in cerebral cortex

      2. Does not support survival of neurons of the sympathetic nervous system

      3. Alters signaling in individual (local) growth cones

  3. explain the role of trophic support from target cells for the development of neuronal circuits

    1. Regulation of neural connections by trophic interactions  

    2. Once synaptic connections are established and initial distribution of synapses is set – neurons become dependent on the presence of their targets for continued survival, further growth, and differentiation of axons and dendrites 

    3. In the absence of synaptic partners, the axons and dendrites of developing neurons atrophy and die off 

    4. The nervous system initially produces a surplus of nerve cells and the final population is established by the death of the neurons that fail to interact successfully with targets

      1. This is mediated by neurotrophins 

      2. Necessary for developing the appropriate circuits to support specific functional demands of each organism 

    5. Target tissue releases trophic molecules (neurotrophins) that regulate the number of related neurons 

      1. Differentiation, growth, survival of neurons

    6. Neurotrophic influences - cell survival or death, growth, and modulation of synaptic activity- help determine which neurons remain in a neural circuit, how they are connected, and how the continue to change 

  4. explain why neurotrophins can act locally

    1. NGF can support the growth of axons even though other parts of the neuron, such as the cell body, are starved of NGF; therefore, NGF can act locally to regulate growth events

  5. explain the concept of competition of synapse formation

    1. fewer target (postsynaptic) cells than targeting (presynaptic) neurons

    2. Number of targeting motor neurons depends on number of target muscle cells 

    3. Synapse elimination is competition-based and is thought to be modulated by electrical activation. Treatment with curare and blocking APs prevents synapse elimination. Thus, both APs in the motor neuron and the muscle cell are required for synapse elimination.

  6. describe role of tyrosine kinase receptors (trk) in neurotrophin action

Neurotrophins bind and activate tyrosine receptor kinases (Trk)

  1. TrkA – binds → NGF

  2. TrkB – binds → BDNF, NT-3, NT- 4 / 5

  3. TrkC- binds → NT-3

  4. Trk’s bind processed neurotrophins

  5. Trk receptor activation by neurotrophin binding activates cell signaling pathways (3)

  6. Second messenger pathways alter functions of proteins  Or change gene expression in the target cell 

    1. RAS pathway

      1. Receptors activate GTPase ras

      2. Ras activates mitogen activated protein (MAP) kinases 

      3. Stimulates neurite outgrowth and neuronal differentiation 

      4. Kinases cellular response maybe alter gene expression 

  7. Trk receptors activate two enzymes that modify or release phospholipid second messengers

    1. PLC/PI3 – influence function of existing proteins in cell or cause changes in gene expression

    2. PLC pathway 

      1. Influences cellular responses that lead to activity-dependent synapse plasticity

      2. Increases Ca2+ levels and PKC activity 

    3. PI3 kinase pathway 

      1. interacts with pathways that regulate the activity of Akt kinase 

      2. Akt kinase modulates proteins that either prevent or promote cell death 

      3. Stimulate cell survival 



SG 30 Regeneration I: Peripheral Nervous System Development IV

You should understand

  1. that peripheral nerves can regenerate almost completely

  2. that the regrowth of axons after injury requires the ECM

  3. that Schwann cells support the regrowth of axons

  4. that synapses can form again after injury

Terms you should know

  • Schwann cell

  • ECM

  • Nerve graft

  • Reinnervation

  • activity-dependent regeneration

You should be able to

  1. describe the steps of nerve regeneration

  1. cut /injury 

  2. distal part of nerve degenerates

    1. (Wallerian degeneration) 

    2. Axon segment distal to the site of the cut degenerates 

  3. macrophages remove cell debris 

    1. remove degenerated part 

  4. 4: growth cone forms 

    1. proximal axon stump transforms into a growth cone, and this growth cone interacts with the adjacent Schwann cells 

  5. 5: interaction with schwann cells 

    1. stimulate and guide regeneration 

    2. the extracellular matrix – within the spaces defined by the schwann cell processes – provides a channel?? For the regenerating axon 

  1. explain the mediator function of Schwann cells in nerve regeneration

    1. Schwann cells provide molecular support that facilitates regeneration by recreating a similar environment to the environment that supports axon guidance and growth during early development

