{"title":"终纹床核促肾上腺皮质激素释放因子神经元的活性以一种依赖于发情期的方式减少雌性大鼠的焦虑增强惊吓。","authors":"Rachel Chudoba, Joanna Dabrowska","doi":"10.1016/j.biopsych.2025.07.017","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The prevalence of posttraumatic stress disorder (PTSD) and anxiety disorders is higher in women than men. The severity of hallmark symptoms including hypervigilance and fear reactivity to unpredictable threats varies with sex and reproductive cycle, but the underlying mechanisms remain unclear. Here, we investigated corticotropin-releasing factor (CRF) neurons in the dorsolateral bed nucleus of the stria terminalis (BNST<sub>DL</sub>) as a potential nexus for the influence of biological sex and reproductive cycle on fear- and anxiety-related behaviors.</p><p><strong>Methods: </strong>A total of 125 male and 156 cycle-monitored female CRF-Cre rats were used. BNST<sub>DL</sub>-CRF neuron excitability and synaptic activity were recorded with slice electrophysiology. Chemogenetic manipulations of BNST<sub>DL</sub>-CRF neurons were performed before elevated plus maze, predator odor exposure, shock-induced startle sensitization, and anxiety-potentiated startle (APS) following unpredictable fear conditioning.</p><p><strong>Results: </strong>BNST<sub>DL</sub>-CRF neurons in females exhibited higher excitability (cycle independent) and lower sensitivity to excitatory synaptic inputs (proestrus and diestrus) than males. BNST<sub>DL</sub>-CRF neuron inhibition reduced open-arm time in estrus females but not males. In the APS, BNST<sub>DL</sub>-CRF neuron inhibition attenuated short-term startle potentiation in males, whereas it caused persistent APS in diestrus females. Notably, chemogenetic activation of BNST<sub>DL</sub>-CRF neurons reduced APS in diestrus females.</p><p><strong>Conclusions: </strong>Unpredictable fear conditioning elicits sex- and estrous phase-specific APS, differentially regulated by BNST<sub>DL</sub>-CRF neurons. Persistent APS in females aligns with hormonal phases marked by low levels of reproductive hormones, mirroring human PTSD findings. Widely used in human studies, APS may bridge animal and human research, supporting the development of biomarkers and more effective pharmacotherapies.</p>","PeriodicalId":8918,"journal":{"name":"Biological Psychiatry","volume":" ","pages":""},"PeriodicalIF":9.0000,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12442882/pdf/","citationCount":"0","resultStr":"{\"title\":\"Activity of Corticotropin-Releasing Factor Neurons in the Bed Nucleus of the Stria Terminalis Reduces Anxiety-Potentiated Startle in Female Rats in an Estrous Phase-Dependent Manner.\",\"authors\":\"Rachel Chudoba, Joanna Dabrowska\",\"doi\":\"10.1016/j.biopsych.2025.07.017\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>The prevalence of posttraumatic stress disorder (PTSD) and anxiety disorders is higher in women than men. The severity of hallmark symptoms including hypervigilance and fear reactivity to unpredictable threats varies with sex and reproductive cycle, but the underlying mechanisms remain unclear. Here, we investigated corticotropin-releasing factor (CRF) neurons in the dorsolateral bed nucleus of the stria terminalis (BNST<sub>DL</sub>) as a potential nexus for the influence of biological sex and reproductive cycle on fear- and anxiety-related behaviors.</p><p><strong>Methods: </strong>A total of 125 male and 156 cycle-monitored female CRF-Cre rats were used. BNST<sub>DL</sub>-CRF neuron excitability and synaptic activity were recorded with slice electrophysiology. Chemogenetic manipulations of BNST<sub>DL</sub>-CRF neurons were performed before elevated plus maze, predator odor exposure, shock-induced startle sensitization, and anxiety-potentiated startle (APS) following unpredictable fear conditioning.</p><p><strong>Results: </strong>BNST<sub>DL</sub>-CRF neurons in females exhibited higher excitability (cycle independent) and lower sensitivity to excitatory synaptic inputs (proestrus and diestrus) than males. BNST<sub>DL</sub>-CRF neuron inhibition reduced open-arm time in estrus females but not males. In the APS, BNST<sub>DL</sub>-CRF neuron inhibition attenuated short-term startle potentiation in males, whereas it caused persistent APS in diestrus females. Notably, chemogenetic activation of BNST<sub>DL</sub>-CRF neurons reduced APS in diestrus females.