Synchronizing a Fear Regulation Circuit By Temporally Patterned Closed-LoopNeurostimulation

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This project will develop methods for linking together groups of cells in two brain areas (infralimbic cortex, IL, and basolateral amygdala, BLA). This circuit is related to fear and threat response, and changing it may improve fear regulation. We will do this with electrical brain stimulation, which has also shown promise as a new treatment for severe mental illness. Using rats as a pre-clinical model, we hope to show that we can alter two specific brain areas at a single frequency, as opposed to methods like drugs that act on the whole brain at once. Our Hypothesis is that connectivity will increase from "closed loop" electrical stimulation – monitoring one area and stimulating the other when the first becomes active. We believe this will cause the two areas to become strongly wired together. That should mean "ensembles" of brain cells synchronizing their activity between IL and BLA, especially in the theta (5-12 Hz) band. The Objective is to develop tools that can change brain coupling, then measure the effects of those changes on behavior. For brain connectivity, we will record IL and BLA and measure how strongly the activity in the two areas correlates. We will also inject electrical current into each area and measure how much the other responds. For behavior, we will use a conditioning paradigm where rats learn that a tone predicts an unpleasant electrical shock. We will then apply our electrical stimulations just before rats repeatedly hear the tone without the shock, a process called extinction. If our hypothesis is correct, our plasticity-based stimulations will make the animals more able to remember this new "safety memory" on later days. We will approach that Objective through two Aims. Aim 1 is time domain: we will make BLA active within a few milliseconds of an increase in IL neuron firing. Aim 2 is frequency domain: we will measure the theta (5- 12 Hz) oscillation in IL, then stimulate with single pulses in BLA when the IL theta reaches a critical phase. These two techniques should change IL-BLA connectivity in different ways, and we will measure the effects of both on electrical connectivity and defensive behavior. We expect to show that Aim 2's approach is better at increasing theta-band synchrony. By looking at multiple types of electrical connectivity, we hope to understand which ones matter for changing behaviors. That should ultimately be relevant for designing better treatments for mood and anxiety disorders.