1 THE PHYSIOLOGY OF LEARNING & MEMORY Dr. MTHE PHYSIOLOGY OF LEARNING & MEMORY Dr. M. Wesner, Biopsych 2401 Part 4: The Changing Brain: [Chs. 23, 24, 25] FINAL EXAM TIME: Thursday, April 13, :00PM - 09:00PM Ryan Bldg 1023

2 When talking about learning and memory, we are really talking about neural or brain plasticity - changes in the substrate due to environmental (molecular-, system- or behavior- based) influences.

3 Plasticity first came about in our understanding of neural development..much of which came from the retinogeniculostriate ( or retinogeniculocortical) pathway: Notice the ermergence of neurons

4 3 stages of neuronal morphological developmentCell proliferation Cell migration Cell differentiation

5 Cell Proliferation

6 The 3 brain “vesicles”

7 Cell Proliferation Precursor cells divide into daughterVast majority of neocortical cells are born between the 5th week and 5th month of gestation. 250,000 new neurons per minute! Precursor cells divide into daughter cells. Cells extend radial glia towards pial surface and descend back to ventricular zone to continue with mitotic division. (note: Vertical cleavage)

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9 Cell Proliferation & Migration~2/3 follow along radial glia process towards subplate. Precursor cells divide into daughter cells. Cells that undergo horizontal cleavage migrate towards the pial surface and remain there as a differentiated cell. Occurs later in development

10 Horizontal cleavage instigates migration to proper precursor zones that defines functionality of the neurons. Transcription factor proteins Notch-1, unopposed by Numb is free to activate gene expression (transcription & translation).

11 Cell Migration & DifferentiationCell migration-neuroblasts are moving along fibrils that radiate from glia in the ventricular zone. The first “horizontally-cleaved” migrating daughter cells form subplate just under the cortical plate. Subsequent daughter cells move past the subplate into the cortical plate and begin differentiating into functionally-specific neurons in cortical layers. subplate eventually disappears with further development.

12 The Genesis of Neurons Cell MigrationPyramidal 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 IN PRIMATES, Subventricular zone cells proliferate and are destined for upper layers of the cortex (Layers II & III)—part of the corticocortical associative connections. in primates: cells differentiate into neocortical layers II & III

13 Cell Migration & DifferentiationCell differentiation-neuroblasts arrive at cortical subplate. Subsequent neuroblasts migrate from ventricular zone through the subplate and differentiate in the cortical plate as layers VI and later V. Later still, layers IV, III, II develop in that order (inside out). Later, neuroblasts begin forming into neurons (i.e., arborization). Note: All cortical cells (& glia-from ventral surface) have common precursor cells (neural stem cells). Functionality (differentiation) depends on the microenvironment and time of development (spatiotemporal gene expression). removal of subplate & withdrawal of subcortical plate

14 ADULT NEUROGENESIS (particularly around hippocampus) parallels ontogeny

15 ..this staging can even happen in vitro!NOTE: Neurons are first to differentiate, followed by glial (astrocytic then oligodendrocytic) differentiation.

16 NOTE: Differentiation of neural precursor into pyramidal neuron in Layer V

17 What about non-cortical projection influences?So far, we looked at cortical proliferation, migration and differentiation based on radial glial guidance (i.e., a protomap). What about those protocells that end up distanced from mature site? E.g., developing thalamic cells may send fibers that are attracted to the developing V1 subplate. Once mature, thalamic subplate cells invade the cortex instigating cell differentiation. In other words, not a complete protomap for all neuroblasts, but a premature “cortical quilt” awaiting migrating thalamic projections to activate differentiation in the subplate (e.g., Shlaggar & O’Leary, parietal cortex replaced by occipital cortex ïn rat still developed “barrels”.) How do developing, projecting axons connect?

