Effects of adolescent social isolation on glial dysfunction and social behavior in adulthood

About This Grant

Project Summary/Abstract Adolescence is a dynamic developmental period marked by brain circuit refinement. Social stress during adolescence can influence the development of maladaptive behaviors and increase the risk of later-life psychiatric disorder. Despite wide appreciation for this link, the mechanisms connecting adolescent stress to later psychiatric risk remain unclear. The nucleus accumbens (NAc) is a critical integrative hub within the brain that undergoes refinement during adolescence and is essential for processing social information. Within the NAc, astrocytes are uniquely positioned to sense a diversity of neurotransmitters and regulate incoming circuit projections. As astrocytes are susceptible to stress-induced dysfunction, it is likely that they contribute to the behavioral deficits seen after adolescent social isolation. In support of this, preliminary data reveal that socially isolating rats during adolescence induces a dramatic decrease in astrocyte structural complexity within the NAc core, compared to group-housed controls, in adulthood. Isolation also increased microglia phagocytosis, and phagolysosomes within microglia contained the astrocyte marker GLT-1, suggesting that microglia engulf astrocytic elements. This proposal will test the novel hypothesis that adolescent social isolation stress induces microglial pruning of astrocytes, resulting in astrocyte/synaptic decoupling in the NAc core across development. Aim 1 will examine how social isolation stress induces microglia phagocytosis of astrocytes and astrocyte/synapse decoupling throughout adolescent social isolation using confocal microscopy and three- dimensional cellular image analysis and will test the prediction that isolation-induced astrocyte and behavioral deficits can be rescued by pharmacological blockade of phagocytosis in vivo. Aim 2 will assess how isolation stress affects the ability of astrocytes to sense and/or regulate synaptic transmission in the NAc core using a combination of ex vivo slice calcium imaging and electrophysiology. Together, these findings will reshape appreciation of microglia/astrocyte interactions and provide novel insights into how glial dysfunction affects neural circuit activity in response to stress. The Mentored Research Scientist Development Award will additionally provide essential training in the conceptual and technical approaches needed for a long-term program of study to investigate how adolescent social stress shapes astrocyte-neuron interactions and neural circuit function. Building upon prior training in microglia physiology and developmental neuroscience, this proposal will specifically provide additional advanced training in 1) the methodological and experimental design for models of early life adversity, 2) ex vivo slice astrocyte calcium imaging, and 3) patch clamp electrophysiology, to establish a strong foundation for an independent research career. Results obtained from the proposed studies will also pave the way for future evidence-based studies regarding maladaptive effects of stress on glial function.