Chronic stress impairs recall of extinction of conditioned fear

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Abstract

Chronic restraint stress produces retraction of apical dendrites of pyramidal neurons in medial prefrontal cortex. To begin to examine the functional significance of this dendritic reorganization, we assessed the effects of chronic restraint stress on a prefrontally mediated behavior, extinction of conditioned fear. After bar press training to obtain a baseline of activity against which to measure freezing, rats were either unstressed or stressed via placement in a plastic restrainer (3 h/day for 1 week). After an additional day of bar press training, rats underwent fear conditioning and extinction. Rats received five habituation trials to a 30-s tone (4.5 kHz, 80 db) followed by seven pairings of tone and footshock (500 ms, 0.5 mA). One hour later, rats received tone-alone extinction trials to criterion. The next day, rats received 15 additional extinction trials. Percent freezing was assessed during all phases of training. Stress did not significantly affect unconditioned responding to tone, acquisition of conditioned fear, or initial extinction, but significantly increased freezing on extinction day 2. Thus, consistent with the regressive dendritic changes seen in medial prefrontal cortex, one week of restraint stress specifically impaired recall of extinction, a pattern of deficits typical of animals with impaired medial prefrontal function.

Introduction

Medial prefrontal cortex (mPFC) is a target for glucocorticoids involved in the stress response (Meaney & Aitken, 1985), and exposure to stressors results in a variety of neurochemical changes in mPFC, including increases in glutamate and acetylcholine release (Bagley and Moghaddam, 1997, Jedema and Moghaddam, 1994, Mark et al., 1996, Moghaddam, 1993). Dendritic morphology of mPFC appears to be particularly sensitive to chronic stress: either six (Radley et al., 2004) or three hours (Cook & Wellman, 2004) of restraint per day for three weeks results in retraction of apical dendrites of layer II–III pyramidal neurons in mPFC. This effect occurs with as little as one week of brief daily restraint (Brown, Henning, & Wellman, 2005), suggesting that the morphology of mPFC is exquisitely sensitive to stress.

Given that the geometry of the dendritic arbor (e.g., dendritic branching patterns, distribution, and overall shape) determines many functional properties of neurons (e.g., Grudt and Perl, 2002, Koch and Segev, 2000, Lu et al., 2001, Mainen and Sejnowksi, 1996, Rall et al., 1992), the pronounced stress-induced dendritic changes in mPFC likely result in important functional changes that may have consequences for the behaviors mediated by mPFC. To begin to examine the functional significance of chronic stress effects in mPFC, we assessed the effects of chronic restraint stress on a prefrontally mediated behavior, extinction of conditioned fear. Lesions of mPFC impair extinction learning (Morgan and LeDoux, 1995, Quirk et al., 2000); in addition, electrophysiological data have demonstrated that firing of neurons in ventral mPFC is correlated with memory for fear extinction (Milad & Quirk, 2002), and consolidation of extinction is impaired by blockade of protein synthesis in ventral mPFC (Santini, Ge, Ren, de Ortiz, & Quirk, 2004).

Section snippets

Animals

Male Sprague–Dawley rats (175–200 g, 48–50 days old at initiation of experiment; Harlan, Indianapolis, IN), were individually housed in a vivarium with a 12:12 h light/dark cycle (lights on at 7 AM) and ambient temperature of 23–25 °C. To motivate rats for bar pressing, weights were gradually reduced to 85% of free-feeding weight; rats were then maintained at this weight with weekly increases allowed for normally occurring weight gain. All experimental procedures occurred between 9:30 AM and 5:00

Results

One week of daily restraint stress significantly attenuated weight gain. By day seven of restraint, average weight of unstressed rats increased to 119.93 ± 3.45% of their starting weight, whereas in stressed rats, average weight increased to only 107.30 ± 3.69% of their starting weight (t (14) = −7.07, p < .05).

To rule out potential confounds due to differences in activity level between stressed and unstressed groups, average bar presses per min on the days immediately preceding and following chronic

Discussion

The present study demonstrates a specific effect of one week of restraint stress on recall of extinction of conditioned fear. Chronic stress did not significantly affect unconditioned responding to the tone, acquisition of conditioned fear, or initial extinction. However, 24 h after initial extinction, stressed rats showed markedly attenuated recall of extinction from day one, showing twice as much freezing to the tone as did unstressed rats. This effect on recall of extinction remained after

Acknowledgments

We thank Dale R. Sengelaub and an anonymous reviewer for helpful comments on the manuscript. Supported by MH067607 to C.L.W.

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