Amygdala hyper-connectivity in a mouse model of unpredictable early life stress

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Abstract Childhood maltreatment increases the risk for anxiety and other psychopathologies in a dose-dependent manner. The mechanisms by which multiple adverse events early in life synergize to affect anxiety is poorly understood in humans and little effort has been made to clarify this issue in animal models of early life stress (ELS). We recently showed that exposure to UPS, which is a complex and unpredictable mouse model of ELS, leads to robust increase in anxiety that was not seen in mice exposed to a simple and predictable paradigm of ELS known as the limited bedding (LB). Interestingly, exposure to LB or UPS did not affect anxiety-like behavior in female mice. Since amygdala connectivity with fronto-limbic brain regions such as the hippocampus (HPC) and the prefrontal cortex (PFC) play an important role in anxiety-like behavior and exposure to childhood maltreatment leads to abnormal connectivity between these brain regions we used resting state fMRI (rsfMRI) to compare amygdala connectivity with the HPC and the PFC in UPS and control male mice. We found increased connectivity between the amygdala and the PFC and between the amygdala and the HPC in UPS males. Importantly, the strength of theses connections was highly correlated with anxiety- like behavior. In this application we hypothesize that amygdala connectivity with the PFC and the HPC undergo microglial-mediated pruning during the perinatal period. In males, more severe forms of ELS, such as UPS, lead to greater reduction in the expression of the master regulator PU.1 in postnatal microglia. This in turn causes a dose-dependent impairment in the refinement of fronto-limbic connections that regulate anxiety. Exposure to LB or UPS has no effect on PU.1 levels and microglial function in females. As a result, females show normal amygdala connectivity and anxiety when exposed to LB or UPS. Work in aim 1 will use rsfMRI and high resolution DTI to test how different types of ELS (UPS and LB) interact with sex to alter fronto-limbic connectivity. In aim 2 we will use optogenetics and chemogenetics viruses to label and manipulate basolateral amygdala (BLA) projections to the PFC and HPC. This approach will allow us to precisely map the size of these projections, determine their contribution to anxiety, and assess their ability to induce c-fos activation and to alter BOLD signal using fMRI. Studies proposed in aim 3 will use rsfMRI and high resolution DTI to characterize functional and structural connectivity in PU.1-hets mice. The strength of this approach lies in the diverse expertise of our team. This multidisciplinary effort allows us to use microglial specific genetic manipulations, rigorously test causality using optogenetic and chemogenetic tools, and utilize human imaging tools to assess brain connectivity in a mouse model of ELS.