The glutamatergic projections from the PVT to mPFC govern methamphetamine-induced conditional place preference behavior in mice

Abstract

Background: Drug addiction is closely related to the dysregulation of complex neural circuits. However, the neural connections underlying the symptoms of methamphetamine (METH)-induced addiction have yet to be elucidated.

Methods: We conducted ΔFosB (Delta FBJ murine osteosarcoma viral oncogene homolog B) associated immunofluorescence and electrophysiological recording experiments to measure neural activity of paraventricular thalamus (PVT) neurons in METH treated mice. Then, the METH-mediated conditional place preference (CPP) behaviors were evaluated after chemogenetic manipulation of PVT neurons. Additionally, the neural projection from PVT to medial prefrontal cortex (mPFC) was verified through Adeno-associated virus (AAV) mediating neural tracing method, and its role on METH-mediated CPP behaviors was determined using chemogenetic and neural ablation strategies.

Results: We found that glutamatergic neurons in PVT were activated by METH. Activating the glutamatergic neurons in PVT promoted the METH-mediated CPP behaviors, while inhibiting these neurons attenuated the CPP behaviors. Moreover, we observed PVT neurons showed robust neuronal projections to mPFC, activation of the mPFC→projecting neurons in PVT or the afferent terminals in mPFC derived from PVT enhanced METH-mediated CPP performance, and ablating the mPFC neurons receipting neural projection from PVT impeded the METH-mediated CPP phenotype.

Limitations: The underlying molecular mechanism of the dysfunctional PVT neurons after METH treatment and the PVT neurons regulating the activity of mPFC target neurons remains unclear.

Conclusions: These results shed light on that PVT is a key METH addiction-controlling nucleus, and PVT → mPFC projection regulated METH-mediated CPP behavior, which could serve as a vital pathway for morbidity and treatment for METH-mediated addiction.

Keywords: Conditional place preference (CPP); Medial prefrontal cortex (mPFC); Methamphetamine; Neuronal projection; Paraventricular thalamus (PVT).