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Major depressive disorder is a major psychiatric disorder and a leading cause of disability around the world. Females have about twice as high an incidence of depression as males. However, preclinical animal models of depression have seldom investigated the molecular alterations associated with higher depression risk in females. In this study, adopting the early-life stress (ELS) paradigm of limited bedding and nesting material, we found that ELS induced depression-like behaviors only in adult female mice, as evaluated by sucrose preference and tail suspension tests. We then examined the ELS effects on monoamine neurotransmission (transporters for monoamine reuptake and release) in depression-related brain regions in female mice. We found that ELS resulted in widespread changes of the expression levels of these transporters in four brain regions. Moreover, systemic 21-day treatment with vortioxetine, a novel multimodal antidepressant, successfully reversed depression-like behaviors and normalized some molecular changes, including that of the norepinephrine transporter in the medial prefrontal cortex, vesicular monoamine transporter 2 in nucleus accumbens core, and serotonin transporter in amygdala. Collectively, these results provide evidence for the validity of using the limited bedding and nesting material paradigm to investigate sex differences in depression and demonstrate that the region-specific alterations of monoamine neurotransmission may be associated with depression-like behaviors in female mice. This article is part of the special issue on 'Stress, Addiction and Plasticity'., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The sex difference that females are more vulnerable to depression than males has been recently replicated in an animal model of early-life stress (ES) called the limited bedding and nesting material (LBN) paradigm. Adopting this animal model, we have previously examined the effects of ES on monoamine transporter (MATs) expression in stress-related regions in adult female mice, and the reversal effects of a novel multimodal antidepressant, vortioxetine. In this study, replacing vortioxetine with a classical antidepressant, fluoxetine, we aimed to replicate the ES effects in adult female mice and to elucidate the commonality and differences between fluoxetine and vortioxetine. We found that systemic 30-day treatment with fluoxetine successfully reversed ES-induced depression-like behaviors (especially sucrose preference) in adult female mice. At the molecular level, we largely replicated the ES effects, such as reduced serotonin transporter (SERT) expression in the amygdala and increased norepinephrine transporter (NET) expression in the medial prefrontal cortex (mPFC) and hippocampus. Similar reversal effects of fluoxetine and vortioxetine were observed, including SERT in the amygdala and NET in the mPFC, whereas different reversal effects were observed for NET in the hippocampus and vesicular monoamine transporters expression in the nucleus accumbens. Overall, these results demonstrate the validity of the LBN paradigm to induce depression-like behaviors in female mice, highlight the involvement of region-specific MATs in ES-induced depression-like behaviors, and provide insights for further investigation of neurobiological mechanisms, treatment, and prevention associated with depression in women. • Fluoxetine reversed ES-induced depression-like behaviors in adult female mice. • We confirmed ES-induced widespread alterations of MATs/VMAT2 expression. • Fluoxetine reversed amygdala SERT decreases and mPFC/hippocampal NET increases. [ABSTRACT FROM AUTHOR]

Emerging evidence supports an essential role of trace amine-associated receptor 1 (TAAR1) in neuropsychiatric disorders such as depression and schizophrenia. Stressful events are critical contributors to various neuropsychiatric disorders. This study examined the role of TAAR1 in mediating the negative outcomes of stressful events. In mice that experienced chronic social defeat stress but not acute stress, a significant reduction in the TAAR1 mRNA level was found in the medial prefrontal cortex (mPFC), a brain region that is known to be vulnerable to stress experience. Conditional TAAR1 knockout in the mPFC mimicked the cognitive deficits induced by chronic stress. In addition, chronic treatment with the selective TAAR1 partial agonist RO5263397 ameliorated chronic stress-induced changes in cognitive function, dendritic arborization, and the synapse number of pyramidal neurons in the mPFC but did not affect chronic stress-induced anxiety-like behaviors. Biochemically, chronic stress reduced the ratio of vesicular transporters of glutamate-1 (VGluT1) / vesicular GABA transporter (VGAT) in the mPFC，most prominently in the prelimbic cortex, and RO5263397 restored the excitatory-inhibitory (E/I) imbalance. Together, the results of this study reveal an essential role of TAAR1 in mediating chronic stress-induced cognitive impairments and suggest that TAAR1 agonists may be uniquely useful to treat MDD-related cognitive impairments. [Display omitted] • Chronic social defeat stress (CSDS) downregulated the TAAR1 mRNA level in the medial prefrontal cortex (mPFC) in mice. • Conditional TAAR1 knockout in the mPFC mimicked the cognitive deficits induced by CSDS. • TAAR1 partial agonist RO5263397 treatment restored most of the negative effects caused by CSDS in the mPFC. • TAAR1 in the mPFC is involved in the regulation of chronic stress vulnerability. • The regulation of E/I balance may be an important contributor underlying the anti-stress effect of TAAR1 agonists. [ABSTRACT FROM AUTHOR]