Stress induces microglia-associated synaptic circuit alterations in the dorsomedial prefrontal cortex

Abstract

The mammalian dorsomedial prefrontal cortex (dmPFC) receives diverse inputs and plays important roles in adaptive behavior and cognitive flexibility. Stress, a major risk factor for many psychiatric disorders, compromises the structure and function of multiple brain regions and circuits. Here we show that 7-day restraint stress impairs reversal learning in the 4-choice odor discrimination test, a decision-making task requiring an intact dmPFC. In vivo two-photon imaging further reveals that stress increases dmPFC dendritic spine elimination, particularly those of the mushroom morphology, without affecting spine formation. In addition, stress alters dmPFC microglial branching complexity and elevates their terminal process dynamics. In stressed mice, dmPFC microglia contact dendrites more frequently, and dendritic spines with microglial contact are prone to elimination. In summary, our work suggests that stress-induced changes in glial-synapse interaction contributes to synaptic loss in dmPFC, resulting in neuronal circuit deficits and impaired cognitive flexibility.

Microglial P2Y12 mediates chronic stress-induced synapse loss in the prefrontal cortex and associated behavioral consequences in male mice

“…Consistent with prior studies, we found that CUS increased microglia-mediated remodeling of apical dendrites in the mPFC [2, 3]. Genetic loss or pharmacological blockade of microglial P2Y12 prevented microglia-mediated neuronal remodeling and attenuated synapse loss in the mPFC.…”

“…Clinical and preclinical findings suggest that microglia, the brain-resident macrophages, may contribute to synaptic alterations in the PFC and MDD-associated symptoms. In fact, chronic stress has been shown to induce microglia-mediated remodeling of synapses in the medial PFC (mPFC) of mice and subsequent deficits in PFC-mediated behaviors, including working memory function and cognitive flexibility [2, 3]. Despite these findings, relatively little is known regarding the pathways that drive microglia-neuron interactions in stress and microglial interventions in stress-linked disorders remain elusive.…”

Neuroinflammation triggers microglial phagocytosis of synapses via induction of synaptic filopodia

“…We observed that the enhanced and prolonged recruitment of activated microglia processes to the site of photodamage was directly involved in synaptic elimination. This is in line with accumulated evidence obtained in animal models of ischemia (Wake et al, 2009), systemic in ammation (Chen et al, 2014;Gallo et al, 2022), stress (Liu et al, 2021) and AD (Gervais et al, 2021;Gratuze et al, 2021;Wright et al, 2013). Together, these ndings complement previous studies and support the hypothesis that early in ammatory changes may lead to synaptic loss and therefore contribute to the cognitive impairment in neurodegenerative diseases such as AD.…”

High-Fat Diet Consumption in Adolescence Induces Emotional Behavior Alterations and Hippocampal Neurogenesis Deficits Accompanied by Excessive Microglial Activation

“…Microglia, known as “brain gardeners,” have been found to influence neuronal proliferation, differentiation, and maturation [ 65 , 66 , 67 ]. Microglial morphology is closely linked to microglial functions [ 68 , 69 ], and changes in microglial phenotype are related to the impairment of hippocampal neurogenesis under pathological conditions [ 70 ]. In the healthy brain, microglia have a ramified morphology with a small soma and fine processes [ 68 ].…”