Chandan Singh | Development

development

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

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
      4. neuroblasts = classic stem cells
    • assymetric division - cells generate themselves and differentiated progeny
    • ultimate stem cell - fertilized eggs
      1. 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
        1. 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
      1. axon guidance (ch 23)
    • each cell born and axon grows and are guided to a target
    • dendrite basically follows same rules
      1. 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 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

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

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

26 diseases

alzheimer’s

  • overview
    • age-associated - tons of people get it
    • doesn’t kill you, secondary complications like pneumonia will kill you
    • rate is going up
    • very expensive to treat
  • declarative memories are affected by Alzheimer’s
    • these are memories that you know
  • first 2 areas to go in Alzheimer’s
    1. hippocampus
      • patient HM had no hippocampus
        • no anterograde memory - learning new things
      • hippocampus stores 1 day of info
        • offloading occurs during sleep (REM sleep) to prefrontal cortex, temporal lobe, V4
        • dreaming - might see images as you are offloading
    2. basal forebrain - spread synapses all over cortex
      • uses Ach
      • ignition key for entire cortex
  • alzheimer’s characteristics only found in autopsy
    • amyloid plaques
      • maybe A-beta causes it
      • A-beta comes from APP
      • A-beta42 binds to itself
        • prion (starts making more of itself)
        • this cycle could be exacerbated by injury
        • clumps and attracts immune system which kills local important cells
          • this could cause Alzheimer’s
        • rare genetic mutations in A-beta increase probability you get Alzheimer’s
        • anti-inflammation may be too late
        • can take drugs that increase Ach functions - ex. cholinergic agonists, cholinesterase inhibitors
    • tangles
      • tangles made of protein called Tau
    • most people think these are just dead cells resulting from Alzheimer’s but some think they cause it

parkinson’s

  • loss of substantia nigra pars compacta dopaminergic neurons
    • when you get down to 20% what you were born with
    • dopaminergic neurons form melanin = dark color
    • hits to head can give inflammation
  • know what they need to do - don’t have enough dopamine to act
  • treat with L Dopa -> something like dopamine -> take out globus pallidus
  • Lewy bodies are clumps of alpha synuclein - appear at dopaminergic synapses
    • clumps like A-beta42
    • associated with early-onset Parkinson’s (rare) associated with genetic mutations
  • bradykinesia - slowness of movement
  • age can give parksinson’s
  • no evidence that toxins can induce parkinsons
  • PTP/ pesticides can induce Parkinson’s in test animals
  • 1/500 people