18 early thalamic innervations direct subplate population of cells lying in wait.Thalamus- Adapted from Schlagger and O'Leary 1991

19 Again, evidence of projection guidance comes from the retinogeniculostriate ( or retinogeniculocortical) pathway: Retinotopy Ocular dominance Parallel stream specificity ..all this precision maintained from retina to LGN to cortex. How? Notice the ermergence of neurons

20 Proper projections require..Pathway selection - growing axons must find a pathway to various target sites (e.g., nasal & temporal retinal ganglia projecting through contralateral & ipsilateral optic chiasm, respectively). Target selection - growing axons must recognize coarse target sites along the pathway (e.g., retinal ganglion axons entering into LGN of thalamus). Address selection - growing axons must sort out which layer (or portion) of target is important for establishing communication with other neurons (e.g., ganglion cells establishing a retinotopic visual field organization within the 6 layers of LGN).

21 How is this done? Each of the 3 phases of pathway formation depends on communication between cells via: Cell contact with diffusible chemicals over long distances (concentration differences). Cell contact with secretions from other cells Cell-to-cell contact

22 address target pathway

23 Pathway selection: Neurites form growth cones to develop later into dendrites and axons. Cytoskeleton: Rhythmic undulations of lamellipodia with the filopodia probing the environment. Extracellular matrix (laminin glycoprotein) binds to surface molecules (integrins) that form “tracks”. Fasciculation: unison growth of multiple axons along molecular highway. Forms bundles of axonal projections. fill-oh = a cytoskeletal protein actin projection on the mobile edge of a cell.

24 Migration: ..the formation of “bundles” of axons.(Cell adhesion molecules)

25 netrin and slit released by midline cellsAxon Guidance CHEMOAFFINITY HYPOTHESIS- specific, complementary chemical markers on growing axons and on tracks in the extracellular space. Netrin-attractant Slit-repellant. netrin and slit released by midline cells Robo receptor is upregulated once reaching midline. Axon is now repelled by high [SLIT] at midline. Diffuse gradient signals: Chemoattractants Chemorepellants

26 Target selection is based on synapse formation through the interaction of proteins and chemical surface markers (e.g. chemoaffinity hypothesis)

27 Address selection: Proper addressing is based on synaptic formation & competition at target. Neurotrophins [e.g., Brain-Derived Neurotrophic Factor (BDNF)] act on the cell surfaces of presynaptically stable neurons. The trophins act on 2nd messenger receptors and inhibit genetically preprogrammed cellular apoptosis (suicide). Note: More cells die than survive (e.g., in visual cortex 5000 cells/sec commit suicide during adolescence).

28 (BDNF) NOTE: These type of biochemical systems have also been described in adult brain! Tyrosine kinase (trk) receptors Multiple kinases Extracellular signal Regulated Kinase (ERK) Ribosomal S6 Kinase (RSK) -this altered transcription function can result in the up-regulation of receptors “validating” the cell or it can result in the shut down of genetically predisposed apoptosis!

29 apoptosis Necrosis is death due to trauma.

30 Address selection: Proper addressing is based on synaptic formation (e.g., agrin binding to MuSK) & competition at target. Neurotrophins act on the cell surfaces of presynaptically stable neurons. The trophins act on 2nd messenger receptors and inhibit genetically preprogrammed cellular apoptosis (suicide). Note: More cells die than survive (e.g., in visual cortex 5000 cells/sec commit suicide during adolescence). Synaptic activity reinforces surviving neurons. (“use it or lose it” can also apply to adult plasticity)

31 The Genesis of ConnectionsSynapse Formation-Steps in the formation of a CNS synapse: Dendritic filopodium contacts axon Synaptic vesicles and active zone proteins recruited to presynaptic membrane (synaptic stability begins) Receptors accumulate on postsynaptic membrane

32 Synaptic Rearrangement-final step in “address selection”The innervation pattern is based on synaptic experience. The more activity across a synapse, the greater the strength of future synaptic connections. The remainder inactive synapses will die through apoptosis.

33 (e.g., a-bungarotoxin) Partially block AChR with alpha-bungarotoxin (antagonist) will evetually lead to loss of receptors and presynaptic terminals at that application site – even localized within the same presynaptic cell.

