Significance Arginine–vasopressin (AVP) acting on V1a receptors (Avpr1as) represents a key signaling mechanism in a brain circuit that increases the expression of social communication and aggression. We produced Syrian hamsters that completely lack Avpr1as ( Avpr1a knockout [KO] hamsters) using the CRISPR-Cas9 system to more fully examine the role of Avpr1a in the expression of social behaviors. We confirmed the absence of Avpr1as in these hamsters by demonstrating 1) a complete lack of Avpr1a-specific receptor binding throughout the brain, 2) a behavioral insensitivity to centrally administered AVP, and 3) an absence of the well-known blood-pressure response produced by activating Avpr1as. Unexpectedly, however, Avpr1a KO hamsters displayed more social communication behavior and aggression toward same-sex conspecifics than did their wild-type (WT) littermates.

Deficits in social memory, cognition, and aberrant responses to stimulants are common among persons affected by schizophrenia and other conditions with a presumed developmental etiology. We previously found that expression changes in the adenosine metabolizing enzyme adenosine kinase (ADK) in the adult brain are associated with deficits in various cognitive domains. To distinguish between developmental and adult functions of ADK, we used two transgenic mouse lines with widespread disruption of ADK expression in the adult brain, but differences in the onset of ADK deletion. Specifically, we compared Nestin-Cre:ADK-flox (ADK) mice with global loss of ADK in the whole brain, beginning in mid-gestation and persisting for life, with Gfa2-Cre:ADK-flox (ADK) mice that have normal ADK expression throughout development, but lose astrocyte-specific ADK-expression in young adulthood. Because ADK-expression in adulthood is generally confined to astrocytes, adult ADK mice show a similar expression profile of ADK in key areas of the brain related to neuropsychiatric behavior, compared to adult ADK mice. We sought to determine a neurodevelopmental role of ADK on the expression of psychiatric behaviors in adult male and female mice. Adult ADK mice showed significant deficits in social memory in males, significant contextual learning impairments in both sexes, and a hyper-responsiveness to amphetamine in males. In contrast, ADK mice showed normal social memory and contextual learning but hypo-responsiveness to amphetamine in males. Our results demonstrate a key developmental role of ADK in mediating behaviors in adulthood related to neuropsychiatric disease and support the greater prevalence of these disorders among males.

Background: Age predisposes individuals to a myriad of disorders involving inflammation; this includes stress-related neuropsychiatric disorders such as depression and anxiety, and neurodegenerative diseases. Obesity can further exacerbate these effects in the brain. We investigated whether an inexpensive dietary supplement, s-adenosylmethionine (SAMe), could improve age- and/or obesity-related inflammatory and affective measures in the hippocampus. Methods: Mice were placed on their diets at six weeks of age and then aged to 14 months, receiving SAMe (0.1 g/kg of food) for the final six weeks of the experiment. Prior to tissue collection, mice were tested for anxiety-like behaviors in the open field test and for metabolic outcomes related to type 2 diabetes. Results: SAMe treatment significantly improved outcomes in aged control mice, where fasting glucose decreased, liver glutathione levels increased, and hippocampal microglia morphology improved. SAMe increased transforming growth factor β-1 mRNA in both control mice, potentially accounting for improved microglial outcomes. Obese mice demonstrated increased anxiety-like behavior, where SAMe improved some, but not all, open field measures. Conclusions: In summary, SAMe boosted antioxidant levels, improved diabetic measures, and hippocampal inflammatory and behavioral outcomes in aged mice. The effects of SAMe in obese mice were more subdued, but it could still provide some positive outcomes for obese individuals dealing with anxiety and having difficulty changing their behaviors to improve health outcomes.

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