Long-Term Impact of Early-Life Stress on Serotonin Connectivity

BackgroundChronic 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.MethodsUsing a mouse model of chronic developmental stress, we determined the long-lasting consequences of ELS on 5-HT circuits and behavior in female and male mice. 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.ResultsAdult 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 (mOFC). Optogenetic stimulation of 5-HT terminals in the mOFC elicited an anxiolytic effect in ELS mice in a sex-dependent manner.ConclusionThese 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-mOFC circuit stimulation provides potential implications for developing targeted stimulation-based treatments for affective disorders that arise from early life adversities.