Functional interactions between the entorhinal cortex and hippocampus are critical for spatial navigation and episodic memories related to people, places, objects and events. Canonically, medial entorhinal cortex (MEC) processes spatial information while lateral entorhinal cortex (LEC) processes non-spatial contextual information. This ‘where’ and ‘what’ information is then projected to the hippocampus for formation of long-term representations associating the sensory and spatial features of the environment. Flexibility in hippocampal representations is critical for generating adaptive learnt behaviors and relies on plasticity. We propose a new role for entorhinal cortex in modulating hippocampal plasticity and spatial representations. To test this, we will dissociate the lesser known organization and function of long-range and local circuit dialogue between LEC vs. MEC and area CA3 of hippocampus during spatial coding. The PI (Basu) and co-PI (Clopath), both early stage investigators, are combining their complementary expertise in experimental and computational approaches to build an integrated circuit centric model of plasticity in the hippocampus across multiple levels. This study will test the hypothesis that beyond the classically biased role of LEC inputs in non-spatial coding, coordinated activity of glutamatergic and newly discovered GABAergic input (Basu et al., 2016) from both LEC and MEC is necessary for context-dependent plasticity of hippocampal place cells via gating of local excitation-inhibition dynamics and dendritic integration. To test this idea, we have established innovative set of tools on the experimental and computational fronts to examine place cell plasticity across multiple levels. We will perform intracellular electrophysiology from soma and dendrites of CA3 neurons in acute slices to functional map the LEC-CA3 circuit (Aim 1), and read out CA3 place cell behavior at sub-cellular resolution with in vivo two-photon imaging of CA3 soma and dendrites as well as LEC axons in behaving animals during a head-fixed context morphing spatial navigational task (Aim 2). In collaboration with Dr. Cliff Kentros, we will develop LEC cell type specific mouse lines for multiplexed optogenetic activation and silencing of glutamatergic and GABAergic inputs simultaneously or alternatingly and read-out how these manipulations impact CA3 plasticity. We are building a unique computational model of hippocampal place cell coding at single neuron (Aim 1) and network (Aim 2) levels incorporating modulation of dendritic excitation-inhibition and long-term plasticity (Bono and Clopath 2010). Drs. György Buzsáki and Dmitry Chklovskii will provide expert consultation on place cell and large-scale imaging data analysis. Our study will provide a unique perspective on long-range and local circuit dynamics that impart flexibility to otherwise stable neuronal representations of space based on environmental demands. This will help better identify circuits underlying maladaptive association of sensory contexts and their location, as seen in PTSD where CA3 is a major target, and in Alzheimer’s disease where entorhinal cortex is affected early on.

Project Narrative Our study will provide a new and extensive circuit model for how long-range projections from the lateral entorhinal cortex, shapes excitatory and inhibitory microcircuit dynamics and plasticity of hippocampal neurons involved in spatial representation. By defining circuit mechanisms that specifically control dendritic integration and plasticity of hippocampal place cells, we will obtain a fundamental understanding of critical brain computations that support behavioral flexibility to learn and adapt to environmental changes based on context. Our study will isolate candidate circuits that could be targeted in neuropsychiatric disorders such as PTSD, and Alzheimer’s disease in which patients suffer from maladaptive association of sensory and spatial contexts.