Chemogenetic activation of VTA neurons induces anxiety-like behavior in a Parkinson's disease model.

Abstract

As Parkinson's disease (PD) advances, there may be a compensatory activation of neurons in the ventral midbrain, potentially linked to the manifestation of non-motor symptoms in individuals with PD. These non-motor symptoms, such as anxiety, often precede the onset of motor symptoms, with female patients generally exhibiting higher levels of anxiety. Nonetheless, the precise mechanisms underlying this phenomenon remain inadequately elucidated. The ventral tegmental area (VTA) of the midbrain functions as a pivotal nucleus capable of encoding both positive and negative emotional signals, potentially contributing to the development of anxiety comorbidities in patients with PD. In this study, we utilized a combination of chemogenetics, behavioral assessments, and morphological analyses to demonstrate that the heightened activity of VTA neuron populations, especially dopaminergic neurons induces sex-specific anxiety-related behaviors in mice. This phenomenon may be associated with the activation of the VTA-NAC and VTA-vHPC neural circuits. Our findings highlight the critical role of VTA neuron populations, especially dopaminergic neurons in early PD-related anxiety. They offer a valuable experimental framework for elucidating the neural mechanisms underlying anxiety in PD, thereby establishing a foundation for the development of early intervention strategies.