Individual differences in reactivity to social stress predict susceptibility and resilience to a depressive phenotype: role of corticotropin-releasing factor

Abstract

Previous social stress exposure is a common risk factor for affective disorders. However, factors that determine vulnerability or resiliency to social stress-induced psychopathologies remain unclear. Using a rodent model of social stress, the present study was designed to identify putative neurobiological substrates that contribute to social stress-induced psychopathology and factors that influence or predict vulnerability. The resident-intruder model of defeat was used as a social stressor in adult male Sprague Dawley rats. The average latency to assume a subordinate posture (signaling defeat) over seven daily defeat exposures was calculated and examined with respect to endpoints of hypothalamic-pituitary-adrenal activity, components of the corticotropin-releasing factor (CRF) system, and behaviors that are relevant to human depression. In the present studies, a bimodal distribution emerged in an otherwise homogeneous population of Sprague Dawley rats such that 42% of rats exhibited short defeat latencies (<300 sec), whereas 58% of rats resisted defeat and exhibited longer latencies (>300 sec). These two phenotypes were associated with distinct endocrine and behavioral profiles as well as differences in components of the CRF system. Notably, the short-latency subpopulation exhibited hypothalamic-pituitary-adrenal dysregulation and behavior similar to that observed in melancholic depression. Examination of components of the CRF system suggested that proactive behavior in resisting defeat exhibited by long-latency rats was associated with decreased efficacy of CRF. Together, these data suggest that inherent differences in stress reactivity, perhaps as a result of differences in CRF regulation, may predict long-term consequences of social stress and vulnerability to depressive-like symptoms.

Figure 1

Individual differences in the latency to be defeated. A, A frequency distribution indicated that the average latency to exhibit a supine position (signaling defeat) over seven consecutive social defeat exposures was bimodally distributed among all rats used in these studies (n = 82). Based on this distribution, we used 300 sec as a cutoff to further subdivide rats. Rats with an average defeat latency of less than or greater than 300 sec were termed SL and LL, respectively. B, These data represent a subset of SL (n = 18) and LL (n = 21) rats from A that were exposed to the same colony of residents. Two distinct populations emerged by d 3 of stress as indicated by the average daily latency to assume a submissive posture. One-way ANOVA indicated an effect of group.

Figure 2

SL defeated rats exhibited delayed HPA habituation to social defeat. A, Rats exhibiting the SL phenotype displayed a nonsignificant decrease in defeat-induced ACTH release by d 7. Rats exhibiting the LL phenotype, on the other hand, displayed significant habituation in defeat-induced ACTH release as early as d 4. B, Social defeat-induced corticosterone (Cort) release exhibited the same trends as observed with ACTH release. SL rats exhibited a nonsignificant decrease in corticosterone by d 7. LL rats exhibited habituation to social defeat as early as d 4 as indicated by reduced corticosterone release on d 4 and 7. C, Representative photomicrographs of cFos staining within the parvocellular division of the PVN of control and SL and LL defeated rats. D, cFos-expressing cell count was increased in SL, but not LL rats, compared with controls. All groups contain n = 5–9. Average defeat latencies (seconds ± se) for SL and LL rats included in d 1, 4, and 7 were 242 ± 32 and 539 ± 37 (P = 0.0003), 254 ± 42 and 652 ± 18 (P < 0.0001), and 264 ± 58 and 565 ± 58 (P = 0.007), respectively (A and B). Average defeat latencies (seconds) for rats included in the cFos study were 164 ± 26 and 524 ± 43 (P < 0.0001) in SL and LL rats, respectively (D). *, P < 0.05, one-way ANOVA within each group (A and B); *, P < 0.05, Bonferroni post hoc vs. control (D).

Figure 3

Distinct changes in CRF and AVP mRNA in the PVN and in pituitary receptor of defeated rats. Representative autoradiographic films of CRF (A) and AVP (B) mRNA expression within the parvocellular PVN depict differences between SL and LL responses to social stress 24 h after the final defeat. A, CRF mRNA was decreased in SL rats (n = 5) but not in LL rats (n = 8) as compared with controls (n = 9). B, In contrast, AVP mRNA was comparable between controls (n = 10) and SL rats (n = 6), whereas LL defeated rats exhibited a decrease in AVP mRNA (n = 8) compared with controls. C, A representative Western blot of CRF₁ receptor expression in the pituitary of control, SL, and LL rats is shown. A defeat-induced decrease in receptor number in SL rats (n = 7) compared with controls (n = 7) was observed, whereas there was no effect in LL rats (n = 7). D, A representative Western blot of V1b receptor expression in the pituitary of control and defeated (SL and LL) rats is shown. V1b receptors were unaltered in SL (n = 14) and LL (n = 14) rats compared with controls (n = 13). Average defeat latencies of rats included in the in situ and Western studies are 234 ± 22 and 429 ± 36 (P = 0.0013) for SL and LL, respectively. *, P < 0.05, Bonferroni post hoc vs. controls.

Figure 4

SL and LL rats exhibit distinct differences in novel restraint- and CRF-induced HPA response but not in dexamethasone-induced negative feedback. A, LL rats (n = 8) exhibited a facilitated response to restraint with higher ACTH at 15 min compared with SL rats (n = 7) and higher ACTH at 30 min compared with both SL and control rats (n = 9). In addition, SL rats exhibited significantly lower ACTH compared with controls at 30 min. B, Restraint-induced increases in corticosterone release were similar in SL (n = 5) and LL (n = 9) rats compared with controls (n = 10). C, Intravenous CRF (0.03 μg/kg) stimulated robust ACTH release in control (n = 7) and SL rats (n = 6) above that of vehicle treatment, whereas CRF (n = 7) was ineffective in stimulating ACTH release above that of vehicle-treated LL rats (n = 6). However, CRF-induced ACTH release was decreased in both SL and LL defeated rats compared with controls. D, Rats were treated with vehicle or dexamethasone (DEX, 0.03 mg/kg) 90 min before restraint stress. Compared with vehicle treatments (n = 6–9), dexamethasone blunted restraint-induced ACTH in control (n = 8), SL (n = 5), and LL (n = 7) rats. The dexamethasone suppression of restraint-induced ACTH release was consistent across groups. Average defeat latencies (seconds ± se) for rats in the novel restraint study (A and B) were 190 ± 21 and 415 ± 17 (P < 0.0001) for SL and LL rats, respectively. Average defeat latencies (seconds ± se) for rats in the CRF challenge study (C) were 261 ± 32 (SL, vehicle) and 558 ± 33 (LL, vehicle) (P = 0.0024) and 204 ± 67 (SL, CRF) and 521 ± 58 (LL, CRF) (P = 0.014). Latencies (seconds ± se) for rats in the dexamethasone challenge (D) were 225 ± 39 (SL, vehicle) and 559 ± 37 (LL, vehicle) (P < 0.0001) and 287 ± 40 (SL, DEX) and 574 ± 40 (LL, DEX) (P = 0.003). *, P < 0.05; **, P < 0.01; ***, P < 0.001, Bonferroni post hoc vs. vehicle treatment.

Figure 5

SL rats exhibited behavioral despair. SL rats (n = 7) demonstrated greater levels of immobility during d 2 of the Porsolt FST compared with controls (n = 11). LL defeated rats were not different from controls and were therefore resistant to developing depressive-like behaviors (n = 9). Average defeat latencies (seconds ± se) for rats in this study were 198 ± 25 and 449 ± 11 (P < 0.0001) in SL and LL rats, respectively. *, P < 0.05, Bonferroni post hoc vs. control.