Corticosteroid Treatment During Sepsis Alters Hippocampal Function in Male and Female Survivors.

Background: Millions of sepsis survivors annually face neuropsychiatric sequelae of their illness. Corticosteroids are frequently administered for sepsis, and their use improves neuropsychiatric outcomes, but the mechanisms are unknown. In light of prior work that has shown persistent inflammation in sepsis survivors, we hypothesized that short-term corticosteroid treatment during illness would reverse the long-term impact of sepsis on inflammatory gene expression in the hippocampus and rescue associated changes to affective behaviors. Methods: Male and female mice underwent cecal ligation and puncture or a sham surgery to induce acute infection and were treated for 5 days with corticosterone or vehicle. Starting 2 weeks after the surgery, we performed functional phenotyping in the survivor mice followed by hippocampal RNA sequencing to identify underlying mechanisms. Results: Long-term cecal ligation and puncture survivors exhibited anxiety-like behavior, increased central hypothalamic-pituitary-adrenal axis activity, and persistent systemic and neuroinflammation. Corticosterone treatment during illness did not reverse anxiety-like behavior or inflammation in survivors. Instead, corticosterone treatment impaired object memory and increased active coping behavior in females. History of corticosterone treatment influenced the expression of >10% of detectable transcripts in the dorsal and ventral hippocampus, including a coordinated downregulation of activity-dependent genes. Conclusions: Corticosterone treatment during sepsis impaired memory formation in survivors and caused a lasting decrease in hippocampal neural activity, which could underlie its effect on memory. Future studies should focus on how this lasting effect of corticosteroid treatment on hippocampal activity and memory translates into improved neuropsychiatric outcomes in human sepsis survivors.

Forebrain Glucocorticoid Receptor Overexpression Alters Behavioral Encoding of Hippocampal CA1 Pyramidal Cells in Mice.

Glucocorticoid signaling influences hippocampal-dependent behavior and vulnerability to stress-related neuropsychiatric disorders. In mice, lifelong overexpression of glucocorticoid receptor (GR) in forebrain excitatory neurons altered exploratory behavior, cognition, and dorsal hippocampal gene expression in adulthood, but whether GR overexpression alters the information encoded by hippocampal neurons is not known. We performed in vivo microendoscopic calcium imaging of 1359 dorsal CA1 pyramidal cells in freely behaving male and female wild-type (WT) and GR-overexpressing (GRov) mice during exploration of a novel open field, where most CA1 neurons are expected to respond to center location and mobility. Most neurons showed sensitivity to center location and/or mobility based on single-neuron calcium amplitude and event rate, but these sensitivity patterns differed between genotypes. GRov neurons were more likely than WT neurons to display center sensitivity and less likely to display mobility sensitivity. More than one-third of these responsive GRov neurons were sensitive only to center location and not mobility, while uniquely center-sensitive neurons were rare in WT. Most center-sensitive neurons exhibited anticipatory activity, suggesting they could drive behavior. We conclude that, compared with wild-type, dorsal CA1 pyramidal cells in GRov mice preferentially respond to center location rather than mobility in a novel open field. Such changes in the information encoded by individual hippocampal neurons in an aversive environment could underlie changes in stress vulnerability because of genetic or epigenetic variations in glucocorticoid receptor signaling.

Recent Treatment Strategies in Alzheimer's Disease and Chronic Traumatic Encephalopathy.

Neurotrauma has been well linked to the progression of neurodegenerative disease. Much work has been done characterizing chronic traumatic encephalopathy, but less has been done regarding the contribution to Alzheimer's Disease. This review focuses on AD and its association with neurotrauma. Emerging clinical trials are discussed as well as novel mechanisms. We then address how some of these mechanisms are shared with CTE and emerging pre-clinical studies. This paper is a user-friendly resource that summarizes the emerging findings and proposes further investigation into key areas of interest. It is intended to serve as a catalyst for both research teams and clinicians in the quest to improve effective treatment and diagnostic options.

Sex- and stress-dependent effects of a single injection of ketamine on open field and forced swim behavior.

Ketamine has emerged as a novel treatment for common psychiatric conditions such as Major Depressive Disorder (MDD) and anxiety disorders, many of which can be initiated and exacerbated by psychological stress. Sex differences in the frequency of both anxiety and depressive disorders are well known and could be due to sex differences in neuroendocrine responses to stress. Ketamine is known to modulate the hormonal response to stress, specifically corticosterone. It is not clear if the acute effect of ketamine on corticosterone differs by sex, or what role this could play in subsequent behavior. Here we test whether a single injection of (R,S)-ketamine (30 mg/kg, i.p.), administered either with or without unpredictable chronic stress (UCS), has different sustained effects on open field test (OFT), elevated zero maze (EZM) or forced swim test (FST) behavior in female versus male C57BL/6J mice. In the OFT (24 h post-injection), ketamine increased center square exploration in males but not females. In contrast, in the FST (72 h post-injection), females showed a trend toward a decrease in immobility after ketamine whereas males were not strongly modulated. These behavioral effects of ketamine were stronger in the presence of UCS than in unstressed animals. UCS animals also showed lower corticosterone after injection than unstressed animals, and in the presence of UCS ketamine increased corticosterone; these effects were similar in both sexes. Corticosterone post-injection did not predict subsequent behavior. These findings complement a growing preclinical literature suggesting both stress-dependency and sex differences in OFT and FST behavioral responses to ketamine.LAY SUMMARYIn humans, it is known that major depression and anxiety disorders, which can be caused or made worse by exposure to psychological stress, occur roughly twice as frequently in women than in men, but the underpinnings of these effects are not well characterized. In the current study, we explored how sex interacts with stress and ketamine (a rapidly acting antidepressant) by assessing both open field and forced swim behavior in mice after chronic mild stress. We report the novel finding that male mice exhibit greater exploration of the aversive center square in the open field after ketamine, whereas females trended toward lower immobility (often interpreted as an antidepressant-like effect) in the forced swim test after this drug, and these effects were amplified by prior stress exposure.