Chapter 23: Wiring the

Introduction

• Operation of the brain – Precise interconnections among 100 billion • Brain development – Begins as a tube – Neurogenesis, , pathway formation, connections formed and modified • Wiring in brain – Establishing correct pathways and targets – Fine tuning based on experience The Genesis of Neurons • Example: Mammalian retinogeniculocortical pathway The Genesis of Neurons

• Cell Proliferation – Neural stem cells give rise to neurons and glia The Genesis of Neurons • Cell Proliferation (Cont’d) – Cleavage plane during cell division determines fate of daughter cells The Genesis of Neurons

– Pyramidal cells and migrate vertically from ventricular zone by moving along thin radial glial fibers – Inhibitory interneurons and oligodendroglia generate from a different site and migrate laterally The Genesis of Neurons

• Cell Migration – 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” The Genesis of Neurons

• Cell Differentiation – Cell takes the appearance and characteristics of a after reaching its destination but programming occurs much earlier The Genesis of Neurons

• Differentiation of Cortical Areas – Adult cortical sheet is a “patchwork quilt – Cortical “protomap” in the ventricular zone replicated by radial glial guides – But some neurons migrate laterally – Thalamic input contributes to cortical differentiation The Genesis of Connections • The three phases of pathway formation: – (1) pathway, (2) target, (3) address The Genesis of Connections • The Growing : Growing tip of a neurite The Genesis of Connections

– Challenge in wiring the brain • Distances between connected structures • But in early stages nervous system is a few centimeters long – Pioneer stretch as nervous system expands • Guide neighbor axons to same targets – Pioneer neurons grow in the correct direction by “connecting the dots” The Genesis of Connections • Axon Guidance – Guidance Cues: Chemoattractant (e.g., netrin), Chemorepellent (e.g., slit) The Genesis of Connections

• Axon Guidance – Establishing Topographic Maps • Choice point; Retinal axons innervate targets of LGN and superior colliculus • Sperry (1940s): Chemoaffinity hypothesis • CNS axons regenerate in amphibians, not in mammals • Factors guiding retinal axons to tectum • /eph (repulsive signal) The Genesis of Connections

• Axon Guidance – Establishing Topographic Maps The Genesis of Connections • Formation – Modeled in the The Genesis of Connections

• Synapse Formation – Steps in the formation of a CNS synapse: – Dendritic filopodium contacts axon – Synaptic vesicles and proteins recruited to presynaptic membrane – Receptors accumulate on postsynaptic membrane The Elimination of Cells and

• The mechanisms of pathway formation – Large-scale reduction in neurons and synapses • Development of brain function – Balance between genesis & elimination of cells and synapses • Apoptosis: Programmed Cell Death – Importance of trophic factors, e.g., nerve growth factor The Elimination of Cells and Synapses • Changes in Synaptic Capacity – Synapse elimination modeled in the neuromuscular junction Activity-dependent Synaptic Rearrangement • Synaptic rearrangement – Change from one pattern to another – Consequence of neural activity/synaptic transmission before and after birth – Critical Period Activity-dependent Synaptic Rearrangement • Synaptic segregation – 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) Activity-dependent Synaptic Rearrangement

• Segregation of Retinal Inputs to the LGN (Cont’d) – Plasticity at Hebb synapses – “Winner-takes- all” Activity-dependent Synaptic Rearrangement • Segregation of LGN Inputs in the Striate Cortex – Visual cortex has ocular dominance columns (cat, monkey) - segregated input from each eye – Synaptic rearrangement is activity-dependent – Plastic during critical period Activity-dependent Synaptic Rearrangement

• Synaptic Convergence – Anatomical basis of binocular vision and binocular receptive fields – Monocular deprivation: • Ocular dominance shift • Plasticity of binocular connections • Synaptic competition

Activity-dependent Synaptic Rearrangement

• Critical period for plasticity of binocular connections Activity-dependent Synaptic Rearrangement

• Effect of strabismus on cortical binocularity Activity-dependent Synaptic Rearrangement

