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

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.

Inhibition of CSF1R, a receptor involved in microglia viability, alters behavioral and molecular changes induced by cocaine

“…In the present study, both cocaine and microglia depletion reduced the levels of BDNF in the hippocampus. In agreement with our results, it has been shown that repeated administration of cocaine leads to a reduction of this neurotrophic factor in the hippocampus 78 , 79 . Although microglia may not represent the main source of BDNF in the brain, the release of this neurotrophin by these cells seems to be important in physiological and pathological conditions 80 .…”

Melamine disrupts spatial reversal learning and learning strategy via inhibiting hippocampal BDNF-mediated neural activity

“…Similarly, intrahippocampal infusion of BDNF facilitates strategy shifting by minimizing response perseveration to the previously acquired strategy [ 36 ]. Additional evidence has shown that the flexible memory system was associated with up-regulation of BDNF expression and transcriptionally permissive histone acetylation in the HPC [ 37 ]. Moreover, compelling evidence showed BDNF-mediated neural excitability verifying successful learning [ 38 , 39 ].…”

Identification of novel BDNF-specific corticostriatal circuitries

“…Similar to what was previously reported (Hofer et al, 1990), we did not detect BDNF-positive neurons in the striatum. Interestingly, although basal BDNF levels in the rodent striatum are negligible, a robust increase in BDNF message is detected in response to behaviors such as voluntary alcohol intake (McGough et al, 2004;Jeanblanc et al, 2009), and cocaine (Liu et al, 2006;Harvey et al, 2019), as well as in response to exercise (Marais et al, 2009). Reconciling these potentially conflicting observations merits further investigation.…”