Adolescent Corticosterone and TrkB Pharmaco-Manipulations Sex-Dependently Impact Instrumental Reversal Learning Later in Life

Abstract

Early-life trauma can increase the risk for, and severity of, several psychiatric illnesses. These include drug use disorders, and some correlations appear to be stronger in women. Understanding the long-term consequences of developmental stressor or stress hormone exposure and possible sex differences is critically important. So-called “reversal learning” tasks are commonly used in rodents to model cognitive deficits in stress- and addiction-related illnesses in humans. Here, we exposed mice to the primary stress hormone corticosterone (CORT) during early adolescence (postnatal days 31–42), then tested behavioral flexibility in adulthood using an instrumental reversal learning task. CORT-exposed female, but not male, mice developed perseverative errors. Despite resilience to subchronic CORT exposure, males developed reversal performance impairments following exposure to physical stressors. Administration of a putative tyrosine kinase receptor B (trkB) agonist, 7,8-dihydroxyflavone (7,8-DHF), during adolescence blocked CORT-induced errors in females and improved performance in males. Conversely, blockade of trkB by ANA-12 impaired performance. These data suggest that trkB-based interventions could have certain protective benefits in the context of early-life stressor exposure. We consider the implications of our findings in an extended “Discussion” section.

Prefrontal cortical trkB, glucocorticoids, and their interactions in stress and developmental contexts

“…Nevertheless, de Sousa et al (2015) report that chronic CORT exposure in female mice decreases BDNF protein levels in the PFC and induces anhedonic-like and depressive-like behavior. This pattern is consistent with our own findings that the trkB agonist 7,8-DHF can correct PFC-dependent decision-making abnormalities in CORT-exposed female adolescent mice (Barfield et al, 2017a; Barfield & Gourley, 2017b). In another report, chronic unpredictable stress decreases PFC BDNF in adult female, but not male, mice.…”

“…The authors of the present review have similarly reported that oral CORT exposure in mice during early adolescence (P31–42), but not adulthood (P70–81), disrupts goal-directed decision making several weeks after the cessation of CORT (Barfield et al, 2017a). Additionally, CORT, repeated forced swimming, or trkB antagonism during the same early-adolescent period (P31–42) impairs OFC-dependent behavioral flexibility in adulthood (Barfield & Gourley, 2017b). Although studies directly comparing the long-term effects of stress or CORT during different periods of adolescence/adulthood on PFC BDNF-trkB and function are somewhat lacking, current evidence suggests that stressors during early adolescence may be more impactful than those in adulthood.…”

“…Some of the effects of chronic stress in impairing negative feedback of the HPA axis may be associated with ovarian steroids, regulators of the GR and its co-regulators (Bourke et al, 2012, 2013; Malviya et al, 2013). Certain forms of chronic stress during adolescence can disrupt behavioral, HPA axis, and GR functioning in female, but not male, rats (Bourke et al, 2013; Bourke & Neigh, 2011), and behavioral vulnerabilities are also reported in adolescent female mice (Barfield & Gourley, 2017b). Greater susceptibility to stress-induced GR dysfunction in females may have implications for understanding increased incidence of depression in women (Kessler, 2003).…”

Bridging the Gap between Brain-Derived Neurotrophic Factor and Glucocorticoid Effects on Brain Networks

“…The rationale for this hypothesis relies on epigenetic, transcriptomic and proteomic regulation of BDNF expression in rodent models and human tissues (24)(25)(26). The consensus view is that expression of BDNF and/or its receptor TrkB is diminished in the corticolimbic system (mostly prefrontal cortex and hippocampus) whereas BDNF is upregulated in the mesolimbic system (mostly nucleus accumbens, amygdala, VTA) long after cessation to stressor exposure in animal models and in postmortem human brains (27)(28)(29)(30)(31). A reduction of BDNF/TrkB signaling in the corticolimbic areas of the brain is associated with synaptic loss, decreased neuronal plasticity and regressing network connectivity, while an elevation of BDNF/TrkB signaling in the mesolimbic areas of the brain is associated with synaptic growth, increased neuronal plasticity and expanding network connectivity (32)(33)(34)(35)(36)(37).…”

Sex-Dependent Effects of Environmental Enrichment on Spatial Memory and Brain-Derived Neurotrophic Factor (BDNF) Signaling in a Developmental “Two-Hit” Mouse Model Combining BDNF Haploinsufficiency and Chronic Glucocorticoid Stimulation

“…It has been reported that chronic glucocorticoid treatment disrupts the interaction between glucocorticoid receptors and TrkB with subsequent dampening of the PLCγ signaling pathway (Numakawa et al, 2013 ), with implications for cognition. Yan et al ( 2016 ) recently demonstrated that chronic CORT treatment decreased pTrkB, and Barfield and Gourley ( 2017 ) showed truncated TrkB, the inactive form, to be increased in relation to FL-TrkB after chronic adolescent CORT treatment. Our study adds to this literature by investigating the activation of the distinct residues, and the results discussed above contribute to creating a comprehensive molecular map of how glucocorticoids and the BDNF-TrkB signaling pathway dynamically interact.…”