Neurobiology 2 - Early Brain Dev't

Invagination of epiblast from primitive streak. Sets up spatial coordinates of body & brain.

meso, ecto, endo-derm

cylinder of mesodermal cells condensed at midline of mesoderm, determines position of nervous system - anterior -> posterior

R->C:
Tel-, Di-, Mes- Met- Myel- encephalon

Forebrain - proencephalon
Midbrain - Mesencephalon
Hindbrain - Rhombencephelon

Metencephelon
Myelencephalon

Pons
Cerebellum

Medulla

peptide hormone; signaling molecule - establishes identity of neurons (esp motor neurons) in ventral portion of spinal cord and hindbrain

Notochord

Diffuses intracellularly --> Shh binds to receptor protein patched, promotes accumulation of receptor protein smoothened on cell surface --> disassembles inhibitory complex [Gli1, 2, 3] and Gli1/2 translocates to nucleus to positively regulate gene expression.

Scaffold on which neuroblasts can climb/migrate. Also can act like stem cells.

Horizontal, can't divide. Climbs & builds up to periphery

Cells that aren't motor or sensory

?? - inhibitory cells reach cortex late, invade, inhibit w/ GABA

"million hands to Boston" - disproved by Sperry; neurons can detect the right place/target

Neurons can find targets because they "match" - aka zip code

Navigates axon, has filopodia, senses environment, like a "hand"

travel - break up journey w/ different guideposts

chemoattraction
chemorepulsion
contact-mediated attraction
contact-mediated repulsion

chemicals floating around that attract growth cone (ex: netrin)

secreted by target, diffused extracellularly, gradient [similar to SLIT]

asymmetric. rapid, "transit amplifying cell"

Die after development

induction signals - read about them!!

inject [3H]-thymidine in monkes, find position.

give rise to neurons + glia of sensory & visceral motor ganglia, neurosecretary cells of adrenal gland, + neurons of enteric nervous. Also contributes to pigment cells, cartilage, and bone [face]

extracellular matrix molecules btwn cells, CAMs, Cadherins

proteins + sugars in viscous fluid, integrin receptors "hook", "stitching" control cytoskeleton --> movement

cell adhesion molecules. like "sticky tape" - molecules w/ lower adhesion affinity. (NCAM, L1)

Forms low-affinity junction, turns on kinase, cytoskeleton growth

transmembrane protein. repeated motifs. similar to CAM, but require Ca2+ in extracellular area.
interacts directly w/ actin cytoskeletin thru beta-catenin

"sniffing" and reading gradients that attract growth cones (spinal cord) .. also i.e. netrin/Slit binds to receptor --> Rho/GAP start polymerization of Actin

repels - depolymerize instead of polymerize actin [ too much Ca2+ can depolymerize actin] i.e. semaphorins, Slits, Netrins, Ephrins.

Sperry, Ephrins - generate repulsion, signals gradient, see APAP strips.

Synthesized/generated by tectum
bind to Eph receptors
generate repulsion
signals are in gradient
how brain can build topographic map

Cadherins
Protocadherins

SynCAM
EphrinB/EphBR
Neurexin
Neuroligin
Neuregulin

presynaptic protein - binds to neuroligin - mark contact, turn into synapse - adhesion molecule - helps localize synaptic vesicles, docking proteins, and fusion molecules

Drosophila cell addition molecules - famly of protein - "zipcode" for every marker cell - gives neurons identity, territorial marking, pathfinding

originate from target tissues - regulate differentiation, growth, and survival of nearby cells, play role in cell death

NGF [free nerve ending]
BDNF [merkel disk]
NT4/NT5 [hair follicle]
NT3 [muscle spindle]

cut right optic nerve

cut optic chiasm

cut right optic tract

cut top part of right striate

"Neurons that fire together, wire together. Neurons that fail to synch, fail to link."

Something in post-synaptic cell to respond to temporal "coincidence" from stronger axon [inputs] - sends retrograde signals from target neuron to pre-synaptic cell to strengthen input [NMDA receptor - coincidence detector, BDNF - retrograde signal it sends back to the axons]

opens when glutamate binds, only lets Ca2_ in

receptive fields like retina
relay station
possibly related to awareness/consciousness

edges/bars

every step, brain is computing more abstract info, then sending it up
Photoreceptors: light
RGCs: contrast
V1: orientation
higher: object recognition

Ectoderm
Neural plate
Patterning
Neurogenesis
Migration
Axonal pathfinding
Synaptogenesis
Death
Refinement
Critical period
Adult neuronal plasticity

