Neurogenesis during Abstinence Is Necessary for Context-Driven Methamphetamine-Related Memory

Abstract

Abstinence from methamphetamine addiction enhances proliferation and differentiation of neural progenitors and increases adult neurogenesis in the dentate gyrus (DG). We hypothesized that neurogenesis during abstinence contributes to context-driven drug-seeking behaviors. To test this hypothesis, the pharmacogenetic rat model (GFAP-TK rats) was used to conditionally and specifically ablate neurogenesis in the DG. Male GFAP-TK rats were trained to self-administer methamphetamine or sucrose and were administered the antiviral drug valganciclovir (Valcyte) to produce apoptosis of actively dividing GFAP type 1 stem-like cells to inhibit neurogenesis during abstinence. Hippocampus tissue was stained for Ki-67, NeuroD, and DCX to measure levels of neural progenitors and immature neurons, and was stained for synaptoporin to determine alterations in mossy fiber tracts. DG-enriched tissue punches were probed for CaMKII to measure alterations in plasticity-related proteins. Whole-cell patch-clamp recordings were performed in acute brain slices from methamphetamine naive (controls) and methamphetamine experienced animals (+/-Valcyte). Spontaneous EPSCs and intrinsic excitability were recorded from granule cell neurons (GCNs). Reinstatement of methamphetamine seeking enhanced autophosphorylation of CaMKII, reduced mossy fiber density, and induced hyperexcitability of GCNs. Inhibition of neurogenesis during abstinence prevented context-driven methamphetamine seeking, and these effects correlated with reduced autophosphorylation of CaMKII, increased mossy fiber density, and reduced the excitability of GCNs. Context-driven sucrose seeking was unaffected. Together, the loss-of-neurogenesis data demonstrate that neurogenesis during abstinence assists with methamphetamine context-driven memory in rats, and that neurogenesis during abstinence is essential for the expression of synaptic proteins and plasticity promoting context-driven drug memory. Our work uncovers a mechanistic relationship between neurogenesis in the dentate gyrus and drug seeking. We report that the suppression of excessive neurogenesis during abstinence from methamphetamine addiction by a confirmed phamacogenetic approach blocked context-driven methamphetamine reinstatement and prevented maladaptive changes in expression and activation of synaptic proteins and basal synaptic function associated with learning and memory in the dentate gyrus. Our study is the first to demonstrate an interesting and dysfunctional role of adult hippocampal neurogenesis during abstinence to drug-seeking behavior in animals self-administering escalating amounts of methamphetamine. Together, these results support a direct role for the importance of adult neurogenesis during abstinence in compulsive-like drug reinstatement.

Image‐guided cranial irradiation‐induced ablation of dentate gyrus neurogenesis impairs extinction of recent morphine reward memories

“…Prior to the present work, it was unknown if dentate gyrus ABGCs were involved in the retrieval or extinction of recent versus remote reward‐associated memories in the context of opiate use. Of particular relevance to the current work, ABGCs appear to play roles in the temporal separation of events (Aimone et al, ; Rangel et al, ), discrimination of similar contexts (Guo et al, ; Rangel et al, ; Tronel et al, ), memory consolidation (Kitamura & Inokuchi, ), and in the extinction of reward memories (Deschaux et al, ; Castilla‐Ortega, Blanco, et al, ; Galinato et al, ). These roles fit with the known role of the hippocampus and brain regions upstream of the hippocampus, dentate gyrus, and ABGCs in the processing of recent and remote memory (Hales et al, ).…”

“…self‐administration (Noonan et al, ), (c) methamphetamine i.v. self‐administration (Galinato et al, ), and (d) morphine self‐administration (Bulin et al, ). Interestingly, pharmacological enhancement of adult hippocampal neurogenesis also enhances extinction of a cocaine place memory in mice (Ladrón de Guevara‐Miranda et al, ).…”

“…Additionally, extended access to methamphetamine i.v. decreases ABGCs, and decreasing dentate gyrus neurogenesis during abstinence diminishes context‐elicited reinstatement of methamphetamine‐seeking (Galinato et al, ; Mandyam et al, ; Yuan, Quiocho, Kim, Wee, & Mandyam, ). In regards to CPP, IG‐IR does not change retrieval of cocaine CPP in rat (Brown et al, ).…”

Sex Differences in Context-Driven Reinstatement of Methamphetamine Seeking Is Associated with Distinct Neuroadaptations in the Dentate Gyrus<strong> </strong>

“…For example, we used BrdU to tag cells either 20h or 2 weeks after extended access methamphetamine selfadministration, and our findings indicate that withdrawal and abstinence from methamphetamine increase survival of BrdU cells (Recinto et al, 2012;Galinato et al, 2018a). Investigation of endogenous markers of proliferation, e.g., Ki-67-labeled dividing cells [Ki-67 is expressed in actively dividing neural stem cells and provides an estimate of net proliferation (Gerdes et al, 1984)] during protracted abstinence indicated that abstinence from drug use increased the population of progenitor cells that were neuroblasts or preneuronal progenitor cells (Recinto et al, 2012;Sobieraj et al, 2016;Galinato et al, 2018b). (Brown et al, 2003)].…”

“…The hippocampus plays a substantial role in context-driven reinstatement of methamphetamine seeking (Hiranita et al, 2008), and the plasticity in the DG of the hippocampus also regulates context-driven methamphetamine seeking (Galinato et al, 2018a;Galinato et al, 2018b). Previously, in male rats we injected BrdU immediately after an extended access methamphetamine self-administration session to tag dividing neuroblasts and progenitor cells during methamphetamine experience and continued extended access sessions for 4 weeks.…”