Neuroscience Exploring the Brain 4 e Chapter 23

Introduction • Operation of the brain – Precise interconnections among 85 billion neurons • Brain development – Begins as a tube – Neurogenesis, synaptogenesis, pathway formation, connections formed and modified • Wiring in brain – Establishing correct pathways and targets – Fine-tuning based on experience Copyright © 2016 Wolters Kluwer • All Rights Reserved

Mammalian Retinogeniculocortical Pathway Copyright © 2016 Wolters Kluwer • All Rights Reserved

The Genesis of Neurons • Cell proliferation – Radial glial cells give rise to

Cell Proliferation • Transcription factors and cleavage plane during cell division determine fate of

Cell Migration • Pyramidal cells and astrocytes migrate vertically from ventricular zone by moving along thin radial glial fibers. • Inhibitory interneurons and oligodendroglia generate from a different site and migrate laterally. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Cell Migration—(cont. ) • First cells to migrate take up residence in subplate layer, which eventually disappears. • Next cells to divide migrate to the cortical plate. • The first to arrive become layer VI, followed V, IV, and so on: “inside out. ” Copyright © 2016 Wolters Kluwer • All Rights Reserved

Cell Differentiation • Cell takes the appearance and characteristics of a neuron after reaching its destination, but programming occurs much earlier. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Differentiation of Cortical Areas • Adult cortical sheet like a “patchwork quilt” • Cortical protomap in the ventricular zone replicated by radial glial guides – Radial unit hypothesis • Some neurons migrate laterally. • Thalamic input contributes to cortical differentiation. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Differentiation of Cortical Areas—(cont. ) • Differentiation of monkey striate cortex requires LGN input

The Three Phases of Pathway Formation (1) Pathway selection, (2) target selection, (3) address

The Growing Axon • Growth cone: growing tip of a neurite Copyright © 2016

Axon Guidance • Challenge in wiring the brain – Distances between connected structures – In early stages, nervous system is only a few centimeters long. • Pioneer axons stretch as nervous system expands. – Guide neighbor axons to same targets • Pioneer neurons grow in the correct direction by “connecting the dots. ” Copyright © 2016 Wolters Kluwer • All Rights Reserved

Axon Guidance—(cont. ) • Growth guidance cues: chemoattractant (e. g. , netrin), chemorepellent (e.

Establishing Topographic Maps • “Choice point” at optic chiasm: to innervate targets such as LGN and superior colliculus • Sperry (1940 s): chemoaffinity hypothesis • CNS axons regenerate in amphibians (useful for study), not in mammals. • Factors guiding retinal axons to tectum – Ephrins/eph (repulsive signal) Copyright © 2016 Wolters Kluwer • All Rights Reserved

Establishing Retinotopy in Frog Retinotectal Projection Copyright © 2016 Wolters Kluwer • All Rights

Steps in Formation of Neuromuscular Synapse Copyright © 2016 Wolters Kluwer • All Rights

Steps in Formation of CNS Synapse (1) Dendritic filopodium contacts axon (2) Synaptic vesicles and active zone proteins recruited to presynaptic membrane (3) Receptors accumulate on postsynaptic membrane Copyright © 2016 Wolters Kluwer • All Rights Reserved

The Elimination of Cells and Synapses • Large-scale reduction in neurons and synapses • Development of brain function – Balance between genesis and elimination of cells and synapses • Apoptosis: programmed cell death – Importance of trophic factors, for example, nerve growth factor Copyright © 2016 Wolters Kluwer • All Rights Reserved

Changes in Synaptic Capacity • Synapse elimination in the neuromuscular junction Copyright © 2016

Activity-Dependent Synaptic Rearrangement • Change from one pattern to another • Consequence of neural activity and synaptic transmission before and after birth • Critical period Copyright © 2016 Wolters Kluwer • All Rights Reserved