      1. And secretes additional extracellular matrix molecules that provide substrate for axon growth via activation of signaling that supports growth cone pathfinding and re-extension of the axon

    2. Schwann cells secrete 

      1. ECM molecules (adhesion molecules) 

        1. Lamin 

        2. Fibronectin 

        3. Collagen 

        4. These provide a substrate for axon growth via activation of signaling that supports growth cone pathfinding and re-extension of the axon 

      2. Increase the amount of cell surface adhesion molecules on schwann surface (NCAM)

        1. Regenerating axon expresses complementary adhesion molecules and co-receptors  = Mediate signaling that facilitates growth cone motility, force generation, and microtubule assembly in the new axon 

      3. Secretion of neurotrophins // schwann cells distal end - aids in 

        1. NGF

        2. BDNF

      4. Increased expression of neurotrophin Trk and p75 receptors 

        1. In growth cone of the regenerating axon 

    3. The local availability of neurotrophins may promote a ‘growth’ state  reactivate the capacity for trophic signaling  for the damaged axons 

    4. AND: attract the growing axons to appropriate local targets distal to the site of damage  tropic effects 

  2. describe the fate of the motor endplate after severing the innervating nerve

  3. describe the role of BDNF and NGF in reinnervation of muscles

    1. Enhance the tropic (guide) and trophic (survival) signaling necessary to repeat target recognition and synaptogenesis 

  4. explain the role of activity in regenerating axons for synapse re-formation

    1. Polyneuronal innervation of neuromuscular synapses returns during regeneration and reinnervation 

    2. This innervation is eliminated via activity-dependent mechanisms (same as early post natal) 

    3. If electrical activity is blocked during regeneration - polyneuronal innervation stays on the endplate 

  5. explain why nerve graft can be used to facilitate regeneration of nerves

    1. severed axons in the optic nerve or spinal cord can be provided with a peripheral nerve graft containing Schwann cells, basal lamina, and connective tissue components that support peripheral nerve regeneration

    2. Schwann cells define an environment in the peripheral nerve sheath that is particularly adapted to initiate and support the regrowth of damaged axons in adults

      1. Indicates that Schwann cells provide factors that stimulate regrowth of axons  


SG 31 Regeneration II - Central Nervous // System and Neurogenesis Development V

You should understand

  1. that the cell death of neurons is caused by hypoxia and epileptic seizures

  2. that regeneration in the CNS is generally inhibited by glial scars

  3. that glial scarring occurs in response to chemical injury of neurons in the CNS

  4. that regeneration of axons can take place in the olfactory nerve

  5. that neurogenesis can take place in brains of adult vertebrate animals and humans

  6. that stem niches in the adult brain of vertebrates and humans is maintained by neurotrophins and neurotrophin receptors

  7. that neuroblast migrate from stem cell niches to their target region

Terms you should know

  • Apoptosis

  • BCL-2

  • Cytochrome2

  • Caspases 3 and 9

  • Astrocyte

  • Oligodendrocyte

  • Microglia

  • glial scar

  • FGF

  • TGF

  • IGF

  • Interleukins

  • NoGo-A

  • HVC

  • SVC

  • SGZ

  • TAC

  • Rostral migratory stream (RMS)

  • olfactory ensheathing cells

You should be able to

  1. describe the mechanism of neuronal cell death caused by hypoxia or in epilepsy

    1. Called excitotoxicity 

    2. Injury to nerve cells causes the release of glutamate→elevated neuronal activity 

    3. The release of glutamate causes an influx of Ca2+ into the cell (postsynaptic)

    4. calcium ions block Bcl-2 

      1. Bcl-2 molecules oppose changes in mitochondria / are antiapoptotic 

    5. Diminished Bcl-2 allows cytochrome C to be released from mitochondria into cytoplasm

    6. increased cytochrome C breakdown 

      1. cytochrome c facilitates activation of caspase 3

    7. activation of 

      1. caspases 9 (activates) → caspase 3

    8. activation of apoptosis or phagocytosis 

  2. describe the process of glial scarring

    1. Glial cells found at the site of injury contribute to the degeneration 

    2. 3 types of glial cells oppose neuronal growth 

      1. Astrocytes (GFAP marker) 

      2. Oligodendrocytes (NG2 marker)

      3. Microglia (CD1-1b marker)

    3. Brain lesions cause local proliferation of glial precursors and the growth of existing glial cells around the site of the injury 