Forebrain - cerebral hemispheres (cortex, basal ganglia, hippocampus, amygdala), diencephalon (thalamus, epithalamus, hipothalamus)
Midbrain
Hindbrain - medulla, pons, cerebellum
Spinal Cord

endogenous signaling molecules that can modify gene expression

inductive signal - activates transcription factor, retinoid receptors - derivative of vitamin A & is member of steroid/thyroid hormones.

bone morphogenetic proteins - is a transforming growth factor/inductive signal

serine/threonine kinases

double gradient (from top and bottom) - binds to BMP extracellularly. noggin/chordin - prevents BMP receptors*

repeating units organized in neural tube --> segmentation - fruit fly, drosophila

in fruit flies, guides differentiation of embryo into distinct segments, give rise to head, thorax, and abdomen

similar to homeobox genes in fruit fly, but in mammals. regionalization of neural tube development, mostly in hindbrain and spinal cord

in chick hindbrain - "bulges" in rhombencephalon

fibroblast growth factor - receptor: tyrosine kinase (study pg 550)

G1: nucleus near lumen/ventricular surface.
S: nucleus migrates towards pial surface/DNA replicates
G2: cell grows, nucleus migrates towards lumen again
Mitosis: cells lose connection to pial surface and divide

divides into neural stem cells, symmetric!

neuroblast + progenitor

transcription factors

inject [3h]-thymidine in pregnant monkeys, sacrifice baby monkey, look at structure of cerebral cortex - function of age at which he does injection, label cells that are in progressively higher portions of cerebral cortex

6

forebrain, excitatory neurons, NT expressed: glutamate

glutamate

GABA

from ganglionic eminence, "invasion" of inhibitory cells, they get there late. travel laterally along telencephalon

inhibitory cells - gaba-nergic neurons (long dist neural migration)

neural crest cells - generate diff subsets of cells in diff parts of body - Dorsal root ganglion cells [next to spinal cord] - sensory, ganglion cells [neuronal equivalent of DRG], eye,

neural crest cells - neural cells become what environment makes you become :), lucky cells become sensory cells! unlucky goes to kidney :(

binding partner of neurexin - adhesion molecule in postsynaptic membrane - promotes clustering of receptors and channels of postsynaptic density as synapse matures

cell adhesion molecule - chromosome 21 - present in drosophila fly, expressed at synaptic sites

involved in formation of synapse. Without these, lose synaptic contact

originate from target tissues - regulate differentiation, growth, and survival in nearby cells - limited to neurons and muscles

surplus neurons, those that fail to contact target died - mediated by neurotrophins

bc of surplus, neurons compete with one another for targets; more targets, more neural survival (i.e. adding another limb)

targets are initially innervated by axons of several neurons

not really elimination of synapse - elimination of INPUTS at synapse (one to one)

enzyme? - trophic protein - present in sympathetic targets - supports neuronal survival - appears only after axons have reached their targets (unlikely that they are guiding axons). TrkA receptor

neurotrophic factor - supports survival of certain sensory ganglion neurons - neural survival in forebrain - TrkB receptor

TrkC & TrkB receptor * CHART - p605

activated by all neurotrophins, high affinity for unprocessed neurotrophins

high affinity for processed ligands - TrkA - for NGF,
TrkB - BDNF and NT-4/5
TrkC - NT-3

1) neurotrophins locally available
2) combination of receptors on relevant neuron
3) intracellular signaling pathways expressed by the neuron

culmination of everything in the CNS - movement is behavior, it all ends in movement - expressing emotions, behavior, etc

Dorsal - Distal
Ventral - Proximal

SENSORY - spatial location is more important than identity markers
MOTOR - identity markers more important than spatial location

Sensory information --> Motor movement in ONE SYNAPSE - knee-jerk (patellar) reflex

Limb movement

ONLY MOTOR NEURONS!

motor neurons cell bodies in ventral region of spinal cord - axons to periphery muscles [flex/ext] - sends info to muscle, sensory neurons [bi-polar with cell body outside spinal cord] senses state of muscle contraction/etc and sends it directly back to motor neuron.

burst of flexor muscles alternates with extensor muscles

about 50-60 muscle groups

sensory forms synapses at variable strength with multiple motor neurons? - homonymous, synergist, etc.

experience? no (not like ocular dominance)- specificity is predictive - hardwired from the start

patterns don't change - connectivity is hardwired

propose that patterning "narrows down" and filters, then surface labels take over.

