hippocampal circuits 1

the case of HM

• in 1953, patient HM underwent surgery to cure his epilepsy

• the surgeon removed two thirds of this hippocampus bilaterally

  • as well as other nearby regions

• afterwards it was found that he has severe memory problems

HMs memory test results

• following the surgery, HM scored very poorly on certain memory tests, such as recalling lists of paired words, or events after his surgery

• he would also forget that he had done the test afterwards, and new people he had met

• he also showed loss of recent memories and some stretching back years, but not from childhood

anterograde amnesia

inability to form new memories

of at least some types

moderate anterograde amnesia

graded loss of recent, but not remote memories

selective memory deficits from HMs lesion

mirror tracing task was still accurate - procedural memory still intact

digit span tests still accurate - STM intact

hippocampal lesion led to memory deficits in specific types of LTM, including semantic and episodic

types of LTM

declarative memory (explicit)

• semantic (facts) - medial temporal lobe

• episodic (events) - medial temporal lobe

non-declarative memory (implicit)

• priming (priory exposure) - neocortex

• procedural (skills, habits) - striatum

• associative learning (classical and operant conditioning)

  • emotional responses - amygdala

  • skeletal musculature - cerebellum

• non-associative learning (habituation, sensitisation) - reflex pathways

hippocampus neuroanatomy

many studies on the hippocampus took place in the rat brain. it is a very preserves structure across many animals

trisynaptic circuit

• entorhinal cortex (EC) - perception stimuli - stellate cells

  • preforant path

• dentate gyrus (DG) - pattern separation - granule cells

  • mossy fibres

• CA3 - associative memory and pattern completion - pyramidal cells

  • Schaffer collateral

• CA1 - episodic memory - pyramidal cells

entorhinal cortex (EC)

major input/output gateway to the hippocampus from cortex

• inputs from EC (L2 and 3) - spatial and sensory / contextual info

• outputs to EC (L5) - spatial map info, episodic info, temporal sequences

what do hippocampal neural circuits do

brain needs to be understood at 3 levels of analysis, the computational, algorithmic, and implementational/physical levels

DG circuitry specialised for pattern separation, and CA3 circuitry specialised for pattern completion

dentate gyrus (DG)

~200,000 EC cell projecting to Dg

• representations may be overlapping- risk of interference

~1,000,000 DG granule cells

• only a very small subset of cells (<3%) are active at any time

• huge number of possible combinations of active neurons (~10^50,000)

• supports ability of hippocampus to distinguish contexts / memories

CA3

DG granule cell inputs:

• only 46 mossy fibre inputs per cell

• but they form giant presynaptic boutons

• provide a potent, distinctive signal that configures CA3 network

EC (L2) preforant path inputs:

• relatively weaker, less distinct inputs carrying contextual info from cortex

recurrent collateral (RC) inputs:

• CA3 pyramidal cells form large number of excitatory synapses on each other

• auto-associative network- CA3 network tends to reactivate known representations (pattern completion)

evidence for hippocampal role in spatial learning

the Morris water maze showed that:

• the hippocampus is necessary for successful spatial learning

• the cortex is not necessary for spatial learning

role of NMDA receptors in spatial learning

initial evidence that Hebbian learning is involved in spatial learning mediated by the hippocampus, was that rats treated with a NMDAR blocker injected into the hippocampus were unable to locate the platform in transfer tests

genetic knock-out of hippocampal NMDARs

more targeted disruption of NMDARs has been produced with knock out mice- genetically engineered mice in which NMDARs could be removed selectively either from CA1 or CA3 at some specified stage of development, while leaving them unaffected in the neocortex

hippocampus as a region for rapid learning

NMDARs in CA3 are knocked out, leaving those in CA1 intact. normal long-term learning is unaffected, but rapid learning and pattern completion are disrupted

CA3 NMDARs are crucial for pattern completion during memory retrieval

wildtype and full cue → NMDARs contribute to full memory trace acquisition in CA1 and CA3, which is reliably reactivated by full cues during retrieval

wildtype and partial cue → recurrent CA3 collaterals allow pattern completion of Ca3 inputs to CA1 based on memory traces stored in NMDAR-dependent manner during memory acquisition

mutant and full cue → cues are enough to reactivate CA1 memory trace

mutant and partial cue → cues insufficient, poor memory recall performance

cell types involved in spatial navigation

• place cells (in CA1)

• boundary vector cells

• head direction cells (e.g. in anterior thalamic nucleus)

• grid cells (in medial EC)

  • a single grid cell fires when the rat enters particular location that fall on a hexagonal pattern

• angular head velocity cells

place cells

• place specific firing properties of hippocampal CA1 pyramidal cells of a linear tack

• the place specific firing is not attached to a single cell

  • a given place is encoded by a population of simultaneuosly active cells with partly overlapping fields