    4. Glial scars 

      1. Form when glial cells proliferate

      2. Prevent axon growth  

  3. explain the mechanism of glial-cell mediated inhibition of regeneration in the brain

    1. Proteins secreted in glial scars release chemicals that promote apoptosis

      1. TGF (transforming GF)

      2. FGF (fibroblast GF)

      3. IGF (Insulin GF)

      4. TNF-a (tissue necrosis factor)

      5. interleukins

      6. Interferon-y

    2. Astrocytes produce molecules that inhibit growth 

      1. Ephrins, semaphorins, slit 

    3. Oligodendrocytes: produce NoGo-A 

      1. Inhibits neurite outgrowth 

    4. ECM molecules - inhibit axons growth are enriched within extracellular space glial scar

      1. Tenascin, chondroitin, sulfate proteoglycan 

  4. describe the role of astrocytes and microglia in axon growth inhibition in the CNS

    1. Microglia: clearing of debris by microglia,which act as phagocytic cells in the CNS

      1. Also release inhibitory factors 

    2. Astrocytes: produce molecules that inhibit axon growth 

      1. Semaphorin - causes growth cone to collapse and withdraw 

      2. Ephrin 

      3. Slit 

        1. The receptors for these are upregulated in the growth cones of axons that approach the glial scar = distortions of direction of growth = axons turn away 

  5. explain the function of NoGo-A

    1. causes growth inhibition and growth cone collapse when binding to its receptor in neuron membrane

    2. activates the ROHA pathway that destabilizes the actin filaments that make up the filapodia in growth cones = breakdown of growth cones = axon terminates extension 

  6. describe the concept of adult neurogenesis in vertebrate animals and humans

    1. Precursor cells are always needed to form new nerve cells 

    2. Nerve cells can not divide 

  7. describe how a neural stem cell niche is organized maintained

  8. describe adult neurogenesis in the hippocampus, bird song brain and fish retina

Fish: Retinal precursor cells  

  • Goldfish grow throughout life and so do their sensory structures (eyes)

  • Growth of the eye is accompanied by the generation of new retinal neurons 

  • These new neurons are generated from a subset of precursor retinal cells 

  • Retinal precursor cells distributed at the edge of the retina 

  • Retinal precursor cells migrate into retina and form synaptic connections 

  • Can replace most retinal cells except rods and cones 

  • Constant remapping of retinal projections - new retinal inputs be constantly remapped along with existing retinal projection 

    • Shining light stimulates retinal precursor cells asn they go into the retina and divide

    • Regeneration and replacing damaged retina ex. Macula degeneration 

Bird brain 

  • song birds, HVC: stem cells maintained as radial glial cells

  • neuroblasts migrate from VZ along radial processes of precursor cells and integrate into circuits with existing neurons

  • Neural precursor cells that lead to migrating neuroblasts 

  • Allows the bird to form more connections and strengthen neural network 

  • Brain region continuously expands in winter and shrinks in summer - related to proliferation 