• Modulatory Influences – Increasing age – Before and after birth – Enabling factors Elementary Mechanisms of Cortical

• Two rules for synaptic modification – Wire together fire together (Hebbian modifications) – Out of sync lose their link – Correlation: heard and validated Elementary Mechanisms of Cortical Synaptic Plasticity • Excitatory Synaptic Transmission in the Immature Visual System – Focus on 2 glutamate receptors (Rs): • AMPARs: glutamate-gated ion channels • NMDARs: Unique properties Elementary Mechanisms of Cortical Synaptic Plasticity

• Excitatory Synaptic Transmission – NMDA receptors have two unique properties • Voltage-gated owing to Mg2+ • Conducts Ca2+ • Magnitude of Ca2+ flux signals level of pre- and postsynaptic activation Elementary Mechanisms of Cortical Synaptic Plasticity

• Long-Term Synaptic Potentiation – Monitor synaptic strength before and after episodes of strong NMDA activation – Accounting for LTP • AMPA insertion (“AMPAfication”) • Splitting synapses (doubling) Elementary Mechanisms of Cortical Synaptic Plasticity • Lasting synaptic effects of strong NMDA receptor activation Elementary Mechanisms of Cortical Synaptic Plasticity

• Long-Term Synaptic Depression (LTD) – Neurons fire out of sync – Synaptic plasticity mechanism opposite of LTP • Loss of synaptic AMPARs • Loss of synapses? (unknown) – Mechanism for consequences of monocular deprivation Elementary Mechanisms of Cortical Synaptic Plasticity • Brief monocular deprivation leads to reduced visual responsiveness • Depends on retinal activity, NMDA activation, postsynaptic calcium Why Critical Periods End

• Why do critical periods end? – 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 Concluding Remarks

• Generation of brain development circuitry – Placement of wires  before birth – Refinement of synaptic  infancy • Developmental critical periods – Visual system and other sensory and motor systems • Environment influences brain modification throughout life Chapter 24: Systems

Introduction

• Learning: Lifelong adaptation to environment • Several similarities between experience dependent brain development and learning – Similar mechanisms at different times and in different cortical areas • range from stated facts to ingrained motor patterns • Anatomy: Several memory systems – Evident from brain lesions Types of Memory and Amnesia

• Learning: Acquisition of new information • Memory: Retention of learned information • Declarative memory (explicit) – Facts and events • Nondeclarative memory (implicit) – Procedural memory — skills, habits

Types of Memory and Amnesia • Long-Term, Short-Term, and Working Memory

Sensory Short-term Consolidation Long-term information memory memory

Short-term memory

Sensory Consolidation Long-term information memory

Time – Working memory: Temporary information storage Types of Memory and Amnesia

• Amnesia: serious loss of memory and/or ability to learn • Causes: concussion, chronic alcoholism, encephalitis, brain tumor, stroke – Limited amnesia (common) – Dissociated amnesia: no other cognitive deficit (rare) Types of Memory and Amnesia

• Amnesia (Cont’d) – Retrograde amnesia: forget things you already knew – Anterograde amnesia: inability to form new memories Types of Memory and Amnesia

• Amnesia (Cont’d) – Transient global amnesia: shorter period, temporary ischemia (e.g., severe blow to head) – Symptoms: disoriented, ask same questions repeatedly; attacks subside in couple of hours; permanent memory gap The Search for the Engram • Lashley’s Studies of Maze Learning in Rats

Engram: memory trace The Search for the Engram

• Hebb and the Cell Assembly – External events are represented by cortical cells – Cells reciprocally interconnected  reverberation – Active neurons — cell assembly • Consolidation by “growth process” • “Fire together, wire together” – Hebb and the engram • Widely distributed among linked cells in the assembly • Could involve neurons involved in sensation and perception The Search for the Engram

