BAZ1B in Nucleus Accumbens Regulates Reward-Related Behaviors in Response to Distinct Emotional Stimuli

Abstract

ATP-dependent chromatin remodeling proteins are being implicated increasingly in the regulation of complex behaviors, including models of several psychiatric disorders. Here, we demonstrate that Baz1b, an accessory subunit of the ISWI family of chromatin remodeling complexes, is upregulated in the nucleus accumbens (NAc), a key brain reward region, in both chronic cocaine-treated mice and mice that are resilient to chronic social defeat stress. In contrast, no regulation is seen in mice that are susceptible to this chronic stress. Viral-mediated overexpression of Baz1b, along with its associated subunit Smarca5, in mouse NAc is sufficient to potentiate both rewarding responses to cocaine, including cocaine self-administration, and resilience to chronic social defeat stress. However, despite these similar, proreward behavioral effects, genome-wide mapping of BAZ1B in NAc revealed mostly distinct subsets of genes regulated by these chromatin remodeling proteins after chronic exposure to either cocaine or social stress. Together, these findings suggest important roles for BAZ1B and its associated chromatin remodeling complexes in NAc in the regulation of reward behaviors to distinct emotional stimuli and highlight the stimulus-specific nature of the actions of these regulatory proteins.

Significance statement: We show that BAZ1B, a component of chromatin remodeling complexes, in the nucleus accumbens regulates reward-related behaviors in response to chronic exposure to both rewarding and aversive stimuli by regulating largely distinct subsets of genes.

Keywords: Addiction; Baz1b; chromatin; depression; epigenetics; remodeler.

Figure 1.

BAZ1B in NAc in cocaine action. A, Baz1b and Smarca5 mRNA levels in NAc 30 min, 24 h, and 7 d after 7 daily intraperitoneal injections of 20 mg/kg cocaine or saline (0.9% w/v). B, Baz1b and Smarca5 mRNA levels in NAc 24 h after cocaine self-administration. C, BAZ1B protein levels in NAc 24 h after cocaine self-administration. D, Validation of HSV viral overexpression of BAZ1B and SMARCA5 in mouse NAc. E, BAZ1B + SMARCA5 overexpression in NAc enhances cocaine reward as measured by CPP. F, BAZ1B + SMARCA5 overexpression in NAc enhances cocaine-induced locomotor activity. G, BAZ1B + SMARCA5 overexpression in NAc enhances cocaine self-administration at lower doses. H, BAZ1B + SMARCA5 overexpression in NAc enhances cue-induced drug seeking. For A, B, E, F, experimental paradigms are shown above each panel. #0.05 < p < 0.10, *p < 0.05, **p < 0.01 in respective comparisons.

Figure 2.

BAZ1B in NAc in CSDS. A, Representative SI ratios for control, susceptible, and resilient animals 24 h after 10 d of CSDS. B, Baz1b and Smarca5 mRNA levels in NAc 48 h after CSDS. C, Baz1b and Smarca5 mRNA levels in NAc 10 d after CSDS. D, BAZ1B and SMARCA5 protein levels in NAc 48 h after CSDS. E, BAZ1B + SMARCA5 overexpression in NAc increases SI ratios after a 4 d accelerated defeat paradigm, indicating a pro-resilience effect. For B–E, experimental paradigms are shown above each panel. *p < 0.05, **p < 0.01, ***p < 0.001 in respective comparisons.

Figure 3.

Genome-wide mapping of BAZ1B in NAc after cocaine or CSDS. A, Differential BAZ1B binding sites in NAc between chronic cocaine and saline treatment. B, Differential BAZ1B binding sites in NAc between resilient and control animals. C, Differential BAZ1B binding sites in NAc between resilient and susceptible animals. D, Overlap between upregulated (top) and downregulated (bottom) BAZ1B genic binding sites in NAc in resilient versus control and cocaine versus saline conditions. E, IGV (integrative genomics viewer) visualization of BAZ1B and SMARCA5 ChIP-seq tracks at Sphkap genomic loci in either separate (left) or overlaid (right) tracks in NAc of cocaine and saline groups (top), as well as control and resilient groups (bottom). F, Correlation between the binding of BAZ1B, SMARCA5, and several histone marks at promoter regions genome-wide in NAc. Corrgram package analysis was used to calculate correlation/r-values. To help with visualization, horizontal and vertical dotted lines were extended from each factor/chromatin mark. The piechart where the two lines intersect represents the correlation value between the two factors/marks. The size of the shaded region within the pie reflects correlation/r-values (bigger shaded region represents higher correlation or r-value), whereas the color of the shaded region represents the direction of correlation (blue reflects positive correlation and red reflects negative correlation). p < 2.2 × 10⁻¹⁶ for all correlations. For A–C, χ² test, *p < 0.05, **p < 0.01, ***p < 0.001 in respective comparisons.