biostudies-literatureBickle JGNational Alliance for Research on Schizophrenia and DepressionSunovionNIMH NIH HHSBrain and Behavior Research FoundationNational Institute of Mental Health800-809https://www.ebi.ac.uk/biostudies/studies/S-EPMC10978305biostudies-literatureUnknown95(8)<h4>Background</h4>Hyperactivity of granule cells in the ventral dentate gyrus (vDG) promotes vulnerability to chronic stress. However, which receptors in the vDG could be targeted to inhibit this hyperactivity and confer stress resilience is not known. The serotonin 1A receptor (5-HT_1AR) is a G_i protein-coupled inhibitory receptor that has been implicated in stress adaptation, anxiety, depression, and antidepressant responses. 5-HT_1ARs are highly expressed in the DG, but their potential to promote stress resilience by regulating granule cell activity has never been examined.<h4>Methods</h4>We exposed male and female mice expressing 5-HT_1ARs only in DG granule cells to 10 days of chronic social defeat stress (CSDS) and treated them with the 5-HT_1AR agonist 8-OH-DPAT every day 30 minutes before each defeat throughout the CSDS paradigm. We then used whole-cell current clamp recordings, immunohistochemistry for the immediate early gene cFos, corticosterone immunoassays, and behavioral testing to determine how activating 5-HT_1ARs on granule cells affects DG activity, neuroendocrine stress responses, and avoidance behavior.<h4>Results</h4>We found that activating 5-HT_1ARs hyperpolarized DG granule cells and reduced cFos+ granule cells in the vDG following CSDS, indicating that 5-HT_1AR activation rescued stress-induced vDG hyperactivity. Moreover, 5-HT_1AR activation dampened corticosterone responses to CSDS and prevented the development of stress-induced avoidance in the social interaction test and in the open field test.<h4>Conclusions</h4>Our findings show that activating 5-HT_1ARs on DG granule cells can prevent stress-induced neuronal hyperactivity of the vDG and confer resilience to chronic stress.Biological psychiatry5-HT&lt;sub&gt;1A&lt;/sub&gt; Receptors on Dentate Gyrus Granule Cells Confer Stress Resilience.PMC10978305R00MH10871929223P50MH090964R00 MH108719R01MH126105P50 MH090964R01 MH126105Luna VMLi YMillette ADixon RWu SBickle JGAnacker CArias ECfalse5-HT&lt;sub&gt;1A&lt;/sub&gt; Receptors on Dentate Gyrus Granule Cells Confer Stress Resilience.<h4>Background</h4>Hyperactivity of granule cells in the ventral dentate gyrus (vDG) promotes vulnerability to chronic stress. However, which receptors in the vDG could be targeted to inhibit this hyperactivity and confer stress resilience is not known. The serotonin 1A receptor (5-HT_1AR) is a G_i protein-coupled inhibitory receptor that has been implicated in stress adaptation, anxiety, depression, and antidepressant responses. 5-HT_1ARs are highly expressed in the DG, but their potential to promote stress resilience by regulating granule cell activity has never been examined.<h4>Methods</h4>We exposed male and female mice expressing 5-HT_1ARs only in DG granule cells to 10 days of chronic social defeat stress (CSDS) and treated them with the 5-HT_1AR agonist 8-OH-DPAT every day 30 minutes before each defeat throughout the CSDS paradigm. We then used whole-cell current clamp recordings, immunohistochemistry for the immediate early gene cFos, corticosterone immunoassays, and behavioral testing to determine how activating 5-HT_1ARs on granule cells affects DG activity, neuroendocrine stress responses, and avoidance behavior.<h4>Results</h4>We found that activating 5-HT_1ARs hyperpolarized DG granule cells and reduced cFos+ granule cells in the vDG following CSDS, indicating that 5-HT_1AR activation rescued stress-induced vDG hyperactivity. Moreover, 5-HT_1AR activation dampened corticosterone responses to CSDS and prevented the development of stress-induced avoidance in the social interaction test and in the open field test.<h4>Conclusions</h4>Our findings show that activating 5-HT_1ARs on DG granule cells can prevent stress-induced neuronal hyperactivity of the vDG and confer resilience to chronic stress.2024-01-01T00:00:00Z2024 Apr2025-07-03T03:06:51.468Z2025-07-03T03:06:51.468ZS-EPMC109783053786324510.1016/j.biopsych.2023.10.007