34 Back to visual system (Donald Hebb, 1949)Retinotopy or ocular dominance final refinement defined by synchronized activity of neighboring cells Synchronized firing from each eye reinforces and “stabilizes” the segregated synapses. RE RE LE Because these cells can undergo Hebbian modifications, these cells’ synapses are referred to as Hebb synapses. NOTE: some molecular preprogramming occurs to begin to establish segregation prenatally. LE

35 ..leads to reciprocation & stability“Neurons that fire together, wire together.” Donald Hebb (1949) The Organization of Behavior -- The Hebbian Synapse: To strengthen synapse A, it helps to have activity from nearby B as well (i.e., postsynaptic depolarization along with presynaptic excitatory NT release. This is synchrony.. ..leads to reciprocation & stability A B

36 Hebb used a more parsimonious model to characterize memoryHebb used a more parsimonious model to characterize memory. It is not in a special “location” of the CNS, but in the very cells that are involved with the processing of information in the first place. This means there are multiple consolidation areas, each unique to the sensory modality processing pathways involved.

37 Environmental experience can alter synaptic arrangements (e. gEnvironmental experience can alter synaptic arrangements (e.g., Hubel & Wiesel’s visual deprivation studies of the macaque).

38 RE LE Nasal hemiretina projects contralaterallyTemporal hemiretina projects ipsilaterally.

39 CORTICAL PLASTICITY! -Changes in ocular dominance columns due to monocular deprivation. The dominance columns of the active eye* spread into the former inactivated eye columns. Binocular cell counts are also reduced after deprivation. *Injected radioactive PRL in nondeprived eye (film exposed-white)

40 true binocular cells binocular cells w/bias towards LE binocular cells w/bias towards RE Monocular LE cells Monocular RE cells NOTE: Histogram categories are found in Layer III.

41 See similar type of binocular columnn modulation with strabismus (“cross-eyed” or “wall-eyed” results in loss of stereopsis)..

42 NOTE: Histogram categories are electrophysiological counts for Layer III.

43 What are the physiological (or biochemical) correlates of the Hebbian “use it or lose it” synapse?

44 Most common Amino Acid NTs: Glutamatergic system-excitatory GABAergic system-inhibitory

45 Metabotropic receptorTransamination Pyridoxal phosphate Metabotropic receptor a-amino-3-hydroxy-5-methyl-4-isoxazole proprionic acid (AMPA) N-methyl-D-aspartate (NMDA)

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47 Anesthetic phencyclidine“angel dust” Blocks NMDA Removal depends on the duration of membrane depolarization (making this process voltage dependent).

48 ++ ++ ++ ++

49 NOTE: If there is no strong EPSPs while tetanus is delivered presynaptically, you will get an opposite long-term depression (LTD) effect! A bidirectional influence! Calcium activates kinases (e.g. CamKII).

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52 Long-term potentiation (LTP)- evidence for Hebbian synapse+ +

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54 Conscious recollection direct experience-less likely to be forgottenexplicit implicit Conscious recollection direct experience-less likely to be forgotten There are different types of memory systems. REMEMBER: Learning is the acquisition of information

55 Can use English experimental psychologist Donald Broadbent’sSensory Register - STM - LTM Multistage Filter Model to describe information consolidation and disorders… May 6, April 10, 1993

56 Working memory déjà vu?

57 Retrograde amnesia-prior events forgottenanterograde amnesia-no new memories

58 Complex Sensory informationStructures in the medial temporal lobe are involved in declarative memory formation.

59 Hippocampus = involved with declarative memoryHippocampus = involved with declarative memory. Very plastic region of the CNS. Focus on dissociated amnesia.. mental disorders in which the normally well-integrated functions of memory, identity, perception, or consciousness are separated (dissociated). (Wilfred Penfield) Temporal lobe stimulation vs. Ablation for epilepsy. Some seizures symptomatically elicit combinations of sensations, behaviors & memories. Some of Penfield’s patients when stimulated in the medial temporal lobe region experienced detailed flashbacks. A combination of sensations, behaviors, and memories.

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61 -cornu ammonis (CA) 3 2 1 LTP with high frequency stimulation.Most studied systems in vitro. -cornu ammonis (CA) pyramidals 3 2 pyramidals Granule cells 1

62 Temporal lobes - declarative function. Famous case study: Patient H.M.Some retrograde a few years before surgery, severe anterograde amnesia. Henry Molaison Note: some working memory is intact--consolidation with rehearsal. Severe inability to form new declarative memories.

