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theses

The dorsolateral striatum (DLS) is a prominent target of research on control of voluntary movement and sensorimotor integration. The DLS is comprised mainly (95%) of medium spiny projection neurons that receive direct monosynaptic projections from primary somatosensory (S1) and motor (M1) cortices. Roughly 50% of these neurons are type IIb GABAergic, medium spiny projection neurons (MSNs) whose firing rates (FRs) are related to sensorimotor activity of individual body parts. There is also a hypothesized dual organization of DLS outputs known as the “direct and indirect pathways”. According to this model, direct pathway MSNs project to the substantia nigra pars reticulata (SNr) and the internal segment of the globus pallidus (GPi), leading to disinhibition of the thalamus and facilitation of movement. Conversely the indirect pathway projects to the SNr via the globus pallidus external segment (GPe) and then the subthalamic nucleus (STN), inhibiting the thalamus and reducing movement. In addition to their distinct projections, MSNs of the direct and indirect pathway are characterized by differential expression of dopamine receptors. Dopamine Drd1 is expressed by direct pathway MSNs, whereas Drd2 is expressed by indirect pathway MSNs. While there has been a significant amount of research testing the functional hypotheses generated by iii the direct and indirect pathways framework, no study has attempted to reconcile the very well classified striatal type IIb neurons with the aforementioned functional tenet of the hypothesis. The present study utilized AAV-EF1a-FLEx-Chronos-GFP to visualize and optogenetically identify Drd1 and Drd2 MSNs in Cre-animals. We then performed somatosensory motor exams in order to identify type IIb MSNs and fill the gap in the literature. We found that in Drd1-Cre animals, Chronos-GFP expressing neurons projected to GPi, while in Drd2-Cre animals, Chronos-GFP expressing neurons projected to GPe, providing evidence that Drd1-Cre and Drd2-Cre animals are valid models of the direct and indirect pathways. Further, we were able to unambiguously identify Drd1 and Drd2 MSNs in the striatum of awake, behaving mice using light stimulation. We were subsequently able show that both the direct (Drd1) and indirect (Drd2) pathways contain type IIb neurons with firing related to stimulation of body parts. This evidence brings into question the notion that Drd1 neurons promote movement, while Drd2 neurons inhibit it. Rather, it seems that Drd1 and Drd2 neurons process sensorimotor information similarly, with both Drd1 and Drd2 neurons exhibiting increased phasic firing during body part stimulation and movement. While the anatomical aspects of the direct and indirect pathways hypothesis are strongly corroborated, the functional aspect appears to need a critical reevaluation.

ETD_7474

Ph.D.

Includes bibliographical references

by Kevin Coffey

doi:10.7282/T3B85BDC

ETD doctoral

The author owns the copyright to this work.