7.8. development¶

notes from Neuroscience, 5th edition + Intro to neurobiology course at UVA

7.8.1. 22 early development¶

  • ways to study

    1. top-down: rosy retrospection

    2. bottom-up: e.g. LTP/LTD

    3. human disease: stroke-by-stroke

    4. development=ontogeny

  • timeframe

    • month 1 - gastrulation

      • most sensitive time for mom

    • month 2-5 - cells being born

    • up to year 2 - axon guidance / synapse formation

  1. gastrulation - process by which early embryo undergoes folds = shapes of NS

    • diseases

      • spina bifida - neural tube fails to seal

        • vitamin B12 can fix this

      • anencephaly - neural tube fails to close higher up

    • parts

      1. roofplate at top (back)

      2. floorplate on bottom (stomach)

      3. neural crest - pinches off top of roofplate

  2. neuroblasts = classic stem cells

    • assymetric division - cells generate themselves and differentiated progeny

    • ultimate stem cell - fertilized eggs

  3. differentiation

    • cells made by neuroblasts decide what they are going to become

    • morphogens

      • BMP - roofplate

        • cyclopia - fatal defect in BMP

      • Hedge hogs - at floor plate

      • Retinoids - axial, affect skin

        • affected by thalidomide - helps morning sickness but causes missing limb segments

        • also affected by accutane

      • FGFs - axial symmetry

      • Wnts - skin, gut, hair

        • loss of wnts is loss of hair

    • floor plate loses function after embryogenesis except glioblastoma

    • measure BMP and HH gradient to figure out where you are

      • treat ALS by adding HH to make more alpha motor neurons

    1. dorsal direction

      • roofplate makes BMP

      • low HH - interneurons, sensory neurons (ex. nociceptors)

      • even BMP/HH - sympathetic

      • high HH - more motor neurons

      • floorplate makes HH (hedge hog)

    2. axial specification (anterior/posterior)

      • tube swells into bulbs that become cerebellum, superior colliculus, cortex

    • homeotic genes = hox genes - set of genes (transcription factors) in order on chromosome

      • order corresponds to order of your body parts

      • rhombomeres - segments in brainstem made by hox gene patterns

  4. lineages

    • when neuroblast is born, starts producing progeny (family tree of neuron types)

    • very often, cells are produced in certain order

    • timing: cell-cell interations and tyrosine kinases determine order

    • first alpha neurons, then GABAergic to control those, last is glia

    • neural crest function

      • migratory - moves out and divides:

      • neuroblastoma - developed early - severe problem because missing parts of NS

      • makes DRG and associated glial cells (schwann cells)

      • makes sympathetic NS and target ganglia, enteric NS, parasympathetic NS targets

      • makes melanocytes - know how to migrate and divide but can make melanoma (cancer)

    • cortex is made inside out (6->1)

      • starts with stem cells called radial glia

      • cortical dysplasia - missing a layer / duplicating a layer

        • small part with 2 layer 3s - severe epilepsy

  5. cell death

    • 1/2 of cells die in development

  6. axon guidance (ch 23)

    • each cell born and axon grows and are guided to a target

    • dendrite basically follows same rules

  7. synapse formation (ch 23, 24)

    • pruning and plasticity

    • NMDA receptor type

    • form synapses and if they don’t look right - get rid of them

    • K1/K-1 synapses breaking and forming

    • after age 21, K-1 starts increasing and net loss of synapses

7.8.2. 23 circuit formation¶

  • growth cone - motile tip of axon

    • actin tip

      1. lamellipodium - sheet (hand)

      2. filopodium - huge curves (fingers)

        • chemo attraction (actin assembly) and chemo repulsion (actin disassembly)

    • microtubule shaft - tubulin is much more cemented in

    • mauthner cell of tadpole - first recorded growth cone

    • can’t regrow (that’s why we can’t regrow spinal cord)

  • signals in growing axons

    1. pioneer axons (Betz cells) are first - often die

    2. follower axons (other Betz cells) can jump onto these and connect before pioneer dies

    • trophic support - neuron survives on contact

  • frog tectum (has superior colliculus) with map of retina:

    • ephrin (EPH) repulses axon

      • retinal NT -> tectum AP

      • axons have different amount of EPH receptors (in retina temporal has more than nasal)

      • gradient of EPH (in tectum anterior has less than posterior)

      • if we flip eye upside down (on nasal-temporal axis), image will be upside down

  • 3 classes of axon guidance molecules:

    1. ECM/integrins

    2. NCAM (homophilic—binds to another neuron that is NCAM),

      • follower neurons bind to pioneer through NCAM-NCAM interactions

    3. Cadherin (homophilic)

      • involved in recognition of being some place

  • 4 important ligands/receptors

    1. ephrins/eph

      • gradient of eph receptor

    2. netrin/dcc = guidance moleculereceptor = DCC

      • attracts axons to floorplate (midline)

      • cells without DCC don’t cross midline

    3. slit/robo - receptor is slit

      • chases axons off (away from midline)

      • axons not destined to cross midline are born expressing robo

      • axons destined to cross the midline only express robo after crossing

      • if DCC (-) and robo (-) will continue wandering around

      • robo 4 is associated with Tourette’s

    4. semaphorins/plexins

    • combinatorial code - use combinations of these to guide axons

    • these are the same genes that move cancer around

  • synaptic formation

    • neuroexins - further recognition

      • turn up in autism and schizophrenia

    • DSCAM

      • associated with Down’s syndrome

      • doesn’t use gradients

      • makes different kinds of proteins by differential slicing

  • competition

    • neurotrophins are secreted by muscle

      • in early development, a muscle fiber has many alpha motor neurons innervating it

