1.  spatial learning  cells that code for space  synaptic plasticity in the hippocampus  experiments that are knockouts  summary PART 4: BEHAVIORAL PLASTICITY #25: SPATIAL NAVIGATION IN RATS II

2.  spatial learning  cells that code for space  synaptic plasticity in the hippocampus  experiments that are knockouts  summary PART 4: BEHAVIORAL PLASTICITY #26: SPATIAL NAVIGATION IN RATS II

3. CODING SPACE – HIPPOCAMPAL PLACE CELLS  place cells encode more than simple space  T-maze, trained (fruit loops) to alternate L & R turns  subset of place cells showed interesting pattern  e.g., activity (sector 3) anticipating right turns only  suggests hippocampal network represents episodic memories, cells are small segments of an episode  link of cells with overlapping episodes  memories

4.  spatial dreaming  large # space cells  only ~ 15% active in any 1 environ.  some silent in one environ., active in others  time- & labor-intensive to get larger picture  device to measure 150 cells at once  population or ensemble code  code predicts rat behavior in maze  many environments & codes  overlapping, not interfering  used to study plasticity... CODING SPACE – HIPPOCAMPAL PLACE CELLS

5.  spatial dreaming  plasticity  strengthening of code  learning  accompanied by reduced inhibitory activity  does code relate to consolidated (permanent) memory  trained rats in spatial task  measured code during  training  sleeping before training  sleeping after training  dreaming replay of events  memory consolidation CODING SPACE – HIPPOCAMPAL PLACE CELLS

6. CODING SPACE – HEAD DIRECTION CELLS  navigation requires knowledge of  place  direction... another class of cells...  in another structure... postsubiculum  cells fire ~ head position

7.  basic features of head direction cells  retain direction preference in novel environments  ~ 90° arc around preferred direction  populations of cells with different preferences  not ~ rat position in environment  ~ independent of rat’s own behavior CODING SPACE – HEAD DIRECTION CELLS

8.  common features of head direction cells & place cells  influenced by salient external cues  direction cells also fire after cues (light) removed   capable of deduced reckoning  using ideothetic cues  informed by vestibular and visual input  direction cells do not remap in a novel environments CODING SPACE – HEAD DIRECTION CELLS

9.  navigation involves computation by the brain  temporal process (~ video vs photograph)  memory of past events  prediction of future events  processed by sub-populations of head direction cells  2 areas measured in behaving rats  postsubicular cortex (PSC)  anterodorsal nucleus (ADN) of thalamus CODING SPACE – HEAD DIRECTION CELLS

10.  navigation involves computation by the brain  analyzed firing pattern relative to  momentary head direction  both cell types have preferred direction CODING SPACE – HEAD DIRECTION CELLS

11.  navigation involves computation by the brain  analyzed firing pattern relative to  angular velocity  PSC retain preference  ADN shift preference  future position CODING SPACE – HEAD DIRECTION CELLS

12.  navigation involves computation by the brain  ADN shift preference  predict future position  e.g., if a cell (of many) prefers 180° it may fire @  160° when  180°  200° when 180°   180° when @ 180° (future = present) CODING SPACE – HEAD DIRECTION CELLS

13.  why bother with all of this?... in theory...  deductive reckoning circuit  direction cells work by integrating internal cues  ADN cells combine information about  current head direction  head movement (turning)  proposed that PSC & ADN cells...  constitute a looping circuit, compute direction by  integrating motion/time  but... how is “time” measured? CODING SPACE – HEAD DIRECTION CELLS

14. SYNATPTIC PLASTICITY IN THE HIPPOCAMPUS  how do place cells and head directions cells  learn to change their preferences?  maintain their preferences over time?  clues from electrophysiology experiments...  brief, high-frequency stimulation of trisynaptic circuit...  all 3 pathways

