Sydney A. Rowson

Prenatal stress, regardless of concurrent escitalopram treatment, alters behavior and amygdala gene expression of adolescent female rats

Depression during pregnancy has been linked to in utero stress and is associated with long-lasting symptoms in offspring, including anxiety, helplessness, attentional deficits, and social withdrawal. Depression is diagnosed in 10-20% of expectant mothers, but the impact of antidepressant treatment on offspring development is not well documented, particularly for females. Here, we used a prenatal stress model of maternal depression to test the hypothesis that in utero antidepressant treatment could mitigate the effects of prenatal stress. We also investigated the effects of prenatal stress and antidepressant treatment on gene expression related to GABAergic and serotonergic neurotransmission in the amygdala, which may underlie behavioral effects of prenatal stress. Nulliparous female rats were implanted with osmotic minipumps delivering clinically-relevant concentrations of escitalopram and mated. Pregnant dams were exposed to 12 days of mixed-modality stressors, and offspring were behaviorally assessed in adolescence (postnatal day 28) and adulthood (beyond day 90) to determine the extent of behavioral change. We found that in utero stress exposure, regardless of escitalopram treatment, increased anxiety-like behavior in adolescent females and profoundly influenced amygdala expression of the chloride transporters KCC2 and NKCC1, which regulate GABAergic function. In contrast, prenatal escitalopram exposure alone elevated amygdala expression of 5-HT1A receptors. In adulthood, anxiety-like behavior returned to baseline and gene expression effects in the amygdala abated, whereas deficits emerged in novel object recognition for rats exposed to stress during gestation. These findings suggest prenatal stress causes age-dependent deficits in anxiety-like behavior and amygdala function in female offspring, regardless of antidepressant exposure.

Checks and balances: The glucocorticoid receptor and NFĸB in good times and bad

Mutual regulation and balance between the endocrine and immune systems facilitate an organisms stress response and are impaired following chronic stress or prolonged immune activation. Concurrent alterations in stress physiology and immunity are increasingly recognized as contributing factors to several stress-linked neuropsychiatric disorders including depression, anxiety, and post-traumatic stress disorder. Accumulating evidence suggests that impaired balance and crosstalk between the glucocorticoid receptor (GR) and nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB) - effectors of the stress and immune axes, respectively - may play a key role in mediating the harmful effects of chronic stress on mood and behavior. Here, we first review the molecular mechanisms of GR and NFκB interactions in health, then describe potential shifts in the GR-NFκB dynamics in chronic stress conditions within the context of brain circuitry relevant to neuropsychiatric diseases. Furthermore, we discuss developmental influences and sex differences in the regulation of these two transcription factors.

Neuroinflammation and Behavior in HIV-1 Transgenic Rats Exposed to Chronic Adolescent Stress

Highly active antiretroviral therapy (HAART) has improved prognosis for people living with HIV (PLWH) and dramatically reduced the incidence of AIDS. However, even when viral load is controlled, PLWH develop psychiatric and neurological disorders more frequently than those living without HIV. Adolescents with HIV are particularly susceptible to the development of psychiatric illnesses and neurocognitive impairments. While both psychiatric and neurocognitive disorders have been found to be exacerbated by stress, the extent to which chronic stress and HIV-1 viral proteins interact to impact behavior and relevant neuroinflammatory processes is unknown. Determination of the individual contributions of stress and HIV to neuropsychiatric disorders is heavily confounded in humans. In order to isolate the influence of HIV-1 proteins and chronic stress on behavior and neuroinflammation, we employed the HIV-1 transgenic (Tg) rat model, which expresses HIV-1 proteins with a gag and pol deletion, allowing for viral protein expression without viral replication. This Tg line has been characterized as a model of HAART-controlled HIV-1 infection due to the lack of viral replication but continued presence of HIV-1 proteins. We exposed male and female adolescent HIV-1 Tg rats to a mixed-modality chronic stress paradigm consisting of isolation, social defeat and restraint, and assessed behavior, cerebral vascularization, and neuroinflammatory endpoints. Stress, sex, and presence of the HIV-1 transgene impacted weight gain in adolescent rats. Female HIV-1 Tg rats showed decreases in central tendency during the light cycle in the open field regardless of stress exposure. Both male and female HIV-1 Tg rats exhibited decreased investigative behavior in the novel object recognition task, but no memory impairments. Adolescent stress had no effect on the tested behaviors. Microglia in female HIV-1 Tg rats exhibited a hyper-ramified structure, and gene expression of complement factor B was increased in the hippocampus. In addition, adolescent stress exposure increased microglial branching and junctions in female wild-type rats without causing any additional increase in HIV-1 rats. These data suggest that the presence of HIV-1 proteins during development leads to alterations in behavioral and neuroinflammatory endpoints that are not further impacted by concurrent chronic adolescent stress.

Pharmacological stimulation of Hypoxia Inducible Factor-1α facilitates the corticosterone response to a mild acute stressor

While both glucocorticoids (the principal output of the hypothalamic-pituitary-adrenal axis) and oxidative stress have been implicated in outcomes due to an excessive or prolonged stress response, the precise mechanisms linking these two systems remain poorly elucidated. One potential mediator between the hypothalamic-pituitary-adrenal axis and oxidative stress is the hypoxia inducible factor-1 (HIF-1) pathway. HIF-1 is an oxygen-responsive transcription factor with diverse effects including changes in cellular metabolism. The experiments in this manuscript sought to determine if pharmacological stimulation of HIF-1α via administration of dimethyloxalylglycine (DMOG) would facilitate the corticosterone response to a mild acute stressor. DMOG administration significantly increased plasma corticosterone 5 min after an acute airpuff without changing baseline plasma corticosterone or plasma corticosterone level two hours post-startle. DMOG administration also reduced hippocampal gene expression of the pro-translocation co-chaperone for the glucocorticoid receptor, FKBP4, two hours after airpuff startle. At this same two-hour time point, hippocampal expression of FKBP5, an anti-translocation co-chaperone of the glucocorticoid receptor, in the DMOG-treated group was also positively correlated with plasma corticosterone levels. These data indicate that there is significant crosstalk between the hypothalamic-pituitary-axis and the HIF-1 pathway and extend the current knowledge of glucocorticoid and hypoxia interactions in an ethologically relevant stress model.