</p><p><strong>Conclusions: </strong>Unpredictable fear conditioning elicits sex- and estrous phase-specific APS, differentially regulated by BNST<sub>DL</sub>-CRF neurons. Persistent APS in females aligns with hormonal phases marked by low levels of reproductive hormones, mirroring human PTSD findings. Widely used in human studies, APS may bridge animal and human research, supporting the development of biomarkers and more effective pharmacotherapies.</p>\",\"PeriodicalId\":8918,\"journal\":{\"name\":\"Biological Psychiatry\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":9.0000,\"publicationDate\":\"2025-07-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12442882/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biological Psychiatry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.biopsych.2025.07.017\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"NEUROSCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biological Psychiatry","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.biopsych.2025.07.017","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
Activity of Corticotropin-Releasing Factor Neurons in the Bed Nucleus of the Stria Terminalis Reduces Anxiety-Potentiated Startle in Female Rats in an Estrous Phase-Dependent Manner.
Background: The prevalence of posttraumatic stress disorder (PTSD) and anxiety disorders is higher in women than men. The severity of hallmark symptoms including hypervigilance and fear reactivity to unpredictable threats varies with sex and reproductive cycle, but the underlying mechanisms remain unclear. Here, we investigated corticotropin-releasing factor (CRF) neurons in the dorsolateral bed nucleus of the stria terminalis (BNSTDL) as a potential nexus for the influence of biological sex and reproductive cycle on fear- and anxiety-related behaviors.
Methods: A total of 125 male and 156 cycle-monitored female CRF-Cre rats were used. BNSTDL-CRF neuron excitability and synaptic activity were recorded with slice electrophysiology. Chemogenetic manipulations of BNSTDL-CRF neurons were performed before elevated plus maze, predator odor exposure, shock-induced startle sensitization, and anxiety-potentiated startle (APS) following unpredictable fear conditioning.
Results: BNSTDL-CRF neurons in females exhibited higher excitability (cycle independent) and lower sensitivity to excitatory synaptic inputs (proestrus and diestrus) than males. BNSTDL-CRF neuron inhibition reduced open-arm time in estrus females but not males. In the APS, BNSTDL-CRF neuron inhibition attenuated short-term startle potentiation in males, whereas it caused persistent APS in diestrus females. Notably, chemogenetic activation of BNSTDL-CRF neurons reduced APS in diestrus females.
Conclusions: Unpredictable fear conditioning elicits sex- and estrous phase-specific APS, differentially regulated by BNSTDL-CRF neurons. Persistent APS in females aligns with hormonal phases marked by low levels of reproductive hormones, mirroring human PTSD findings. Widely used in human studies, APS may bridge animal and human research, supporting the development of biomarkers and more effective pharmacotherapies.
期刊介绍：
Biological Psychiatry is an official journal of the Society of Biological Psychiatry and was established in 1969. It is the first journal in the Biological Psychiatry family, which also includes Biological Psychiatry: Cognitive Neuroscience and Neuroimaging and Biological Psychiatry: Global Open Science. The Society's main goal is to promote excellence in scientific research and education in the fields related to the nature, causes, mechanisms, and treatments of disorders pertaining to thought, emotion, and behavior. To fulfill this mission, Biological Psychiatry publishes peer-reviewed, rapid-publication articles that present new findings from original basic, translational, and clinical mechanistic research, ultimately advancing our understanding of psychiatric disorders and their treatment. The journal also encourages the submission of reviews and commentaries on current research and topics of interest.
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