Search

The link between dysregulated serotonergic activity and depression and anxiety disorders is well established, yet the molecular mechanisms underlying these psychopathologies are not fully understood. Here, we explore the role of microRNAs in regulating serotonergic (5HT) neuron activity. To this end, we determined the specific microRNA "fingerprint" of 5HT neurons and identified a strong microRNA-target interaction between microRNA 135 (miR135), and both serotonin transporter and serotonin receptor-1a transcripts. Intriguingly, miR135a levels were upregulated after administration of antidepressants. Genetically modified mouse models, expressing higher or lower levels of miR135, demonstrated major alterations in anxiety- and depression-like behaviors, 5HT levels, and behavioral response to antidepressant treatment. Finally, miR135a levels in blood and brain of depressed human patients were significantly lower. The current results suggest a potential role for miR135 as an endogenous antidepressant and provide a venue for potential treatment and insights into the onset, susceptibility, and heterogeneity of stress-related psychopathologies. [ABSTRACT FROM AUTHOR]

In response to physiological or psychological challenges, the brain activates behavioral and neuroendocrine systems linked to both metabolic and emotional outputs designed to adapt to the demand. However, dysregulation of integration of these physiological re- sponses to challenge can have severe psychological and physiological consequences, and inappropriate regulation, disproportional intensity, or chronic or irreversible activation of the stress response is linked to the etiology and pathophysiology of mood and metabolic disorders. Using a transgenic mouse model and lentiviral approach, we demonstrate the involvement of the hypothalamic neuropeptide Urocortin-3, a specific ligand for the type-2 corticotropin-releasing factor receptor, in modulating septal and hypothalamic nuclei responsible for anxiety-like behaviors and metabolic functions, respectively. These results position Urocortin-3 as a neuro-modulator linking stress-induced anxiety and energy homeostasis and pave the way toward better understanding of the mechanisms that mediate the reciprocal relationships between stress, mood and metabolic disorders. [ABSTRACT FROM AUTHOR]

A growing body of experimental and clinical studies supports, a strong association between psychological stress land cardiovascular disease. An important endogenous cardioprotective role in heart physiology has been attributed to corticotropin-releasing factor receptor type 2β (CRFR2β). Here, we report the isolation of cDNA from mouse (m) heart encoding a novel CRFR2β splice variant. Translation of this insertion variant (iv)-mCRFR2β isoform produces a 421-aa protein that includes a unique C-terminal cytoplasmic tail. Our functional analysis and cellular localization studies demonstrated that when coexpressed with wild-type mCRFR2β, iv-mCRFR2β significantly inhibited the wild-type mCRFR2β membrane expression and its functional signaling by ER-Golgi complex retention, suggesting a dose-dependent dominant negative effect. Interestingly, mice exposed to a 4-wk paradigm of chronic variable stress, a model of chronic psychological stress A humans, presented significantly lower levels of mCRFR2β and higher levels of iv-mCRFR2β mRNA expression in their hearts, compared to nonstressed control mice. The dominant-negative effect of iv-mCRFR2β and its up-regulation by psychological stress suggest a new form of regulation of the mCRFR2β cardioprotective effect and a potential role for this novel isoform in stress-induced heart disease. [ABSTRACT FROM AUTHOR]

Background: The corticotropin-releasing factor type 2 receptor (CRFR2) is suggested to play an important role in aiding recovery from acute stress, but any chronic effects of CRFR2 activation are unknown. CRFR2 in the midbrain raphé nuclei modulate serotonergic activity of this key source of serotonin (5-HT) forebrain innervation. Methods: Transgenic mice overexpressing the highly specific CRFR2 ligand urocortin 3 (UCN3OE) were analyzed for stress-related behaviors and hypothalamic-pituitary-adrenal axis responses. Responses to 5-HT receptor agonist challenge were assessed by local cerebral glucose utilization, while 5-HT and 5-hydroxyindoleacetic acid content were quantified in limbic brain regions. Results: Mice overexpressing urocortin 3 exhibited increased stress-related behaviors under basal conditions and impaired retention of spatial memory compared with control mice. Following acute stress, unlike control mice, they exhibited no further increase in these stress-related behaviors and showed an attenuated adrenocorticotropic hormone response. 5-HT and 5-hydroxyindoleacetic acid content of limbic nuclei were differentially regulated by stress in UCN3OE mice as compared with control mice. Responses to 5-HT type 1A receptor challenge were significantly and specifically reduced in UCN3OE mice. The distribution pattern of local cerebral glucose utilization and 5-HT type 1A receptor messenger RNA expression levels suggested this effect was mediated in the raphé nuclei. Conclusions: Chronic activation of CRFR2 promotes an anxiety-like state, yet with attenuated behavioral and hypothalamic-pituitary-adrenal axis responses to stress. This is reminiscent of stress-related atypical psychiatric syndromes such as posttraumatic stress disorder, chronic fatigue, and chronic pain states. This new understanding indicates CRFR2 antagonism as a potential novel therapeutic target for such disorders. [ABSTRACT FROM AUTHOR]