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.

Public Health Relevance

In this work, we will test methods for improving neural communication in circuits of emotion regulation, using a rat model of fear and safety learning. We propose to show that carefully designed electrical stimulation can 're- wire' circuits in ways that improve fear regulation, which is broadly impaired in anxiety, trauma-related, and obsessive disorders. By identifying circuit-modification techniques that should be safe to use in human, we hope to move towards new brain-stimulation treatments for those disorders.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH109722-02
Application #
9315935
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Vicentic, Aleksandra
Project Start
2016-08-01
Project End
2019-07-31
Budget Start
2017-08-24
Budget End
2019-07-31
Support Year
2
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02114
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Dougherty, Darin D; Widge, Alik S (2017) Neurotherapeutic Interventions for Psychiatric Illness. Harv Rev Psychiatry 25:253-255
Philip, Noah S; Nelson, Brent G; Frohlich, Flavio et al. (2017) Low-Intensity Transcranial Current Stimulation in Psychiatry. Am J Psychiatry 174:628-639