• Hebb’s Cell Assembly and Memory Storage The Search for the Engram

• Localization of Declarative Memories in the Neocortex – Inferotemporal Cortex (area IT), higher-order visual area in macaques – Lesion impairs discrimination task despite intact visual system at lower levels – Area IT may encode memory for faces The Search for the Engram • Localization of Declarative Memories in the Neocortex – At first, all cells respond to newly presented faces the same amount – With repeated exposures, some faces evoke a greater response than others — i.e., cells become more selective

(Adapted from Rolls et al., 1989 Exp Brain Res 76:153-164, Figure 1.) The Search for the Engram

• Localization of Declarative Memories in the Neocortex – Human extrastriate cortex differentially activated in car and bird experts The Search for the Engram

• Electrical Stimulation of the Human Temporal Lobes – Temporal lobe stimulation • Different from stimulation of other areas of neocortex – Penfield’s experiments • Stimulation  Sensations like hallucinations, recall past experiences – Temporal lobe: Role in memory storage – Caveat: Minority of patients, all with abnormal (epilepsy) The Temporal Lobes and Declarative Memory • The Effects of Temporal Lobectomy (HM) The Temporal Lobes and Declarative Memory

• The Effects of Temporal Lobectomy (HM) – Removal of temporal lobes had no effect on perception, intelligence, personality – Anterograde amnesia so profound cannot perform basic human activities (and partial retrograde amnesia) – Still does not recognize Brenda Milner, who has studied him for nearly 50 years – Impaired declarative memory, but spared procedural memory (mirror drawing) The Temporal Lobes and Declarative Memory • The Medial Temporal Lobes and Declarative Memory The Temporal Lobes and Declarative Memory

• The Medial Temporal Lobes and Declarative Memory – Information flow through medial temporal lobe The Temporal Lobes and Declarative Memory • The Medial Temporal Lobes and Memory Processing (Cont’d) – DNMS: Delayed non-match to sample – Medial temporal lobe structures: important for memory consolidation The Temporal Lobes and Declarative Memory

• The Medial Temporal Lobes and Memory Processing (Cont’d) – Effect of medial temporal lobe lesions on DNMS – Recognition memory The Temporal Lobes and Declarative Memory

• The Diencephalon and Memory Processing – Brain regions associated with memory and amnesia outside the temporal lobe The Temporal Lobes and Declarative Memory • The Diencephalon and Memory Processing – Radio technician 1959 accidentally stabbed through left dorsomedial thalamus with fencing foil • Less severe but like HM; anterograde and some retrograde amnesia – Korsakoff’s Syndrome: alcoholics — thiamin deficiency • Symptoms: confusion, confabulations, severe memory impairment, apathy, abnormal eye movements, loss of coordination, tremors • Lesions to dorsomedial thalamus and mamillary bodies – Treatment: Supplemental thiamin The Temporal Lobes and Declarative Memory

• Memory Functions of the – Hippocampal responses to old and new stimuli The Temporal Lobes and Declarative Memory • Radial arm maze (a) – (b) Normal rats go down each arm for food only once but not with hippocampal lesions – () Normal and lesioned rats learn which arms are baited and avoid the rest The Temporal Lobes and Declarative Memory

• Spatial Memory and Hippocampal Place Cells – Morris water maze: requires NMDA receptors in hippocampus – Place cells fire when animal is in a specific place – Dynamic The Temporal Lobes and Declarative Memory

• Spatial Memory and Hippocampal Place Cells – PET imaging in human brain related to spatial navigation of a virtual town The Striatum and Procedural Memory

• Caudate nucleus + Putamen = Striatum – Lesions to striatum disrupt procedural memory (habit learning) – Standard radial arm maze depends on hippocampus – Modified radial arm maze, with lighted arms, depends on striatum. • Damaged hippocampal system: degraded performance on standard maze task • Damaged striatum: impaired performance of the modified task; double dissociation The Striatum and Procedural Memory • Habit Learning in Humans and Nonhuman Primates – Parkinson’s patients show that human striatum plays a role in procedural memory The Neocortex and Working Memory

