Encoding of environmental location and navigational behavior in mammals involves large ensembles of specific neuron types across multiple interacting brain regions. ?Place cell? and ?grid cell? mapping of spatial location in the CA1 region of hippocampus and medial entorhinal cortex (EC), respectively, is thought to be fed forward to associative cortical brain regions including the posterior parietal cortex (PPC) and retrosplenial cortex (RSP) to map conjunctions of egocentric and external spatial relationships. This notion implies that the hippocampal-neocortical pathway involves a gradual transformation of spatial cognition to action along with encoding of specific route information at intermediate processing stages. While the characterization of this hippocampal feedforward output to the neocortical system has been conceptually useful for our understanding of spatial navigation processes, it is now time to consider the role of the largely unexplored ?top-down? neocortical inputs from RSP to the hippocampus. The subiculum (SUB) is an under-investigated brain structure well positioned to mediate circuit interactions between the hippocampal and neocortical systems. Based on our recent discoveries, we hypothesize that specific subsets of SUB neurons receive significant direct ?top-down? inputs from RSP and that these inputs yield specialized SUB encoding of multiple spatial relationships including the axis of travel, boundary vectors, and route sub-spaces. These SUB neurons are expected to overlap with the population of CA1-projecting SUB neurons that exert direct feedback regulation of hippocampus-associated spatial mapping and learning. We propose to study the synaptic circuit organization and functional implications of this ?top-down? pathway from RSP cortex, to SUB, to hippocampal CA1, using recent technological advancements. To test the hypothesis, in Aim 1, we will map brain-wide circuit input connections of CA1-projecting SUB neurons and compare these to EC-projecting, and RSP-projecting SUB neurons using new viral tracing and optogenetic stimulation mapping. A combinatorial viral and genetic strategy will be used to selectively label projection-specific SUB neurons for circuit studies and physiological characterization.
In Aims 2 and 3, we will link circuit connection mapping to neurophysiological function and behavior. Tetrode recordings and in vivo GCaMP6-based calcium imaging of CA1 at single-cell resolution in freely moving animals will resolve how RSP inputs and projection-specific SUB neurons modulate CA1 place cell activities and how they contribute to spatial learning and navigation. The studies will be conducted in conjunction with behavioral analyses addressing how animals learn object-place associations and routes through environments having multiple interconnected pathways. Genetically targeted neuronal inactivation will be used to establish the causality of circuit connections and function. The proposed studies are aligned with the specified goals of Targeted Brain Circuits Projects, and will contribute to a mechanistic understanding of how dynamic patterns of specific SUB neural activity are transformed into spatial navigation and cognition.

Public Health Relevance

The hippocampal formation plays essential roles in learning and memory and spatial navigation. This brain region is implicated in many neurological diseases including Alzheimer's disease and temporal lobe epilepsy. The proposed studies of functionally significant retrosplenial cortex-subicular-CA1 connections will increase our mechanistic understanding of hippocampal circuit organization and function. Given earlier findings implicating early-stage degeneration of CA1 and the subiculum in the progression of Alzheimer's disease in humans and animal models, the proposed research will lead to better understanding of the neural circuit mechanisms that underlie this neurological disorder.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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David, Karen Kate
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University of California Irvine
Anatomy/Cell Biology
Schools of Medicine
United States
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