Regulation of BAZ1A and nucleosome positioning in the nucleus accumbens in response to cocaine

Abstract

Chromatin regulation, in particular ATP-dependent chromatin remodelers, have previously been shown to be important in the regulation of reward-related behaviors in animal models of mental illnesses. Here we demonstrate that BAZ1A, an accessory subunit of the ISWI family of chromatin remodeling complexes, is downregulated in the nucleus accumbens (NAc) of mice exposed repeatedly to cocaine and of cocaine-addicted humans. Viral-mediated overexpression of BAZ1A in mouse NAc reduces cocaine reward as assessed by conditioned place preference (CPP), but increases cocaine-induced locomotor activation. Furthermore, we investigate nucleosome repositioning genome-wide by conducting chromatin immunoprecipitation (ChIP)-sequencing for total H3 in NAc of control mice and after repeated cocaine administration, and find extensive nucleosome occupancy and shift changes across the genome in response to cocaine exposure. These findings implicate BAZ1A in molecular and behavioral plasticity to cocaine and offer new insight into the pathophysiology of cocaine addiction.

Keywords: addiction; chromatin; chromatin remodeling; cocaine; epigenetics.

Fig. 1

Regulation of BAZ1A in NAc after cocaine exposure in mice and humans. (A) Intraperitoneal (i.p.) saline/cocaine injection paradigm in mice. Saline: 7 daily saline injections. Acute cocaine: 6 daily saline injections followed by a single cocaine injection (20 mg/kg) on day 7. Repeated cocaine: 7 daily cocaine injections (20 mg/kg). (B) Baz1a mRNA levels in NAc 1 and 24 hours after saline, acute cocaine, and repeated cocaine treatment. (C) Baz1a mRNA levels in NAc 7 days after repeated saline or cocaine treatment. (D) BAZ1A protein levels in NAc 24 hours after saline, acute cocaine, and repeated cocaine treatment. (E) BAZ1A protein levels in NAc of postmortem human cocaine-addicted subjects compared to controls. * P<0.05, ** P<0.01 in respective comparisons.

Fig. 2

BAZ1A in NAc controls cocaine-induced behaviors. Experimental paradigms are shown above each panel. (A) BAZ1A overexpression in NAc reduces cocaine reward as measured by CPP. (B) BAZ1A overexpression in NAc enhances cocaine-induced locomotor activity. (C) BAZ1A overexpression in NAc further enhances increased locomotor activity following a cocaine challenge. * P< 0.05 ** P < 0.01, *** P < 0.001 in respective comparisons.

Fig. 3

Regulation of nucleosome positioning in NAc by cocaine. (A) Workflow for generation of nucleosome positioning maps in NAc after saline or repeated cocaine treatment. (B) Genome–wide identification of nucleosome occupancy changes after repeated cocaine vs saline controls. (C) Genome–wide identification of nucleosome shift events after repeated cocaine vs saline controls.