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Lesions in the Bed Nucleus of the Stria Terminalis Disrupt

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Lesions in the Bed Nucleus of the Stria Terminalis Disrupt Neuroscience 128 (2004) 7–14 LESIONS IN THE BED NUCLEUS OF THE STRIA TERMINALIS DISRUPT CORTICOSTERONE AND FREEZING RESPONSES ELICITED BY A CONTEXTUAL BUT NOT BY A SPECIFIC CUE-CONDITIONED FEAR STIMULUS G. M. SULLIVAN,a* J. APERGIS,b D. E. A. BUSH,b Activation of the hypothalamic–pituitary–adrenal (HPA) L. R. JOHNSON,b M. HOUb AND J. E. LEDOUXb axis, including release of glucocorticoids, is a central com- aDepartment of Psychiatry, Columbia University College of Physicians ponent of the adaptive response to real or anticipated and Surgeons, 1051 Riverside Drive, Unit #41, New York, NY 10032, aversive physical or psychological challenge. Surprisingly USA little is known about the neural circuits by which environ- bCenter for Neural Science, New York University, 4 Washington Place, mental stimuli come to elicit HPA responses. Fear condi- New York, NY 10003, USA tioning, a behavioral model of emotional stress, is poten- tially useful for exploring this issue since the neural path- Abstract —The bed nucleus of the stria terminalis (BNST) is ways by which stimuli initiate fear behaviors and believed to be a critical relay between the central nucleus of associated autonomic responses have been characterized the amygdala (CE) and the paraventricular nucleus of the in detail (LeDoux, 2000; Davis and Whalen, 2001; Maren, hypothalamus in the control of hypothalamic–pituitary– 2001). adrenal (HPA) responses elicited by conditioned fear stimuli. Through fear conditioning an organism learns that a If correct, lesions of CE or BNST should block expression of simple sensory stimulus (a cue), or more complex environ- HPA responses elicited by either a specific conditioned fear mental representation (a context), predicts imminent ad- cue or a conditioned context. To test this, rats were subjected versity. The neural pathways that mediate the acquisition to cued (tone) or contextual classical fear conditioning. Two days later, electrolytic or sham lesions were placed in CE or and expression of conditioned fear crucially involve the BNST. After 5 days, the rats were tested for both behavioral amygdala. Incoming stimuli are processed by the lateral (freezing) and neuroendocrine (corticosterone) responses to nucleus of the amygdala, which, by way of direct and tone or contextual cues. CE lesions attenuated conditioned indirect intra-amygdala connections, activate the central freezing and corticosterone responses to both tone and con- nucleus of the amygdala (CE). CE, in turn, connects with text. In contrast, BNST lesions attenuated these responses to areas involved in the expression of aversive responses. contextual but not tone stimuli. These results suggest CE is Thus, while damage to CE disrupts the expression of a indeed an essential output of the amygdala for the expres- broad spectrum of conditioned fear responses, including sion of conditioned fear responses, including HPA re- sponses, regardless of the nature of the conditioned stimu- HPA responses, localized damage to areas that CE lus. However, because lesions of BNST only affected behav- projects to affect only individual components of the fear ioral and endocrine responses to contextual stimuli, the response mediated by the particular region (Davis, 1992; results do not support the notion that BNST is critical for HPA LeDoux, 1996, 2000; Maren and Fanselow, 1996). responses elicited by conditioned fear stimuli in general. The point of origin in the brain of the HPA axis is the Instead, the BNST may be essential specifically for contex- paraventricular nucleus of the hypothalamus (PVN; Guil- tual conditioned fear responses, including both behavioral lemin and Rosenberg, 1955; Saffran et al., 1955). CE has and HPA responses, by virtue of its connections with the direct, albeit relatively sparse, projections to PVN (Gray et hippocampus, a structure essential to contextual condition- al., 1989; Prewitt and Herman, 1998). In addition, CE ing. The results are also not consistent with the hypothesis that BNST is only involved in unconditioned aspects of fear projects to the bed nucleus of the stria terminalis (BNST), and anxiety. © 2004 IBRO. Published by Elsevier Ltd. All which, in turn, has dense projections to PVN (Swanson, rights reserved. 1987). Previous studies have found that lesions of the BNST attenuate the release of glucocorticoid hormone Key words: Pavlovian, amygdala, bed nucleus of the stria ter- (corticosterone, CORT) in response to conditioned fear minalis, hypothalamic–pituitary–adrenal (HPA) axis, lesion, glu- stimuli (Gray et al., 1993). These anatomical and neuroen- cocorticoids. docrine findings have led to the view that connections from CE to BNST and, in series, connections from BNST to ϩ ϩ *Corresponding author. Tel: 1-212-543-6760; fax: 1-212-543-5437. PVN, mediate HPA responses elicited by conditioned fear E-mail address: [email protected] (G. M. Sullivan). Abbreviations: ANOVA, analysis of variance; AP, anteroposterior; stimuli (LeDoux, 1996, 2000). BNST, bed nucleus of the stria terminalis; CE, central nucleus of the If the BNST is the primary link between CE and PVN, amygdala; CORT, corticosterone; CS, conditioned stimulus; DV, dor- lesions of BNST should block the expression of HPA re- soventral; HPA, hypothalamic–pituitary–adrenal; LSD, least significant difference; ML, mediolateral; PVN, paraventricular nucleus of the hy- sponses regardless of whether those responses are elic- pothalamus; US, unconditioned stimulus. ited by a specific cue stimulus or a contextual stimulus. 