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.

Background The opioid peptide β-Endorphin (β-E) is synthesized and released in response to stressful stimuli as well as acute alcohol administration. The release of β-E following exposure to an inescapable aversive situation may mediate behaviors that contribute to allostasis of the stress response. The present study examines the effects of β-E on immobility in assays involving inescapable stress, both under basal conditions as well as after acute administration of EtOH. Methods Female and male transgenic mice with varying capacities to translate β-E were subject to either the forced swim (FST, Experiment 1) or tail suspension test (TST, Experiment 2). In Experiment 3, mice were divided into three groups based on hormonal status (male, female-estrous and female-nonestrous) and injected with either 1 g/kg EtOH or equivolume saline 14 min prior to behavioral assessment on the TST. Results Experiments 1 and 2 demonstrated a direct relationship between β-E levels and immobility. There were also sex differences in behavior in these tests, with males displaying more immobility than females. A main effect of genotype in Experiment 3 replicated findings in Exp 1 & 2. There was also an effect of EtOH (increasing immobility) and a significant interaction reflecting a particularly robust effect of the drug in mice with low β-E. In addition, there were interactions between β-E, EtOH effects and hormonal status. Conclusions These findings support the contention that β-E moderates behavioral responses to stressful stimuli and suggest a role for this peptide in coping behavior. Furthermore, the effects of EtOH on the response to stress may be mediated by β-E. Sex differences in this influence may contribute to sex differences in disease susceptibility and expression.

The tyrosine receptor kinase B (trkB) and glucocorticoid receptor (GR) regulate neuron structure and function and the hormonal stress response. Meanwhile, disruption of trkB and GR activity (e.g., by chronic stress) can perturb neuronal morphology in cortico-limbic regions implicated in stressor-related illnesses like depression. Further, several of the short- and long-term neurobehavioral consequences of stress depend on the developmental timing and context of stressor exposure. We review how the levels and activities of trkB and GR in the prefrontal cortex (PFC) change during development, interact, are modulated by stress, and are implicated in depression. We review evidence that trkB- and GR-mediated signaling events impact the density and morphology of dendritic spines, the primary sites of excitatory synapses in the brain, highlighting effects in adolescents when possible. Finally, we review the role of neurotrophin and glucocorticoid systems in stress-related metaplasticity. We argue that better understanding the long-term effects of developmental stressors on PFC trkB, GR, and related factors may yield insights into risk for chronic, remitting depression and related neuropsychiatric illnesses.

Although stress is implicated in the pathophysiology of mood and anxiety disorders, not all individuals who suffer stressful life events develop psychopathology. Differential susceptibility to stress may be influenced by genetically mediated differences in hypothalamic-pituitary-adrenal (HPA) axis activity and moderation of the stress response by the opioid peptide β-endorphin (β-E). The present study investigated genetic contributions to coping behavior by examining anxious behavior of transgenic mice with varying capacities to synthesize β-E [B6.129S2-Pomctm1Low/J; regulated by insertion of a premature stop codon into one or both copies of the proopiomelanocortin (POMC) gene], both under normal conditions and following 3 min of forced swim (FS). Ten minutes after this stress exposure or a control manipulation, acutely food-deprived female and male transgenic mice were subjected to a novelty-suppressed feeding (NSF) test, during which their interaction with an almond slice located in the center of an open field box was measured. There was an interaction between genotype and stress for latency to approach the almond and whether or not the almond was approached, such that mice with low or absent β-E displayed a stronger aversion to novelty-feeding after stress exposure than did mice with normal levels. These data provide evidence for a moderating effect of β-E on the behavioral response to stress. Genotypic differences in anxious behavior emerged when mice were stressed prior to behavioral assessment, suggesting that β-E plays a role in coping behavior. These findings indicate that genetic variability in sensitivity of the β-E system to stress may contribute, at least in part, to heritable differences in stress reactivity as well as vulnerability to stress-related psychopathology.

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