Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Hippocampal Gating by Entorhinal Cortex Long-Range Inhibition


Science  08 Jan 2016: Vol. 351, Issue 6269, pp.

Gating of hippocampal activity, plasticity, and memory by entorhinal cortex long-range inhibition

Jayeeta Basu,

Department of Neuroscience, Kavli Brain Institute, Columbia University Medical Center, 1051 Riverside Drive, New York, NY 10032, USA.

University of Texas at Austin, Austin, TX 78712, USA.


The precise association of contextual cues with a behavioral experience enables an animal to discriminate between salient (harmful or rewarding) versus neutral environments. What signaling mechanisms during learning help select specific contextual signals to be stored as long-term memories? Hippocampal CA1 pyramidal neurons integrate direct multisensory excitatory input from entorhinal cortex (EC) with indirect, mnemonic excitatory input from the upstream hippocampal CA3 area, and both pathways have been implicated in memory storage. Paired activation of the direct and indirect inputs at a precise timing interval that matches the dynamics of the cortico-hippocampal circuit induces a long-term enhancement of the activation of CA1 neurons by their CA3 inputs (input timing–dependent plasticity or ITDP). However, EC additionally sends long-range inhibitory projections (LRIPs) to CA1, the function of which is largely unknown. Here, we explore the role of the LRIPs in regulating hippocampal synaptic activity and memory.

GABAergic neurons (which release the inhibitory transmitter γ-aminobutyric acid or GABA) in medial entorhinal cortex (MEC) were recently found to send to hippocampus LRIPs that form relatively weak and sparse synapses on CA1 GABAergic interneurons. As lateral entorhinal cortex (LEC) conveys important contextual and object-related information to hippocampus, we examined whether this region also sends LRIPs to CA1. We expressed channelrhodopsin-2 (ChR2) selectively in LEC inhibitory neurons and examined the synaptic effects of LRIP photostimulation. The behavioral impact of the LRIPs was determined by selectively silencing these inputs locally in CA1 during contextual fear conditioning (CFC) and novel object recognition (NOR) tasks. We also used in vivo Ca2+ imaging to assess how different sensory and behavioral stimuli that typically make up a contextual experience activate the LEC LRIPs. Finally, we examined how the LRIPs influence information flow through the cortico-hippocampal circuit and contribute to ITDP.

LRIPs from LEC produced strong inhibitory postsynaptic potentials in a large fraction of CA1 interneurons located in the region of the EC inputs. Although pharmacogenetic silencing of LRIPs in hippocampus did not prevent CFC or NOR memory, it caused mice to show an inappropriate fear response to a neutral context and a diminished ability to distinguish a novel object from a familiar object. Calcium imaging revealed that the LRIP axons and presynaptic terminals responded to various sensory stimuli. Moreover, pairing such signals with appetitive or aversive stimuli increased LRIP activity, consistent with a role of the LRIPs in memory specificity.

Intracellular recordings demonstrated that the LRIPs powerfully suppressed the activity of a subclass of cholecystokinin-expressing interneurons (CCK+ INs). These interneurons were normally strongly excited by the CA3 inputs, which results in pronounced feedforward inhibition (FFI) of CA1 pyramidal neuron dendrites. By transiently and maximally suppressing the INs in a 15- to 20-ms temporal window, the LRIPs enhanced CA3 inputs onto CA1 pyramidal neurons that arrived within that timing interval. This disinhibition enabled temporally precise, paired activation of EC–Schaffer collateral (EC-SC) inputs (15 to 20 ms apart) to trigger dendritic spikes in the distal dendrites of CA1 PNs and to induce ITDP.

LRIPs from EC act as a powerful, temporally precise disinhibitory gate of intrahippocampal information flow and enable the induction of plasticity when cortical and hippocampal inputs arrive onto CA1 PNs at a precise 20-ms interval. We propose that the LRIPs increase the specificity of hippocampal-based long-term memory by assessing the salience of mnemonic information relayed by CA3 to the immediate sensory context conveyed by direct excitatory EC inputs.

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