Adult 

  1. Subventricular zone - cells here can divide and migrate into the hippocampus

    1. Can proliferate and eventually dendrites = increases plasticity - related to learning and memory 

  2. Subventricular zone 

    1. Neural cells generate transit amplifying cells 

    2. Proliferative regino - can form neural stem cells and migrate from this region 

  3. Subgranular zone - migrate to olfactory bulb 

  1. explain the migration of neuroblasts in the adult vertebrate brain

    1. Combine with regulin - stimulates growth of neuroblasts 

    2. Cell bodies migrate and form synaptic connections 

  2. describe the function of olfactory ensheathing cells

    1. Inject them into parts of the brain - stimulate regrowth 

    2. Axons can regenerate in the olfactory nerve 



SG 32 Organization of the Autonomic // Nervous System Autonomic Nervous System I

You should understand

  1. the structural organization of the sympathetic nervous system

  2. the structural organization of the parasympathetic nervous system

  3. that the ANS balances stimulatory and inhibitory function

  4. the cholinergic system

  5. the adrenergic system

  6. the central control of the ANS by the hypothalamus and brain stem

Terms you should know

  • Apoptosis

  • sympathetic nervous system

  • parasympathetic nervous system

  • Acetylcholine

  • Noradrenaline

  • nicotinic acetylcholine receptor

  • muscarinic acetylcholine receptors

  • noradrenergic receptors

  • G-proteincoupledreceptors

  • beta-adrenergic receptors

  • Hypothalamus

  • nucleus of the solitary tract

  • autonomic brainstem

You should be able to

  1. describe the structural organization of the autonomic nervous system

  • Sympathetic : Fight vs flight 

  • Parasympathetic: Rest and digest 

  • Autonomic ganglia 

    • Preganglionic 

      • Cholinergic (acetylcholine; binds to nicotinic receptors on postganglionic neurons)

    • Postganglionic 

      • Sympathetic: norepinephrine released;binds to adrenergic receptors (a/b on effector)

      • Parasympathetic: acetylcholine released; binds to muscarinic receptors (on effector)

      • All: synapse at target organs via G-protein coupled receptors

  • Central autonomic networks 

    • In the brainstem

    • Cortical and subcortical structures in the ventral and medial part of the forebrain 


  1. describe the function of the sympathetic nervous system

  • Preganglionic → releases ACh → ACh binds to nicotinic receptors on the postganglionic 

    • Effect is to excite postsynaptic neuron to send signal to effector tissue from second neuron 

  • Postganglionic → release NORE → NORE binds to a/b receptors on effector tissue

    • Cardiac, smooth muscle, or glands 

    • a/b receptors affect depends on the tissue they are on

    • receptors = G-protein coupled receptors on target 

  • Dilates pupils 

  • Constricts blood vessels 

  • Relaxes airway 

  • Accelerated heartbeat 

  • Stimulates sweat glands 

  • Inhibits digestion 

  • Stimulates breakdown of glycogen and release of glucose 

  • Stimulates secretion of epinephrine and norepinephrine 

  • Inhibits activity of intestines, Relaxes urinary bladder

  • Goes to lower extremities via spinal nerves 


  1. describe the function of the parasympathetic nervous system

Parasympathetic 

  • Preganglionic → releases ACh → ACh binds to nicotinic receptors on the postganglionic 

    • Effect is to excite postsynaptic neuron to send signal to effector tissue from second neuron 

  • Postganglionic → release ACh → ACh binds to muscarinic receptors on effector tissue

    • G-protein coupled receptors on target 

    • Cardiac, smooth muscle, or glands 

    • When muscarinic receptors are stimulated, they often cause inhibition, thus we see the reduction of the heart rate, the reduction of bronchiole diameter, etc

  • Constricted pupils 

  • Stimulation of salivation 

  • Constricts airways 

  • Slows heartbeat 

  • Stimulates digestion 

  • (slight) Stimulation of glucose uptake/glycogen synthesis 

  • Inhibits gluconeogenesis 

  • stimulates/ contracts urinary bladder 


  1. describe the role of the cholinergic neurons in the ANS

    1. Cholinergic = acetylcholine is the neurotransmitter 

  • Synthesis: from acetyl co a 

    • By: choline acetylcholine transferase  (CAT)

  • Degradation: acetylcholine esterase (AChE) in the synaptic cleft

  • Transporter: 

    • NA+/choline 

      • Presynaptic = For reuptake of choline 

    • Vesicular Ach transporter - loading so it can be released 

Nicotinic receptors = excitatory 

  • Receptors are on postganglionic neurons 

    • Bind nicotine that is released from preganglionic neurons (both para and sympathetic)

  • Excitatory

    • Opens Na2+ channels → depolarization → EPSP

  • Rapid synaptic transmission

Muscarinic receptors 

  • Excitatory or inhibitory 

  • Slow onset 

  • M2/M4 = inhibitory 

    • Activate G-protein coupled receptors 

    • Inhibition of AC → reduces the concentration of cAMP = Hyperpolarization 

    • Close K+ channels, making the neurons more excitable and generating a prolonged EPSP