• The Prefrontal Cortex and Working Memory – Primates have a large frontal lobe – Function of prefrontal cortex: self-awareness, capacity for planning and problem solving The Neocortex and Working Memory The Neocortex and Working Memory

• The Prefrontal Cortex and Working Memory – Working memory activity in monkey prefrontal cortex The Neocortex and Working Memory

• The Prefrontal Cortex and Working Memory – Wisconsin card-sorting task The Neocortex and Working Memory

• The Prefrontal Cortex and Working Memory (Cont’d) – Imaging Working Memory in the Human Brain – Six frontal lobe areas show sustained activity correlated with working memory – Blue: Facial memory – Green: Facial and spatial memory The Neocortex and Working Memory • Lateral Intraparietal Cortex (Area LIP) and Working Memory – Area LIP: Guiding eye movements – Delayed-saccade task Concluding Remarks • Learning and memory – Occur throughout the brain • Memories – Duration, kind of information stored, and brain structures involved – Distinct types of memory – Different types of amnesia • Multiple brain systems for memory storage • Engrams in temporal lobe neocortex – Physiological basis? – Long-term memories: structural basis? Chapter 25: Molecular Mechanisms of Learning and Memory

Introduction • Neurobiology of memory – Identifying where and how different types of information are stored • Hebb – Memory results from synaptic modification • Study of simple invertebrates – Synaptic alterations underlie memories (procedural) • Electrical stimulation of brain – Experimentally produce measurable synaptic alterations — dissect mechanisms Procedural Learning

• Procedural memories amenable to investigation • Nonassociative Learning – Habituation • Learning to ignore stimulus that lacks meaning – Sensitization • Learning to intensify response to stimuli Procedural Learning

• Associative Learning – Classical Conditioning: pair an unconditional stimulus (UC) with a conditional stimulus (CS) to get a conditioned response (CR) Procedural Learning

• Associative Learning (Cont’d) – Instrumental Conditioning • Experiment by Edward Thorndike • Learn to associate a response with a meaningful stimulus, e.g., reward lever pressing for food • Complex neural circuits related to role played by motivation Simple Systems: Invertebrate Models of Learning

• Experimental advantages in using invertebrate nervous systems – Small nervous systems – Large neurons – Identifiable neurons – Identifiable circuits – Simple genetics Simple Systems: Invertebrate Models of Learning

• Nonassociative Learning in Aplysia – Gill-withdrawal reflex – Habituation Simple Systems: Invertebrate Models of Learning • Nonassociative Learning in Aplysia (Cont’d) – Habituation results from presynaptic modification at L7 Simple Systems: Invertebrate Models of Learning

• Nonassociative Learning in Aplysia (Cont’d) – Repeated electrical stimulation of a sensory neuron leads to a progressively smaller EPSP in the postsynaptic motor neuron Simple Systems: Invertebrate Models of Learning • Nonassociative Learning in Aplysia (Cont’d) – Sensitization of the Gill-Withdrawal Reflex involves L29 axoaxonic synapse Simple Systems: Invertebrate Models of Learning

• Nonassociative Learning in Aplysia (Cont’d) – 5-HT released by L29 in response to head shock leads to G-protein coupled activation of adenylyl cyclase in sensory axon terminal. – Cyclic AMP production activates protein kinase A – Phosphate groups attach to a potassium channel, causing it to close Simple Systems: Invertebrate Models of Learning

• Nonassociative Learning in Aplysia (Cont’d) – Effect of decreased potassium conductance in sensory axon terminal – More calcium ions admitted into terminal and more transmitter release Simple Systems: Invertebrate Models of Learning • Associative Learning in Aplysia – Classical conditioning: CS initially produces no response but after pairing with US, causes withdrawal Simple Systems: Invertebrate Models of Learning • The molecular basis for classical conditioning in Aplysia – Pairing CS and US causes greater activation of adenylyl cyclase because CS admits Ca2+ into the presynaptic terminal Vertebrate Models of Learning

