Review
Stress-induced prefrontal reorganization and executive dysfunction in rodents

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Abstract

The prefrontal cortex (PFC) mediates a range of higher order ‘executive functions’ that subserve the selection and processing of information in such a way that behavior can be planned, controlled and directed according to shifting environmental demands. Impairment of executive functions typifies many forms of psychopathology, including schizophrenia, mood and anxiety disorders and addiction, that are often associated with a history of trauma and stress. Recent research in animal models demonstrates that exposure to even brief periods of intense stress is sufficient to cause significant structural remodeling of the principle projection neurons within the rodent PFC. In parallel, there is growing evidence that stress-induced alterations in PFC neuronal morphology are associated with deficits in rodent executive functions such as working memory, attentional set-shifting and cognitive flexibility, as well as emotional dysregulation in the form of impaired fear extinction. Although the molecular basis of stress-induced changes in PFC morphology and function are only now being elucidated, an understanding of these mechanisms could provide important insight into the pathophysiology of executive dysfunction in neuropsychiatric disease and foster improved strategies for treatment.

Introduction

The prefrontal cortex (PFC) plays an integral role in mediating a range of executive functions that subserve the selection and processing of information necessary to plan, control and direct behavior in a manner appropriate to current environmental demands (Bush et al., 2000, Goldman-Rakic, 1996, Miller and Cohen, 2001, Robbins, 2005, Rolls, 1996, Tremblay and Schultz, 1999). A growing literature from studies in laboratory animals demonstrates that the PFC not only plays a major role in orchestrating the behavioral and systemic response to stress, but that neurons in the rodent PFC are highly sensitive to stress and undergo significant remodeling following stress exposure. These findings support the notion that stress-induced alterations in PFC function represent a principle neural insult underlying deficits in executive function observed in stressed rodents, and the executive component of many neuropsychiatric diseases.

In this article, we review this emerging field of research. We begin with a note on the anatomy and connectivity of the rodent PFC and current views about its functional homology with the corresponding anatomical region's in the primate brain. We then describe evidence demonstrating the important role of the PFC in regulating rodent neuroendocrine and autonomic responses to stress, and modulating anxiety- and depression-related behaviors. Next, we turn to the intriguing finding that the morphology of rodent PFC neurons is highly sensitive to stress and speculate on how this might impact PFC functions. Finally, we address how such stress-induced changes might manifest in terms of impairment of three forms of rodent behavior related to executive function (working memory, cognitive flexibility and fear extinction).

Section snippets

Anatomy and connectivity of the rodent PFC

The rodent provides an invaluable model system for studying neural processes underlying complex behaviors including higher order cognitive and executive functions. However, given the evolutionary differentiation of the primate and rodent PFC, a discussion of the utility of rodent models for studying the PFC must first acknowledge the issue of the cross-species functional and anatomical homology of this region. On the basis of criteria including granular cytoarchitecture and connectivity with

PFC modulation of rodent neuroendocrine and autonomic responses to stress

By quantifying the expression of immediate-early genes such as c-Fos (Singewald, 2007), the rodent PFC, particularly the medial subregions (IL, PL, and AC), has been shown to be strongly activated by exposure to various forms of stress. These stressors include acute exposure to restraint (Cullinan et al., 1995, Ostrander et al., 2003), footshock (Morrow et al., 2000), forced swimming (Cullinan et al., 1995), loud noise (Campeau et al., 2002, Campeau et al., 1997), tests for anxiety-like

PFC modulation of rodent anxiety- and depression-related behaviors

Stress responsivity and anxiety are not synonymous, but are intimately linked in terms of rodent behavior and clinical pathology. For example, one consequence of stress exposure in rodents can be heightened anxiety (Cryan and Holmes, 2005). The PFC appears to have a rather complex role in mediating rodent anxiety-like behavior. Electrolytic lesions of the rodent IL have been shown to decrease state anxiety-like behavior in the elevated plus-maze, shock-probe burying and Vogel conflict tests (

Stress effects on rodent PFC neuronal morphology

The seminal work of McEwen, Sapolsky, de Kloet and others has shown how prolonged exposure to glucocorticoids or stress produces significant neuronal atrophy in the hippocampus, characterized by a retraction of dendrites on pyramidal neurons in the CA3 subregion (de Kloet et al., 2005, McEwen and Milner, 2007, Sapolsky, 2003). It was subsequently found that neurons in other limbic regions also undergo morphological changes following stress. Of particular note, Chattarji and co-workers have

Stress effects on rodent executive functions

The rodent PFC subserves a range of cognitive and behavioral processes analogous to some of the executive functions mediated by the human PFC (Heidbreder and Groenewegen, 2003, Markowitsch and Pritzel, 1977, Robbins, 2005, Uylings et al., 2003). Executive functions measurable in rats and mice include working memory (e.g., delayed alternation in the T-maze), cognitive flexibility (e.g., reversal learning and set-shifting), sustained attention (e.g., 5-choice serial reaction time task), and

Concluding remarks

In this review, we have described how the PFC plays a significant, if as yet not fully clarified, role in regulating rodent neuroendocrine and autonomic responses to stress, and anxiety- and depression-related behaviors. We also discussed the important discovery that pyramidal neurons in several regions of the rodent PFC undergo dramatic remodeling with exposure to stressors, even those of brief or ostensibly mild nature. These pronounced structural changes likely result in important functional

Acknowledgments

This work was supported by the National Institute on Alcohol Abuse and Alcoholism Intramural Research Program (A.H.) and National Institute of Mental Health Grant MH067607 (C.L.W.).

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