Insidious Transmission of a Stress-Related Neuroadaptation

Abstract

Stress is highly pervasive in humans, impacting motivated behaviors with an enormous toll on life quality. Many of the effects of stress are orchestrated by neuropeptides such as corticotropin-releasing factor (CRF). It has previously been shown that in stress-naïve male mice, CRF acts in the core of the nucleus accumbens (NAc) to produce appetitive effects and to increase dopamine release; yet in stress-exposed male mice, CRF loses its capacity to modulate NAc dopamine release and is aversive. In the current research, we tested whether this effect is comparable in females to males and whether the neuroadaptation is susceptible to social transmission. We found that, like in males, CRF increased dopamine release in stress-naïve but not stress-exposed female mice. Importantly, this persistent physiological change was not accompanied by overt behavioral changes that would be indicative of depression- or anxiety-like phenotype. Nonetheless, when these mice were housed for 7 days with stress-naïve conspecifics, the cage mates also exhibited a loss of dopamine potentiation by CRF. These data demonstrate the asymptomatic, yet pervasive transmission of stress-related neuroadaptations in the population.

Keywords: CRF; dopamine; fast-scan cyclic voltammetry; nucleus accumbens; social stress; stress; stress transmission.

Figure 1

Corticotropin-releasing factor (CRF) increases dopamine release in the nucleus accumbens (NAc) in stress-naïve males and females. (A) In the stress-naïve experimental group, mice remained in their home cage for the duration of the experiment. (B) Representative dopamine release evoked by electrical stimulation (dashed line) before and after application of 100 nM CRF to a NAc brain slice collected from a stress-naïve male (mean ± SEM for five consecutive stimulations, top) and corresponding two-dimensional plots depicting changes in faradaic current (pseudocolor) with time as the abscissa and applied potential as the ordinate (bottom). (C) Baseline-normalized mean peak amplitude of electrically evoked dopamine release over time in response to vehicle (n = 9) or 100 nM CRF (n = 11) application to NAc slices from stress-naïve males. (D) Baseline-normalized mean peak amplitude of dopamine release 20–30 min after vehicle (n = 9) or 100 nM CRF (n = 11) application to NAc slices from stress-naïve males. (E) Representative dopamine release evoked by electrical stimulation (dashed line) before and after application of 100 nM CRF to a NAc brain slice from a stress-naïve female (mean ± SEM for five consecutive stimulations, top) and corresponding color plots (bottom). (F) Baseline-normalized mean peak amplitude of electrically evoked dopamine release over time in response to vehicle (n = 10), 100 nM CRF (n = 8), or 1 μM CRF (n = 8) application to NAc slices from stress-naïve females. (G) Baseline-normalized mean peak amplitude of dopamine release 20–30 min after vehicle (n = 10), 100 nM CRF (n = 8), or 1 μM CRF (n = 8) application to NAc slices from stress-naïve females. Error bars, SEM. *P < 0.05, **P < 0.01, ***P < 0.001 vs. vehicle.

Figure 2

Direct stress disrupts CRF-mediated dopamine release in the NAc 1 week after repeated forced swim stress (rFSS) exposure in males and females. (A) In the direct stress experimental group, mice were exposed to rFSS and tested 7 days later. (B) Cumulative time spent immobile for the first 5 min of Swim 1 on rFSS Day 1 and Swims 1–4 on rFSS Day 2 in males (n = 6) and females (n = 10) belonging to the direct stress group. (C) Representative dopamine release evoked by electrical stimulation (dashed line) before and after application of 100 nM CRF to a NAc brain slice (mean ± SEM for five consecutive stimulations, left) and baseline-normalized mean peak amplitude of electrically evoked dopamine release over time in response to vehicle (n = 5) or 100 nM CRF (n = 5) application to NAc slices (right) from directly stressed males 1 week after stress exposure. (D) Representative dopamine release evoked by electrical stimulation before and after application of 100 nM CRF (left) or 1 μM CRF (middle) to a NAc slice (mean ± SEM for five consecutive stimulations) and baseline-normalized mean peak amplitude of electrically evoked dopamine release over time in response to vehicle (n = 5), 100 nM CRF (n = 5), or 1 μM CRF (n = 5) application to NAc slices (right) from directly stressed females 1 week after stress exposure. Error bars, SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. rFSS Swim 1 Day 1 immobility.