0306-4522/04$30.00ϩ0.00 © 2004 IBRO. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.neuroscience.2004.06.015 7 8 G. M. Sullivan et al. / Neuroscience 128 (2004) 7–14 Surgery The rats were randomly assigned to “sham” and “lesion” groups for the two target brain regions, CE and BNST. Surgery took place 2 days after classical conditioning and 5 days before behavioral testing, as described below. CE lesions. The rats were anesthetized with 100 mg/kg i.p. of ketamine HCl (Ketaset; Phoenix Pharmaceutical, St. Joseph, MO, USA) and placed into a stereotaxic frame using blunt ear bars to protect the tympanic membranes. Flat skull coordinates are given in millimeters, obtained from Paxinos and Watson (1997). The anteroposterior (AP), mediolateral (ML), and dorsoventral (DV) coordinates were referenced from bregma. CE lesions were made in three locations bilaterally: (1) APϭϪ1.8 mm, MLϭϮ4.4 mm, DVϭϪ8.4 mm to skull surface; (2) APϭϪ2.3 mm, MLϭϮ4.4 mm, DVϭϪ8.4 mm to skull surface; and (3) APϭϪ2.8 mm, MLϭϮ4.4 mm, DVϭϪ8.4 mm to skull surface. All animals had six burr holes placed in the skull, carefully exposing Fig. 1. Schematic of general procedures carried out for each of the but not damaging the dura mater at the three sites per ML side. four experimental components. For animals in lesion groups, small bilateral electrolytic lesions were prepared for each selected coordinate as follows: a small Studies performed to date have used either contextual incision was made in the dura; a monopolar electrode (RH NE-100 stimuli alone, or a combination of contextual stimuli and a 01ϫ50 mm, David Kopf Instruments, Tujunga, CA, USA), insu- ␮ specific cue stimulus, and therefore do not address the lated with epoxy to within 200 m of the tip, was lowered to each selected coordinate; 60 s was allowed to pass; positive current question of whether BNST lesions block HPA responses (0.5 mA) was passed for 13 s; and the electrode was removed. elicited by specific cues (Van de Kar et al., 1991; Gray et Sham groups were treated identically to the lesion groups except al., 1993; Goldstein et al., 1996). In the present study we that coordinates of the electrode tips were 1.0 mm dorsal (i.e. therefore assessed the effects of lesions of CE or BNST on Ϫ7.4 mm DV) to the lesion coordinates and no current was the HPA neuroendocrine (CORT) response and behavioral passed. After completion of surgery the wound was closed, ket- amine anesthesia was discontinued, one dose of 0.3 mg/kg s.c. of response (freezing) elicited by either a conditioned cue (a buprenorphine HCl (Henry Schein Inc., Melville, NY, USA) was tone) or a conditioned context. The lesions were made administered, and the animal recovered under a heat lamp until after training to isolate the effects of localized brain dam- mobilizing. age on the expression of the responses, avoiding the BNST lesions. The surgical procedure was identical to that potentially confounding effects of lesion on acquisition of for CE lesions except for the following differences. Coordinates for fear memory. the three lesions per side in were: (1) APϭ0.0 mm, MLϭϮ1.5 mm, DVϭϪ7.0 mm; (2) APϭϪ0.5 mm, MLϭϮ1.5 mm, DVϭϪ7.0 mm; and (3) APϭϪ1.0 mm, MLϭϮ1.5 mm, DVϭϪ7.0 mm. Current EXPERIMENTAL PROCEDURES was passed for 16 s for each of the six lesion sites. Sham groups Ϫ Subjects had electrode tips 1.0 mm dorsal (i.e. 6.0 mm DV) to the coor- dinates of the lesion groups and no current was passed. Adult male Sprague–Dawley rats (Hilltop Laboratories, Scotts- dale, PA, USA) weighing 275–325 g at the start of the experiments Classical fear conditioning were used. All animals were acclimated for 2 weeks prior to experimentation. Animals were housed individually in plastic Nal- Apparatus. Prior to each phase of the experiment, animals gene cages (Nalge Nunc International, Rochester, NY, USA). The were transported to a holding room in the vivarium that was animal colony was on a 12-h light/dark cycle (lights on at 08:00 h) distinct from the rooms in which behavioral procedures took place. with food and water provided ad libitum. All animals utilized were The chambers used for conditioning and testing were of two types, behaviorally naive. All procedures were conducted in accordance each housed in sound attenuated cubicles, “Chamber A” (Coul- bourn Instruments, Lehigh Valley, PA, USA; model E10-10 and with the National Institutes of Health Guide for the Care and Use model E10-20) and “Chamber B” (Med Associates, Inc Georgia, of Experimental Animals and with approval by the New York VT, USA; model ENV-001 and model ENV-022M).
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