Lieu: Neurocentre Magendie
Giulia de Maio
Equipe Deroche
Neurocentre Magendie
Title
The Role of the Histone Methyltransferase Prdm2 in the Prelimbic Cortex: Behavioral and Molecular Implications in Cocaine-Related Behaviors in Rats
Abstract
Cocaine use is rising worldwide, particularly in Europe, with prevalence among 15–64-year-olds increasing. About 20% of users develop addiction, a chronic disorder marked by loss of control over drug seeking and drug taking. No approved pharmacotherapies exist, and behavioral treatments remain limited. Epigenetic mechanisms, i.e., heritable regulation of gene expression without altering DNA sequence, are increasingly recognized in addiction-related neuroplasticity. While cocaine alters histone modifications and DNA methylation in the mesocorticolimbic system, most studies rely on non-compulsive models, making it difficult to distinguish drug exposure-driven from addiction-specific molecular changes. Building on studies in alcohol addiction, where the histone methyltransferase Prdm2 emerged as a key player, this thesis investigates Prdm2 as an epigenetic marker and modulator of compulsive cocaine use. Prdm2 methylates lysine 9 on histone H3, regulating chromatin accessibility and transcription. In alcohol post-dependent rats, Prdm2 expression is reduced in the dorsomedial prefrontal cortex (dmPFC), and local knockdown (KD) via AAV-shRNA promotes compulsive drinking and stress-induced relapse. Using the DSM-based ‘3crit’ rat model of cocaine addiction, which identifies ~20% of animals as “addicted-like” after prolonged cocaine self-administration, we measured Prdm2 mRNA levels in the dmPFC via qPCR. Similar to alcohol models, Prdm2 expression was reduced in addicted-like rats as compared to non-addicted rats, whose levels were similar to cocaine naïve rats. Moreover, Prdm2 levels negatively correlated with individual addiction scores: the lower the expression the more pronounced the maladaptive self-administration behavior. To probe causality, we knocked down Prdm2 expression before cocaine exposure at a high dose (0.8 mg/kg/infusion). While KD did not induce addiction-like behavior directly, it altered cocaine self-administration: KD rats stabilized intake at lower levels and maintained stable responding at reduced doses, suggesting enhanced cocaine effects without compulsive use at this stage. However, when KD was induced after cocaine self-administration training, KD rats escalated intake over time, whereas controls remained stable, suggesting increased vulnerability to cocaine-induced seeking in Prdm2-deficient rats. To assess whether these effects extended beyond drug rewards, we evaluated sucrose self-administration using a comparable protocol alternating reward/no-reward access periods. KD rats showed increased overall sucrose intake. However, motivation and palatability indices (e.g., licks per delivery, performance in progressive ratio) were similar between groups. Interestingly, KD rats adapted more rapidly to reward availability changes, suggesting a broader role for Prdm2 in regulating reward-related behaviors. To uncover molecular mechanisms underlying these effects, we performed RNA-seq on dmPFC tissue from KD and control rats, both cocaine-naïve and cocaine-exposed. Prdm2 appeared to maintain synaptic integrity by repressing genes involved in vesicle trafficking, extracellular matrix remodeling, and astrocytic regulation. KD led to upregulation of these pathways, possibly lowering the threshold for cocaine-induced plasticity and promoting maladaptive drug-seeking. In summary, Prdm2 downregulation in the dmPFC is a specific molecular signature of cocaine addiction-like behavior, correlating with symptom severity. The behavioral and transcriptomic consequences of Prdm2 KD support its physiological role in adaptability to experimental contingencies, ultimately contributing to the regulation of control over cocaine-induced drug-seeking behavior. A key perspective of this work is to investigate the respective contributions of innately reduced Prdm2 expression and the long-term, cocaine-induced downregulation of Prdm2 in the transition from heightened to diminished control over maladaptive cocaine-seeking behavior.
Keywords: dmPFC, Prdm2, reward sensitivity, behavioral control