1. Mode shifting between storage and recall based on novelty detection in oscillating hippocampal circuits M. Meeter J. M. J. Murre L. M. Talamini Date of Presentation: 05/09/2012

2. Introduction

3. Role of Acetylcholine in Mode Shifting Hippocampal novelty detection may regulate levels of acetylcholine – Shifts hippocampal dynamics between encoding or retrieval Information with high novelty content would induce a learning state Input similar to already stored patterns would induce a retrieval state – Little learning takes place during retrieval to protect existing patterns from modification.

4. Role of Acetylcholine in Mode Shifting Hippocampal novelty detection may regulate levels of acetylcholine – Shifts hippocampal dynamics between encoding or retrieval Retrieval mode: low ACh levels Learning mode: high ACh levels

5. Role of Acetylcholine in Mode Shifting Hippocampal novelty detection may regulate levels of acetylcholine – Shifts hippocampal dynamics between encoding or retrieval Information with high novelty content would induce a learning state Input similar to already stored patterns would induce a retrieval state – Little learning takes place during retrieval to protect existing patterns from modification.

6. Learning State

7. Role of Acetylcholine in Mode Shifting Hippocampal novelty detection may regulate levels of acetylcholine – Shifts hippocampal dynamics between encoding or retrieval Information with high novelty content would induce a learning state Input similar to already stored patterns would induce a retrieval state – Little learning takes place during retrieval to protect existing patterns from modification.

8. Retrieval State

9. Opposition to ACh’s Role in Mode Shifting ACh has a slow and sustained influence on hippocampal activity – Depolarization develops a few seconds after ACh release – Lasts 10 s or more Dynamics are too slow to underlie mode shifting. Opposers support a fast mode shift – On the order ot 10s or 100s of milliseconds

10. Opposition of ACh’s Role in Mode Shifting ACh has a slow and sustained influence on hippocampal activity – Depolarization develops a few seconds after ACh release – Lasts 10 s or more Dynamics are too slow to underlie mode shifting. Opposers support a fast mode shift – On the order of 10s or 100s of milliseconds

11. Opposition to the Opposition of ACh’s Role in Mode Shifting Time scale at which natural learning and retrieval take place is slow – Rats take minutes to familiarize themselves to new environments – Fear conditioning takes several seconds to take (in rats) – In humans, long-term recall deteriorates when study times are less than 2 s

12. The System

13. Structural and functional properties of the subregions and connections Feedback and feedforward inhibition Oscillatory population dynamics Theta (4-10 Hz) and Gamma (20-40 Hz) Features Integrate-and-fire nodes (Sodium, potassium, chloride, and leak currents Hebbian learning (LTP) and negative Hebbian learning (LTD)

15. Entorhinal Cortex Main cortical input structure of the hippocampus Considered as one single input layer that propagates the same information to the DG, CA3, and CA1

17. Dentate Gyrus Receives the majority of the input from the EC Sparseness of activation – High number of granule cells but very few fire at a given moment – Divergent input Orthogonalizes input Orthogonalization – Patterns that are correlated in a given layer (i.e. EC) generate uncorrelated representations in the projection field (i.e. DG) No Hebbian plasticity between the DG and CA3 Feedforward inhibition to CA3

19. CA3 Involved in either: – Autoassociative learning and pattern completion – Heteroassociative learning and sequence recall Both cases are inferred from extensive recurrent connections among CA3 Difference in time scale: – Autoassociation: learning over short intervals – Heteroassociation: learning over longer intervals

21. CA1 Receives a direct projection from the EC (Yeckel and Berger, 1990) Indirect projection from tri-synaptic loop Proposed to be a translator between the code of the CA3 and the cortical code Model associates the CA3 pattern with the EC pattern

23. Medial Septal Nuclei Fibers from the CA1 and CA3 target GABAergic septal projection neurons and ACh neurons – Hippocampal activity inhibits the septum Modulates the hippocampus using ACh – Nonspecific target – Seems to affect the entire hippocampus

24. Hippocampus Summary EC: - Major input DG: - Orthogonalizer CA3: - Storage CA1: - Translator Septum: - ACh modulation

26. Acetylcholine as a Novelty Signal Experiments – During exploration of a new environment, ACh is increased relative to baseline – ACh levels decrease during consecutive explorations of the same test enviornment

27. Effects of Acetylcholine Dampens transmission between CA3 and CA1 Slow, subthreshold depolarization of hippocampal principal neurons lasting several seconds Enhancement of LTP at CA3, CA1, and DG Reduction of adaptation in CA3, CA1, and DG Suppressed inhibition of DG and pyramidal cells (supression of basket cells)

28. Effects of Acetylcholine Learning mode – High ACh – CA3-CA1 transmission dampened – Activity in CA1 is dominated by EC – Allows CA3-CA1 connection to store the association between the EC pattern and CA3 pattern Retrieval mode – Low ACh – CA1 relays the reinstated CA3 pattern to the EC and other output structures

