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. 2019 Nov;29(11):1101-1113.
doi: 10.1002/hipo.23127. Epub 2019 Jun 17.

Hippocampal BDNF regulates a shift from flexible, goal-directed to habit memory system function following cocaine abstinence

Eric Harvey  1 , Matthew Blurton-Jones  2   3   4 , Pamela J Kennedy  1   5
Affiliations

Hippocampal BDNF regulates a shift from flexible, goal-directed to habit memory system function following cocaine abstinence

Eric Harvey et al. Hippocampus. 2019 Nov.

Retraction in

Abstract

The transition from recreational drug use to addiction involves pathological learning processes that support a persistent shift from flexible, goal-directed to habit behavioral control. Here, we examined the molecular mechanisms supporting altered function in hippocampal (HPC) and dorsolateral striatum (DLS) memory systems following abstinence from repeated cocaine. After 3 weeks of cocaine abstinence (experimenter- or self-administered), we tested new behavioral learning in male rats using a dual-solution maze task, which provides an unbiased approach to assess HPC- versus DLS-dependent learning strategies. Dorsal hippocampus (dHPC) and DLS brain tissues were collected after memory testing to identify transcriptional adaptations associated with cocaine-induced shifts in behavioral learning. Our results demonstrate that following prolonged cocaine abstinence rats show a bias toward the use of an inflexible, habit memory system (DLS) in lieu of a more flexible, easily updated memory system involving the HPC. This memory system bias was associated with upregulation and downregulation of brain-derived neurotrophic factor (BDNF) gene expression and transcriptionally permissive histone acetylation (acetylated histone H3, AcH3) in the DLS and dHPC, respectively. Using viral-mediated gene transfer, we overexpressed BDNF in the dHPC during cocaine abstinence and new maze learning. This manipulation restored HPC-dependent behavioral control. These findings provide a system-level understanding of altered plasticity and behavioral learning following cocaine abstinence and inform mechanisms mediating the organization of learning and memory more broadly.

Keywords: BDNF; dorsolateral striatum; gene transcription; hippocampus; learning and memory; psychostimulants.

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Figures

Figure 1
Figure 1
Memory system bias following abstinence (21 days) from experimenter‐administered cocaine (20 mg/kg/day, 14 days). (a) Timeline for experimenter‐administered cocaine experiments. Probe testing for future gene expression and western blot analyses was conducted at 1 and 24 hr after performance criterion was met, respectively. (b) Schematic representation of the dual‐solution task used for all experiments. (c) Number of days to reach criterion levels of performance. Data presented as mean ± SEM. (d) Saline‐treated rats used an HPC‐dependent place strategy to solve the task while cocaine‐treated rats showed a bias toward the use of a DLS‐dependent response strategy. DLS, dorsolateral striatum; HPC, hippocampal [Color figure can be viewed at http://wileyonlinelibrary.com]
Figure 2
Figure 2
Memory system bias following abstinence (21 days) from cocaine self‐administration (fixed ratio one, 0.75 mg/kg/infusion). (a) Experimental timeline. (b) Cocaine self‐administration. (c) Yoked‐saline rats used an HPC‐dependent place strategy to solve the task while cocaine self‐administering rats showed a bias toward the use of a DLS‐dependent response strategy. DLS, dorsolateral striatum; HPC, hippocampal
Figure 3
Figure 3
Memory system bias following abstinence (21 days) from experimenter‐administered cocaine (20 mg/kg/day, 14 days) is associated with bidirectional changes in permissive histone acetylation and Bdnf expression in dHPC and DLS. (a and b) Quantification and representative Western blots of total AcH3 in the dHPC and DLS 24 hr after probe testing (N = 5‐6/group). (c–f) mRNA expression in the dHPC (c and e) and DLS (d and f) 1 hr after criterion performance on the plus maze and immediately following probe testing (N = 6–9/group). Data presented as mean ± SEM. #p = .074. *p < .05. DHPC, dorsal hippocampus; DLS, dorsolateral striatum; HPC, hippocampal
Figure 4
Figure 4
Overexpression of Bdnf in dHPC prevents cocaine‐induced memory system bias. (a) Experimental timeline. (b) Immunohistological image showing viral expression in dHPC using mCherry (red) and DAPI (blue). (c) Number of days to reach criterion levels of performance (N = 9/group). Data presented as mean ± SEM. (d) BDNF overexpression in dHPC during cocaine abstinence and maze learning restored an HPC‐dependent place strategy to solve the task. BDNF, brain‐derived neurotrophic factor; DHPC, dorsal hippocampus; HPC, hippocampal [Color figure can be viewed at http://wileyonlinelibrary.com]
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