Abstract

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.

Highlights

  • Goal-directed actions are defined as behaviors directed towards achieving a specific outcome

  • We first confirmed that exogenous CORT exposure elevated blood serum CORT late in the active period when mice had been active and ingesting CORT for several h

  • Adrenal and thymus glands atrophied during the CORT exposure period, as expected (t8 = 5.7, p < 0.001; t8 = 4.24, p = 0.003) (Fig 1b)

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Summary

Introduction

Goal-directed actions are defined as behaviors directed towards achieving a specific outcome. Habits are stimulus elicited and insensitive to action–outcome relationships. Individuals who experience early-life stress have an increased incidence of behaviors that can lead to addiction and obesity as adults, and Patterson et al [1] provided evidence that these behaviors may result from an overreliance on outcome-insensitive habits. Chronic stressor exposure biases behavioral response strategies towards habits [2], and the primary glucocorticoid corticosterone (CORT) is sufficient to induce habit biases in both rats and mice [3]. Exogenous glucocorticoids enhance habit-based learning and memory in humans [4]. Like early-life stress [1], prenatal stress in humans and maternal separation in neonatal rats induce inflexible habit behavior [5,6]

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