Neuroinflammatory Dynamics Underlie Memory Impairments after Repeated Social Defeat

Abstract

Repeated social defeat (RSD) is a murine stressor that recapitulates key physiological, immunological, and behavioral alterations observed in humans exposed to chronic psychosocial stress. Psychosocial stress promotes prolonged behavioral adaptations that are associated with neuroinflammatory signaling and impaired neuroplasticity. Here, we show that RSD promoted hippocampal neuroinflammatory activation that was characterized by proinflammatory gene expression and by microglia activation and monocyte trafficking that was particularly pronounced within the caudal extent of the hippocampus. Because the hippocampus is a key area involved in neuroplasticity, behavior, and cognition, we hypothesize that stress-induced neuroinflammation impairs hippocampal neurogenesis and promotes cognitive and affective behavioral deficits. We show here that RSD caused transient impairments in spatial memory recall that resolved within 28 d. In assessment of neurogenesis, the number of proliferating neural progenitor cells (NPCs) and the number of young, developing neurons were not affected initially after RSD. Nonetheless, the neuronal differentiation of NPCs that proliferated during RSD was significantly impaired when examined 10 and 28 d later. In addition, social avoidance, a measure of depressive-like behavior associated with caudal hippocampal circuitry, persisted 28 d after RSD. Treatment with minocycline during RSD prevented both microglia activation and monocyte recruitment. Inhibition of this neuroinflammatory activation in turn prevented impairments in spatial memory after RSD but did not prevent deficits in neurogenesis nor did it prevent the persistence of social avoidance behavior. These findings show that neuroinflammatory activation after psychosocial stress impairs spatial memory performance independent of deficits in neurogenesis and social avoidance.

Stress-Induced Microglia Activation and Monocyte Trafficking to the Brain Underlie the Development of Anxiety and Depression

“…In the RSD model, stress-induced neuroinflammation impaired hippocampal neurogenesis and promoted cognitive and affective behavioral deficits [51]. In this study, mice that were exposed to stress showed transient impairments in spatial memory recall that resolved within 28 days after stress cessation.…”

“…Treatment with minocycline, an antibiotic that has antiinflammatory properties at the periphery and in the brain, prevented microglia activation and abrogated impairment in spatial memory after RSD. Minocycline did not prevent deficits in neurogenesis nor did it prevent the persistence of social avoidance behavior in mice exposed to stress [51]. These findings suggest that neuroinflammatory activation after psychosocial stress impairs spatial memory performance independent of deficits in neurogenesis and social avoidance [51].…”

“…In assessment of neurogenesis, the number of proliferating neural progenitor cells and the number of young, developing neurons were significantly impaired when examined 10 and 28 days after stress termination. In addition, social avoidance, a measure of depressive-like behavior associated with caudal hippocampal circuitry, persisted 28 days after RSD [51]. Treatment with minocycline, an antibiotic that has antiinflammatory properties at the periphery and in the brain, prevented microglia activation and abrogated impairment in spatial memory after RSD.…”

Repeated Social Defeat, Neuroinflammation, and Behavior: Monocytes Carry the Signal

“…In support of this notion, microglia activation was inhibited by pharmacological treatment with minocycline in a variety of stress models. In each case, inhibiting microglia during stress exposure attenuated the increase of pro-inflammatory cytokines normally produced by stress (Hinwood, Morandini et al 2012, Hinwood, Tynan et al 2013, Kreisel, Frank et al 2014, McKim, Niraula et al 2016). …”

A Neurological Perspective upon Diabetes and Obesity, What They Are, and How They Can Be Measured

“…in type 1 and type 2 diabetes [19]. It influences brain function [20], memory [20], appetite [21] [22] and the cognitive response i.e. the ability of the brain to function and is associated with the regulatory and/or causal mechanism rather than the visceral or symptomatic consequences.…”