In unilateral 6‑OHDA Parkinsonian rats, chemogenetic activation (hM3Dq) of ventral hippocampus CaMKIIα+ neurons produced antidepressant and anxiolytic effects and raised dopamine in mPFC, dHIP and vHIP, whereas inhibition (hM4Di) produced region‑specific monoamine decreases without behavioral…

This work pinpoints a specific hippocampal cell‑type circuit that modulates limbic dopamine/serotonin and alleviates PD‑related depression/anxiety, offering a plausible target for neuromodulation or circuit‑based therapies even though the chemogenetic approach itself is not yet directly…

Comorbidity of depression and anxiety is quite common in Parkinson's disease (PD). The ventral hippocampus (vHIP) has been widely implicated in depression and anxiety. However, the roles of CaMKⅡα-positive neurons in the vHIP in depression- and anxiety-like behaviors associated with PD in rats remain unclear. Here, we used chemogenetic techniques, such as designer receptors exclusively activated by designer drugs (DREADDs), to activate or inhibit CaMKⅡα-positive neurons in the vHIP of rats. In the present study, the unilateral 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle (MFB) led to depression- and anxiety-like behaviors, as well as decreased levels of dopamine (DA) but not 5-hydroxytryptamine (5-HT) in the medial prefrontal cortex (mPFC), striatum, amygdala, lateral habenula (LHb), dorsal hippocampus (dHIP) and vHIP in rats. hM3Dq-induced activation of vHIP CaMKⅡα-positive neurons produced antidepressant and anxiolytic effects, and increased DA levels in the mPFC, dHIP and vHIP only in the 6-OHDA-lesioned rats. In contrast, hM4Di-induced inhibition of vHIP CaMKⅡα-positive neurons had no effect on depression- or anxiety-like behaviors in both sham operated and the 6-OHDA-lesioned rats, but decreased DA levels in the amygdala in both groups, as well as decreased DA levels in the LHb and mPFC, and decreased 5-HT levels in the mPFC of the 6-OHDA-lesioned rats. Our findings suggest that hM3Dq-induced chemogenetic activation of vHIP CaMKⅡα-positive neurons produces antidepressant and anxiolytic effects in the 6-OHDA-lesioned rats. Meanwhile, DREADDs-induced changes in the behaviors may be related to DA and 5-HT levels in the limbic and limbic-related brain regions.