Chapter 25: Molecular Mechanisms of Learning and Memory

1. Neuroscience: Exploring the Brain, 4e Chapter 25: Molecular Mechanisms of Learning and Memory ..

2. Introduction • Neurobiology of memory • Identifying where and how different types of information are stored • Hebb • Memory results from synaptic modifications. • Study of simple invertebrates (Kandel) • Molecular mechanisms lead to synaptic plasticity. • Electrical stimulation of brain • Experimentally produce measurable synaptic alterations

3. Memory Acquisition • Learning and memory in two stages • Acquisition of a short-term memory • Physical modification of brain caused by incoming sensory information • Modifying synaptic transmission between neurons • Consolidation of long-term memory • Requires new gene expression and protein synthesis

4. Flow of Sensory Information into Long-Term Memory

5. Cellular Reports of Memory Formation • Every neuron can form a memory of recent patterns of activity. • Area IT • Visual area • Area involved in memory storage of objects • Property of stimulus selectivity

6. Responses to Faces in Inferotemporal Cortex

7. Distributed Memory Storage • Neural network model • Unique pattern or ratio of activity of neuronal activity • Distributed memory • No single neuron represents specific memory. • Advantage: Memories survive damage to individual neurons. • Graceful degradation of memories with gradual neuron loss • Physical change of memory  modification of synaptic weight (Kandel)

8. Model of Distributed Memory

9. Strengthening Synapses • Increases and decreases in synaptic weights • Shift neuronal selectivity and store information • Synaptic plasticity—long-term potentiation (LTP) • The trisynaptic circuit of the hippocampus 1. Entorhinal cortex → dentate gyrus (perforant path) synapses 2. Dentate gyrus → CA3 (mossy fiber) synapses 3. CA3 → CA1 (Schaffer collateral) synapses

10. Some Microcircuits of the Hippocampus

11. Properties of LTP in CA1 • Bliss and Lomo • High-frequency electrical stimulation (tetanus) of excitatory pathway produces LTP. • Most excitatory and many inhibitory synapses support LTP. • Schaffer collateral synapses • Property of input specificity • Spatial summation of EPSPs: cooperativity • LTP causes association of inputs.

12. The three neuroscientists have independently and collectively shown how the connections – the synapses - between brain cells in the hippocampus (a structure vital for the formation of new memories) can be strengthened through repeated stimulation. LTP is so-called because it can persist indefinitely.

13. Long-Term Potentiation in CA1

14. LTP can last a long, long time

15. NMDARs are activated by simultaneous pre- and postsynaptic activity

16. Box 25.2 Synaptic plasticity: Timing is everything.. • Presynaptic release coinciding with postsynaptic action potential is important for LTP • LTP is generated when postsynaptic synaptic action potential follows EPSP within about 50 msec

17. Mechanisms of LTP in CA1 • Glutamate receptors mediate excitatory synaptic transmission. • NMDA receptors and AMPA receptors

18. The growth of dendritic spines following LTP

19. Weakening Synapses • BCM theory: Synapses undergo synaptic weakening when active as postsynaptic cell is only weakly depolarized by other inputs. • Homosynaptic long-term depression (LTD) • Bidirectional plasticity governed by two simple rules • Synapses during strong depolarization of postsynaptic neuron causes LTP. • Synapses during weak depolarization of postsynaptic neuron causes LTD. • Spike timing–dependent plasticity

20. Homosynaptic LTD in the Hippocampus

21. Spike timing-dependent plasticity

22. Mechanisms of LTD in CA1—(cont.) • Two forms of homosynaptic LTD at Schaffer collateral–CA1 synapse • G-protein coupled metabotropic glutamate receptors (mGluRs) • NMDA receptors • Rise in postsynaptic [Ca2+] is necessary to trigger LTD. • LTP and LTD: bidirectional regulation

23. NMDA Receptor Activation and Bidirectional Synaptic Plasticity • 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)

24. How Ca2+ Can Trigger Both LTP and LTD in the Hippocampus

25. 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 • “Egg carton” model of AMPA receptors • Role of protein PSD-95

26. Egg Carton Model of AMPA Receptor Trafficking at Synapse

27. LTP, LTD, and Memory • Morris experiments with inhibitory avoidance • First evidence of NMDA-receptor-dependent processes in memory • Tonegawa, Silva, and colleagues • Genetic “knockout” mice • Consequences of genetic deletions (CaMK11 subunit) • Parallel deficits in hippocampal LTP and memory • Limitations of using genetic mutants to study LTP/learning • Hippocampal NMDA receptors play a key role in synaptic LTP and LTD and learning and memory.

28. Bidirectional Synaptic Modifications in Human Area IT

29. LTP in CA1 Induced by Learning

30. Synaptic Homeostasis • Unchecked synaptic plasticity could lead to unstable neuronal responses. • Homeostatic mechanisms needed to provide stability and keep synaptic weights within useful dynamic range • Metaplasticity • Synaptic scaling

31. Metaplasticity • Synaptic modification threshold • NMDA receptor activation between that required for LTD and for LTP. • When activity rises, the modification threshold slides up. • If activity levels fall, the modification threshold slides down. • Metaplasticity: Rules of synaptic plasticity change depending on history of synaptic or cellular activity. • Adjustments in composition of NMDA receptors

32. The sliding modification threshold

33. Synaptic Scaling • Adjustment of absolute synaptic effectiveness that preserves the relative distribution of synaptic weights • Result of multiple mechanisms • Voltage-gated Ca2+ channels • Elevated activity increases CaMKIV-dependent gene expression. • Period of inactivity decreases CaMKIV-dependent gene expression. • Occurs over hours to days

34. Memory Consolidation • Phosphorylation insufficient as long-term memory consolidation mechanism • Phosphorylation of a protein is not permanent. • Memories would be erased. • Protein molecules themselves are not permanent. • Other mechanisms needed for long-term consolidation • Protein kinases • Protein synthesis

35. Regulation of CaMKII • Phosphorylation maintained: kinases stay “on” • CaMKII and LTP • Molecular switch hypothesis

36. Protein Kinase M Zeta • Role in maintenance of LTP and certain forms of memory • Sacktor and colleagues • “ZIP (PKMzeta inhibitory peptide) zaps memories” • Maintains changes in synaptic strength by continuing to phosphorylate substrates • Specific mechanisms still unclear.

37. Protein Synthesis and Memory Consolidation • Protein synthesis required for formation of long-term memory • Protein synthesis inhibitors • Deficits in learning and memory • New protein synthesis required during the period of memory consolidation

38. Synaptic Tagging and Capture • Experiments of Julietta Frey and Richard Morris • Weak stimulation endows synapses with a tag. • Enables them to capture newly synthesized proteins that consolidate LTP • An event that would otherwise be forgotten might be seared into long-term memory • If it occurs within 2 hours of a momentous event that triggers a wave of new protein synthesis • Molecular mechanisms still not fully understood

40. CREB and Memory • CREB: cyclic AMP response element binding protein • Functions to regulate expression of neighboring genes • Tully and Yin • CREB regulates gene expression required for memory consolidation.

41. Regulation of Gene Expression by CREB

42. 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% • Altering visual or tactile environment stimulates formation of new dendritic spines. • Limits to structural plasticity in adult brain • But the end of a critical period does not necessarily signify an end to structural changes

43. Synaptic remodeling in the cerebral cortex during learning and memory

44. Concluding Remarks • Learning and memory • Occur at synapses • Underlying mechanisms appear universal. • Unique features of Ca2+ • Critical for neurotransmitter secretion and muscle contraction and every form of synaptic plasticity • Unique ability to directly couple electrical activity with long-term changes in brain