Project description:Anxiety disorders refer to a group of costly psychiatric disorders characterized by feelings of fear, panic and worry and related behavioral disturbances. Up to 275 million people worldwide (4% of the global population) are affected by anxiety disorders, which was ranked 8th of the top 25 leading causes of years lived with disability (YLDs) in 2019. According to a recent article published in the Lancet, the COVID-19 pandemic has led to a substantial rise in prevalence of GAD globally, consequently contributing to an elevated disease burden and a deteriorated economic situation. However, around 50% of patients diagnosed with generalized anxiety disorder (GAD) do not respond to the conventional pharmacological and psychological interventions due to the individual variability. Moreover, the limited accessibility to mental health professionals, the risk of dependence on benzodiazepines and the side effects of selective serotonin reuptake inhibitors (SSRIs) can negatively influence the medication adherence of patients. Hence, there is an urgent need to investigate the underlying pathological mechanisms and develop innovative therapeutic interventions for GAD.
Project description:Emerging evidence has shown that noncoding RNAs, particularly microRNAs (miRNAs), contribute to the pathogenesis of mood and anxiety disorders, although the molecular mechanisms are poorly understood. Here we show altered levels of miR-17-92 in adult hippocampal neural progenitors have a significant impact in neurogenesis and anxiety- and depression-related behaviors in mice. miR-17-92 deletion in adult neural progenitors causes a decrease, while its overexpression an increase of neurogenesis in the dentate gyrus, through regulating genes in the glucocorticoid pathway, especially serum- and glucocorticoid-inducible protein kinase-1 (Sgk1). miR-17-92 knockout mice show anxiety- and depression-like behaviors, whereas miR-17-92 overexpressing mice exhibit anxiolytic and antidepression-like behaviors. Furthermore, we show that miR-17-92 expression in the adult mouse hippocampus responds to chronic stress, and miR-17-92 rescues proliferation defects, induced by corticosterone, in hippocampal neural progenitors. Our study uncovers a crucial role for miR-17-92 in adult neural progenitors to regulate neurogenesis and anxiety- and depression-like behaviors.
Project description:Investigating the molecular basis and correlates of anxiety-related and depression-like behaviors, we generated a mouse model consisting of high (HAB) and low (LAB) anxiety-related behavior mice. We utilized the elevated plus-maze for testing the genetic predisposition to anxiety-related behavior and, consequently, used this as selection criterion for the inbreeding of our animals. In depression-related tests, HAB mice display a more passive, depression-like coping strategy than LAB mice, resembling clinical comorbidity of anxiety and depression as observed in psychiatric patients. Using a microarray approach, the hypothalamic paraventricular nucleus (PVN), the basolateral/lateral (BLA), the medial (MeA) and central amygdala (CeA), the nucleus accumbens (NAc), the cingulate cortex (Cg) and the supraoptic nucleus (SON) – centers of the central nervous anxiety and fear circuitries – were investigated and screened for differences between HAB and LAB mice. Analysis was performed from six animals per line (HAB and LAB, respectively) pooled per brain region in ten technical replicates, thereof five with a dye-swapped design giving a total of 70 array slides analyzed. The LAB mouse line is referred to as reference.
Project description:Interleukin 17a (IL-17a) is a cytokine that has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Recent studies in mouse models of maternal immune activation suggest that IL-17a is also linked to behavioral changes reminiscent of those seen under pathological conditions such as autism spectrum disorders (ASD)1 and in aggregation behavior in Caenorhabditis elegans2, raising the intriguing possibility that this cytokine might have evolved for the homeostatic regulation of neuronal activity. Here, by in-depth cellular and molecular characterization of a unique population of meningeal-resident gd17 T cells, we characterized the nearest central nervous system (CNS)-associated source of IL-17a under homeostasis. Meningeal gd T cell-derived IL-17a was associated with anxiety-like behaviors in mice, which partially depended on T-cell receptor engagement and commensal microbiota. IL-17a receptor was highly expressed in glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice by shaping the transcriptional landscape and synaptic transmission of neurons in the medial prefrontal cortex (mPFC). From an evolutionary perspective, these findings suggest that IL-17a production by tissue-resident meningeal gd17 T cells may represent an evolutionary bridge between conserved anti-pathogen molecules and avoidance/survival behavioral traits in vertebrates.
Project description:Interleukin 17a (IL-17a) is a cytokine that has been highly conserved during evolution of the vertebrate immune system and widely studied in contexts of infection and autoimmunity. Recent studies in mouse models of maternal immune activation suggest that IL-17a is also linked to behavioral changes reminiscent of those seen under pathological conditions such as autism spectrum disorders (ASD)1 and in aggregation behavior in Caenorhabditis elegans2, raising the intriguing possibility that this cytokine might have evolved for the homeostatic regulation of neuronal activity. Here, by in-depth cellular and molecular characterization of a unique population of meningeal-resident gd17 T cells, we characterized the nearest central nervous system (CNS)-associated source of IL-17a under homeostasis. Meningeal gd T cell-derived IL-17a was associated with anxiety-like behaviors in mice, which partially depended on T-cell receptor engagement and commensal microbiota. IL-17a receptor was highly expressed in glutamatergic neurons under steady state and its genetic deletion decreased anxiety-like behavior in mice by shaping the transcriptional landscape and synaptic transmission of neurons in the medial prefrontal cortex (mPFC). From an evolutionary perspective, these findings suggest that IL-17a production by tissue-resident meningeal gd17 T cells may represent an evolutionary bridge between conserved anti-pathogen molecules and avoidance/survival behavioral traits in vertebrates.
Project description:Investigating the molecular basis and correlates of anxiety-related and depression-like behaviors, we generated a mouse model consisting of high (HAB), normal (NAB) and low (LAB) anxiety-related behavior mice. We utilized the elevated plus-maze for testing the genetic predisposition to anxiety-related behavior and, consequently, used this as selection criterion for the inbreeding of our animals. In depression-related tests, HAB mice display a more passive, depression-like coping strategy than LAB mice, resembling clinical comorbidity of anxiety and depression as observed in psychiatric patients. Using a microarray approach, the hypothalamic paraventricular nucleus (PVN), the basolateral (BLA) and central amygdala (CeA), the cingulate cortex (Cg) and the dentate gyrus (DG) – centers of the central nervous anxiety and fear circuitries – were investigated and screened for differences between HAB, NAB and LAB mice. Analysis was performed from four to six animals per line (HAB, NAB and LAB from generation 25, respectively) per brain region, giving a total of 78 individual arrays analyzed. The LAB mouse line is referred to as reference.