Lysophosphatidic acid‐induced increase in adult hippocampal neurogenesis facilitates the forgetting of cocaine‐contextual memory

Abstract

Erasing memories of cocaine-stimuli associations might have important clinical implications for addiction therapy. Stimulating hippocampal plasticity by enhancing adult hippocampal neurogenesis (AHN) is a promising strategy because the addition of new neurons may not only facilitate new learning but also modify previous connections and weaken retrograde memories. To investigate whether increasing AHN prompted the forgetting of previous contextual cocaine associations, mice trained in a cocaine-induced conditioned place preference (CPP) paradigm were administered chronic intracerebroventricular infusions of lysophosphatidic acid (LPA, an endogenous lysophospholipid with pro-neurogenic actions), ki16425 (an LPA receptor antagonist) or a vehicle solution, and they were tested 23 days later for CPP retention and extinction. The results of immunohistochemical experiments showed that the LPA-treated mice exhibited reduced long-term CPP retention and an approximately twofold increase in the number of adult-born hippocampal cells that differentiated into mature neurons. Importantly, mediation analyses confirmed a causal role of AHN in reducing CPP maintenance. In contrast, the ki16425-treated mice displayed aberrant responses, with initially decreased CPP retention that progressively increased across the extinction sessions, leading to no effect on AHN. The pharmacological treatments did not affect locomotion or general exploratory or anxiety-like responses. In a second experiment, normal and LPA -receptor-deficient mice were acutely infused with LPA, which revealed that LPA -mediated signaling was required for LPA-induced proliferative actions. These results suggest that the LPA/LPA pathway acts as a potent in vivo modulator of AHN and highlight the potential usefulness of pro-AHN strategies to treat aberrant cognition in those addicted to cocaine.

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

“…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, ). Together, these data support that diminished ABGCs interfere with the neural mechanisms necessary for extinction of a recent—but not remote—reward‐associated memory.…”

Memory Traces Diminished by Exercise Affect New Learning as Proactive Facilitation

“…Although neurogenesis is one of the primary mechanisms whereby exercise benefits cognitive enhancement, neurogenesis-induced forgetting has also been widely shown (Akers et al, 2014;Gao et al, 2018;Ladron de Guevara-Miranda et al, 2018;Ishikawa et al, 2019). This kind of forgetting was discovered in the phenomenon of "infantile amnesia."…”

Therapeutic Potential of Porcine Liver Decomposition Product: New Insights and Perspectives for Microglia-Mediated Neuroinflammation in Neurodegenerative Diseases

“…Based on the results of research over the last two decades, lysophospholipids have served not only as structural components of biological membranes, but also as biologically active molecules. They are known to influence a broad variety of processes, including neurogenesis, immunity, vascular development, and regulation of metabolic diseases [ 15 , 44 , 58 , 59 , 60 ]. With growing interest in the involvement of extracellular lysophospholipids in both normal physiology and pathology, it has become increasingly evident that these small mediators may have therapeutic potential for anti-neurodegenerative indications.…”