Synaptic Segregation • Final refinement of synaptic connections • Segregation of retinal inputs to the LGN – Retinal waves (in utero) (Carla Shatz) • Activity of the two eyes not correlated -> segregation in LGN – Process of synaptic stabilization • Hebbian modifications (Donald Hebb) Copyright © 2016 Wolters Kluwer • All Rights Reserved

Segregation of Retinal Inputs to the LGN • Plasticity at Hebb synapses • “Winner-takesall”

Segregation of LGN Inputs in the Striate Cortex • Visual cortex has ocular dominance columns (cat, monkey)—segregated input from each eye • Synaptic rearrangement – Activity-dependent – Experience-dependent • Plasticity during critical period Copyright © 2016 Wolters Kluwer • All Rights Reserved

Synaptic Convergence • Anatomical basis of binocular vision and binocular receptive fields • Monocular deprivation experiments – Ocular dominance shift – Plasticity of binocular connections – Synaptic competition Copyright © 2016 Wolters Kluwer • All Rights Reserved

Ocular Dominance Shift Copyright © 2016 Wolters Kluwer • All Rights Reserved

Critical Period for Plasticity of Binocular Connections Copyright © 2016 Wolters Kluwer • All

Effects of Strabismus on Cortical Binocularity Copyright © 2016 Wolters Kluwer • All Rights

Modulatory Influences on Cortical Circuits • Retinal activity before birth • Visual environment after

Elementary Mechanisms of Cortical Synaptic Plasticity • Two rules for synaptic modification – Fire together, wire together (Hebbian modifications) – Fire out of sync, lose their link • A single synapse has little influence on firing rate of postsynaptic neuron. – Activity of a synapse must be correlated with activity of many other inputs converging on the same postsynaptic neuron. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Excitatory Synaptic Transmission in the Immature Visual System • Focus on two glutamate receptors – AMPA receptors: glutamate-gated ion channels – NMDA receptors: unique properties Copyright © 2016 Wolters Kluwer • All Rights Reserved

Excitatory Synaptic Transmission • NMDA receptors have two unique properties. – Voltage-gated owing to action of Mg 2+ – Conducts Ca 2+ • Magnitude of Ca 2+ flux signals level of pre- and postsynaptic coactivation. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Long-Term Synaptic Potentiation (LTP) • Hypothesis – NMDA receptors serve as Hebbian detectors of simultaneous presynaptic and postsynaptic activity. – Ca 2+ entry through the NMDA receptor channel triggers the biochemical mechanisms that modify synaptic effectiveness. • Testing: Monitor synaptic strength before and after episodes of strong NMDA activation. • Strong NMDA receptor activation strengthening of synaptic transmission (LTP) Copyright © 2016 Wolters Kluwer • All Rights Reserved

Lasting Synaptic Effects of Strong NMDA Receptor Activation Copyright © 2016 Wolters Kluwer •

Long-Term Synaptic Depression (LTD) • Neurons fire out of sync. • Synaptic plasticity mechanism opposite of LTP – Loss of synaptic AMPA receptors – Loss of synapses? • Mechanism for consequences of monocular deprivation • With fewer AMPA receptors, synapses lose influence over responses of cortical neurons. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Brief Monocular Deprivation Leads to Reduced Visual Responsiveness Copyright © 2016 Wolters Kluwer •

Why Critical Periods End • Three hypotheses why plasticity diminishes – When axon growth ceases – When synaptic transmission matures – When cortical activation is constrained • Intrinsic inhibitory circuitry late to mature • Understanding developmental regulation of plasticity may help recovery from CNS damage. Copyright © 2016 Wolters Kluwer • All Rights Reserved

Concluding Remarks • Generation of brain development circuitry – Placement of wires before birth – Refinement of synaptic connections in infancy • Developmental critical periods – Visual system and other sensory and motor systems • Environment influences brain modification throughout life. Copyright © 2016 Wolters Kluwer • All Rights Reserved