    • M2: cardiovascular

      • inhibiting the rate at which the neurons fire action potentials, or slowing the beating of cardiac muscle

  • M1/3/5 = excitatory 

    • Activates G-Protein 

    • leads to activation of PKC

    • increases intracellular Ca2+ concentrations 

    • Stimulatory 

    • Results in smooth muscle contraction 

    • M1: usually in the gut 

    • M3: smooth muscle and glandular tissue 


  1. describe the role of the adrenergic neurons in the ANS

alpha receptors 

  • A1: slow depolarization and inhibition of K+ channels ?

    •  smooth muscle, heart, sweat, kidney 

    • Contraction of smooth muscle 

    • Gluconeogenesis 

  • A2: slow hyperpolarization from activation of K+ channels  ?

    • adipose tissue, smooth muscle 

    • Contraction of smooth muscle

Beta receptors 

  • B1: heart muscle, kidney → increases heart rate

  • B2: smooth muscle relaxation → relax airway, urinary/ constricts blood vessels

  • B3: adipose 

  • Activates AC → increases cAMP (from ATP) → camp is a second messenger that initiates a cascade of variable events depending on the tissue 

  1. explain the inhibitory and excitatory function of the ANS

  2. describe the central regulation of the ANS

  • reflexes in autonomic motor system - elicited through sensory pathways and are hierarchically organized organization allows for coordination between different divisions of ANS

  • Visceral sensory information reaches brain mainly through 2 cranial nerves (IX and X), which end in nucleus of the solitary tract (NTS) (in medulla) 

  • The NTS relays sensory information

    • NTS project to network in brainstem/spinal cord that control/ coordinate autonomic reflexes

      • = visceral sensory signals relayed through the NTS regulate vagal motor control of the heart and gastrointestinal tract directly

    •  Neurs in NTS project to neurs in reticular formation- control blood pressure

    • NTS sends ascending projections the hypothalamus

      • Hypothalamus uses this information to coordinate autonomic, neuroendocrine, and behavioral responses

  • Core = hypothalamus and autonomic brainstem 

  • output= preganglionic neurons 

  • Sensory feedback = nucleus of the solitary tract 

  • Input = amygdala (involved in emotion) 

  • Major output of hypothalamus is toward autonomic brainstem / reticular formation = coordinate preganglionic visceral motor neurons → cardiac reflexes, bladder control 


  1. explain the role of the hypothalamus and autonomic nervous system of the ANS

    1. Hypothalamus 

      1. Controls visceral motor function 

      2. Controls somatic motor function 

      3. Affects behavior 

      4. Controls hormone release from the pituitary gland 



Class 33: ANS 2- obesity 1 

  1. Describe different types of obesity

  2. Describe the distribution of fat tissue in the human body

  3. Describe how hormones could contribute to obesity

  4. Describe the concept of genetic predisposition to obesity

  5. Describe the how the brain regulates the metabolism of white adipose tissue

  6. Describe which health conditions could be caused by obesity

  7. Describe the role of the autonomic nervous system in obesity



Class 34// ANS 3 obesity 2

  1. Describe the functions of leptin?

  2. Describe the function of ghrelin?

  3. Describe the function of NPY/Agouti-related peptide (AgRP) containing neurons in the arcuate nucleus of the hypothalamus

  4. Describe the function of alpha MSH/POMC neurons in the arcuate nucleus of the hypothalamus

  5. Describe the function of the melanocortin neuron systems in the arcuate nucleus of the hypothalamus

  6. Explain who the neural network in the arcuate nucleus of the hypothalamus regulates food intake

  7. Describe how the arcuate nucleus integrates hormonal and neuronal inputs to signal food availability. 


Class 35// ANS 4 obesity 3

  1. Describe the function of liraglutide

  2. Describe the mechanism of liraglutide action to lower appetite.

  3. Which neurons in the hypothalamus are primarily affected or regulated by liraglutide

  4. Explain why liraglutide leads to the reduction of adipose tissue and body weight loss.

  5. Describe how liraglutide can access neurons in the hypothalamus.

  6. Explain the role of the GLP-1 Receptor in regulation of food intake. 


Physiological Concept of Emotion Emotions I

You should understand

  1. that emotional states are controlled by the limbic system

  2. that emotional states is associated with a specific responses of the autonomic system