15.   increased excitatory postsynaptic potentials (EPSPs) in postsynaptic hippocampal neurons  synaptic facilitation  increase lasts for hours  3 sites, 3 patterns, CA1   measured in brain “slices”  phenomenon called long-term potentiation (LTP)  a very big deal in mammalian cell.-phys. of learning  but... difficult to demonstrate relevance for behavior SYNATPTIC PLASTICITY IN THE HIPPOCAMPUS

16.  3 properties of LTP in hippocampus CA1 neurons  cooperativity: a minimum # of CA1 fibers must be activated together (1  weak, 2 bottom strong) SYNATPTIC PLASTICITY – LTP IN CA1

17.  3 properties of LTP in hippocampus CA1 neurons  associativity: a weak tetanus paired with a strong will gain - by association - value of strong  measured in response after “training” (3 top)  features ~ behavior, associative learning SYNATPTIC PLASTICITY – LTP IN CA1

18.  3 properties of LTP in hippocampus CA1 neurons  specificity: LTP can be restricted to single activated pathway (2 bottom), others unchanged (2 top)  localized to  regions of hippocampus  inputs regions on single cells (2)

19. SYNATPTIC PLASTICITY – LTP IN POSTSYNAPTIC CELLS  CA1 pyramidal neurons  LTP in CA1 is dependent on pyramidal neurons (PNs)  inhibition of PN activity blocks LTP in CA1  hyperpolarize PN membrane blocks LTP in CA1  blocked inhibition of PN facilitates LTP in CA1  depolarize PN membrane  facilitates LTP in CA1 during weak tetanus  not on its own ( i.e., effect is associative)  the postsynaptic cell must be depolarized for LTP to occur in the presynaptic cell

20. SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS  glutamate (GLU), main excitatory transmitter (brain)  N -methyl-D-aspartate (NMDA) 1 (of many) receptors  LTP requires depolarization to open NMDA channel  doubly gated channel, by.. GLU (receptor) & voltage (sensor)

21.  evidence for NMDA involvement in LTP  NMDA blockers, e.g. aminophosphnovalerate (APV)  blocks NMDA activity  blocks LTP  cooperativity: GLU from  weak input  depolarize postsynaptic cell  strong input  depolarizes postsynaptic cell  associativity: GLU from  strong input  depolarizes postsynaptic cell  weak input (paired)  opens NMDA channels* SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS

22.  evidence for NMDA involvement in LTP  Hebb’s Rule: synapses are strengthened if a presynaptic cell repeatedly participates in driving spikes in a postsynaptic cell  GLU & NMDA receptor satisfies the rule  have coincident activity of cells  presynaptic release of GLU  receptors  postsynaptic depolarization by non-NMDA receptors SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS

23.  Ca ++ influx into the postsynaptic cell is required for LTP  block calcium (buffer)  blocks LTP  calcium influx through NMDA receptor/channel SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS

24.  evidence for NMDA involvement in LTP  specificity: dendritic spines  NMDA receptors on dendritic spine heads   Ca ++ entry restricted by necks   anatomical subdivisions SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS

25.  evidence for NMDA involvement in LTP  specificity: dendritic spines  NMDA receptors on dendritic spine heads   Ca ++ entry restricted by necks   anatomical subdivisions SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS

26.  Ca ++ influx into the postsynaptic cell is required for LTP  Ca ++  LTP mediated by 2 nd messenger signaling  Ca ++ /calmodulin kinase (CaMKII)  protein kinase C (PKC) SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS

27.  2 types of LTP described in CA1 neurons  early-phase LTP (E-LTP)  1  3 h  cAMP & protein synthesis-independent  late-phase LTP (L-LTP)  10 h +  cAMP & protein synthesis-dependent  LTP in rats ~  long-term synaptic facilitation in Aplysia  long-term memory in Drosophila SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS

28.  2 types of LTP described in CA1 neurons  early-phase LTP (E-LTP)  1  3 h  cAMP & protein synthesis-independent  late-phase LTP (L-LTP)  10 h +  cAMP & protein synthesis-dependent  LTP in rats ~  long-term synaptic facilitation in Aplysia  long-term memory in Drosophila

29. SYNATPTIC PLASTICITY – LTP & SPATIAL LEARNING  does LTP have anything to do with learning?... difficult  spatial learning & memory in the water maze  block LTP with AP5  block memory  ask the 3 Qs...  correlation?  necessity?  sufficiency?

