NEUROBIOLOGY D2

• Premotor and motor cortex (song control systems) show annual increase via neurogenesis, triggered by increased testosterone
• Benefits of adult neural stem cells appear to be via release of trophic (growth) factors supporting remaining neurons
• Neural stem cells are mobile and attracted to processes of brain pathologies
• Neural stem cell therapy would not be useful for recreating synoptically-connected replacements as there would be no command signals for stem cells
• Axon outgrowth

  • Growth cones extend lamellipodia and filopodia, providing navigation and elongation
  • Microtubules and actin polymerisation using ATP are required
• Axon outgrowth

  • Both attractive and repellant cues guide axonal pathfinding and this network establishment
  • Growth cone regulation by intracellular Ca2+-dependent kinases governs stalling and retraction
• Axon outgrowth

  • Balance between kinase and phosphatase activity influences cellular steering
  • Phosphatase > kinase: steering towards higher phosphatase activity
  • Phosphatase < kinase: steering towards higher kinase activity
• Axon outgrowth

  • Kinase function: adds phosphate groups to proteins (phosphorylation)
  • Phosphatase function: removes phosphate groups from proteins (dephosphorylation)
• Adhesion molecules

  • Cell adhesion molecule (CAMs): membrane glycoproteins that enable selective cell-cell adhesion via tyrosine kinase signalling
  • CAMs define growth pathways over cell layers; and allowing bundling of axons together in fascicles
  • Extracellular matrix adhesion molecules define growth pathways over matrix substrates
• Axon pathfinding

  • Axons from the retina project to the thalamus
  • Chemical signals dominate in early outgrowth, but activity (experience) finalises the synaptic pattern
• Neurotrophins and receptors

  • Nerve growth factor (NGF) was the first neurotrophin found; it binds to Trk receptor and low affinity NGF receptor
  • NGF stimulates PNS outgrowth and protects CNS neurons after injury
• Neurotrophin receptor

  • Loss of cholinergic neurons is a marker of early Alzheimer's disease
  • Decreased NGF receptor (Trk) is seen in subjects diagnosed with early Alzheimer's
  • In a mouse model, TrkA knockout in forebrain resulting in loss of cholinergic networks, and deficits in cognition
• Axonal outgrowth in the spinal cord

  • Chemical gradients create environmental cues
  • Long-range: attract (netrin) or repel (semaphorins and ephrins)
  • Local: extracellular matrix and adhesion molecules provide short-range cues - allowing bundling of axons
• Axonal outgrowth in the spinal cord

  • Motor neurons located in the ventral horn directly exit the spinal cord due to repulsion signals
  • Commisural interneuron located in dorsal horn of spinal cord
  • Growth cones must cross the midline at the ventral side, following a temporal sequence of long-range attractants, local cues and repllant
• Guidance of commissural neurons

  1. Long range attraction: Netrin released from floorplate cells attracts commissural neurons
  2. Short range attraction: The neurons cross the midline, influenced by short range attractants
  3. Short range repulsion: after crossing, floorplate receptor expression changes, causing short range repulsion to prevent backtracking
• Myelin-producing glial cells alter regeneration

  • PNS glial Schwann cells have growth promoting effects, attracting growth cones and enabling regeneration
  • CNS oligodendrocyte glial cells repress growth with inhibitory factors
• Development of the neuromuscular junction

  • Nicotinic acetylcholine receptors change in subunit composition and location during formation of the neuromuscular junction
  • High conductance channels are associated with mature and innervated states
  • Low conductance channels are found in immature and denervated states
• Formation of the neuromuscular junction

  1. Muscle cells and nerve terminals make initial contact
  2. The synapse forms as nAChRs cluster at site of nerve contact
  3. The nerve terminal becomes myelinated, enhancing signal transduction
  4. A fully functional neuromuscular junction is formed = allowing for precise muscle control

   
• Early development of synapse

  • Immature stage: multiple nerves connect to a single muscle fibre
  • Mature stage: redundant nerves are removed, leaving one nerve per muscle fibre
  • Positive feedback from forming synaptic region to maintain synapse connections
• Modification of synapse

  • nAChR blockers disrupt nerve activity, less active nerves retract
  • Only most active nerve remains connected
• CNS synapse formation

  • CNS neurons receive both excitatory and inhibitory inputs
  • Networks are 'pruned' based on activity
• Sensory homunculus: visual representation of the sensory areas of the brain, showing how different parts of the body are represented in the brain based on sensory input
• Retinal projection to the thalamus is patterned by activity

  • Spontaneous waves of activity across the retina establish retinotopic maps in the thalamus
  • Amacrine cells are needed for conductive waves across the retina
  • Transgenic mice (lacking a nAChR β subunit) have impaired retinal function resulting in small waves, and thus poor spatial mapping
• If synapses compete for establishment, how are inhibitory synapses possible?

  • In developing neurons, binding of GABA causes EPSPs (depolarisation) rather than mature neuronal IPSPs
  • Active transport of chloride into the cell shifts ECl to a positive potential
  • Accomplished by transient embryonic expression of a cotransporter that uses Na+ influx to drive K+ and Cl- influx - allows short-term reversal of chloride gradient
• • Cytochalasin blocks actin polymerisation and immobilises growth cones