Fear behaviors serve to protect the organism from dangers, but they can become maladaptive during mental illness. Amygdala is the main area of the brain responsible for control of fear behaviors, and we are trying to understand how its synaptic properties relate to its fear-regulating functions in normal and pathological states. This knowledge will provide information that will help in developing treatments for mental disorders associated with pathological fear. Amygdala operations can be reduced to two functions: the executive function and the learning function. The executive function comprises two activities: 1) analysis of incoming sensory information, 2) triggering of defensive responses if the incoming signals predict danger. The learning (associative) function consists of making association between neutral and aversive stimuli;it enables defensive responses to the danger-predicting signals. The first question of our investigation is how amygdala distinguishes, at the synaptic level, between different types of information, which arrives from different areas of the brain. To address this question, one needs to interrogate a specific input by selectively stimulating fibers coming from a specific brain area. In the past several years, such studies, including those in our laboratory, were mainly limited to comparative analysis of synaptic transmission in the cortical fiber that enter amygdala via the external capsule and thalamic fibers that enter amygdala via the internal capsule, because these two inputs are well separated anatomically and can be stimulated in isolation from each other. Yet, most of other inputs are intermingled with one another and cannot be stimulated in isolation by using an electrode. However, analysis of any neuronal input in isolation became possible recently following development of opsin-based techniques for selective activation or silencing of specific neurons or axons. During the last fiscal year, our goals were to establish opsin-based techniques in the laboratory and to initiate comparative analysis of amygdala inputs, which bring different types of information into amygdala. To this end, we incorporated 472 nM blue laser and LED into our electrophysiology setups for whole cell recording in slice, and began adeno-associated virus mediated expression of channelrhodopsin in the mouse brain. In the initial series of channelrhodopsin-based experiments, we compared properties of two amygdala inputs, the input from perirhinal cortex, which carries multimodal sensory information, and the input from anterior cingulate cortex (ACC), which carries highly processed information including that about unpleasantness of pain. Both inputs target same amygdala neurons and are intermingled inside amygdala. We found significant difference in synaptic plasticity between the two pathways. While long-term potentiation of synaptic transmission (LTP) in the input from perirhinal cortex required suppression of GABAa receptor-mediated inhibition, LTP in the ACC-amygdala pathway did not. Moreover, severing connections between external capsule and amygdala enabled LTP in the input from perirhinal cortex even in the presence of GABAa receptor-mediated inhibition. These findings have two implications: first, inhibitory neurons of the external capsule appear to gate plasticity in the amygdala input from perirhinal cortex, and, second, highly refined information from ACC encounters a less stringent gate at amygdala than the less processed information from perirhinal cortex. Our future goal is to use optogenetics for testing how specific amygdala inputs, investigated in vitro, modulate fear behaviors in free-moving animals. In addition, by targeting expression of opsins in subpopulations GABAergic neurons, we plan to investigate how interneuronal populations of amygdala contribute in analysis of incoming sensory information and in generation of defensive response.
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