Development

Neuroscience  ·  chapter 6 of 8  ·  7 min read

Development#

notes from Purves et al. "Neuroscience", 5th edition (chapter numbers in headers) + Intro to neurobiology course at UVA

About this chapter

Purves chapters 22 to 25, in the order a nervous system is built. Early development folds the embryo into a neural tube, and gradients of morphogens (BMP from the roof plate, hedgehog from the floor plate) tell each cell what to become. Growth cones then steer axons to their targets with attractive and repulsive cues such as netrin, slit and ephrins.

Once axons arrive they compete. Targets make only a limited amount of neurotrophin, so many of the first connections are removed, and activity decides which ones stay during critical periods (the ocular dominance experiments in cats are the main example). The last section asks why the peripheral nervous system can regrow and the central one mostly can’t.

22 early development#

A cell’s position along the neural tube sets its fate: low hedgehog near the roof plate gives sensory neurons and interneurons, high hedgehog near the floor plate makes motor neurons. Hox genes then pattern the head-to-tail axis.

  • 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

        The neural crest pinches off the top of the neural tube (B) and migrates through the embryo (A). Its cells become sensory neurons, sympathetic adrenergic and cholinergic neurons, melanocytes and chrom

        Fig. 133 Figure 1. The neural crest pinches off the top of the neural tube (B) and migrates through the embryo (A). Its cells become sensory neurons, sympathetic adrenergic and cholinergic neurons, melanocytes and chromaffin cells, depending on the signals they meet (C).#

      • 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

23 circuit formation#

Growth cones read a combinatorial code of guidance molecules. Ephrin gradients map the retina onto the tectum, netrin draws axons to the midline, and slit pushes them away once they have crossed. Then neurotrophins decide which connections survive.

Interactive 1. Several motor axons start out innervating one muscle fiber and share its fixed supply of neurotrophin; an axon that takes up more grows and takes up more still. With equal axons, whichever starts a little bigger ends up with the whole fiber and the rest retract. Give axon 1 (orange) an activity advantage, as an open eye has over a patched one, and press "new random start" a few times: the bigger the advantage, the more often it wins. (A toy model of the note's "whichever sucks up most, kills all the others".)

  • 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

    Mapping the retina onto the tectum (superior colliculus). Temporal retinal axons, which carry more Eph receptor, are repelled by the high ephrin in posterior tectum and stop in anterior tectum. In a s

    Fig. 134 Figure 2. Mapping the retina onto the tectum (superior colliculus). Temporal retinal axons, which carry more Eph receptor, are repelled by the high ephrin in posterior tectum and stop in anterior tectum. In a stripe assay (C) temporal axons avoid posterior membranes while nasal axons grow on both. A frog with its eye rotated (B) strikes in the wrong direction because the map is hard-wired.#

    • 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

    The main classes of axon guidance molecules: extracellular matrix with integrins, CAMs such as NCAM, cadherins, netrin and slit with their receptors DCC and Robo, semaphorins with plexins, and ephrins

    Fig. 135 Figure 3. The main classes of axon guidance molecules: extracellular matrix with integrins, CAMs such as NCAM, cadherins, netrin and slit with their receptors DCC and Robo, semaphorins with plexins, and ephrins with Eph receptors.#

    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

24 plasticity in systems#

Experience shapes circuits most during critical periods, which differ by system (the table). Hebb’s rule is the mechanism: inputs that fire together, like the two eyes, strengthen their synapses through NMDA receptors, and inputs that are silenced lose territory.

  • experience-dependent plasticity - critical periods and molecular regulators for some neural systems (table 24.1)

    system

    species

    critical period (postnatal)

    confirmed molecular regulators

    neuromuscular junction

    mouse

    prior to day 12

    ACh

    cerebellum

    mouse

    day 15–16

    NMDA, mGluR1, Gq, PLCβ, PKCγ

    lateral geniculate nucleus layers

    mouse, ferret, cat

    prior to day 10

    ACh, cAMP, MAOA, NO, MHC1, CREB

    ocular dominance

    cat, rat, mouse, ferret

    3 weeks–months

    GABA, NMDA, PKA, ERK, CaMKII, CREB, BDNF, tPA, protein synthesis, NE, ACh

    orientation bias

    cat, mouse

    prior to day 28

    NR1, NR2A, PSD95

    somatosensory map

    mouse, rat

    prior to day 7–16

    NR1, MAOA, 5HT1B, cAMP, mGluR5, PLCβ, FGF8

    tonotopic map (cortex)

    rat

    days 16–50

    ACh

    absolute pitch

    human

    before 7 years

    unknown

    taste, olfaction

    mouse

    none

    GABA, mGluR2, NO, neurogenesis

    imprinting

    chick

    14–42 hours

    catecholamines

    stress, anxiety

    rat, mouse

    prior to day 21

    hormones, 5HT1A

    slow-wave sleep

    cat, mouse

    day 40–60

    NMDA

    sound localization

    barn owl

    prior to day 200

    GABA, NMDA

    birdsong

    zebra finch

    prior to day 100

    GABA, hormones, neurogenesis

    language

    human

    0–12 years

    unknown

    • 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

25 repair and regeneration#

The PNS regrows along the Schwann cell sheath at about the speed of slow axonal transport. The CNS forms a glial scar instead, and adult neurogenesis is limited to a few places such as the hippocampus and the olfactory bulb.

  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

Key ideas

  • Position sets fate: BMP from the roof plate and hedgehog from the floor plate tell neural tube cells what to become, and Hox genes pattern head to tail.

  • Growth cones steer with a combinatorial code of attractive and repulsive cues: netrin, slit, ephrins and semaphorins.

  • About half of developing cells die, and targets make only enough neurotrophin for some connections, so inputs compete and the losers retract.

  • Activity decides the competition during critical periods: closing one eye early shrinks its ocular dominance columns.

  • The PNS regrows along Schwann cells at 1-2 mm a day; the CNS forms a glial scar, and new neurons appear only in a few places such as the hippocampus.

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