Measuring corticosterone concentrations over a physiological dynamic range in female rats

Accurate assessment of plasma corticosterone, the primary stress hormone in rodents, is an essential part of characterizing the stress response in experimental animals. To this end, both enzyme-linked immunosorbent assay (ELISA) and radioimmunoassay (RIA) remain widely used. However, considerable assay-specific variability exists among commercially available corticosterone assays due to differing assay principles, detection methods, range, and sensitivity. While technical comparisons of commercially available corticosterone assays have previously been conducted, the ability to detect acute stress-induced endocrine changes has not been compared among these methods to date. Using the forced swim test, a commonly utilized behavioral paradigm in rodents as a physiologically-relevant acute stress challenge, we compared four commercial corticosterone assays - three ELISA kits and one RIA kit - in their ability to detect corticosterone across a dynamic range of both baseline and acute swim stress-driven concentrations. While all methods yielded results that were consistent at measuring relative differences between samples, only two of the four assays evaluated detected a statistically significant increase in corticosterone in rats exposed to acute swim stress compared to rats at baseline. The ELISA kit from Enzo Life Sciences demonstrated the greatest percent increase in plasma corticosterone from baseline to acute stress conditions. The RIA kit from MP Biomedicals also detected a significant corticosterone increase and yielded higher concentrations of corticosterone both at baseline and in the acute stress condition relative to the other three assays. We conclude that choice of assay can impact interpretation of data due to differences in efficacy across a dynamic range of physiological concentrations of corticosterone.

Sex Differences in Immunity and Inflammation: Implications for Brain and Behavior

Abstract The immune system is the body’s defense against disease; however, inherent differences in how the male and female immune systems detect and respond to immune threats dictate susceptibility to illness and immune-related diseases. Sex differences in the immune system begin during development and continue throughout life, with males and females showing different periods of immune susceptibility and resilience. Given that these differences likely stem from sex-dependent requirements for species survival, this chapter discusses how this evolutionary “need” for sex differences in immune function carries with it far reaching effects on both the periphery and the brain. This chapter highlights basic immune-related differences between men and women, describes how these differences translate into sex-dependent risk for immune-related diseases, discusses the implications for brain function, and outlines potential mechanisms to explain these differences. Finally, we conclude by discussing sex-dependent immune effects on behavior and how differential immune function drives the manifestation of comorbid disease states.

Locomotor sensitization to cocaine in adolescent and adult female Wistar rats

HighlightsAdolescent but not adult female Wistar rats sensitize to 15 mg/kg cocaine.Chronic adolescent stress attenuates the initial locomotor response to novelty.Chronic adolescent stress does not impact locomotor sensitization to cocaine. Abstract Adolescent stress exposure is a risk factor for drug abuse, and sex differences contribute to psychostimulant responses. Although many studies have utilized the Wistar rat strain in adolescent stress paradigms, the impact of adolescent stress exposure on addiction‐like outcomes has not been rigorously tested in female Wistar rats. In this study, locomotor sensitization was assessed in adolescent and adult female Wistar rats following either chronic stress during adolescence (CAS) or no stress (NS). Adolescent, but not adult, female Wistar rats developed locomotor sensitization to 15 mg/kg cocaine over 5 days of treatment, regardless of stress history. CAS reduced the initial locomotor response to novelty in both adolescent and adult rats compared to NS controls but had no effect on locomotor sensitization to cocaine in adolescents or adult female rats. These studies expand our understanding of age and adolescent stress on cocaine‐induced behavioral plasticity in female Wistar rats.

Diet, development, and sex: Factors of resilience and susceptibility to chronic stress?

Stress-related psychiatric disorders, including depression and anxiety, are commonly associated with low levels of physical activity. Data derived from epidemiological studies consistently suggest a relationship exists between physical inactivity and increased risk for depression and/or anxiety disorders. Additionally, recent literature reviews maintain that exercise compares favorably to antidepressant medications as a first-line and/or adjuvant treatment for mild to moderate depression in adults. While the mechanisms underlying the antidepressant and anxiolytic effects of exercise training are still under investigation, research has indicated that the antidepressant effects of regular exercise training might be mediated through neurobiological adaptations, (e.g., increased availability of neurotransmitters including serotonin and dopamine, positive effects on HPA axis reactivity to stressors) which may be protective against the deleterious psychological effects of stress. The potential for exercise to prevent or treat psychiatric disorders might, therefore, involve adaptations resulting from regular physical exercise training which also positively impact physiological adaptations to psychological stressors. Moreover, research suggests that the protective and treatment effects of physical exercise for depression and anxiety might be mediated through the positive impact of exercise on fundamental psychological processes of affective dysregulation (e.g., emotion regulation, mood) and/or comorbid conditions (e.g., sleep problems). Importantly, research on the effects of early life adversity in precipitating and maintaining physiological and psychological processes underlying depression and anxiety disorders highlights not only the importance of early identification of vulnerability factors in the development of psychiatric disease, but also a potential role for exercise in mitigating these factors in children and adults.