Engineering Plasticity and Connectivity in a Fear Regulation Circuit

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This is a pre-clinical project to develop new methods that might translate to clinical brain stimulation for severe mental illness. We will test techniques for increasing the connectivity of two key brain areas: infralimbic cortex (IL) and basolateral amygdala (BLA). This circuit is related to fear and threat response. Increasing IL's influence over BLA may improve fear regulation, which in turn would be relevant for treating human anxiety, trauma, and mood disorders. We will manipulate IL-BLA connectivity with two methods: optogenetics, which is a powerful tool for studying circuits in animals, and electrical brain stimulation, which has promise as a treatment for severe mental illness. Optogenetic techniques are very specific, but difficult to translate to humans because of the viral manipulations and hardware involved. Our Hypothesis is that we can achieve specific connectivity changes from "closed loop" electrical stimulation – monitoring IL and stimulating BLA when IL becomes active. That precise co-activation should evoke plasticity. Closed-loop stimulation has previously been developed for motor-circuit applications, and has successfully increased connectivity between brain, spinal cord, and muscle. We will now attempt to show that it can also be used in this IL-BLA fear circuit. To specifically demonstrate the advantage of the closed-loop approach, we will compare it against "paired pulse" stimulation. Paired pulse methods attempt the same kind of timing- dependent plasticity by stimulating two areas in quick succession, forcing them to be active together. Our Preliminary Data indicate that paired pulse techniques can increase IL-BLA connectivity. In Aim 1, we will optimize optogenetic and electrical parameters that increase IL-BLA connectivity during closed-loop stimulation. We will measure connectivity actively (by probing each area with electrical stimulation and seeing how the other responds) and passively (correlation of signals in the two areas during free behavior). We will directly compare optical and electrical stimulation, using a novel opto-electrode that allows us to test both techniques in the same animal. We expect to show that the two techniques produce similar results, and that both can substantially improve IL-BLA connectivity. We further expect to show that the closed-loop approach produces more connectivity change than the "open loop" paired pulse method. In Aim 2, we will use the same protocols to look for long-term effects that last hours to days. Long-lasting effects would be important both for clinical translation and for use of these stimulation methods in basic experiments. If successful, we will have shown that we can control an emotional circuit's connectivity with electrical stimulation, a finding with direct and near-term clinical relevance. The project PI is an interventional psychiatrist, and is prepared to take these findings forward into human use in future studies.