Friday, May 3, 2024
5/3/2024
Project Summary For decades, Pavlovian fear conditioning has been the dominant paradigm to study the amygdala. However, this paradigm is poorly suited to examine the relation between amygdala activity and behavior. Indeed, conditioning changes the likelihood that conditioned stimuli (CS) will elicit conditioned responses (CRs) making it difficult to disentangle whether training-induced alterations in activity are related to the valence or identity of CSs, to the behaviors they elicit, or a mixture thereof. To circumvent these limitations, we will examine how amygdala activity controls different conditioned behaviors using a novel task, the Risk- Reward Interaction (RRI) task, which allows one to compare, in the same rats and neurons, activity related to different conditioned behaviors triggered by the same CS. The RRI task takes advantage of the rats' natural ability to associate places with behaviors. Rats are trained to respond to the same light CS in different ways depending on where the CS is presented. They learn that in some positions, the CS signals reward availability and in others, an impending footshock. The footshock can be avoided passively or actively, depending on the rats' position with respect to the CS. Therefore, in Aim 1, we will determine whether amygdala cells encode the location or valence of the CS, or the CRs they elicit, by simultaneously recording neurons in different nuclei of the basolateral amygdaloid complex (BLA= lateral, LA + basolateral, BL + basomedial, BM) while rats perform the RRI task. We will compare the dependence of firing rates on CS location and type of conditioned behaviors on correct vs. error trials, allowing us to determine whether the same, different, or overlapping subsets of cells fire in relation to reward-seeking, freezing, active avoidance, and passive avoidance. Then, in Aim 2, we will examine whether valence and behavior coding varies as a function of the neurons' projection sites. Different BLA nuclei contribute projections to a variety of cortical and subcortical sites, including nucleus accumbens, the prefrontal cortex, the mediodorsal thalamic nucleus, the ventromedial hypothalamus and central amygdala. To determine the projection sites of the different subsets of cells identified in Aim #1, rats will be implanted with stimulating electrodes in different BLA projection sites while recording BLA cells in the RRI task. Finally, in Aim 3, we will test whether specific subsets of BLA neurons, as defined by their projection sites and increased activity in relation to particular behaviors, actually contribute to generate these behaviors. Here, building on the results of Aim 2, we will infuse CAV2-Cre in different projection sites of BLA nuclei and an AAV driving the expression of NpHR or ChR2 in specific BLA nuclei. Then, by delivering light stimuli of the appropriate wavelength, we will test whether we can respectively block or facilitate different conditioned behaviors in the RRI task. Our pilot data imply that even after experience has led to the potentiation of some sensory inputs to LA neurons, their coupling to emotional behaviors is not fixed. After completing the above work, we plan on examining the neural substrates of this flexibility, an endeavor of great translational significance.
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