first, Dorsal-Ventral - depends on gradient of SHH, to make motor neurons, then Rostral-Caudal - depends on FGF and RA to see what KIND of Motor Neuron and what it will innervate (it's character)

gradients of SHH/RA/FGF is not enough - individual cell by cell level depends on hox genes. certain hox genes "win" in different cells - leads to diversity

pool orgnization - positionally constrained, but also have different transcription factors

clustering is done by cadherins. inactivate cadherins will scramble position, but neurons still have identity (transcription factors) - turns out that the identity still predicts connectivity, positioning is not needed for target muscle innervation, might be important for INPUT specificity

INPUT specificity - strip motor neurons of identity in a way that they still innervate muscle, but when sensory neurons come in, they come across motor neurons that are indistinguishable molecularly

hox genes - 39 evolutionary conserved hox genes [make top of embryo diff from bottom end] - 21 of 39 makes motor neurons different, ideally you would strip the 21 genes

short cut: transcription factor FoxP1 - DNA binding protein, knock it out.

lose correlation to position! also, uncoordinated activity.

by ACTIVITY

ipsi - same in the same side of the brain
contra - cross over

lateral geniculate nucleus (LGN)

primary visual cortex - form radiation and converge on occipital lobe

optic nerve

optic tract

optic radiation

binocular visual field - seen by both eyes
monocular portions - left/right eye only sees
nasal - visual field close to nose
temporal - outer parts

temporal retina stay ipsilateral, nasal retina (look at lateral sides of visual field) cross over

tunnel vision - nasal retina axons cut, can't see lateral/monocular parts, can only see centers

left temperal retina (sees right), right nasal retina (sees right) - sees RIGHT side of the world

blindness in right eye - cut optic nerve

lesion in optic chiasm - lose lateral visual field

lesion on right optic tract (or wiped out right LGN)

lesion in optic radiation - top, right

area of visual field that stimulates the neuron to fire

respond to BARS of light - elongated

if you mess up and don't give activity the eye/etc needs - destroy connection eye makes to brain.

Neurons that wire together fire together, fail to synch, fail to link - temporal patterns/excitatory

part of retina w/ highest sensitivity

no photoreceptors because light needs to get out - blind spot

photoreceptors - rods & cones - send signal to bipolar/horizontal cells to ganglion cells, fire AP down axon that leaves thru optic disk

rods - rhodopsin
cones - conopsin

11-cis retinal - captures photon, isomerize from cis to trans, (flattens) pushes against cavity and rhodopsin is activated.

during dark - depolarized, and channels are open. light hits, the channels close, hyperpolarize cells

can be detected by photoreceptor - single photon - single rhodopsin - tultiple tranducin - many phosphodiesterace - millions of changes

all cones

"short" - blue

"middle" - green

"long" - red

fire/AP - responds to light at center of receptive field (increase from baseline).

DARK spot in center- stops firing

STOP firing when light is at center. light off - fires again

DARK spot in center - starts firing

CONTRAST

C = Ic (intensity in center) - Is (intensity in surround) / Is

spatially located, can inhibit neighboring photoreceptors. reciprical - receive excess glutamate by darkness - inhibit PR, "cancel" hyperpolarizing photoreceptor and try to prevent from firing

cones - day
rods - night, dark, very sensitive to light

light vs dark, night vs day, contrast, directional selectivity, luminance.

thalamus

relay station, possibly awareness/consciousness

edges/bars

(spatial vision) medial temporal - MOTION processing region

(object recognition) - V4 to temporal lobe

edges/borders, depth, color, motion, shape ??

encoded the world - neurons respond to faces

RGC: parvo (slow, sustain, small RFs)
LGN: same as above
V1: Layer 4C beta nd 2/3, oriented RFs
IT: face/hand/spec area - foveal RF

parvo - small, smallest receptive fields, mostly around foveal region
LGN L3-L6

magno - large - retina
LGN: L1, L2

large receptive field, detail is not important
- magno cell
-FAST
dx/dt = pos/time

RGC: magno [fast, transient, large RF]
LGN: same as above
V1: layer 4c alfa, oriented RFs, motion
MT: huge RFs, akinetopsias, isoluminance

motion - predict future

shape

measurements in different points of spectrum (3) - compute resemblance of true spectrom?

cones -> bipolar -> p-ganglion (parvo/small)

Medium and Long are similar, Short is different.

missing pigments - mostly red

computing color contrast --> wavelengths, respond to combinations of colors - mostly:
green vs red, blue vs yellow

... rich in cytochrome oxidase *read about*

can't see color - PERCEPTION