Glucocorticoid-sensitive ventral hippocampal-orbitofrontal cortical connections support goal-directed action – Curt Richter Award Paper 2019
Introduction
An organism’s survival in an ever-changing world requires the ability to predict rewards or threats in the environment. Learned associations between antecedents and outcomes must be used and flexibly updated to orchestrate appropriate behavioral responses. An inability to update associations when environmental contingencies change can produce maladaptive behaviors resembling core symptoms of a number of psychiatric disorders, including depression, post-traumatic stress disorder (PTSD) and substance use disorder (SUD). For example, in depression, outcomes can be misattributed to current situations rather than to an individual’s chosen action; thus, depressed individuals may abstain from initiating actions to achieve goals (Griffiths et al., 2014). In SUD, continued drug abuse may have increasingly negative consequences, yet individuals struggle to modify behaviors and instead, exhibit persistent drug seeking (Everitt and Robbins, 2016). Stressor exposure, which also promotes rigid, outcome-insensitive habits (Schwabe, 2013), can trigger or exacerbate disease symptomatology. Dysfunction in the stress-sensitive circuits that guide flexible outcome-based behavior may be a common feature of seemingly disparate disorders (Griffiths et al., 2014).
The ventral hippocampus (vHC) and orbital prefrontal cortex (oPFC) are involved in guiding actions based on expected outcomes (Wikenheiser and Schoenbaum, 2016). The oPFC is thought to generate internal representations of “task spaces,” integrating abstract information about response-outcome and stimulus-outcome relationships, and even spatial information about goals (Feierstein et al., 2006), into on-going behavior. The vHC appears to integrate context features, rules for obtaining outcomes, and predictive associations into representations that support integrative coding in the oPFC (Wikenheiser and Schoenbaum, 2016; Wikenheiser et al., 2017). Goal-relevant contextual information provided by vHC inputs (Komorowski et al., 2013) can also be used by the oPFC to help select appropriate behavioral responses for a given context (Wikenheiser and Schoenbaum, 2016; Mizumori and Tryon, 2015). Thus, the oPFC and vHC support outcome-based learning and memory necessary for flexible adaptation of behavior.
In humans, early-life adversity induces biases towards habit-based behaviors at the expense of response-outcome, “goal-directed” decision-making strategies (Patterson et al., 2013; see also Schwabe et al., 2012). Early-life stress also triggers volume atrophy and neuronal morphological alterations in the oPFC and hippocampus that are detectable in adulthood (Teicher and Samson, 2016). Developmental stress or stress hormone exposure in rodents confers similar long-term behavioral deficits (Barfield et al., 2017; Zhang et al., 2017) and cortico-limbic structural changes (Sheth et al., 2017). Stress hormones could conceivably cause decision-making biases by modifying cortico-limbic development.
Here, we examined the long-term neurobehavioral consequences of prolonged exposure to elevated levels of the primary stress hormone, corticosterone (CORT), during early adolescence in mice. We report that mice with a history of adolescent CORT exposure fail to adjust reward-seeking behavior when outcome-predictive associations change. Deficiencies are long lasting, and they coincide with the loss of dendritic spines in the lateral oPFC (loPFC), as well as inputs from the vHC. To determine causal relationships, we inactivated vHC→loPFC projections in typical healthy mice, revealing that they are indispensable for sustainably selecting actions based on their likely outcomes.
Section snippets
Subjects
Group-housed male wild-type C57BL/6 mice (Jackson Labs) were used, except for dendritic spine imaging experiments, which used male mice expressing thy1-driven yellow fluorescent protein (YFP; H line from Feng et al., 2000) that were fully back-crossed onto a C57BL/6 background. Mice were maintained on a 12-h light cycle (0800 on) and provided food and water ad libitum except during instrumental conditioning when body weights were maintained at ∼90% of baseline to motivate responding. Animal
Excess CORT during adolescence has long-term behavioral consequences
In both humans and rodents, excess glucocorticoid exposure can induce biases towards habit-based behavior, at the expense of goal-directed action (Gourley et al., 2012; Guenzel et al., 2014). Further, stressor exposure during early developmental periods appears to confer long-term habit biases across rodent and primate species (Grissom et al., 2012; Patterson et al., 2013). Here, we attempt to clarify the long-term effects of excess CORT during adolescence on key neurocircuits associated with
Discussion
We report that excess glucocorticoid exposure during adolescence impairs the ability of adult mice to modify behaviors based on response-outcome relationships. Instead, mice with a history of excess CORT defer to habitual response strategies that are insensitive to consequences. While chronic CORT exposure can induce the same behavioral deficiencies in adults (Gourley et al., 2012), we find that even subchronic exposure triggers behavioral abnormalities in adolescents and yet, is without
Author contributions
EB and SG designed the experiments. EB conducted the experiments and analyzed the data. EB and SG prepared the manuscript.
Funding
This work was supported by the National Institutes of Health (grant numbers MH101477, MH117103, and OD011132) and the National Science Foundation Graduate Research Fellowship Program under grant number DGE-1444932.
Declaration of Competing Interest
None.
Acknowledgements
We thank Dr. Bryan Roth and Dr. R. Jude Samulski of the UNC Viral Vector Core for the chemogenetic materials used here.
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