29. Results

30. Storage

31. “Correct CA1 Nodes” Correct CA1 Nodes: number of firing CA1 nodes that receive a one-to-one connection from an EC node Incorrect CA1 Nodes: number of firing CA1 nodes that are not connected to an EC node Missing CA1 nodes: number of CA1 nodes that receive a one-to-one connection from an EC node that does not fire

32. Retrieval Retrieval mode (ACh = 0.1)

33. Pattern Completion After storing one pattern, a variable number of EC nodes associated with the pattern are deactivated Test in retrieval mode (ACh = 0.1) and learning mode (ACh = 0.75) Pattern completion measured as the maximum proportion of correct CA1 nodes that were simultaneously active during the theta cycle

34. Pattern Completion CA1 activity is strongly correlated with DG activity Pattern completion occurs in DG Number of correct nodes increases Number of incorrect nodes increases ACh depolarizes all cells making activation easier

35. Pattern Completion With small cue-sizes, more of the pattern is completed in learning mode than in retrieval mode but comes at a price of a compromised integrity of retrieval Hypothesis: During effortful retrieval, input cues do not lead to an instatement of a stored pattern, so the hippocampus shifts to learning mode Consistent with the “retrieval practice effect” – Implies that effortful and successful retrieval constitutes a power learning method – Effort retrieval has a stronger effect on retention than fast, easy recall

36. Novelty Detection and Dentate Gyrus After acquisition of one pattern, the network was cued with patterns that were either the same as the stored pattern (old), completely different (new), or consisted of a variable ratio between old and new EC nodes DG same: Same DG nodes activated as during the stored pattern DG diff: Different DG nodes activated than with stored pattern Correct CA1 nodes

37. Novelty Detection and Dentate Gyrus DG and CA1 liked old stuff, not new stuff Little overlap under areas of same and diff All types of input elicit strong activity in DG and CA1 Larger range of mixed input activates mixture of old and new DG nodes

38. Effects of ACh on Pattern Storage -New pattern was presented during one theta cycle with different levels of ACh modulation - Acquisition was evaluated by presenting the pattern during one theta cycle with ACh modulation set at 0.1 - Maximum number of correct CA1 nodes simultaneously active during retrieval phase was used to assess ACh effects on learning performance - If ACh was too high during learning phase, then learning was inhibited - If ACh is too high, then EC alone can cause CA1 to fire before CA3 can stimulate CA1 - CA1 cells that do not receive EC input will form stronger connections with their CA3 input, which does not reflect EC firing for diminished retrieval performance

39. Effects of ACh on Novelty Detection Stored one pattern and presented either the “old” pattern or a randomly selected new pattern while varying ACh modulation Look at difference in activity from the old pattern versus the new pattern

40. Effects of ACh on Novelty Detection Novelty detection decreases as ACh increases Difference in activity is first seen in DG

41. Insights from the Model Prominent role of DG in novelty detection Reasoning for the existence of separate learning and retrieval modes – Retrieval in learning mode is unreliable through the activation of features that were no part of the original memory Separation of learning and retrieval modes enhances accurate retrieval Hippocampus incorporates a low band filter to ensure that ACh modulation fluctuates with novelty and not with theta or gamma rhythms

42. Slow Shift vs. Fast Shift Slow Shift – Mediated by ACh – Mode shifting induced by novelty of input – Most learning takes place when a pattern is new Fast Shift Mediated by theta modulation where LTP and LTD dominate in different phases of the cycle Occurs automatically due to differing learning and retrieval dynamics on different phases of theta Old and new patterns are continuously learned, unlearned, and relearned

43. Predictions of the Model Learning should occur more quickly in experimentally induced high ACh states versus low ACh states Novel configurations lead to increased activation of cholinergic cells leading to a surge in hippocampal ACh release Novel configurations produce enhanced synaptic plasticity in the hippocampus New patterns should elicit little activity in the hippocampus in the absence of ACh Model suggests that balance of strength between direct perforant path and trisynaptic input to CA1 is essential to pattern encoding

44. Other Possible Novelty Signals Novelty signal over the CA3 through intermediaries of lateral septum, and raphe nuclei, reticular formation – Could influence levels of arousal Novelty signal via the EC to the ventral striatum – Could influence chain of events that facilitate a change of behavioral strategy

45. Uses of the Model Explore the significance of different parallel inputs (input from different layers of the EC) to the hippocampus for memory processing Explore how autoassociation and heteroassociation may be implemented in circuitry How suppression of familiar objects in parahippocampal cortex affects configuration novelty detection in hippocampus How hippocampal subdivisions differentially contribute to neuropsychological constructs such as recall, recognition, and familiarity processing

46. Problems “Therefore, at present there is no direct evidence for a hippocampal influence on ACh release during behavioral learning.” !!!!!!!!! “That is, the GABAergic cells would disinhibit ACh cells in response to hippocampo-septal stimulation.” – Opposite of what the model says it should do – “However, the inhibitory hippocamp-medioseptal projection directly onto ACh neurons may be sufficient to regulate activity of ACh neurons during mode- shifting.”

47. Extra Stuff