Chemogenetic activation of CaMKⅡα positive neurons in the ventral hippocampus produces antidepressant and anxiolytic effects in unilateral 6-hydroxydopamine-lesioned rats

Tao Wang; Yuan Guo; Xiaoying Li; Xinfeng Wang; Li Zhang; Jian Liu

doi:10.1016/j.bbr.2026.116231

Chemogenetic activation of CaMKⅡα positive neurons in the ventral hippocampus produces antidepressant and anxiolytic effects in unilateral 6-hydroxydopamine-lesioned rats

Behav Brain Res. 2026 Apr 17:509:116231. doi: 10.1016/j.bbr.2026.116231. Online ahead of print.

Authors

Tao Wang¹, Yuan Guo¹, Xiaoying Li², Xinfeng Wang¹, Li Zhang³, Jian Liu⁴

Affiliations

¹ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China.
² Hospital of Xi'an Jiaotong University, Xi'an 710061, China.
³ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. Electronic address: zhangli1998@xjtu.edu.cn.
⁴ Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, Xi'an 710061, China. Electronic address: liujian@xjtu.edu.cn.

PMID: 42002003
DOI: 10.1016/j.bbr.2026.116231

Abstract

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.

Keywords: Anxiety; DREADDs; Depression; Parkinson's disease; Ventral hippocampus.