Enhanced social reward response and anxiety-like behavior with downregulation of nucleus accumbens glucocorticoid receptor in BALB/c mice

Abstract

Social anhedonia is a psychological state with difficulty in experiencing pleasure from social interactions and is observed in various diseases, such as depressive disorders. Although the relationships between social reward responses and anxiety- and depression-like behaviors have remained unclear, a social reward conditioned place preference (SCPP) test can be used to analyze the rewarding nature of social interactions. To elucidate these relationships, we used 5-week-old male mice of AKR, BALB/c, and C57BL/6J strains and conducted behavioral tests in the following order: elevated plus-maze test (EPM), open field test (OFT), SCPP, saccharin preference test (SPT), and passive avoidance test. The nucleus accumbens of these mice were collected 24 hr after these behavioral tests and were used for western blotting to determine the levels of receptors for brain-derived neurotrophic factors and glucocorticoids. BALB/c mice displayed the highest levels of anxiety-like behavior in EPM and OFT as well as physical anhedonia-like behaviors in SPT. They also showed increased responses to social rewards and huddling behaviors in SCPP, with downregulated glucocorticoid receptor (GR). Regression analysis results revealed positive influences of anxiety- and physical anhedonia-like behaviors and expressions of GR on social reward responses. Collectively, temperament associated with anxiety and physical anhedonia may affect social reward responses, which possibly is influenced by the expression of GR that can modify these psychological traits.

Keywords: anhedonia; anxiety; depression; glucocorticoid receptor; nucleus accumbens; social reward.

Fig. 1.

Schema showing the sequence of behavioral tests for the mouse study. The light blue bar represents the duration of each test performed. The dark blue bar indicates the period of social isolation. EPM: elevated plus-maze test, OFT: open field test, PAT: passive avoidance test, SCPP: social reward conditioned place preference test, SMP: sampling of nucleus accumbens, SPT: saccharin preference test.

Fig. 2.

The preference score in the social-reward conditioned place preference test in BALB/c exceeded those in other strains. BALB: BALB/c, C57: C57BL/6J, Columns and bars represent mean and SEM. N=12 (AKR), 11 (C57BL/6J), and 8 (BALB/c). *, P<0.05.

Fig. 3.

Strain differences in the anxiety- and depression-like behavior and memory/learning in inbred mice. Percentage of time spent in open arms of elevated-plus maze test (EPM; A) and that in center of open field test (OFT; B) was the shortest in BALB/c, followed by AKR and C57BL/6J. Saccharin preference was lower in BALB/c mice than in the other strains during the first 24 hr (left) and the next 40 hr (right) in saccharin preference test (SPT; C). The latency of entry into the dark box on day 2 was shorter for the AKR strain than for the other strains although the difference was not statistically significant (D). Open columns: day 1 (conditioning); columns with diagonal lines: day 2 (retention test). A: AKR, B or BALB: BALB/c, C or C57: C57BL/6J. Data represent mean and SEM. N=12 (AKR), 8 (BALB/c), and 11 (C57BL/6J). *, P<0.05.

Fig. 4.

Low expression of glucocorticoid receptor (GR) in the nucleus accumbens of BALB/c mice. Representative image of the band obtained by western blotting of GR, mineralocorticoid receptor (MR), tropomyosin receptor kinase B (TrkB), p75, and β-actin in the three inbred strains of mice (A). Quantitative data with densitometry are shown in (B). BALB: BALB/c, C57: C57BL/6J. Data represent mean and SEM. N=5. *, P<0.05.