SNORD90 induces glutamatergic signaling following treatment with monoaminergic antidepressants.

Pharmacotherapies for the treatment of major depressive disorder were serendipitously discovered almost seven decades ago. From this discovery, scientists pinpointed the monoaminergic system as the primary target associated with symptom alleviation. As a result, most antidepressants have been engineered to act on the monoaminergic system more selectively, primarily on serotonin, in an effort to increase treatment response and reduce unfavorable side effects. However, slow and inconsistent clinical responses continue to be observed with these available treatments. Recent findings point to the glutamatergic system as a target for rapid acting antidepressants. Investigating different cohorts of depressed individuals treated with serotonergic and other monoaminergic antidepressants, we found that the expression of a small nucleolar RNA, SNORD90, was elevated following treatment response. When we increased Snord90 levels in the mouse anterior cingulate cortex (ACC), a brain region regulating mood responses, we observed antidepressive-like behaviors. We identified neuregulin 3 (NRG3) as one of the targets of SNORD90, which we show is regulated through the accumulation of N6-methyladenosine modifications leading to YTHDF2-mediated RNA decay. We further demonstrate that a decrease in NRG3 expression resulted in increased glutamatergic release in the mouse ACC. These findings support a molecular link between monoaminergic antidepressant treatment and glutamatergic neurotransmission.

Hypothalamic miR-219 regulates individual metabolic differences in response to diet-induced weight cycling.

Consumption of a low calorie diet is the most common approach to lose weight. While generally effective at first, it is frequently followed by a relapse where the pre-diet weight is regained, and often exceeded. This pattern of repeated weight loss/regain is referred to as weight cycling and the resulting metabolic response varies greatly between individuals. OBJECTIVE: We attempted to address the issue of individual differences in the response to weight cycling in male mice. METHODS: We first exposed adult wild type mice to repeated cycles of high/low fat food. Next, using a lentiviral approach, we knocked-down or over-expressed miR-219 in the ventromedial hypothalamus (VMH) of an additional mouse cohort and performed a full metabolic assessment. RESULTS: Exposure of wild type males to weight cycling resulted in the division of the cohort into subsets of resistant versus metabolic-syndrome-prone (MS) animals, which differed in their metabolic profile and hypothalamic miR-219 levels. Lentiviral knock-down of miR-219 in the VMH led to exacerbation of metabolic syndrome. In contrast, over-expression of miR-219 resulted in moderation of the metabolic syndrome phenotype. CONCLUSIONS: Our results suggest a role for miR-219 in the mediation of the metabolic phenotype resulting from repeated weight cycling.

Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics.

Social encounters are associated with varying degrees of emotional arousal and stress. The mechanisms underlying adequate socioemotional balance are unknown. The medial amygdala (MeA) is a brain region associated with social behavior in mice. Corticotropin-releasing factor receptor type-2 (CRF-R2) and its specific ligand urocortin-3 (Ucn3), known components of the behavioral stress response system, are highly expressed in the MeA. Here we show that mice deficient in CRF-R2 or Ucn3 exhibit abnormally low preference for novel conspecifics. MeA-specific knockdown of Crfr2 (Crhr2) in adulthood recapitulated this phenotype. In contrast, pharmacological activation of MeA CRF-R2 or optogenetic activation of MeA Ucn3 neurons increased preference for novel mice. Furthermore, chemogenetic inhibition of MeA Ucn3 neurons elicited pro-social behavior in freely behaving groups of mice without affecting their hierarchal structure. These findings collectively suggest that the MeA Ucn3-CRF-R2 system modulates the ability of mice to cope with social challenges.

Family-based study of AVPR1B association and interaction with stressful life events on depression and anxiety in suicide attempts.

The cortisol response to psychosocial stress may become dysregulated in stress-related disorders. It is potentiated by pituitary secretion of adrenocorticotropic hormone (ACTH), which is, in part, regulated by arginine vasopressin receptor-1B (AVPR1B). AVPR1B variants were previously reported to associate with mood and anxiety disorders. This study aims, for the first time, to investigate association of AVPR1B genetic variants with mood and anxiety outcomes in suicidal behavior.Using a family-based study design of 660 complete nuclear family trios with offspring who have made a suicide attempt (SA), we tested the direct association and linkage of AVPR1B single nucleotide polymorphisms (SNPs) with SA, as well as with depression and anxiety in SA. Main findings were the association and linkage of AVPR1B exon 1 SNP rs33990840 and a major 6-SNP haplotype representative of all common AVPR1B-SNPs, on the outcome of high Beck Depression Inventory scores in SA. By contrast, genetic associations with lifetime diagnoses of depression and anxiety in SA or gene-environment interactions between AVPR1B variants and stressful life events (SLEs) were not significant. An exploratory screen of interactions between AVPR1B and CRHR1 (corticotropin-releasing hormone receptor-1), the principal pituitary regulator of ACTH secretion, showed no support for gene-gene interactions on the studied outcomes. The results suggest that AVPR1B genetic variation, eg, non-synonymous SNP rs33990840 mediating putative consequences on ligand binding, has a role in SA etiology characterized by elevated depression symptoms, without involving AVPR1B-moderation of SLEs.