      • all innervating neurons suck up neurotrophin and whichever sucks up most, kills all the others

      • eventually, each muscle fiber is innervated by one alpha motor neuron

      • only enough neurotrophin in target cells for a certain number of synapses

    • happens everywhere

      • ex. sympathetic ganglia

      • ex. sensory neurons in skin get axons to correct cell types based on neurotrophin

        • merkel - BDNF

        • proprioceptor - NT3

        • nociceptor - NGF

      • ex. muscles - produce NGF

        • treating ALS with NGF hyperactivates sensory neurons with trkA -> causes chicken pox

    • signals/receptors

      1. NGF - trk a (Trk receptor - survival signaling pathways)

      2. BDNF - trk b

      3. NT3 - trk b and c

      4. NT4/5 - trk b

      • all bind p75 (death receptor)

      • want to keep neurotrophins local, because there aren’t that many of them

7.8.3. 24 plasticity in systems¶

  • experience-dependent plasticity -

    • ex. ducks imprinting is non-reversable

    • learning is crystallized during critical period

      • CREB and protein synthesis

      • NMDA receptors

      • epigenetics - histones control transcription and other things

    • follow Hebb’s postulate - fire together, wire together

      • different eyes firing together will sync up (NMDA receptors to strengthen synapses)

  • systems

    1. ocular dominance

      • left/right neurons terminate in adjacent zones

      • LGN in cortex uses efferents just like superior colliculus

      • label injected into retina can make it into cortex

      • cat experiments

        • some cells see only one eye, some see both

        • cats need to form visual map in short critical period (<6 days)

        • this is why you need cochlear implant early

        • both eyes open - equal OD columns

          • one eye closed - unequal OD columns

          • branches coming out of LGN neurons grow more branches based on relative light exposure (they compete for eye’s real estate)

      • strabismus = lazy eye - poor coordination with one of the muscles

        • one eye is not quite seeing

        • treat with patch on good eye -> allows bad eye to catch up since eyes compete for ocular dominance columns

        • more stimulus = more branches

      • dye from retina goes through thalamus into cortex

        • rabies virus does same thing: cell->ganglion->brain

    2. tonotopic map

      • connection between MSO and inferior/superior colliculus

      • playing one tone increases representation

      • playing white noise disorganizes map

      • birdsong

        • hear song 10-20 times when young - crystallized

        • afterwards can’t learn new skills

    3. stress

      • early stress sets stress points later in life

      • uses serotonin

  • shifts

    • superior colliculus - integrate visual, auditory, motor to get X,Y coordinate

    • auditory map - plastic (but only when young)

    • visual map - not plastic

    • if you shift visual map (with a prism), auditory map can shift over to meet the visual

    • optic neuritis - ms optic nerve disease that shifts map

    • only young animals can shift unless they were shifted before and are now unadapting

7.8.4. 25 repair and regeneration¶

  1. full repair - human PNS - skin, muscles

    • 1-2 mm/day growth - speed of slow axonal transport

    • thinnest axons first (thermal receptors and nociceptors)

    • proprioceptors last

    • process

      • perinerium / schwann cells surrounds axons - helps regeneration

      • growth cones that are cut form stumps -> distal axons degenerate = walerian degeneration

      • macrophages come in and eat up the damaged stuff

      • neurotrophins are involved

    • miswiring is common - regrow and may not find right target

      • bell’s palsy - loss of facial nerve - recovers with miswiring (salivary / tear)

    • neuromuscular junctions (NMJ)

      • damaged cells leave synaptic ghost = glia and protein matrix for nerve to regrow into

      • repairs easily after heavy training

  2. no repair / glial scar - human CNS

    • no ghost because so spread out

    • glia cover wound (scar) but can’t develop further

    • has astrocytes and oligodendrocytes (types of glial cells)

      • don’t support regrowth

      • involved in scarring

    • microglia - from immune system

      • control inflammation

      • release cytokines

    • nogo - protein that blocks regrowth (but there are other proteins as well)

    • we try repairing with shunts - piece of sciatic nerve from other part of body with schwann cells from PNS to try to repair a connection in the CNS

  3. stem cell regeneration - put new neurons being formed, 2 places in humans

    • non-human examples

      • floor plate of lizards can make new tail

      • fish retina always making new cells

      • canary brain part has stem cells that learn new song every year

    • small C14 incorporation after early development - suggests we don’t regenerate neurons - C14 was from nuclear testing

    • human areas that do regenerate

      1. hippocampus

        • memories you store temporarily

      2. subventricular zone makes glomeruli in olfactory bulb cells

        • turnover daily

        • sensory neurons and their targets constantly die and regenerate

      3. niche - places where stem cells stay alive

        • ex. places in CNS with WINT molecular signals

  • damage control - remove these signals for apoptosis = cell death

    • glutamate increase - excitotoxicity

      • can stop with NMDA blockers

      • induce a coma by cooling them down or GABA drugs

    • cytokines increase - immune system (like neurotrophins), inflammation

    • hypoxia/stress

    • neurotrophin withdrawal

      • in stress times neurotrophin goes down