Jayeeta Basu - US grants

A critical step during sensory processing is the extraction of relevant information about the outside world from a host of distracting sensory inputs. One mechanism for generating salience is to associate sensory information from ongoing experiences with memories derived from past sensory experiences. Where and how these functional associations occur in the brain are central questions in neuroscience. This proposal aims to fill this gap by exploring circuit interactions and single neuron computations that help assign mnemonic valence to sensory signals. In this study, we propose that the hippocampus?the center of learning and memory?plays a crucial role in gating sensory information flow through its reciprocal circuit interactions with the entorhinal cortex, a hub for processing multisensory information. To test this hypothesis, we will use anatomical and functional connectivity mapping experiments to validate how hippocampus communicates with entorhinal cortex output layers (Aim 1). We will assess how hippocampal inputs modulate the short-term plasticity dynamics of excitatory-inhibitory synaptic transmission in the entorhinal cortex (Aim 2). Finally, we will test whether the hippocampus actively modulates the synaptic strength and gain of sensory inputs to entorhinal cortex through dendritic integration and long-term plasticity mechanisms (Aim 3a) and how silencing the CA1 inputs to EC will affect contextual learning behavior (Aim 3b). Despite 60 years of research on memory processing, we know surprisingly little about the organization and function of hippocampal projection circuitry and the mechanisms by which memories modulate ongoing sensory processing in the entorhinal cortex. Our study will combine state-of-the-art in vitro and in vivo approaches, including electrophysiology, behavioral testing, and optogenetics, to provide a functional model of the unexplored hippocampal-entorhinal cortex reciprocal circuit. Exciting pilot experiments from our lab have already revealed a new pathway between the hippocampus and entorhinal cortex that implies a true reciprocal feedback circuit loop. This circuit connects the hippocampus directly to entorhinal cortex output neurons that project sensory information to the hippocampus. Our new circuit model is potentially transformative, for it describes a route by which the hippocampus directly transmits memory input to the entorhinal cortex, with minimal lag and transformation, to refine sensory output based on relevance and to quickly adapt behavior in response to changing environmental demands. Such a function could be used by the brain to facilitate reinforced learning, refine old memories, and form new memory associations. By identifying the neural circuit interactions between the hippocampus and entorhinal cortex, our study will greatly improve our understanding of the mechanisms that underlie the memory-related sensory processing deficits experienced by patients of several neurological and neuropsychiatric illnesses, including Alzheimer?s disease, schizophrenia and PTSD.

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.

SUMMARY What is the right way to investigate neuronal circuits? The dominant strategy in neuroscience is to examine the relationships between stimuli, brain signals and behavior. In this framework, the investigator is in a privileged situation. Because s/he has access to both brain patterns and signals outside the brain, s/he can establish correlations between them. However, without further ?grounding?, it remains unknown whether these experimenter-observed correlations are actually utilized by the brain. The present project will take an alternative approach by investigating how neuronal population patterns in an upstream circuit are ?read out? by a downstream observer circuit/mechanism in memory circuits. Using this strategy, we will investigate how neuronal activity is transformed at each stage in the entorhinal cortex (EC) ? dentate gyrus (DG) ? CA2/3 ? CA1- neocortex loop, and relate such transformations to behavior. The projects will combine large-scale electrophysiology, optogenetics and imaging in behaving rodents. Project 1 will examine the distinct contributions of medial and lateral entorhinal cortex (MEC, LEC) to spatial versus object learning, and will link behavior to EC-DG transmission of theta-gamma oscillatory patterns. Project 2 will examine information transmission within the dentate gyrus and across EC-DG-CA3 synapses. We will first quantify changes in LFP and spike-LFP coupling to test the contributions of EC and DG granule cell input to the firing patterns of DG mossy and CA3 pyramidal cells. We will then test whether DG granule and mossy cell replay is coordinated with hippocampal sharp wave ripples or with EC cell assemblies during post-experience sleep. Finally, we will test whether optogenetic manipulation of dentate spikes affects memory and induces re-configuration of CA3 networks. Project 3 examines whether distinct neuronal trajectories, such as forward and reversed sequences, are read out differentially by target circuits in the CA3-CA1 and CA1-parietal cortical circuits. Finally, Project 4 will test whether different hippocampal patterns are translated to distinct neocortical functional maps and whether such maps are modified by learning. Our ?reader-centric? approach will establish how neuronal patterns are transformed in the entorhinal- hippocampal-entorhinal loop, providing critical insights into physiological mechanisms of learning and memory and relevant diseases.