Adolescent intermittent ethanol reduces serotonin expression in the adult raphe nucleus and upregulates innate immune expression that is prevented by exercise

Abstract

Serotonergic neurons of the raphe nucleus regulate sleep, mood, endocrine function, and other processes that mature during adolescence. Alcohol abuse and binge drinking are common during human adolescence. We tested the novel hypothesis that adolescent intermittent ethanol exposure would alter the serotonergic system that would persist into adulthood. Using a Wistar rat model of adolescent intermittent ethanol (AIE; 5.0 g/kg, i.g., 2-day on/2-day off from postnatal day [P]25 to P55), we found a loss of dorsal raphe nucleus (DRN) serotonin (5-HT)-immunoreactive (+IR) neurons that persisted from late adolescence (P56) into adulthood (P220). Hypothalamic and amygdalar DRN serotonergic projections were reduced following AIE. Tryptophan hydroxylase 2, the rate-limiting 5-HT synthesizing enzyme, and vesicular monoamine transporter 2, which packages 5-HT into synaptic vesicles, were also reduced in the young adult midbrain following AIE treatment. Adolescent intermittent ethanol treatment increased expression of phosphorylated (activated) NF-κB p65 as well as markers of microglial activation (i.e., Iba-1 and CD11b) in the adult DRN. Administration of lipopolysaccharide to mimic AIE-induced innate immune activation reduced 5-HT+IR and increased phosphorylated NF-κB p65+IR similar to AIE treatment. Voluntary exercise during adolescence through young adulthood blunted microglial marker and phosphorylated NF-κB p65+IR, and prevented the AIE-induced loss of 5-HT+IR neurons in the DRN. Together, these novel data reveal that AIE reduces 5-HT+IR neurons in the adult DRN, possibly through an innate immune mechanism, which might impact adult cognition, arousal, or reward sensitivity. Further, exercise prevents the deleterious effects of AIE on the serotonergic system.

Neuroimmune and epigenetic involvement in adolescent binge ethanol‐induced loss of basal forebrain cholinergic neurons: Restoration with voluntary exercise

“…Accumulating evidence reveals that AIE treatment causes a persistent upregulation of neuroimmune signaling molecules resulting in adult neuropathology, including loss of ChAT+IR cells . NF‐κB is a transcription factor known to induce multiple neuroimmune genes, and phosphorylated NF‐κB p65 has been used to follow neuroimmune activation in brain . In a previous study, we reported that exercise initiated at the onset of AIE and continuing throughout experimentation (ie, P24‐P80) prevented the AIE‐induced increase of pNF‐κB p65 in the adult (ie, P80) basal forebrain (see Vetreno and Crews).…”

Differential stress induced c-Fos expression and identification of region-specific miRNA-mRNA networks in the dorsal raphe and amygdala of high-responder/low-responder rats

“…microRNA-mRNA networks likely contribute to overall responsivity and functionality in each region. Inflammation and activation of microglia in the dorsal raphe reduces Tph2 expression and causes serotonergic hypofunction [82, 83]. Thus, we can hypothesize that the unresponsiveness of the LR dorsal raphe to electric shock stress is related to down-regulation of microRNAs miR-206-3p, miR-3559-5p, and/or miR-378-3p, up-regulation of the associated microglia genes Cd74 , Rac2 , Nckap1l , and Cyth4, and increased microglia activation .…”

A cross-sectional comparison of ethanol-related cytokine expression in the hippocampus of young and aged Fischer 344 rats

“…The extent to which these neuroimmune changes might reflect a response to tissue damage and/or repair-related responses produced by acute alcohol exposure is not yet clear. However, it can be noted that most studies examining the involvement of neuroimmune signaling pathways in Alcohol-Related Brain Damage utilize alcohol administration procedures that involve substantially greater alcohol load, often delivered over the course of days to weeks in order to elicit overt damage (Vetreno et al, 2016). Nevertheless, examination of damage- and repair-related processes should be a more directed consideration for future studies.…”