Maladaptive fear responses due to brain circuit pathology have been widely implicated in several psychiatric disorders such as post-traumatic stress disorder (PTSD), anxiety, and panic disorders. Clinical solutions to these disorders thus require a greater understanding of the basic structure and function of neural circuits implementing these memory functions. Here we propose to apply new technologies - cellular-resolution functional neural imaging and cell type-specific manipulations of genetically identified hippocampal circuits in behaving mice - for studying contextual fear learning and storage. Our result will inform our basic understanding of how we learn and remember, and suggest specific targets for treatment and rehabilitation of maladaptive fear responses in disorders of fear, anxiety, and memory.
Conditioned fear is fundamental to survival, allowing animals to acquire fear of a neutral conditioned stimulus (CS) after pairing with an aversive unconditioned stimulus (US). In the case of contextual fear conditioning (CFC) the CS is a multisensory environment. Therefore, learning during CFC is thought to depend upon two neural functions occurring in serial: first developing a unified 'context CS' representation from disparat sensory features of an animal's environment, then associating this CS with the fearful stimulus. Experiments in rodents have demonstrated that the contextual CS is formed in the hippocampus, whose output is subsequently paired with the US in the amygdala. Because the US is a sensory event that will not be present during subsequent CS exposures where the animal must recall their memory, this US should not influence representations of the CS during memory storage. This is a problem for CFC, where the hippocampus has access to sensory inputs of all modalities. Aversive sensory inputs may therefore be actively excluded from the hippocampus, but the neural circuit mechanisms accomplishing this are unknown. We have recently demonstrated that a subpopulation of dendrite-targeting interneurons (dINs) suppresses the integration of excitatory inputs in CA1 pyramidal cells (CA1PCs), which effectively controls hippocampal output. This proposal uses our recently-developed methods for cell-type specific manipulations and in vivo cellular- resolution functional Ca2+ imaging in behaving mice to test the hypothesis that dINs play a central role in selectively inhibiting excitatory inputs carrying sensory information about the US to CA1PCs, thus preventing interference with hippocampal contextual representations. We will test this hypothesis by manipulating and recording from hippocampal GABAergic interneurons during the acquisition and recall of contextual fear memories. We will remotely silence the activity of hippocampal CA1 interneurons in head-restrained and in freely-moving mice during contextual fear learning to assess deficits in performance. We will complement this approach with monitoring the activity of dendrite-targeting and non-dendrite-targeting INs, their subcortical neuromodulatory inputs, and their target CA1PCs using two-photon functional Ca2+ imaging in head-restrained mice. Maladaptive fear responses due to neural circuit pathology have been widely implicated in several psychiatric disorders such as post-traumatic stress disorder (PTSD), anxiety, and panic disorders. Clinical solutions to these deficits require knowledge of the basic structure and function of hippocampal circuits implementing memory functions under healthy conditions. Our proposal will apply novel technologies for observation and perturbation of defined circuit elements in the rodent hippocampus to the study fear learning. A mechanistic understanding of the cellular and circuit mechanisms that enforce fear memory formation in the mammalian brain will provide insight into how we acquire memories, and potentially lead to more effective detection and treatment of anxiety and fear memory dysfunctions in human disorders .
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