Sex-Specific Regulation of Stress Susceptibility by the Astrocytic Gene Htra1.

Major depressive disorder (MDD) is linked to impaired structural and synaptic plasticity in limbic brain regions. Astrocytes, which regulate synapses and are influenced by chronic stress, likely contribute to these changes. We analyzed astrocyte gene profiles in the nucleus accumbens (NAc) of humans with MDD and mice exposed to chronic stress. Htra1 , which encodes an astrocyte-secreted protease targeting the extracellular matrix (ECM), was significantly downregulated in the NAc of males but upregulated in females in both species. Manipulating Htra1 in mouse NAc astrocytes bidirectionally controlled stress susceptibility in a sex-specific manner. Such Htra1 manipulations also altered neuronal signaling and ECM structural integrity in NAc. These findings highlight astroglia and the brain's ECM as key mediators of sex-specific stress vulnerability, offering new approaches for MDD therapies.

Alprazolam exposure during adolescence induces long-lasting dysregulation in reward sensitivity to morphine and second messenger signaling in the VTA-NAc pathway.

Increased use of benzodiazepines in adolescents have been reported, with alprazolam (ALP) being the most abused. Drug abuse during adolescence can induce changes with lasting consequences. This study investigated the neurobiological consequences of ALP exposure during adolescence in C57BL/6J male mice. Mice received ALP (0, 0.5, 1.0 mg/kg) once/daily (postnatal day 35-49). Changes in responsiveness to morphine (2.5, 5.0 mg/kg), using the conditioned place preference paradigm, were assessed 24-h and 1-month after ALP exposure. In a separate experiment, mice received ALP (0, 0.5 mg/kg) and then sacrificed 24-h or 1-month after treatment to assess levels of extracellular signal regulated kinase 1/2 (ERK1/2) gene expression, protein phosphorylation, and downstream targets (CREB, AKT) within the ventral tegmental area (VTA) and nucleus accumbens (NAc). ALP-pretreated mice developed a strong preference to the compartment(s) paired with a subthreshold dose (2.5 mg/kg) of MOR short-term, and this effect was also present in the 1-month group. Adolescent ALP exposure resulted in dysregulation of ERK-signaling within the VTA-NAc pathway 24-h and 1-month after ALP exposure. Results indicate ALP exposure during adolescence potentiates the rewarding properties of MOR and induces persistent changes in ERK-signaling within the VTA-NAc pathway, a brain circuit highly implicated in the regulation of both drug reward and mood- related behaviors.

Role of the mesolimbic dopamine pathway in the antidepressant effects of ketamine.

Depression is a complex and highly heterogeneous disorder which diagnosis is based on an exceedingly variable set of clinical symptoms. Current treatments focus almost exclusively on the manipulation of monoamine neurotransmitter systems, but despite considerable efforts, these remain inadequate for a significant proportion of those afflicted by the disorder. The emergence of racemic (R, S)-ketamine as a fast-acting antidepressant has provided an exciting new path for the study of major depressive disorder (MDD) and the search for better therapeutics for its treatment. Previous work suggested that ketamine's mechanism of action is primarily mediated via blockaded of N-methyl-d-aspartate (NMDA) receptors, however, this is an area of active research and clinical and preclinical evidence now indicate that ketamine acts on multiple systems. The last couple of decades have cemented the mesolimbic dopamine reward pathway's involvement in the pathogenesis of MDD and related mood disorders. Exposure to negative stress dysregulates dopamine neuronal activity disrupting reward and motivational processes resulting in anhedonia (lack of pleasure), a hallmark symptom of depression. Although the mechanism(s) underlying ketamine's antidepressant activity continue to be elucidated, current evidence indicate that its therapeutic effects are mediated, at least in part, via long-lasting synaptic changes and subsequent molecular adaptations in brain regions within the mesolimbic dopamine system. Notwithstanding, ketamine is a drug of abuse, and this liability may pose limitations for long term use as an antidepressant. This review outlines the current knowledge of ketamine's actions within the mesolimbic dopamine system and its abuse potential. This article is part of the Special Issue on 'Ketamine and its Metabolites'.

