From synapses to neural representations: The role of neuromodulatory circuits in shaping contextual memories in the hippocampus

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Project Summary: Memory enables animals to acquire, store, and recall knowledge of the world through experience and use this knowledge to maximize reward and avoid danger. Understanding the circuit mechanisms within and between brain regions that underlie the formation and recall of memories is considered one of the great scientific challenges of our time, and has the potential to drastically influence the treatment of memory disorders. The hippocampus is both necessary and sufficient for the formation and recall of episodic memories—memories of experiences placed in time and space. These memories are encoded in the hippocampus by the firing activity of populations of neurons called place cells, which fire at specific locations as animals move around their environment, creating a cognitive map. Synaptic plasticity in the hippocampus is critical for forming cognitive maps, and in brain slices norepinergic and dopaminergic inputs from the Locus Coeruleus (LC) and the ventral tegmental area (VTA) to the hippocampus modulate synaptic plasticity, suggesting LC and VTA inputs to the hippocampus may influence cognitive map formation and plasticity. However, the activity of VTA and LC inputs to the hippocampus during learning, their synaptic connectivity, and their effect on hippocampal cognitive maps are unknown. Currently, a major technical obstacle in the field is measuring and manipulating the activity of LC and VTA axons during learning, and determining their synaptic connectivity, directly in the hippocampus. To solve this problem, we will implement an innovative approach to directly measure and manipulate the spiking activity of LC and VTA axons, and the spiking activity of large populations of place cells, in the hippocampus of mice during hippocampal-dependent learning tasks—changes in environment context and novel environment exposure. Optogenetic manipulation of LC and VTA axons in hippocampus and locally applied receptor antagonists will reveal the necessity, sufficiency, and mechanism of action of these hippocampal inputs on cognitive map formation and plasticity. Ex-vivo electron microscopy of the axons imaged during behavior will reveal their synaptic connectivity in the hippocampus. We hypothesize that LC and VTA axons in hippocampus will signal environment novelty and changes in context, respectively, with LC signals influencing cognitive map formation during novel environment exposure, and VTA signals reshaping cognitive maps during contextual changes. This will provide the first insight into the information being carried by these neuromodulatory circuits directly in the hippocampus during hippocampal-dependent learning, and will reveal how these signals form and alter memory representations and the synaptic circuitry through which this occurs.