Figure 3

Indirect stress disrupts CRF-mediated dopamine release in the NAc in males and females 1 week after the onset of stress exposure. (A) Mice were housed in groups of four and two mice were subjected to direct stress. The two mice that did not undergo direct stress, termed the indirect stress group, remained in the home cage for the duration of the experiment. (B,C) Cumulative time spent immobile for the first 5 min of Swim 1 on rFSS Day 1 and Swims 1–4 on rFSS Day 2 in panel (B) males (n = 6) and females (n = 8) that were housed with indirectly stressed animals (C) mice (male and female groups combined) belonging to the direct stress (n = 16) and direct stress donors (n = 14) groups. (D) Representative dopamine release evoked by electrical stimulation (dashed line) before and after application of 100 nM CRF to a NAc brain slice (mean ± SEM for five consecutive stimulations, top) and baseline-normalized mean peak amplitude of electrically evoked dopamine release over time in response to vehicle (n = 4) or 100 nM CRF (n = 6) application to NAc slices (bottom) from indirectly stressed males 1 week after cage mates were directly stressed. (E) Representative dopamine release evoked by electrical stimulation before and after application of 100 nM CRF (top, left) or 1 μM CRF (top, right) to a NAc slice (mean ± SEM for five consecutive stimulations) and baseline-normalized mean peak amplitude of electrically evoked dopamine release over time in response to vehicle (n = 8), 100 nM CRF (n = 5), or 1 μM CRF (n = 8) application to NAc slices (bottom) from indirectly stressed females 1 week after cage mates were directly stressed. Error bars, SEM. **P < 0.01, ***P < 0.001, ****P < 0.0001 vs. rFSS Swim 1 Day 1 immobility.

Figure 4

Direct and indirect stress disrupt CRF-mediated dopamine release in the NAc 1 week after stress exposure. Baseline-normalized mean peak amplitude of electrically evoked dopamine release over time in response to vehicle or 100 nM CRF application to NAc slices collected from panel (A) stress-naïve males and females (vehicle and 100 nM CRF: n = 19); (B) directly stressed males and females 1 week after rFSS exposure (vehicle and 100 nM CRF: n = 10); and (C) indirectly stressed males and females 1 week after cage mates were subjected to direct stress (vehicle: n = 12, 100 nM CRF: n = 11). (D) Baseline-normalized mean peak amplitude of dopamine release 20–30 min after vehicle or 100 nM CRF application to NAc slices from stress-naïve (vehicle and 100 nM CRF: n = 19), directly stressed (vehicle and 100 nM CRF: n = 10), or indirectly stressed (vehicle: n = 12, 100 nM CRF: n = 11) males and females. Error bars, SEM. ns: P > 0.05, *P < 0.05 vs. vehicle, **P < 0.01 vs. vehicle, ****P < 0.0001 for interaction.

Figure 5

Direct and indirect stress do not affect social interaction, depression-like behavior, or anxiety-like behavior 1week after stress exposure. (A) Cartoon depicting the three-chamber social approach assay (top) and a representative heatmap of activity during this test (bottom). (B) Time spent in the novel object and novel mouse zones in the three-chamber social approach assay in stress-naïve (n = 8), directly stressed (n = 6), and indirectly stressed (n = 7) males and females. (C) Cartoon depicting the tail suspension test (TST). (D) Time spent immobile for the 6-min duration the TST in stress-naïve (n = 10), directly stressed (n = 11), and indirectly stressed (n = 10) males and females. (E) Cartoon depicting the elevated plus maze (EPM, top) and a representative heatmap of activity in the EPM (bottom). (F) Distance traveled in the EPM in stress-naïve (n = 32), directly stressed (n = 25), and indirectly stressed (n = 29) males and females. (G) Percent of total time spent exploring the open arms of the EPM in stress-naïve (n = 32), directly stressed (n = 25), and indirectly stressed (n = 29) males and females. Error bars, SEM. ns: P > 0.05, *P < 0.05, **P < 0.01, ****P < 0.0001.