Role of VTA-Amygdala Neural Circuit in Mediating Anxiety-Related Behaviors

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PROJECT SUMMARY Anxiety disorders are the most common psychiatric illness, afflicting 273 million people worldwide. The symptoms of anxiety disorders are highly complex and the causes are poorly understood. Additionally, a substantial number of patients suffering from anxiety disorders also present with depressive-like symptoms, which complicates the investigation of the underlying mechanisms. In this project, we propose to take advantage of the repeated social defeat stress (RSDS) model that induces anxiety (A) or mixed anxiety/depression (A/D) phenotypes in separate subgroups of mice, in an effort to dissect the neurophysiological substrate regulating anxiety behaviors. Using this model, we unexpectedly identified that specific neural circuit pathological activity is exclusively correlated with anxiety behaviors. Briefly, while RSDS induces severe anxiety behaviors in all subjects exposed, a subset of mice is segregated based on their depressive phenotypes: profound anhedonia and avoidance-displaying mice (susceptible) from mice not displaying these depressive symptoms (resilient). Thus, in this project, we label them as anxiety (A) and anxiety/depression (A/D) subgroups. Numerous studies have implicated the role of ventral tegmental area (VTA) dopamine (DA) subcircuits in anxiety and depression. We previously observed that maladaptive firing activity occurred in the VTA DA neurons projecting to the medial prefrontal cortex (mPFC) and VTA DA neurons projecting to the nucleus accumbens (NAc) in A/D mice (depression-susceptible mice), but not in A mice (depression-resilient group). We further demonstrated the causal link between the firing maladaptations in those circuits and depression-related behaviors. Surprisingly, with the support of our R21, using ex vivo electrophysiological studies we show that the firing activity of VTA neurons projecting to the amygdala (VTA- AMG) is dramatically decreased in both A/D and A mice, and this VTA-AMG circuit activity correlates with the expression of anxiety phenotype but not depressive-related phenotypes. Based on these preliminary findings, our central hypothesis is that the VTA-AMG circuit plays a crucial role in the anxiety-like behaviors observed in both A/D and A mice following RSDS. To test this, we propose three Specific Aims: (I) to investigate the pathological cellular and molecular alterations of VTA-AMG DA circuit neurons in A/D and A male and female mice by use of in vivo optrode recordings and ex vivo brain slice recordings; (II) To define how RSDS alters the activity of VTA-AMG DA neurons during the emergence and expression of anxiety using in vivo calcium fiber photometry recordings, and finally (III) to determine the functional role of VTA-AMG DA neurons in mediating RSDS-induced anxiety behaviors by optogenetically manipulating these circuits in male and female mice. By utilizing these cell type- and circuit-specific electrophysiological, in vivo calcium imaging and optogenetic techniques, we will determine if a causal relationship exists between the neuronal activity of VTA-AMG DA circuit and anxiety-related behaviors.