Assessing the role of globus pallidus externa in relaying the effect of subthalamic nucleus high-frequency stimulation on the dorsal raphe nucleus

Abstract

Deep brain stimulation (DBS) of the subthalamic nucleus (STN) has become a standard surgical treatment option for Parkinson's disease. However, STN-DBS can cause mood-related side effects such as depression. Previous studies have shown that the inhibition of serotonergic cells in the dorsal raphe nucleus (DRN) is a potential cause of depressive-like behavior in rodents treated with STN-DBS. However, the exact anatomical circuitry behind this effect remains elusive. Given the absence of a direct anatomical connection between the STN and the DRN, relay nuclei such as the lateral habenula have been proposed to mediate those effects. Novel cell-type-specific viral tracing methods have recently unveiled a new connection from the STN to the DRN via the globus pallidus externa (GPe). To investigate whether this newly discovered anatomical connection relays the inhibitory effect of STN-DBS to the DRN, we used the designer receptors exclusively activated by the designer drug (DREADD) to inhibit the GPe. We utilized a cell-type-specific calcium indicator in transgenic 5-HT-Cre (ePet-Cre) mice to assess the activity of serotonergic cells in the DRN in STN-DBS mice while the GPe was challenged with DREADD. We observed that chemogenetic modulation of the GPe does not interfere with the suppression of DRN 5-HT neuronal activity caused by STN-DBS. These results suggest that the GPe may not serve as a relay for transmitting the suppressive effects of STN-DBS to the serotonergic neurons in the DRN or the DREADD modulation on the GPe was insufficient to counteract the effects of DBS in our study.