chronic-stress-shifts-effort-related-choice-behavior-y-maze-barrier

Chronic Stress Shifts Effort-Related Choice Behavior in a Y-Maze Barrier Task in Mice

Mood disorders, including major depressive disorder, can be precipitated by chronic stress. The Y-maze barrier task is an effort-related choice test that ...

The State University of New Jersey

While developmental consequences of parental investment on species-typical social behaviors has been extensively characterized in same-sex parent-offspring interactions, the impact of opposite-sex relationships is less clear. In the bi-parental California mouse (Peromyscus californicus), paternal retrieval behavior induces territorial aggression and the expression of arginine vasopressin (AVP) in adult male offspring. Although similar patterns of territorially emerge among females, the sexually dimorphic AVP system has not been considered since it is generally thought to regulate male-typical behavior. However, we recently demonstrated that male and female P. californicus offspring experience increases in plasma testosterone following paternal retrieval. Since AVP expression is androgen-dependent during development, we postulate that increases in AVP expression may accompany territoriality in female, as well as male offspring. To explore this aim, adult P. californicus offspring that received either high or low levels of paternal care (retrievals) during early development were tested for territoriality and immunohistochemical analysis of AVP within the bed nucleus of the stria terminalis (BNST), paraventricular nucleus (PVN), and supraoptic nucleus (SON). Consistent with previous studies, high care offspring were more aggressive than low care offspring. Moreover, high care offspring had significantly more AVP immunoreactive (AVP-ir) cells within the BNST than low care offspring. This pattern was observed within female as well as male offspring, suggesting an equally salient role for paternal care on female offspring physiology. Regardless of early social experience, sex differences in AVP persisted in the BNST, with males having greater expression than females.

Increased vasopressin expression in the BNST accompanies paternally induced territoriality in male and female California mouse offspring.

Depression is a polygenic and highly complex psychiatric disorder that remains a major burden on society. Antidepressants, such as selective serotonin reuptake inhibitors (SSRIs), are some of the most commonly prescribed drugs worldwide. In this review, we will discuss the evidence that links serotonin and serotonin receptors to the etiology of depression and the mechanisms underlying response to antidepressant treatment. We will then revisit the role of serotonin in three distinct hypotheses that have been proposed over the last several decades to explain the pathophysiology of depression: the monoamine, neurotrophic, and neurogenic hypotheses. Finally, we will discuss how recent studies into serotonin receptors have implicated specific neural circuitry in mediating the antidepressant response, with a focus being placed on the hippocampus.

The role of 5-HT receptors in depression.

Stress-related mood disorders are more prevalent in females than males, yet preclinical chronic stress paradigms were developed in male rodents and are less effective in female rodents. Here we characterize a novel chronic non-discriminatory social defeat stress (CNSDS) paradigm that results in comparable stress effects in both sexes. Male and female C57BL/6J mice were simultaneously introduced into the home cage of resident CD-1 aggressors for 10 daily 5-min sessions. CD-1 aggressors attacked males and females indiscriminately, resulting in stress resilient and susceptible subpopulations in both sexes. CD-1 aggressors attacked C57BL/6J male intruders faster and more frequently than female intruders. However, CNSDS similarly induced negative valence behaviors in SUS mice of both sexes relative to RES and CNTRL mice. Furthermore, SUS male and female mice displayed similar increases in plasma corticosterone levels following CNSDS exposure relative to pre-stress exposure levels. The estrous cycle did not impact CD-1 attack behavior or negative valence behaviors. Thus, CNSDS induces chronic stress behavioral and neuroendocrine effects in both male and female C57BL/6J mice and allows direct comparisons between sexes. Adoption of this modified social defeat paradigm will help advance the initiative to include female rodents in preclinical chronic stress research.

Chronic non-discriminatory social defeat is an effective chronic stress paradigm for both male and female mice.

Despite stress-associated disorders having a higher incidence rate in females, preclinical research mainly focuses on males. Chronic stress paradigms, such as chronic social defeat and chronic corticosterone (CORT) administration, were mainly designed and validated in males and subsequent attempts to use these paradigms in females has demonstrated sex differences in the behavioral and HPA axis response to stress. Here, we assessed the behavioral response to chronic CORT exposure and developed a social stress paradigm, social instability stress (SIS), which exposes adult mice to unstable social hierarchies every 3 days for 7 weeks. Sex differences in response to chronic CORT emerged, with negative valence behaviors induced in CORT treated males, not females. SIS effectively induces negative valence behaviors in the open field, light dark, and novelty suppressed feeding tests, increases immobility in the forced swim test, and activates the hypothalamus-pituitary-adrenal (HPA) axis in both males and females. Importantly, while there were effects of estrous cycle on behavior, this variability did not impact the overall effects of SIS on behavior, suggesting estrous does not need to be tracked while utilizing SIS. Furthermore, the effects of SIS on negative valence behaviors were also reversed following chronic antidepressant treatment with fluoxetine (FLX) in both males and females. SIS also reduced adult hippocampal neurogenesis in female mice, while chronic FLX treatment increased adult hippocampal neurogenesis in both males and females. Overall, these data demonstrate that the SIS paradigm is an ethologically valid approach that effectively induces chronic stress in both adult male and adult female mice.

Social instability is an effective chronic stress paradigm for both male and female mice.

Some mood disorders, such as major depressive disorder, are more prevalent in women than in men. However, historically preclinical studies in rodents have a lower inclusion rate of females than males, possibly due to the fact that behavior can be affected by the estrous cycle. Several studies have demonstrated that chronic antidepressant treatment can decrease anxiety-associated behaviors and increase adult hippocampal neurogenesis in male rodents.

Article	Year
Increased vasopressin expression in the BNST accompanies paternally induced territoriality in male and female California mouse offspring. Hormones and behavior\| PubMed ID: 28359742	2017
The role of 5-HT receptors in depression. Molecular brain\| PubMed ID: 28646910	2017
Chronic non-discriminatory social defeat is an effective chronic stress paradigm for both male and female mice. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology\| PubMed ID: 31493767	2019
Social instability is an effective chronic stress paradigm for both male and female mice. Neuropharmacology\| PubMed ID: 31536736	2019
Fluoxetine effects on behavior and adult hippocampal neurogenesis in female C57BL/6J mice across the estrous cycle. Psychopharmacology\| PubMed ID: 31965254	2020

Christine N. Yohn

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