ReviewStress-induced prefrontal reorganization and executive dysfunction in rodents
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.).
References (254)
- et al.
Charting of type II glucocorticoid receptor-like immunoreactivity in the rat central nervous system
Neuroscience
(1990) - et al.
Activation of the ventral medial prefrontal cortex during an uncontrollable stressor reproduces both the immediate and long-term protective effects of behavioral control
Neuroscience
(2008) - et al.
Stressor invoked exacerbation of amphetamine-elicited perseveration
Pharmacol. Biochem. Behav.
(1985) - et al.
Amygdala input to medial prefrontal cortex (mPFC) in the rat: a light and electron microscope study
Brain Res.
(1996) Fear extinction in rodents: basic insight to clinical promise
Curr. Opin. Neurobiol.
(2005)- et al.
Chronic corticosterone treatment impairs spontaneous alternation behavior in rats
Behav. Neural Biol.
(1994) - et al.
The rostral anterior cingulate cortex modulates depression but not anxiety-related behaviour in the rat
Behav. Brain Res.
(2006) - et al.
Enhanced nucleus accumbens dopamine and plasma corticosterone stress responses in adult rats with neonatal excitotoxic lesions to the medial prefrontal cortex
Neuroscience
(2000) - et al.
Septohippocampal system and the prelimbic sector of frontal cortex: a neuropsychological battery analysis in the rat
Behav. Brain Res.
(1990) - et al.
Cognitive and emotional influences in anterior cingulate cortex
Trends Cogn. Sci.
(2000)
Elicitation and reduction of fear: behavioural and neuroendocrine indices and brain induction of the immediate-early gene c-fos
Neuroscience
Topography of projections from the medial prefrontal cortex to the amygdala in the rat
Brain Res. Bull.
Corticosteroid status influences the volume of the rat cingulate cortex—a magnetic resonance imaging study
J. Psychiatr. Res.
Functions of frontostriatal systems in cognition: comparative neuropsychopharmacological studies in rats, monkeys and humans
Biol. Psychol.
Dissociable aspects of performance on the 5-choice serial reaction time task following lesions of the dorsal anterior cingulate, infralimbic and orbitofrontal cortex in the rat: differential effects on selectivity, impulsivity and compulsivity
Behav. Brain Res.
The neuropsychology of ventral prefrontal cortex: decision-making and reversal learning
Brain Cogn.
Pattern and time course of immediate early gene expression in rat brain following acute stress
Neuroscience
Chronic stress-induced cellular changes in the medial prefrontal cortex and their potential clinical implications: does hemisphere location matter?
Behav. Brain Res.
Prefrontal executive and cognitive functions in rodents: neural and neurochemical substrates
Neurosci. Biobehav. Rev.
A behavioural analysis of rats with damage to the medial prefrontal cortex using the Morris water maze: evidence for behavioural flexibility, but not for impaired spatial navigation
Brain Res.
Effects of medial prefrontal cortex cytotoxic lesions in mice
Behav. Brain Res.
Stress, prefrontal cortex and environmental enrichment: studies on dopamine and acetylcholine release and working memory performance in rats
Behav. Brain Res.
Functional role of rat prelimbic-infralimbic cortices in spatial memory: evidence for their involvement in attention and behavioural flexibility
Behav. Brain Res.
Neuroanatomical characterization of Fos induction in rat behavioral models of anxiety
Brain Res.
Both dorsal and ventral hippocampus contribute to spatial learning in Long–Evans rats
Neurosci. Lett.
Descending projections of infralimbic cortex that mediate stimulation-evoked changes in arterial pressure
Brain Res.
Stress-induced disturbances in Morris water-maze performance: interstrain variability
Physiol. Behav.
The effect of medial frontal cortex lesions on cardiovascular conditioned emotional responses in the rat
Brain Res.
Prefrontal neurons in networks of executive memory
Brain Res. Bull.
Morphological evidence that CA1 hippocampal afferents monosynaptically innervate PV-containing neurons and NADPH-diaphorase reactive cells in the medial prefrontal cortex (Areas 25/32) of the rat
Brain Res.
Medial prefrontal transection enhances social interaction. I: behavioral studies
Brain Res.
Activation of serotonin-immunoreactive cells in the dorsal raphe nucleus in rats exposed to an uncontrollable stressor
Brain Res.
Organization of the afferent connections of the mediodorsal thalamic nucleus in the rat, related to the mediodorsal-prefrontal topography
Neuroscience
Alterations of amphetamine elicited perseveration and locomotor excitation following acute and repeated stressor application
Pharmacol. Biochem. Behav.
An electrophysiological and neuroanatomical study of the medial prefrontal cortical projection to the midbrain raphe nuclei in the rat
Neuroscience
The medial prefrontal cortex in the rat: evidence for a dorso-ventral distinction based upon functional and anatomical characteristics
Neurosci. Biobehav. Rev.
Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis
Prog. Neuropsychopharmacol. Biol. Psychiatry
Genetic variation in cortico-amygdala serotonin function and risk for stress-related disease
Neurosci. Biobehav. Rev.
Mesial prefrontal cortical lesions and timidity in rats. I. Reactivity to aversive stimuli
Physiol. Behav.
A comparison of the effects of medial prefrontal, cingulate cortex, and cingulum bundle lesions on tests of spatial memory: evidence of a double dissociation between frontal and cingulum bundle contributions
J. Neurosci.
Environment and vulnerability to major psychiatric illness: a case control study of early parental loss in major depression, bipolar disorder and schizophrenia
Mol. Psychiatry
Corticosterone exerts site-specific and state-dependent effects in prefrontal cortex and amygdala on regulation of adrenocorticotropic hormone, insulin and fat depots
J. Neuroendocrinol.
The role of the medial prefrontal cortex-amygdala circuit in stress effects on the extinction of fear
Neural Plast.
Medial prefrontal cortex determines how stressor controllability affects behavior and dorsal raphe nucleus
Nat. Neurosci.
Fundamentals of attention-deficit/hyperactivity disorder: circuits and pathways
J. Clin. Psychiatry
Decision making, impulse control and loss of willpower to resist drugs: a neurocognitive perspective
Nat. Neurosci.
Emotion, decision making and the orbitofrontal cortex
Cereb Cortex
Medial frontal cortex mediates perceptual attentional set shifting in the rat
J. Neurosci.
Chronic unpredictable stress induces a cognitive deficit and anxiety-like behavior in rats that is prevented by chronic antidepressant drug treatment
Neuropsychopharmacology
Glutamate: a major excitatory transmitter in neuroendocrine regulation
Neuroendocrinology
Cited by (379)
An automated platform for Assessing Working Memory and prefrontal circuit function
2023, Neurobiology of StressBehavioral flexibility impacts on coping and emotional responses in male mice submitted to social defeat stress
2023, Progress in Neuro-Psychopharmacology and Biological Psychiatry