Elsevier

Psychoneuroendocrinology

Volume 110, December 2019, 104436
Psychoneuroendocrinology

Glucocorticoid-sensitive ventral hippocampal-orbitofrontal cortical connections support goal-directed action – Curt Richter Award Paper 2019

https://doi.org/10.1016/j.psyneuen.2019.104436Get rights and content

Highlights

  • Excess corticosterone in adolescence triggers orbital cortical dendritic spine loss.

  • And it reduces ventral hippocampal axon terminal density in the orbital cortex.

  • These connections are otherwise necessary for goal-directed response flexibility.

  • Their degradation may contribute to stress-related biases towards habitual behaviors.

Abstract

In an ever-changing and often ambiguous environment, organisms must use previously learned associations between antecedents and outcomes to predict future associations and make optimal choices. Chronic stress can impair one’s ability to flexibly adjust behaviors when environmental contingencies change, particularly in cases of early-life stress. In mice, exposure to elevated levels of the primary stress hormone, corticosterone (CORT), during early adolescence is sufficient to impair response-outcome decision making later in life, biasing response strategies towards inflexible habits. Nevertheless, neurobiological mechanisms are still being defined. Here, we report that exposure to excess CORT in adolescence causes a loss of dendritic spines on excitatory pyramidal neurons in the lateral, but not medial, orbital prefrontal cortex (loPFC) of mice, and spine loss correlates with the severity of habit biases in adulthood. Excess CORT also reduces the presence of ventral hippocampal (vHC) axon terminals in the loPFC. To identify functional consequences, we inactivated vHC→loPFC projections in typical healthy mice during a period when mice must update response-outcome expectations to optimally acquire food reinforcers. Inactivation impaired the animals’ subsequent ability to sustainably choose actions based on likely outcomes, causing them to defer to habit-based response strategies. Thus, vHC→loPFC projections are necessary for response-outcome expectancy updating and a target of excess glucocorticoids during early-life development. Their degradation is likely involved in long-term biases towards habit-based behaviors following glucocorticoid excess in adolescence.

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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