Searching for intracollicular neural substrate and neural pathways involved in paradoxical kinesia in rats

• Applicant: Dr. Liana Melo-Thomas, Ph.D.
• Subject Area: Cognitive, Systems and Behavioural Neurobiology
• Term: from 2020 to 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 436414341

Previous results from our group strongly suggest that the inferior collicuus (IC) can modulate motor deficits representing an alternative target for deep brain stimulation (DBS) in patients with Parkinson’s disease and other motor dysfunctions. Based on these studies, we have suggested the IC as part of an alternative pathway that, when activated, induces motor improvement and thus paradoxical kinesia. However, the exact identity of this pathway, and how it is activated, is still unknown. The first goal of the present proposal is to investigate which IC projections are involved in this motor response and which intracollicular neural substrate is activated in order to trigger paradoxical kinesia. Specifically, combining electrophysiological and optogenetic techniques we will investigate descent projections from the IC to the mesencephalic locomotion region and ascending projections from the IC to the medial geniculate nucleus, which projects to both auditory cortex and prefrontal cortex. For that, we will inject CaMKIIa::ChR2 into the IC and use pulsed illumination with a 473-nm laser diode to activate excitatory neurons in the IC. We hypothesize that optogenetic inhibition of intracollicular glutamatergic neurons projecting to MLR will decrease catalepsy time induced by haloperidol in rats and therefore induce paradoxical kinesia, whereas optogenetic activation of these same neurons will increase haloperidol-induced catalepsy. The second goal of the present proposal is to refine intracollicular DBS parameters in order to induce paradoxical kinesia focusing on the IC as a potential target to treat movement disorders. For that, we will search for the best combination between frequency and current amplitude avoiding aversive side effects. Therefore, we will apply 30 Hz frequency combined with two different current intensity 400 or 600 μA. In order to assess the effect of these new DBS parameters on catalepsy and anxiety-related behavior, rats will be submitted to the bar test and to the elevated plus maze test under continuous intracollicular stimulation. Therefore, the present proposal will contribute to refine intracollicular BDS parameters in order to induce paradoxical kinesia, in addition, to establish the optogenetic technique in our lab, which will be of great value in the future allowing us to combine this technique with other behavioral tests currently in use in our group.

• DFG Programme: Research Grants