Melanin-concentrating-hormone (MCH)-expressing neurons (MCH neurons) in the lateral hypothalamus (LH) are critical regulators of energy and glucose homeostasis. Here, we demonstrate that insulin increases the excitability of these neurons in control mice. In vivo, insulin promotes phosphatidylinositol 3-kinase (PI3K) signaling in MCH neurons, and cell-type-specific deletion of the insulin receptor (IR) abrogates this response. While lean mice lacking the IR in MCH neurons (IR) exhibit no detectable metabolic phenotype under normal diet feeding, they present with improved locomotor activity and insulin sensitivity under high-fat-diet-fed, obese conditions. Similarly, obesity promotes PI3 kinase signaling in these neurons, and this response is abrogated in IR mice. In turn, acute chemogenetic activation of MCH neurons impairs locomotor activity but not insulin sensitivity. Collectively, our experiments reveal an insulin-dependent activation of MCH neurons in obesity, which contributes via distinct mechanisms to the manifestation of impaired locomotor activity and insulin resistance.

Schizophrenia is a devastating disease that arises on the background of genetic predisposition and environmental risk factors, such as early life stress (ELS). In this study, we show that ELS-induced schizophrenia-like phenotypes in mice correlate with a widespread increase of histone-deacetylase 1 (Hdac1) expression that is linked to altered DNA methylation. Hdac1 overexpression in neurons of the medial prefrontal cortex, but not in the dorsal or ventral hippocampus, mimics schizophrenia-like phenotypes induced by ELS. Systemic administration of an HDAC inhibitor rescues the detrimental effects of ELS when applied after the manifestation of disease phenotypes. In addition to the hippocampus and prefrontal cortex, mice subjected to ELS exhibit increased Hdac1 expression in blood. Moreover, Hdac1 levels are increased in blood samples from patients with schizophrenia who had encountered ELS, compared with patients without ELS experience. Our data suggest that HDAC1 inhibition should be considered as a therapeutic approach to treat schizophrenia.

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Tauopathies comprise a heterogeneous family of neurodegenerative diseases characterized by pathological accumulation of hyperphosphorylated Tau protein. Pathological changes in serotonergic signaling have been associated with tauopathy etiology, but the underlying mechanisms remain poorly understood. Here, we studied the role of the serotonin receptor 7 (5-HT7R), in a mouse model of tauopathy induced by overexpressing the human Tau[R406W] mutant associated with inherited forms of frontotemporal dementia. We showed that the constitutive 5-HT7R activity is required for Tau hyperphosphorylation and formation of highly bundled Tau structures (HBTS) through G-protein-independent, CDK5-dependent mechanism. We also showed that 5-HT7R physically interacts with CDK5. At the systemic level, 5-HT7R-mediated CDK5 activation induces HBTS leading to neuronal death, reduced long-term potentiation (LTP), and impaired memory in mice. Specific blockade of constitutive 5-HT7R activity in neurons that overexpressed Tau[R406W] prevents Tau hyperphosphorylation, aggregation, and neurotoxicity. Moreover, 5-HT7R knockdown in the prefrontal cortex fully abrogates Tau [R406W]-induced LTP deficits and memory impairments. Thus, 5-HT7R/CDK5 signaling emerged as a new, promising target for tauopathy treatments.