63 Complex Sensory informationCase study: N.A. less severe anteograde declarative memory and similar retrograde amnesia to H.M. for two years. Diencephalon receives input from temporal lobe. Foil through the nose damaged anterior thalamic nuclei, but hippocampus more-or-less intact. Complex Sensory information

64 The dorsomedial nuclei of the thalamus receives input from the hippocampus. But it also receives input from the amygdala, inferotemporal cortex and projects outward to all frontal cortical associative areas.

65 Korsakoff’s anterograde & retrograde amnesia (> H.M or N.A.)Further support for diencephalon’s role in memory (thiamin deficiency called Korsakoff’s syndrome: Korsakoff’s anterograde & retrograde amnesia (> H.M or N.A.) Korsakoff’s disease- shows mostly anterograde amnesia (consolidation of information) with some retrograde amnesia to recent events.

66 Distinct Declarative Memory Functions:Disrupted mechanisms involved with consolidation will produce anterograde amnesia. E.g., Case HM-(hippo., temp lobe), Korsakoff’s-(dorsomedial thalamic n.; mammillary bodies) Disrupted mechanisms involved with retrieval of information will produced retrograde amnesia. E.g., Case N.A.-(ant. thalamic n.) & Korsakoff’s Tempting to think there is information processing localization based on first impressions of these case studies.. Not that simple. Does this mean anterior thalamic n. is the locus for retrieval and dorsomedial n. is the locus for working consolidation? No! Korsakoff’s & H.M. shows some retrograde (varying levels for Korsakoff’s & N.A. also showed anterograde amnesia.

67 Striatum and procedural memory..

68 Prefrontal cortex & working memory..

69 ..and hippocampus is connected to other areas of CNS..This points to the fact that learning (acquisition of information) and memory (retention) is not confined to a single place. Functional localization is not evident here. Associative connections are involved with learning & memory. Hebb’s distributed memory system model promotes equipotentiality in information retention & why it is popular in theoretical neuroscience.

70 More on the biochemical correlates of learning and memoryMore on the biochemical correlates of learning and memory.. Eric Kandel (and associates) at Columbia University worked on the sea snail (Aplysia Californicus)

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73 Nonassociative Learning in AplysiaGill-withdrawal reflex Habituation

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76 Basic principles of LearningNonassociative learning Habituation

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78 L7

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80 2nd set of presentations after day..Enhanced habituation during 2nd trial set 2nd set of presentations after day..

81 Sensory Neuron SN (presynaptic)? Accumulation of depolarizations results in N-type Ca++ channel closures, which leads to lower quantal NT release. Sensory Neuron SN (presynaptic)

82 Basic principles of LearningNonassociative learning Habituation Sensitization

83 Stronger & different # of tapsChange in stimulus type & intensity Verbal stimulus with cognitive assessment

84 D to strong tactile stimulus

85 Sensitization change can also occur with changes in stimulus position..

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87 L29

88 Enhance the synaptic connection via mediating 5-HT L29 neuron.

89 Phosphorylates & closes K+s channel

90 Prolonging the opening of K+ slow channels will keep the axon terminal of the sensory neuron hyperpolarized, thus LESS Ca++ will influx with arrival of action potentials (AP). Phosphorylating K+ slow channels will close the channels and prolong the depolarized state of the sensory neuron terminal, thus MORE Ca++ will influx resulting in more transmitter release.

91 Basic principles of LearningNonassociative learning Habituation Sensitization Associative Learning Operant Conditioning

92 S: R S+R; R S: R P+; R S: R S-R; R S: R P-; R

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94 Basic principles of LearningNonassociative learning Habituation Sensitization Associative Learning Operant Conditioning Classical Conditioning

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97 touch shock UCR CR

98 ++ ++ CaM-KII

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101 Example of a common 2nd-messenger system..Decrease gK+ b g GDP a Adenylyl cyclase GTP cAMP R PO4 C a* GTP Increase gCa++ ATP cAMP PO4 cAMP R C R C Protein Kinase A CaM-KII Ca++-Calmodulin

102 CRE (cAMP response elements)CREB-1

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104 Synaptogenesis