The Top-down of Prefrontal cortex to the Hippocampus Glutamatergic Pathway Regulates Reward memory of Methamphetamine.

Methamphetamine (METH) is a widely abused psychoactive drug that readily establishes reward memories contributing to METH relapse. The medial prefrontal cortex (mPFC) is central to cognition, motivation, reward and emotion and the hippocampus is critically involved reward memory. The mPFC possesses an enormous variety of projection neurons. However, the direct projection from the mPFC to the hippocampus involved in METH addiction has not been studied well. To explore the role of a mPFC-hippocampus pathway of regulating METH reward memory, conditioned place preference (CPP) was used to detect reward memory and recombinant adeno-associated virus 2/9s (rAAV2/9s) were used to label neurons, identify projections, and optogenetically explore involvement of the male mice mPFC-hippocampus pathway in regulating METH-CPP. We found that a novel prelimibic prefrontal cortex (PrL) projection directly to the dorsal hippocampus CA1 (dCA1) regulated CPP induced by METH. Moreover, optogenetic activation or inhibition, and silencing the PrL to dCA1 glutamatergic pathway with tetanus neurotoxin (TeNT) modulated METH-CPP. Our results reveal a PrL to dCA1 glutamatergic pathway that regulates METH-CPP and could serve as a potential target for treating METH use disorder.Significance Statement This study elucidated the intricate molecular, circuit, and functional architecture of the prelimibic prefrontal cortex (PrL) to dorsal hippocampus CA 1(dCA1) and identify CaMKIIα-expressing glutamatergic neurons in the medial prefrontal cortex (mPFC) as a key inversely driver of reward and methamphetamine addiction. These findings open new avenues for exploring how the prefrontal cortex to the hippocampus regulates reward and addiction.