  3. that the dopamine reward systems is formed by the nucleus accumbens and the ventral tegmental area

  4. that drugs of addiction modify the function of the limbic reward circuit

  5. that drugs of addiction bind to endogenous neurotransmitter receptors on neurons in the reward pathway

Terms you should know

  • cingulate cortex

  • prefrontal cortex

  • Hypothalamus

  • Pyramidal and extrapyramidal tract 

  • sham rage

  • limbic system

  • reward pathway

  • ventral tegmental area (VTA) 

  • nucleus accumbens (NAc)

  • limbic loop

  • drugs of addiction

You should be able to

  1. explain the role of pyramidal and extrapyramidal pathways in expressing emotional states

  • Major targets of the hypothalamus are in the reticular formation 

  • Descending control of emotional response entails two parallel systems/pathways that are anatomically and functionally distinct 

  • Somatic: voluntary motor component 

    • Primary motor cortex, basal ganglia, cerebellum 

    • descending pyramidal (direct) and extrapyramidal (indirect) projections from motor cortex and brainstem → convey impulses responsible for voluntary somatic movement 

  • Visceral: emotional expression 

    • Including cortical and subcortical structures in the medial frontal lobe and ventral forebrain, ventral basal ganglia and ventral hypothalamus 

    • Terminate on visceral motor centers in the brainstem and reticular formation 

  • Ex: smiling 

    • Without somatic = facial motor paresis; effect on side of lesion (L lesion=no L contract)

      • Asked to smile = can not contract/ make a symmetrical smile 

      • When told a funny joke/ spontaneous emotion = can make a symmetrical smile 

    • Without visceral = emotional motor paresis; effect opp side (L lesion=no R contract)

      • Asked to smile = can make a symmetrical smile 

      • Spontaneous response to humor = failed to express emotion

  1. outline the organization of the limbic system (list of brain regions)

  • Important for experience and expression of emotion 

    • Orbital and medial prefrontal cortex - including 

      • Portion of basal ganglia

      • Anterior cingulate cortex 

    • Amygdala 

    • Thalamus 

    • Hypothalamus 

  • Areas that process expression of emotion (blue)

    • Parahippocampal gyrus

    • Posterior cingulate cortex 

    • Thalamus 

    • Mammillary body (hypothalamus)

    • Fornix 


  1. describe the role of the limbic system in regulation of emotional states

  • The organization of the somatic motor behavior associated with emotion is organized by circuits in the limbic system, which includes the hypothalamus, the amygdala, and several regions of the cerebral cortex. 

  1. explain the role of the hypothalamus in emotional behavior

  1. Regulates basic functions like hunger, thirst, eating (in obesity) 

  2. autonomic activation and strongly felt emotions - The neural activity by this stimuli is relayed from the forebrain to visceral and somatic motor nuclei via the hypothalamus and brainstem reticular formation, the major structures that coordinate the expression of emotional behavior

  3. hypothalamus as a critical center for coordination of both the visceral and somatic motor components of emotional behavior 

  1. explain the concept of sham rage in cats

  • Transection of the brain above the level of the hypothalamus (caudal/ bottom part of hypothalamus still intact= removes cerebral hemispheres and basal ganglia) = sham rage

  • Contrast = transection below the hypothalamus-leaving only brainstem and spinal cord = no sham rage

    • transection of hypothalamus at the junction of midbrain and hypothalamus prevented sham rage behavior

  • Bards’s experiments generated sham rage behavior in cats without a cerebral cortex and basal ganglia

    • behavior includes: increased blood pressure, increased heart rate, retraction of nictitating membranes, dilation of pupils, erection of hairs on back and tail, arching back, extending claws, lashing the the tail, snarling

  • separating the hypothalamus from cortical areas can cause sham rage - no regulation of the hypothalamus; thus hypothalamus could initiate the release of hormones

