Chronic stress produces deficits in cognition accompanied by alterations in neural chemistry and morphology. Medial prefrontal cortex is a target for glucocorticoids involved in the stress response. We have previously demonstrated that 3 weeks of daily corticosterone injections result in dendritic reorganization in pyramidal neurons in layer II-III of medial prefrontal cortex. To determine if similar morphological changes occur in response to chronic stress, we assessed the effects of daily restraint stress on dendritic morphology in medial prefrontal cortex. Male rats were exposed to either 3 h of restraint stress daily for 3 weeks or left unhandled except for weighing during this period. On the last day of restraint, animals were overdosed and brains were stained using a Golgi-Cox procedure. Pyramidal neurons in lamina II-III of medial prefrontal cortex were drawn in three dimensions, and the morphology of apical and basilar arbors was quantified. Sholl analyses demonstrated a significant alteration of apical dendrites in stressed animals: overall, the number and length of apical dendritic branches was reduced by 18 and 32%, respectively. The reduction in apical dendritic arbor was restricted to distal and higher-order branches, and may reflect atrophy of terminal branches: terminal branch number and length were reduced by 19 and 35%. On the other hand, basilar dendrites were not affected. This pattern of dendritic reorganization is similar to that seen after daily corticosterone injections. This reorganization likely reflects functional changes in prefrontal cortex and may contribute to stress-induced changes in cognition.

Chronic stress produces deficits in cognition accompanied by alterations in neural chemistry and morphology. For example, both stress and chronic administration of corticosterone produce dendritic atrophy in hippocampal neurons (Woolley C, Gould E, McEwen BS. 1990. Exposure to excess glucocorticoids alters dendritic morphology of adult hippocampal pyramidal neurons. Brain Res 531:225-231; Watanabe Y, Gould E, McEwen BS, 1992b. Stress induces atrophy of apical dendrites of hippocampal CA3 pyramidal neurons. Brain Res 588:341-345). Prefrontal cortex is also a target for glucocorticoids involved in the stress response (Meaney MJ, Aitken DH. 1985. [(3)H]Dexamethasone binding in rat frontal cortex. Brain Res 328:176-180); it shows neurochemical changes in response to stress (e.g., Luine VN, Spencer RL, McEwen BS. 1993. Effect of chronic corticosterone ingestion on spatial memory performance and hippocampal serotonergic function. Brain Res 616:55-70; Crayton JW, Joshi I, Gulati A, Arora RC, Wolf WA. 1996. Effect of corticosterone on serotonin and catecholamine receptors and uptake sites in rat frontal cortex. Brain Res 728:260-262; Takao K, Nagatani T, Kitamura Y, Yamawaki S. 1997. Effects of corticosterone on 5-HT(1A) and 5-HT(2) receptor binding and on the receptor-mediated behavioral responses of rats. Eur J Pharmacol 333:123-128; Sandi C, Loscertales M. 1999. Opposite effects on NCAM expression in the rat frontal cortex induced by acute vs. chronic corticosterone treatments. Brain Res 828:127-134), and mediates many of the behaviors that are altered by chronic corticosterone administration (e.g., Lyons DM, Lopez JM, Yang C, Schatzberg AF. 2000. Stress-level cortisol treatment impairs inhibitory control of behavior in monkeys. J Neurosci 20:7816-7821). To determine if glucocorticoid-induced morphological changes also occur in medial prefrontal cortex, the effects of chronic corticosterone administration on dendritic morphology in this corticolimbic structure were assessed. Adult male rats received s.c. injections of either corticosterone (10 mg in 250 microL sesame oil; n = 8) or vehicle (250 microL; n = 8) daily for 3 weeks. A third group of rats served as intact controls (n = 4). Brains were stained using a Golgi-Cox procedure and pyramidal neurons in layer II-III of medial prefrontal cortex were drawn; dendritic morphology was quantified in three dimensions. Sholl analyses demonstrated a significant redistribution of apical dendrites in corticosterone-treated animals: the amount of dendritic material proximal to the soma was increased relative to intact rats, while distal dendritic material was decreased relative to intact animals. Thus, chronic glucocorticoid administration dramatically reorganized apical arbors in medial prefrontal cortex. This reorganization likely reflects functional changes and may contribute to stress-induced changes in cognition.

Extinction of conditioned fear responses is an active learning process resulting from the repeated presentation of a conditioned stimulus in the absence of the unconditioned aversive stimulus. Recent research implicates the medial prefrontal cortex (mPFC) in the mediation of fear extinction in rodents and the pathophysiology of posttraumatic stress disorder. However, there is currently little understanding of precisely how stress can impact fear extinction and the neural circuitry subserving this behavior. The present study examined the effects of brief exposure to an uncontrollable stressor on (1) fear conditioning and fear extinction, and (2) dendritic morphology of pyramidal neurons in the infralimbic (IL) and prelimbic (PL) regions of the mPFC in mice. Exposure to three episodes of stress ending 24 h before fear conditioning significantly attenuated the rate of cued fear extinction relative to nonstressed controls, but did not affect fear conditioning or cue or context recall. Analysis of Golgi-stained neurons showed that one or three exposures to daily swim stress caused significant retraction of terminal branches of apical, but not basilar, dendrites of IL neurons. In contrast, PL neuronal morphology was unaltered by stress. These data demonstrate that IL, but not PL, neurons are highly sensitive to even brief exposure to stress, and that this same form of stress impairs fear extinction. Present findings suggest that trauma may compromise the functional integrity of the mPFC with implications for the pathophysiology of certain neuropsychiatric disorders.

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.

A lesser-expressing form of the human 5-HT transporter (5-HTT) gene has been associated with increased fear and anxiety and vulnerability to the effects of stress. These phenotypic abnormalities are linked to functional and anatomical disturbances in a neural pathway connecting the prefrontal cortex (PFC) and amygdala. Likewise, rodent and nonhuman primate studies indicate a major role for PFC and amygdala in the mediation of fear-and stress-related behaviors. We used a 5-HTT knock-out (KO) mouse to examine the effects of genetically driven loss of 5-HTT function for the following: (1) depression-related behavior in response to repeated stress, and pavlovian fear conditioning, extinction, and extinction recall; and (2) dendritic morphology and spine density of Golgi-stained pyramidal neurons in the infralimbic cortex (IL) and the basolateral amygdala (BLA). 5-HTT KO mice exhibited increased depressive-like immobility after repeated exposure to forced swim stress, compared with wild-type (WT) controls. Whereas fear conditioning and fear extinction was normal, 5-HTT KO mice exhibited a significant deficit in extinction recall. The apical dendritic branches of IL pyramidal neurons in 5-HTT KO mice were significantly increased in length relative to WT mice. Pyramidal neurons in BLA had normal dendritic morphology but significantly greater spine density in 5-HT KO mice compared with WT mice. Together, the present findings demonstrate a specific phenotypic profile of fear-and stress-related deficits in 5-HTT KO mice, accompanied by morphological abnormalities in two key neural loci. These data provide insight into the behavioral sequelae of loss of 5-HTT gene function and identify potential neural substrates underlying these phenotypes.