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

• Published in: Biological psychiatry (1969) Vol. 96; no. 4; pp. 287 - 299
• Main Authors: Ramkumar, Raksha, Edge-Partington, Moriah, Terstege, Dylan J., Adigun, Kabirat, Ren, Yi, Khan, Nazmus S., Rouhi, Nahid, Jamani, Naila F., Tsutsui, Mio, Epp, Jonathan R., Sargin, Derya
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.08.2024
• Subjects: Animals; Anxiety - metabolism; Anxiety - physiopathology; Behavior, Animal - physiology; Disease Models, Animal; Dorsal raphe; Early life stress; Female; Fiber photometry; Functional connectivity; Male; Mice; Mice, Inbred C57BL; Neural Pathways - physiopathology; Optogenetics; Orbitofrontal cortex; Prefrontal Cortex - metabolism; Prefrontal Cortex - physiopathology; Proto-Oncogene Proteins c-fos - metabolism; Raphe Nuclei - metabolism; Serotonin; Serotonin - metabolism; Stress, Psychological - metabolism; Stress, Psychological - physiopathology; Functional connectivity; Early life stress; Orbitofrontal cortex; Dorsal raphe; Serotonin; Fiber photometry
• ISSN: 0006-3223; 1873-2402; 1873-2402
• DOI: 10.1016/j.biopsych.2024.01.024

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. 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. 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. 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.