{Reference Type}: Journal Article
{Title}: Long-Term Impact of Early-Life Stress on Serotonin Connectivity.
{Author}: Ramkumar R;Edge-Partington M;Terstege DJ;Adigun K;Ren Y;Khan NS;Rouhi N;Jamani NF;Tsutsui M;Epp JR;Sargin D;
{Journal}: Biol Psychiatry
{Volume}: 96
{Issue}: 4
{Year}: 2024 Aug 15
{Factor}: 12.81
{DOI}: 10.1016/j.biopsych.2024.01.024
{Abstract}: <B>BACKGROUND: </B>Chronic childhood stress is a prominent risk factor for developing affective disorders, yet mechanisms underlying this association remain unclear. Maintenance of optimal serotonin (5-HT) levels during early postnatal development is critical for the maturation of brain circuits. Understanding the long-lasting effects of early-life stress (ELS) on serotonin-modulated brain connectivity is crucial to develop treatments for affective disorders arising from childhood stress.<BR><B>METHODS: </B>Using a mouse model of chronic developmental stress, we determined the long-lasting consequences of ELS on 5-HT circuits and behavior in females and males. Using FosTRAP mice, we cross-correlated regional c-Fos density to determine brain-wide functional connectivity of the raphe nucleus. We next performed in vivo fiber photometry to establish ELS-induced deficits in 5-HT dynamics and optogenetics to stimulate 5-HT release to improve behavior.<BR><B>RESULTS: </B>Adult female and male mice exposed to ELS showed heightened anxiety-like behavior. ELS further enhanced susceptibility to acute stress by disrupting the brain-wide functional connectivity of the raphe nucleus and the activity of 5-HT neuron population, in conjunction with increased orbitofrontal cortex (OFC) activity and disrupted 5-HT release in medial OFC. Optogenetic stimulation of 5-HT terminals in the medial OFC elicited an anxiolytic effect in ELS mice in a sex-dependent manner.<BR><B>CONCLUSIONS: </B>These findings suggest a significant disruption in 5-HT-modulated brain connectivity in response to ELS, with implications for sex-dependent vulnerability. The anxiolytic effect of the raphe-medial OFC circuit stimulation has potential implications for developing targeted stimulation-based treatments for affective disorders that arise from early life adversities.