Exposure to Vicarious Social Defeat Stress and Western-Style Diets During Adolescence Leads to Physiological Dysregulation, Decreases in Reward Sensitivity, and Reduced Antidepressant Efficacy in Adulthood.

A dramatic increase in the prevalence of major depression and diet-related disorders in adolescents has been observed over several decades, yet the mechanisms underlying this comorbidity have only recently begun to be elucidated. Exposure to western-style diet (WSD), high in both fats (45% kcal) and carbohydrates (35% kcal): e.g., high fat diet (HFD), has been linked to the development of metabolic syndrome-like symptoms and behavioral dysregulation in rodents, as similarly observed in the human condition. Because adolescence is a developmental period highlighted by vulnerability to both stress and poor diet, understanding the mechanism(s) underlying the combined negative effects of WSDs and stress on mood and reward regulation is critical. To this end, adolescent male C57 mice were exposed to vicarious social defeat stress (VSDS), a stress paradigm capable of separating physical (PS) versus psychological/emotional (ES) stress, followed by normal chow (NC), HFD, or a separate control diet high in carbohydrates (same sucrose content as HFD) and low in fat (LFD), while measuring body weight and food intake. Non-stressed control mice exposed to 5 weeks of NC or HFD showed no significant differences in body weight or social interaction. Mice exposed to VSDS (both ES and PS) gain weight rapidly 1 week after initiation of HFD, with the ES-exposed mice showing significantly higher weight gain as compared to the HFD-exposed control mice. These mice also exhibited a reduction in saccharin preference, indicative of anhedonic-like behavior. To further delineate whether high fat was the major contributing factor to these deficits, LFD was introduced. The mice in the VSDS + HFD gained weight more rapidly than the VSDS + LFD group, and though the LFD-exposed mice did not gain weight as rapidly as the HFD-exposed mice, both the VSDS + LFD- and VSDS + HFD-exposed mice exhibited attenuated response to the antidepressant fluoxetine. These data show that diets high in both fats and carbohydrates are responsible for rapid weight gain and reduced reward sensitivity; and that while consumption of diet high in carbohydrate and low in fat does not lead to rapid weight gain, both HFD and LFD exposure after stress leads to reduced responsiveness to antidepressant treatment.

The Resilient Phenotype Induced by Prophylactic Ketamine Exposure During Adolescence Is Mediated by the Ventral Tegmental Area-Nucleus Accumbens Pathway.

BACKGROUND: Major depressive disorder is prevalent in children and adolescents and is associated with a high degree of morbidity throughout life, with potentially devastating personal consequences and public health impact. The efficacy of ketamine (KET) as an antidepressant has been demonstrated in adolescent rodents; however, the neurobiological mechanisms underlying these effects are unknown. Recent evidence showed that KET reverses stress-induced (i.e., depressive-like) deficits within major mesocorticolimbic regions, such as the prefrontal cortex, nucleus accumbens (NAc), and hippocampus, in adult rodents. However, little is known about KET's effect in the ventral tegmental area (VTA), which provides the majority of dopaminergic input to these brain regions. METHODS: We characterized behavioral, biochemical, and electrophysiological effects produced by KET treatment in C57BL/6J male mice during adolescence (n = 7-10 per condition) within the VTA and its major projection regions, namely, the NAc and prefrontal cortex. Subsequently, molecular targets within the VTA-NAc projection were identified for viral gene transfer manipulations to recapitulate the effects of stress or KET treatment. RESULTS: Repeated KET treatment produced a robust proresilient response to chronic social defeat stress. This effect was largely driven by Akt signaling activity within the VTA and NAc, and it could be blocked or recapitulated through direct Akt-viral-mediated manipulation. Additionally, we found that the KET-induced resilient phenotype is dependent on VTA-NAc, but not VTA-prefrontal cortex, pathway activity. CONCLUSIONS: These findings indicate that KET exposure during adolescence produces a proresilient phenotype mediated by changes in Akt intracellular signaling and altered neuronal activity within the VTA-NAc pathway.