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. 2014 Aug 29:8:297.
doi: 10.3389/fnbeh.2014.00297. eCollection 2014.

Overexpression of DeltaFosB in nucleus accumbens mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment

Yafang Zhang  1 , Elizabeth J Crofton  1 , Dingge Li  1 , Mary Kay Lobo  2 , Xiuzhen Fan  1 , Eric J Nestler  3 , Thomas A Green  1
Affiliations

Overexpression of DeltaFosB in nucleus accumbens mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment

Yafang Zhang et al. Front Behav Neurosci. .

Abstract

Environmental enrichment produces protective addiction and depression phenotypes in rats. ΔFosB is a transcription factor that regulates reward in the brain and is induced by psychological stress as well as drugs of abuse. However, the role played by ΔFosB in the protective phenotypes of environmental enrichment has not been well studied. Here, we demonstrate that ΔFosB is differentially regulated in rats reared in an isolated condition (IC) compared to those in an enriched condition (EC) in response to restraint stress or cocaine. Chronic stress or chronic cocaine treatment each elevates ΔFosB protein levels in the nucleus accumbens (NAc) of IC rats, but not of EC rats due to an already elevated basal accumulation of ΔFosB seen under EC conditions. Viral-mediated overexpression of ΔFosB in the NAc shell of pair-housed rats (i.e., independent of environmental enrichment/isolation) increases operant responding for sucrose when motivated by hunger, but decreases responding in satiated animals. Moreover, ΔFosB overexpression decreases cocaine self-administration, enhances extinction of cocaine seeking, and decreases cocaine-induced reinstatement of intravenous cocaine self-administration; all behavioral findings consistent with the enrichment phenotype. In contrast, however, ΔFosB overexpression did not alter responses of pair-housed rats in several tests of anxiety- and depression-related behavior. Thus, ΔFosB in the NAc the shell mimics the protective addiction phenotype, but not the protective depression phenotype of environmental enrichment.

Keywords: adeno-associated virus (AAV); cocaine self administration; depression; environmental enrichment; overexpression; ∆FosB.

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Figures

Figure 1
Figure 1
Stress and ∆FosB in EC and IC rats. (A–D) Representative immunohistochemistry DAB staining of ΔFosB in NAc shell and core of IC (A and B) and EC (C and D) rats with (B and D) and without (A and C) repeated stress (N = 3). (E) Quantification of the number of ΔFosB positive cells (±SEM) in NAc shell induced by repeated restraint stress in IC and EC rats. (F) Number of ΔFosB positive cells (±SEM) in NAc core induced by repeated restraint stress. (G) Fold change of ΔFosB mRNA (±SEM) induced by acute and repeated restraint stress in IC and EC rats (30 min; N = 5). Asterisks (*) denote significant difference from corresponding control.
Figure 2
Figure 2
Cocaine and ∆FosB in EC and IC rats. (A–B) Mean ΔFosB protein (A) and mRNA (B) level (±SEM) in NAc after 14 days of saline or cocaine self-administration in IC and EC rats (N = 7–8). Red bands in Panel a denote β-actin used for normalization; green denotes ΔFosB protein. (C) Fold change of ΔFosB mRNA (±SEM) induced by acute or repeated IP cocaine injection in IC and EC rats (30 min; N = 4). Asterisks (*) denote significant difference from corresponding control.
Figure 3
Figure 3
Overexpression of ∆FosB in NAc shell mimics the protective addiction phenotype of environmental enrichment. (A–B) Representative immunohistochemistry of ΔFosB for hrGFP control (A) and ΔFosB-overexpressing (B) AAV vectors. The bar represents 50 μm (C) Effect of overexpression of ΔFosB on locomotor activity. (D) Effect of overexpression of ΔFosB on sucrose pellet operant responding under hunger-motivated (85% free feed body weight) and non-hunger motivated conditions (100% free feed weight). (E) Effect of overexpression of ΔFosB on extinction of cocaine self-administration. (F) Effects of overexpression of ΔFosB on cumulative cocaine self-administration: FR dose response function. (G) Overexpression of ΔFosB significantly decreased the reinstatement response to cocaine injections. N = 6–10 for all behavior experiments. Asterisks (*) denote differential responding from control vector group.
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