30.  does LTP have anything to do with learning?... difficult  spatial learning & memory in the circular platform maze  aging  LTP ~  aging  memory  ask the 3 Qs...  correlation?  necessity?  sufficiency? SYNATPTIC PLASTICITY – LTP & SPATIAL LEARNING

31. EXPERIMENTS THAT ARE KNOCKOUTS (MOUSE)  genetic engineering - e.g. already with Drosophila  transgenic “knockouts” (also “knockins”)  single gene manipulations  LTP & spatial learning  fyn gene knockout are tyrosine kinase – and...  knockouts of CaMKII –   LTP in CA1 cells   spatial learning  ask the 3 Qs...  correlation?  necessity?  sufficiency?

32.  CaMKII knockouts - enzyme cannot be Ca ++ modulated  LTP impaired (in “functional” range)  place cells  fewer   specificity  focus  stable  platform maze   spatial learning  ask the 3 Qs... EXPERIMENTS THAT ARE KNOCKOUTS (MOUSE)

33.  NMDA receptor knockouts  LTP severely impaired  place cells (multi-elect.)   specificity   coordinated firing  NMDA-receptor-mediated synaptic plasticity required for proper representation of space in CA1 region of hippocampus EXPERIMENTS THAT ARE KNOCKOUTS (MOUSE)

34.  NMDA receptor knockouts  water maze   spatial learning  ask the 3 Qs...  arguments more compelling with each experiment  spatial & temporal targeting of knockout, correlation of lesion, LTP, behavior remains EXPERIMENTS THAT ARE KNOCKOUTS (MOUSE)

35. SUMMARY  spatial navigation uses 2 types of cues  external (landmarks)  internal (ideothetic)  deductive reckoning (memory)  spatial navigation studied in rats using  radial arm maze  T-maze  water maze  circular platform maze

36.  tasks are designated as  spatial (using distal cues)  cued (or non-spatial, using proximal cues)  lesion studies, hippocampus  for spatial learning  if lesions precede learning  working & reference memory tasks are impaired  cued tasks are not impaired  if learning precedes lesions  time between events important  usually older memories are less affected SUMMARY

37.  two classes of neurons encode space  place cells, CA1 hippocampus  firing field  stability ~ weeks, memory  influenced by  external cues (landmarks)  internal cues (vestibular, visual ~ motion)  field in dark ~ active  can be event-related, predictive ( e.g., turning)  work together  ensemble code  replay in sleep... consolidation?... dreaming? SUMMARY

38.  two classes of neurons encode space  head direction cells, CA1 hippocampus  fire ~ head direction  similarly influenced by  external cues (landmarks)  internal cues (vestibular, visual ~ motion)  2 types of cells  PSC cells encode current direction  ADN cells encode future direction SUMMARY

39.  LTP is a prominent form of hippocampal synaptic plasticity, with the following properties:  cooperativity  associativity  specificity  LTP in CA1 neurons ~ NMDA receptor, 2 requirements:  depolarization of the postsynaptic cell  binding of glutamate with the NMDA receptor  allows channel opening, Na + & Ca ++ influx  Ca ++ influx is required for induction of LTP SUMMARY

40.  NMDA receptor  mechanism for Hebb’s Rule  Evidence that LTP underlies (or is involved with) mechanisms for learning  drugs blocking LTP also block spatial learning  aging affects LTP and spatial learning  mice knockouts for “LTP genes” show deficits in  LTP  place cell properties  spatial learning SUMMARY