Search

In humans and rodents, stress promotes habit-based behaviors that can interfere with action—outcome decision-making. Further, developmental stressor exposure confers long-term habit biases across rodent—primate species. Despite these homologies, mechanisms remain unclear. We first report that exposure to the primary glucocorticoid corticosterone (CORT) in adolescent mice recapitulates multiple neurobehavioral consequences of stressor exposure, including long-lasting biases towards habit-based responding in a food-reinforced operant conditioning task. In both adolescents and adults, CORT also caused a shift in the balance between full-length tyrosine kinase receptor B (trkB) and a truncated form of this neurotrophin receptor, favoring the inactive form throughout multiple corticolimbic brain regions. In adolescents, phosphorylation of the trkB substrate extracellular signal-regulated kinase 42/44 (ERK42/44) in the ventral hippocampus was also diminished, a long-term effect that persisted for at least 12 wk. Administration of the trkB agonist 7,8-dihydroxyflavone (7,8-DHF) during adolescence at doses that stimulated ERK42/44 corrected long-lasting corticosterone-induced behavioral abnormalities. Meanwhile, viral-mediated overexpression of truncated trkB in the ventral hippocampus reduced local ERK42/44 phosphorylation and was sufficient to induce habit-based and depression-like behaviors. Together, our findings indicate that ventral hippocampal trkB is essential to goal-directed action selection, countering habit-based behavior otherwise facilitated by developmental stress hormone exposure. They also reveal an early-life sensitive period during which trkB—ERK42/44 tone determines long-term behavioral outcomes. [ABSTRACT FROM AUTHOR]

Background The effects of stress, including neuroendocrine and behavioral sequelae aimed at maintaining homeostasis, are associated with increased alcohol consumption. Because both stress and drinking are multifactorial, the mechanisms underlying the relationship are difficult to elucidate. We therefore employed an animal model investigating the influence of blocked access to a running wheel on drinking in C57 BL/6J (B6) mice. Methods In the first experiment, naïve, adult male and female subjects were individually housed for 2 weeks with 24-hour access to a running wheel and 12% ethanol (EtOH) in a 2-bottle, free choice paradigm. After determining baseline consumption and preference, experimental subjects had the running wheel placed in a locked position for 6 hours, and the Et OH bottle was removed during the first half of this period. Two subsequent experiments, again in adult, naïve B6 mice, examined the influence of locked running wheels on self-administration of 20% Et OH in a limited access paradigm, and blood Et OH concentrations ( BECs) were determined on the final day of this protocol. Results In all 3 studies, using both between- and within-subject analyses, females showed transient yet reliable increases in alcohol drinking during blocked access to a rotating activity, while drinking in male mice was largely insensitive to this manipulation, although both sexes showed appreciable BECs (>130 mg/dl in females and 80 mg/dl in males) following a 2-hour EtOH access period. Conclusions These data add to a burgeoning literature suggesting that the factors contributing to excessive alcohol use differ between males and females and that females may be especially sensitive to the influence of wheel manipulation. Elucidating the sex-dependent mechanisms mediating differences in alcohol sensitivity and response is critical to understanding the causes of alcoholism and in developing effective treatments and interventions. [ABSTRACT FROM AUTHOR]