spatial learning cells that code for space synaptic plasticity in the hippocampus

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

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

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

CODING SPACE – HEAD DIRECTION CELLS • 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 • 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 • 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 • 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 • 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 • 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 • 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?

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

SYNATPTIC PLASTICITY IN THE HIPPOCAMPUS •  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 – LTP IN CA1 • 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 • 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 • 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)

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

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)

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

SYNATPTIC PLASTICITY – LTP & NMDA RECEPTORS • 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 & 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?

SYNATPTIC PLASTICITY – LTP & SPATIAL LEARNING • 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?

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?

EXPERIMENTS THAT ARE KNOCKOUTS (MOUSE) • 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) • 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) • 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

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

SUMMARY • 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 • 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 • 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 • 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 • 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

spatial learning cells that code for space synaptic plasticity in the hippocampus