Stress is a major risk for the onset of several maladaptive processes including pathological anxiety, a diffuse state of heightened apprehension over anticipated threats. Pathological anxiety is prevalent in up to 59% of patients with Tuberous Sclerosis complex (TSC), a neurodevelopmental disorder (NDD) caused by loss-of-function mutations in genes for Tuberin () and/or Hamartin () that together comprise the eponymous protein complex. Here, we generated cell type-specific heterozygous knockout of in cells expressing oxytocin receptor (OTRCs) to model pathological anxiety-like behaviors observed in TSC patient population. The stress of prolonged social isolation induces a sustained negative affective state that precipitates behavioral avoidance, often by aberrant oxytocin signaling in the limbic forebrain. In response to social isolation, there were striking sex differences in stress susceptibility in conditional heterozygote mice when encountering situations of approach-avoidance conflict. Socially isolated male mutants exhibited behavioral avoidance in anxiogenic environments and sought more social interaction for buffering of stress. In contrast, female mutants developed resilience during social isolation and approached anxiogenic environments, while devaluing social interaction. Systemic and medial prefrontal cortex (mPFC)-specific inhibition of downstream effector of TSC, the integrated stress response (ISR), rescued behavioral approach toward anxiogenic environments and conspecifics in male and female mutant mice respectively. Further, we found that deletion in OTRCs leads to OTR-signaling elicited network suppression, i.e., hypofrontality, in male mPFC, which is relieved by inhibiting the ISR. Our findings present evidence in support of a sexually dimorphic role of prefrontal OTRCs in regulating emotional responses in anxiogenic environments, which goes awry in TSC. Our work has broader implications for developing effective treatments for subtypes of anxiety disorders that are characterized by cell-autonomous ISR and prefrontal network suppression.
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http://dx.doi.org/10.1101/2024.06.25.600464 | DOI Listing |
Ecotoxicol Environ Saf
December 2024
College of Forensic Medicine, Hebei Medical University, Hebei Key Laboratory of Forensic Medicine, Collaborative Innovation Center of Forensic Medical Molecular Identification, Research Unit of Digestive Tract Microecosystem Pharmacology and Toxicology, Chinese Academy of Medical Sciences, Shijiazhuang, Hebei Province 050017, PR China; Key Laboratory of Neural and Vascular Biology, Ministry of Education, Shijiazhuang, Hebei Province 050017, PR China. Electronic address:
Oxf Open Neurosci
November 2024
Department of Psychology, The University of Texas at El Paso, El Paso, TX 79968.
Anxiety-related illnesses constitute one of the leading causes of disability across the globe. Consequently, the need for validated preclinical models to uncover the etiology of anxiety phenotypes remains essential. Given the link between social stress experience and the manifestation of anxiogenic-like outcomes, we evaluated whether social defeat stress (SDS) reduces open-space exploratory behavior in prairie voles ().
View Article and Find Full Text PDFSci Rep
November 2024
Neuroscience Department, Muhlenberg College, Allentown, PA, 18104, USA.
Biomedicines
November 2024
Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD 20817, USA.
Purpose Of Review: This review aims to describe the role of limbic system-associated membrane protein (LSAMP) in normal- and pathophysiology, and its potential implications in oncogenesis. We have summarized research articles reporting the role of LSAMP in the development of a variety of malignancies, such as clear cell renal cell carcinoma, prostatic adenocarcinoma, lung adenocarcinoma, osteosarcoma, neuroblastoma, acute myeloid leukemia, and epithelial ovarian cancer. We also examine the current understanding of how defects in LSAMP gene function may contribute to oncogenesis.
View Article and Find Full Text PDFProg Neuropsychopharmacol Biol Psychiatry
October 2024
Department of Neuroscience, Carleton University, Ottawa, ON K1S 5B6, Canada. Electronic address:
Feeding is necessary for survival but can be hindered by anxiety or fear, thus neural systems that can regulate anxiety states are key to elucidating the expression of food-related behaviors. Melanin-concentrating hormone (MCH) is a neuropeptide produced in the lateral hypothalamus and zona incerta that promotes feeding and anxiogenesis. The orexigenic actions of MCH that prolong ongoing homeostatic or hedonic feeding are context-dependent and more prominent in male than female rodents, but it is not clear where MCH acts to initiate feeding.
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