• Neural basis of memory learned from invertebrate studies – Learning and memory can result from modifications of synaptic transmission – Synaptic modifications can be triggered by conversion of neural activity into intracellular second messengers – Memories can result from alterations in existing synaptic proteins Vertebrate Models of Learning

• Synaptic Plasticity in the Cerebellar Cortex – Cerebellum: Important site for motor learning – Anatomy of the Cerebellar Cortex • Features of Purkinje cells • Dendrites extend only into molecular layer • Cell axons synapse on deep cerebellar nuclei neurons • GABA as a Vertebrate Models of Learning • The structure of the cerebellar cortex Vertebrate Models of Learning

• Synaptic Plasticity in the Cerebellar Cortex – Long-Term Depression in the Cerebellar Cortex Vertebrate Models of Learning

• Synaptic Plasticity in the Cerebellar Cortex (Cont’d) – Mechanisms of cerebellar LTD • Learning • Rise in [Ca2+]i and [Na+]i and the activation of protein kinase C • Memory • Internalized AMPA channels and depressed excitatory postsynaptic currents Vertebrate Models of Learning

• Synaptic Plasticity in the Cerebellar Cortex (Cont’d) Vertebrate Models of Learning

• Synaptic Plasticity in the Cerebellar Cortex (Cont’d) Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus – LTP and LTD • Key to forming declarative memories in the brain – Bliss and Lomo • High frequency electrical stimulation of excitatory pathway – Anatomy of Hippocampus • Brain slice preparation: study of LTD and LTP Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus (Cont’d) – Anatomy of the Hippocampus Vertebrate Models of Learning • Synaptic Plasticity in the Hippocampus (Cont’d) – Properties of LTP in CA1 Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus (Cont’d) – Mechanisms of LTP in CA1 • Glutamate receptors mediate excitatory synaptic transmission • NMDA receptors and AMPA receptors Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus (Cont’d) – Long-Term Depression in CA1 Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus (Cont’d) – BCM theory • When the postsynaptic cell is weakly depolarized by other inputs: active synapses undergo LTD instead of LTP • Accounts for bidirectional synaptic changes (up or down) Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus (Cont’d) – LTP, LTD, and Glutamate Receptor Trafficking • Stable synaptic transmission: AMPA receptors are replaced maintaining the same number • LTD and LTP disrupt equilibrium • Bidirectional regulation of phosphorylation Vertebrate Models of Learning

• LTP, LTD, and Glutamate Receptor Trafficking (Cont’d) Vertebrate Models of Learning • LTP, LTD, and Glutamate Receptor Trafficking (Cont’d) Vertebrate Models of Learning

• Synaptic Plasticity in the Hippocampus (Cont’d) – LTP, LTD, and Memory • Tonegawa, Silva, and colleagues • Genetic “knockout” mice • Consequences of genetic deletions, e.g., CaMK11 subunit • Advances (temporal and spatial control) • Limitations of using genetic mutants to study LTP/learning: secondary consequences Vertebrate Models of Learning

• Synaptic Plasticity in Human area IT The Molecular Basis of Long-Term Memory

• Phosphorylation as a long term mechanism: Persistently Active Protein Kinases – Phosphorylation maintained: kinases stay “on” • CaMKII and LTP • Molecular switch hypothesis The Molecular Basis of Long-Term Memory

• Protein Synthesis – Protein synthesis required for formation of long-term memory • Protein synthesis inhibitors • Deficits in learning and memory – CREB and Memory • CREB: Cyclic AMP response element binding protein

The Molecular Basis of Long-Term Memory

• Protein Synthesis (Cont’d) – Structural Plasticity and Memory • Long-term memory associated with formation of new synapses • Rat in complex environment: shows increase in number of neuron synapses by about 25% Concluding Remarks

• Learning and memory – Occur at synapses • Unique features of Ca2+ – Critical for neurotransmitter secretion and muscle contraction, every form of synaptic plasticity – Charge-carrying ion plus a potent second messenger • Can couple electrical activity with long-term changes in brain