Sum of the Parts: Musings on the Function of the Hippocampo-Entorhinal System NaK Group September 24, 2003

“Computational models of the hippocampal region: linking incremental and episodic memory” MA Gluck, M Meeter and C.E. Myers TRENDS in Cognitive Sciences June 2003

Connection Overview Interesting Features: Layer II perforant path splits: one to DG, one to CA3 Layer III projects to CA1 Unidirectional “Tri-synaptic Circuit”

Incremental (Multiple Trial) Learning: Gluck and Myers Hippo system performs info processing that transforms stimulus representations according to specific rules with series of connected nets Compresses (makes similar) co-current or redundant input Differentiates inputs that predict different future events Passes new assemblies to LTM networks in the neocortex and cerebellum, where error between predicted (idealized or random) hippo output and actual output is used to update weights Recently, specifically proposed EC’s anatomy and physiology could compress representations of co- current stimuli

Incremental Learning (Multiple Trials): Schmajuk and DiCarlo Hippo region crucial for forming new stimulus configs (A and B diff from AB) Cortex combines cue info to allow configural learning, then cerebellum learns to map this configural info into a behavior Hippo region calculates error between prediction and actual, then sends the error measure to neocortex and cerebellum, as well as sending predictions to cerebellum Recently, proposed that the prediction signal, used by the hippo region, originates in the EC

Episodic (One Time) Memory Models Stores random vectors (not unreasonable since info may only appear once) Hippo system orthogonalizes conjunctive, overlapping, neocortical patterns by forming relatively sparse patterns, reducing interference from similar memories Using computational arguments, this storage may be temporary (during theta), with older memories passed to the neocortex (during SPWs) GABAergic modulation has been argued to facilitate encoding new memories while not interfering with retrieval of old Hippo system may also play a role in sequence learning and spatial navigation

Episodic Memory: Brain Substrates CA3 Ideal for binding diff parts of one pattern (autoassociative) or binding diff patterns in sequence (heteroassociative), due to high recurrent collateral CA1 “Decodes” hippo patterns, allowing association with the cortical pattern from which it originated May be a pattern separator Dentate Gyrus “Sparsifier” enabling pattern separation Entorhinal Cortex May extract regularities of longer time intervals, forming a familiarity signal

“Physiological patterns in the Hippocampo-entorhinal cortex system” JJ Chrobak, A Lorincz and G Buzsaki HIPPOCAMPUS 2000

Theta and Sharp Waves Theta Waves Seen during exploration, sensory input, etc. EC Layer II and III neurons fire in theta- modulated gamma freq, projecting to the dentate, CA3, CA1, and the subiculum Dentate and CA1 neurons also independently fire theta- modulated gamma as they receive EC input EC Layers V and IV are relatively quiet Thought to allow EC neurons to alter synaptic connectivity in the hippo Sharp Waves Seen during consummatory behaviors, sitting quietly, etc. EC Layers V and IV neurons fire Hz as they receive sharp waves from the hippo (originating primarily in CA3) This discharge coincides with neocortical activity (perirhinal and medial prefrontal cortexes) EC Layers II and III do not increase their firing rates Thought to allow hippo neurons to alter connectivity of neocortical neurons

EC to Hippocampus Projections EC Layer II project to DG and CA3 by perforant path Stellate cells and pyr cells form islands, which may represent functional clusters Stellates exhibit theta-freq, sub-threshold membrane oscillations, firing (gamma) spike clusters on depolarizing phases, conveying patterns to DG/hippo targets EC Layer III projects to CA1 and Subiculum Primarily pyr cells, similar to neocortical neurons Possibly “high fidelity” pattern transmitters of cortical input

Hippocampus to EC Projections Layer V and IV are primary receivers of hippo output, which then project to cortical, subcortical (amygdala, septum, etc.) targets, and Layers II and III Occurring primarily during SPWs Layer III only slightly increased their firing rates and Layer II showed no change Experimental stimulation of deep layers produces inhibition of superficial layers Lesion of Layer III will allow propogation of epileptiform bursts from deep layers to Layer II, implying Layer III may act as a “gate” The gating may be controlled by input from the amygdala, which projects to Layers III and V and is excited by SPWs via CA1

Working Together: EC-Hippocampal Cooperation “Novelty” (error)- detecting “reconstruction network” Assumptions: Neocortical patterns are primarily projected to the hippo via Layer III The hippo reconstructs the neocortical template in order to optimize the pattern into temporal sequences Layer II compares neocortical inputs and feedback inputs from the hippocampus Steps: 1.Primary input from the neocortex and Layer V- transformed output from the hippocampus is compared by Layer II 2.Layer II “calculates” error or novelty, and this is sent to the DG and CA3, where alterations (plasticity) occur in the CA3 network 3.If there is no novelty, then the hippocampus simply reproduces previously stored patterns 4.This will continue until the error is minimized

Working Together: Summary

“Hippocampus as comparator: role of two input and two output systems of the hippocampus in selection and registration of information” OS Vinagradova HIPPOCAMPUS 2001

Two Inputs Reticulo-Septal “Attention” mechanism Theta-modulated, allowing “packeting” May organize hippocampal responses to sensory input and protect them from interference Cortico-Hippocampal Cortical areas, as well as EC, areas gather sensory info DG prelim “mixer,” that generalizes and simplifies (sparsifies?) the signal before CA3

Two Outputs CA3 to Septum (and on to the brain stem) Regulates level of arousal by inhibiting the Reticular Formation During novel stimulus, the RF is released (arousal) due to decreased output of CA3, which is being used for processing and therefore subject to more inhibitory control When novelty is lost, CA3 activity increases again, suppressing RF CA1 Schaffer Collateral as “filter” Thought to shunt dendritic APs, possibly through local I cells, blocking cortical signals Only CA1 cells not receiving CA3 input participate in processing and transmission CA1-Subiculum to Limbic Circuit to Neocortex Encoding preserved as outputs and more differentiated the farther away from hippo This additional processing may be crucial for permanent storage in cortex

Putting It All Together CA3 “compares” cortical (via DG) and brain stem (via Septum) inputs 1.In constant state (no cortical input), CA3 indirectly suppresses RF 2.Change causes regulatory inhibition to dominate CA3, which releases RF Theta activated Cortical pathways to some CA1 cells blocked 3.Cortical signal develops with delay CA3 response starts to habituate CA1 output passes to limbic circuit, which is additionally processed at each higher level and eventually stored 4.CA3 completely habituates as novelty is lost, returning the system to “closed” state 5.If familiar signal appears, the system briefly “opens” again, but quickly closes

Comparator System