Sex differences in microglia-neuron-circuit interactions in adolescence

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A basic understanding of neuron-glia interactions is key to linking altered immune function to disrupted neural circuitry and cognition present in major psychiatric diseases. Microglia are a resident immune cell in the cerebral cortex, and one of their main functions under physiological conditions is to modify synaptic connections among neurons. How these activities extend to influence higher-order functional networks in cortical circuits is not clear, particularly in brain regions crucial for cognitive function, such as the prefrontal cortex (PFC). A key may lie in how neural circuit synchrony stimulates nearby microglial cell motility – i.e. active extension and retraction of fine cellular processes – and, specifically, in how this relationship changes throughout adolescence, a critical period for the development of PFC and higher cognition. Further, sex differences have been established in some aspects of microglial function. Clarifying how sex modulates the role of microglia in PFC circuit development is essential, especially given the dramatic sex differences in vulnerability to adolescent onset of psychiatric diseases such as schizophrenia. The goal of the current project is to obtain a basic understanding of glial-neuronal-circuit interactions in the mammalian prefrontal cortex. The planned approach (Aim 1) employs three-dimensional two-photon microscopy and single neuron optogenetics in awake mouse medial prefrontal cortex (mPFC) to elucidate how the structural dynamics of microglial cells are driven by neuronal activity and oscillatory synchrony in local circuits. This will be examined at distinct time windows from pre-adolescence into early adulthood and compared between males and females. (Aim 2,3) To test whether, how, and when microglia activity is necessary for the establishment of adult mPFC function, microglia will be selectively eliminated during restricted windows during adolescence and early adulthood using a pharmacological strategy. Then in adulthood, sex- and adolescent-period specific effects on the development of i) (Aim 2) spatiotemporal circuit dynamics in mPFC (functional network clustering, gamma oscillations, theta-gamma coupling) will be measured using two-photon calcium imaging and dense electrical recordings and ii) (Aim 3) PFC-dependent cognition will be assessed with an established odor-based attentional set-shifting task. This project employs state-of-the-art optical techniques to study brain function of behaving animals with cell- level precision. Results will identify when and how microglia interact with developing neuronal circuits to support adult-level cognitive function under physiological conditions. Since microglia may be a key mediator of psychiatric disease-relevant neuroimmune dysfunction, the basic science insights from this project, particularly afforded by a sex- and developmental-period stratified approach, could transform the search for core pathophysiological mechanisms and circuit-based treatments.