  • While the subjective experience of emotion might depend on an intact cerebral cortex- the expression of coordination of emotional behaviors does not require cortical areas

  • Hess’s experiments used electrical stimulation of the hypothalamus to trigger rage and attack behavior


  1. explain the role of individual brain areas in the limbic feedback loop

  • Essential for emotional behavior are the non-motor programs of basal ganglia that regulate cognition and affective processing

  • Cortex: Anterior cingulate cortex, orbitofrontal cortex, amygdala 

  • Cortical input: amygdala, hippocampus, orbitofrontal cortex, anterior cingulate cortex, temporal cortex 

    • Convey signals relevant to emotional reinforcement 

      • ACC = pain 

      • Amygdala = fear / associative learning 

      • Hippocampus = explicit memory 

      • OFC= Working memory 

  • Striatum: ventral striatum = Nucleus Accumbens 

    • Contains medium spiny neurons the integrate excitatory inputs 

    • under the modulatory influence of dopamine from the VTA

      • When dop is released in the NAc- the medium spiny neurons are more responsive to coincident cortical input 

    • Related to emotional reinforcement 

  • Pallidum: ventral pallidum, substantia nigra pars reticulata

  • Thalamus: mediodorsal nucleus 

    • Innervates cortical division of the limbic forebrain 

  • Under normal conditions: CTX activates the cortical system/input → this activates the NAc (VS) → project to and inhibit pallidal neurons in the ventral pallidum and SNpR → the suppression of topic activity in the pallidum disinhibits the thalamic target mediodorsal nucleus 

  1. outline the connections of the VTA and NAc within to the limbic loop

  • The NAc integrates excitatory input but it is under the modulatory influence of Dopamine 

  • NAc receives dopaminergic projections from the VTA

  • NAc and VTA: primary sites where drugs of abuse interact with the processing of neural signals related to emotional reinforcement 

  1. explain why drugs of addiction are able to change the function of the reward pathway (VTA- NAc connection)

  • NAc and VTA: primary sites where drugs of abuse interact with the processing of neural signals related to emotional reinforcement 

  • Drugs do this by prolonging the action of dopamine in the NAc or by potentiating the activation of neurons in the VTA and NAc

  • Addictive substances affect the dopaminergic connection between ventral tegmental area (VTA) and nucleus accumbens (NAc; ventral basal ganglia)

  • NAc is part of the limbic loop through the basal ganglia

  • Model

  • stimulation of VTA or increased activity of NAc causes increased feedback to prefrontal cortex and affects decision making process

  • Each drug of abuse increases dopamine transmission via different mechanisms


  1. explain the underlying mechanism of drug actions that change the function of neurons of the reward system in addiction

  • shared initial effects is increased dopaminergic neurotransmission in the nucleus accumbens, via different mechanisms.

  • Actions of drugs of addiction on the reward pathway

    • nicotine binds to nicotinic acetylcholine receptor and activates DA neurons

    • opiates bind to endogenous opioid receptors (for dynorphin) on GABAergic neurons and reduce inhibition of DA neurons

      • activate ventral tegmental area dopamine neuron cell bodies by inhibiting nearby GABAergic interneurons

    • alcohol stimulates GABA receptors and causes inhibition

    • cocaine blocks dopamine transporter in presynaptic ending of DA neurons and increases DA concentrations in the synaptic cleft


  1. Explain how cocaine can interfere with the dopamine synapses between VTa and NAc neurons

    1. psychostimulatory effects of cocaine result from its action to prevent reuptake of dopamine, thereby increasing its extracellular levels

    2. blocking dopamine reuptake transporters located on the terminals of the ventral tegmental neuron

    3. The acute rewarding actions of drugs of abuse do not account for addiction. Rather, addiction is mediated by the brain’s adaptations to the repeated exposure to such acute actions.

    4. repeated cocaine exposure increases the intrinsic excitability of nucleus accumbens neurons, which contributes to reward tolerance. This adaptation is due in part to a decrease in expression of specific types of K+ channels

  2. Describe the properties of the connections between the VTA and NAc in the limbic feedback loop