Chapter 23: Wiring the Brain

Transcription

1 Chapter 23: Wiring the Brain Introduction Operation of the brain Precise interconnections among 100 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

2 The Genesis of Neurons Example: Mammalian retinogeniculocortical pathway

3 The Genesis of Neurons Cell Proliferation Neural stem cells give rise to neurons and glia

4 The Genesis of Neurons Cell Proliferation (Cont d) Cleavage plane during cell division determines fate of daughter cells

5 The Genesis of Neurons 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

6 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

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

8 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

9 The Genesis of Connections The three phases of pathway formation: (1) pathway, (2) target, (3) address

10 The Genesis of Connections The Growing Axon Growth cone: Growing tip of a neurite

11 The Genesis of Connections Axon Guidance Challenge in wiring the brain Distances between connected structures But in early stages nervous system is 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

12 The Genesis of Connections Axon Guidance Guidance Cues: Chemoattractant (e.g., netrin), Chemorepellent (e.g., slit)

13 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 Ephrins/eph (repulsive signal)

14 The Genesis of Connections Axon Guidance Establishing Topographic Maps

15 The Genesis of Connections Synapse Formation Modeled in the neuromuscular junction

16 The Genesis of Connections Synapse Formation Steps in the formation of a CNS synapse: Dendritic filopodium contacts axon Synaptic vesicles and active zone proteins recruited to presynaptic membrane Receptors accumulate on postsynaptic membrane

17 The Elimination of Cells and Synapses 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

18 The Elimination of Cells and Synapses Changes in Synaptic Capacity Synapse elimination modeled in the neuromuscular junction

19 Activity-dependent Synaptic Rearrangement Synaptic rearrangement Change from one pattern to another Consequence of neural activity/synaptic transmission before and after birth Critical Period

20 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)

21 Activity-dependent Synaptic Rearrangement Segregation of Retinal Inputs to the LGN (Cont d) Plasticity at Hebb synapses Winner-takesall

22 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

23 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

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

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

27 Activity-dependent Synaptic Rearrangement Modulatory Influences Increasing age Before and after birth Enabling factors

28 Elementary Mechanisms of Cortical Synaptic Plasticity Two rules for synaptic modification Wire together fire together (Hebbian modifications) Out of sync lose their link Correlation: heard and validated

29 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

30 Elementary Mechanisms of Cortical Synaptic Plasticity Excitatory Synaptic Transmission NMDA receptors have two unique properties Voltage-gated owing to Mg 2+ Conducts Ca 2+ Magnitude of Ca 2+ flux signals level of pre- and postsynaptic activation

31 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)

32 Elementary Mechanisms of Cortical Synaptic Plasticity Lasting synaptic effects of strong NMDA receptor activation

33 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

34 Elementary Mechanisms of Cortical Synaptic Plasticity Brief monocular deprivation leads to reduced visual responsiveness Depends on retinal activity, NMDA activation, postsynaptic calcium

35 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

36 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

37 Chapter 24: Memory 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 Memories range from stated facts to ingrained motor patterns Anatomy: Several memory systems Evident from brain lesions

38 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

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40 Types of Memory and Amnesia Long-Term, Short-Term, and Working Memory Sensory information Short-term memory Consolidation Long-term memory Sensory information Short-term memory Consolidation Long-term memory Time Working memory: Temporary information storage

41 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)

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

43 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

44 The Search for the Engram Lashley s Studies of Maze Learning in Rats Engram: memory trace

45 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

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

47 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

48 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: , Figure 1.)

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

50 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 brains (epilepsy)

51 The Temporal Lobes and Declarative Memory The Effects of Temporal Lobectomy (HM)

52 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)

53 The Temporal Lobes and Declarative Memory The Medial Temporal Lobes and Declarative Memory

54 The Temporal Lobes and Declarative Memory The Medial Temporal Lobes and Declarative Memory Information flow through medial temporal lobe

55 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

56 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

57 The Temporal Lobes and Declarative Memory The Diencephalon and Memory Processing Brain regions associated with memory and amnesia outside the temporal lobe

58 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

59 The Temporal Lobes and Declarative Memory Memory Functions of the Hippocampus Hippocampal responses to old and new stimuli

60 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 (c) Normal and lesioned rats learn which arms are baited and avoid the rest

61 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

62 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

63 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

64 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

65 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

66 The Neocortex and Working Memory

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

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

69 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

70 The Neocortex and Working Memory Lateral Intraparietal Cortex (Area LIP) and Working Memory Area LIP: Guiding eye movements Delayed-saccade task

71 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?

72 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

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

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

75 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

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

77 Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia Gill-withdrawal reflex Habituation

78 Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont d) Habituation results from presynaptic modification at L7

79 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

80 Simple Systems: Invertebrate Models of Learning Nonassociative Learning in Aplysia (Cont d) Sensitization of the Gill-Withdrawal Reflex involves L29 axoaxonic synapse

81 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

82 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

83 Simple Systems: Invertebrate Models of Learning Associative Learning in Aplysia Classical conditioning: CS initially produces no response but after pairing with US, causes withdrawal

84 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 Ca 2+ into the presynaptic terminal

85 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

86 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 neurotransmitter

87 Vertebrate Models of Learning The structure of the cerebellar cortex

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

89 Vertebrate Models of Learning Synaptic Plasticity in the Cerebellar Cortex (Cont d) Mechanisms of cerebellar LTD Learning Rise in [Ca 2+ ]i and [Na + ]i and the activation of protein kinase C Memory Internalized AMPA channels and depressed excitatory postsynaptic currents

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

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

92 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

93 Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont d) Anatomy of the Hippocampus

94 Vertebrate Models of Learning Synaptic Plasticity in the Hippocampus (Cont d) Properties of LTP in CA1

95 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

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

97 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)

98 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

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

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

101 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

102 Vertebrate Models of Learning Synaptic Plasticity in Human area IT

103 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

104 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

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106 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%

107 Concluding Remarks Learning and memory Occur at synapses Unique features of Ca 2+ 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