Early Life Social Stress Causes Sex- and Region-Dependent Dopaminergic Changes that Are Prevented by Minocycline

Abstract

Early life stress (ELS) is known to modify trajectories of brain dopaminergic development, but the mechanisms underlying have not been determined. ELS perturbs immune system and microglia reactivity, and inflammation and microglia influence dopaminergic transmission and development. Whether microglia mediate the effects of ELS on dopamine (DA) system development is still unknown. We explored the effects of repeated early social stress on development of the dopaminergic system in male and female mice through histological, electrophysiological, and transcriptomic analyses. Furthermore, we tested whether these effects could be mediated by ELS-induced altered microglia/immune activity through a pharmacological approach. We found that social stress in early life altered DA neurons morphology, reduced dopamine transporter (DAT) and tyrosine hydroxylase expression, and lowered DAT-mediated currents in the ventral tegmental area but not substantia nigra of male mice only. Notably, stress-induced DA alterations were prevented by minocycline, an inhibitor of microglia activation. Transcriptome analysis in the developing male ventral tegmental area revealed that ELS caused downregulation of dopaminergic transmission and alteration in hormonal and peptide signaling pathways. Results from this study offer new insight into the mechanisms of stress response and altered brain dopaminergic maturation after ELS, providing evidence of neuroimmune interaction, sex differences, and regional specificity.

A Relevant Role for Dopamine Transporter Gene in Highly Sensitive Persons under Stressful Conditions: Focus on Genetic and Epigenetic Regulation

“…This DAT1 gene�c data thus further corroborate the epigene�c ones, since HSP subjects, if repor�ng high levels of perceived stress, have higher levels of DAT1 DNA methyla�on, especially if carrying the 9/9 genotype, and higher expression of DAT1 miR-132. These molecular evidence could poten�ally drive lower DAT availability already reported at the preclinical level evoked by social stress (Catale et al, 2022) and at the clinical level for instance in major depression (Dubol et al, 2020;Meyer et al, 2001;Moriya et al, 2020;Pizzagalli et al, 2019). It is also relevant to point out that we did not observe any relevant change for the other gene under study, SERT, nor at the epigene�c levels when measuring DNA methyla�on and miRNAs expression nor at the gene�c levels when analyzing the 5-HTTLPR polymorphism.…”

A molecular framework for autistic experiences: Mitochondrial allostatic load as a mediator between autism and psychopathology

“…In addition, disruptions to neurotransmitter signaling and neuroendocrinology are implicated in both ELS and ASC. Preclinical studies have shown that chronic stress disrupts glutamate- (304)(305)(306)(307), serotonin- (308) and dopamine- (309)(310)(311)(312) signaling, leading to increased anxiety-like behaviors and impairments in social recognition, social interest and cognitive flexibility. These data are supported by human cohort studies showing that ELS disrupts dopaminergic responses to psychosocial stress (313,314), and alters glutamate/glutamine cycling (315) and serotonin transporter binding (316) in patients with MDD.…”

Psychoneuroimmunology: An Introduction to Immune-to-Brain Communication and Its Implications for Clinical Psychology

“…Importantly, the long-term effects of ELA may not be intractable. In preclinical research, some of the effects of ELA on dopaminergic circuits can be rescued by minocycline (Catale et al 2022). Further, susceptibility to morphine-induced conditioned place preference during adolescence can be mitigated by enriched maternal care during early development in a rodent model (Schwarz et al 2011).…”