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

Hippocampus Dendritic Inhibition Supports Fear Learning


Science 21 February 2014:  Vol. 343  no. 6173  pp. 857-863

Dendritic Inhibition in the Hippocampus Supports Fear Learning

Matthew Lovett-Barron,

Doctoral Program in Neurobiology and Behavior, Columbia University, New York, NY, USA.

Department of Neuroscience, Columbia University, New York, NY, USA.

Division of Integrative Neuroscience, New York State Psychiatric Institute, New York, NY, USA.

Center for Learning and Memory, University of Texas, Austin, TX, USA.

Kavli Institute for Brain Science, Columbia University, New York, NY, USA.


Fear memories guide adaptive behavior in contexts associated with aversive events. The hippocampus forms a neural representation of the context that predicts aversive events. Representations of context incorporate multisensory features of the environment, but must somehow exclude sensory features of the aversive event itself. We investigated this selectivity using cell type–specific imaging and inactivation in hippocampal area CA1 of behaving mice. Aversive stimuli activated CA1 dendrite-targeting interneurons via cholinergic input, leading to inhibition of pyramidal cell distal dendrites receiving aversive sensory excitation from the entorhinal cortex. Inactivating dendrite-targeting interneurons during aversive stimuli increased CA1 pyramidal cell population responses and prevented fear learning. We propose subcortical activation of dendritic inhibition as a mechanism for exclusion of aversive stimuli from hippocampal contextual representations during fear learning.

Aversive stimuli cause animals to associate their environmental context with these experiences, allowing for adaptive defensive behaviors during future exposure to the context. This process of contextual fear conditioning (CFC) is dependent upon the brain performing two functions in series: first developing a unified representation of the multisensory environmental context (the conditioned stimulus, CS), then associating this CS with the aversive event (unconditioned stimulus, US) for memory storage. The CS is encoded by the dorsal hippocampus, whose outputs are subsequently associated with the US through synaptic plasticity in the amygdala. The hippocampus must incorporate multisensory features of the environment into a representation of context but, paradoxically, must exclude sensory features during the moment of conditioning, when the primary sensory attribute is the US. The sensory features of the US may disrupt conditioning. Although the cellular and circuit mechanisms of fear learning and sensory convergence have been extensively studied in the amygdala, much less is known about how the neural circuitry of the hippocampus contributes to fear conditioning.

The primary output neurons of the hippocampus, pyramidal cells (PCs) in area CA1, are driven to spike by proximal dendritic excitation from CA3 and distal dendritic excitation from the entorhinal cortex. Whereas CA3 stores a unified representation of the multisensory context, the entorhinal cortex conveys information pertaining to the discrete sensory attributes of the context. At the cellular level, nonlinear interactions between inputs from CA3 and entorhinal cortex in the dendrites of PCs can result in burst-spiking output and plasticity. PCs can carry behaviorally relevant information in the timing of single spikes, spike rate, and spike bursts, but information conveyed with just bursts of spikes is sufficient for hippocampal encoding of context during fear learning. Distinct CA1 PC firing patterns are under the control of specialized local inhibitory interneurons. Whereas spike timing is regulated by parvalbumin-expressing (Pvalb+) interneurons that inhibit the perisomatic region of PCs, burst spiking is regulated by somatostatin-expressing (Som+) interneurons that inhibit PC dendrites. This functional dissociation suggests that CA1 Som+ interneurons may play an important role in CFC. However, the activity of specific interneurons during CFC and their causal influence remain unknown.

Our data suggest that inhibitory circuits can inhibit selected dendritic compartments to favor integration of one excitatory input pathway (proximal) over another (distal). GABA release localized to lacunosum-moleculare could accomplish this input segregation by inhibiting localized dendritic electrogenesis, which is required for propagating entorhinal excitatory inputs to drive output spikes and for inducing plasticity. This mechanism may also be present in sensory neocortex, where aversive footshocks activate cholinergic input to drive layer 1 interneurons in primary auditory and visual cortex. Layer 1 interneurons inhibit the apical tuft dendrites of layer 5 PCs, the primary output cell of the neocortex, at the site of multimodal association in layer 1. Therefore the same mechanism we describe in CA1 could protect layer 5 PCs in primary sensory cortex from interference by the US, so that their outputs to the amygdala are driven by inputs to their basal dendrites reflecting local sensory processing, rather than inputs to tuft dendrites reflecting cross-modal influences.

These results suggest that dendrite-targeting Som+ interneurons provide US-evoked inhibition that is required for successful contextual fear learning. These interneurons are central to a mechanism by which the hippocampus processes contextual sensory inputs as a CS while excluding the sensory features of the US. Selective inhibitory control over integration of excitatory input pathways could be a general strategy for nervous systems to achieve separate processing channels in anatomically overlapping circuits, a process that could be flexibly controlled by a multitude of inhibitory interneuron types and neuromodulatory systems.

[end of paraphrase]


Return to — Hippocampus

Return to — Learning