The basal ganglia are a set of subcortical nuclei in the forebrain of vertebrates that are highly conserved among mammals. Classically, dysfunction in the basal ganglia has been linked to motor abnormalities. However, it is now widely recognized that in addition to their role in motor behavior, these set of nuclei play a role in reinforcement learning and motivated behavior as well as in many diseases that present with abnormal motivation. In this dissertation, I first provide a review of the literature that describes the current state of research on the basal ganglia and the background for the original studies I later present. I describe the anatomy and physiology of the basal ganglia, including how structures are interconnected to form two parallel pathways, the direct and the indirect pathways. I further review published studies that have investigated how the basal ganglia regulate motor behavior and motivation. And finally, I also summarize findings on how disruption in basal ganglia circuitry function has been linked to a number of neuropsychiatric diseases, with special focus on the symptoms of schizophrenia. I then present original data and discuss the results of three studies investigating basal ganglia function and behavior.
In the first study, I investigated the bridging collaterals, axon collaterals of direct-pathway medium spiny neurons (dMSNs) in the striatum that target the external segment of the globus (GPe), the canonical target of indirect-pathway medium spiny neurons (iMSNs). Previous work in the Kellendonk laboratory has linked these collaterals to increased dopamine D2 receptor (D2R) function and increased striatal excitability, as well as to abnormal locomotor response to stimulation of the direct pathway. I expanded on these findings by first demonstrating that bridging collaterals form synaptic contacts with GPe cells. I was also able to generate a viral vector to selectively increase excitability in specific populations of MSNs. I used this virus to show that chronically increasing excitability of the indirect pathway, but not the direct pathway, leads to a circuit-level change in connectivity by inducing the growth of bridging collaterals from dMSNs in the GPe. I also confirmed that increased density of bridging collaterals are associated with an abnormal locomotor response to stimulation of striatal dMSNs and further demonstrated that chronic pharmacologic blockade of D2Rs can rescue this abnormal locomotor phenotype. Furthermore, I found that motor training reverses the enhanced density of bridging collaterals and partially rescue the abnormal locomotor phenotype associated with increased collaterals, thereby establishing a new link between connectivity in the basal ganglia and motor learning.
In the second study, I conducted a series of experiments in which I selectively increased excitability of the direct or indirect pathway in specific striatal sub-regions that have been implicated in goal-directed behavior, namely the DMS and NA core. I found that this manipulation was not sufficient to induce significant effects in different behavioral assays of locomotion and motivation, including the progressive ratio and concurrent choice tasks. These findings also suggest that increased bridging collateral density does not have a one-to-one relationship with the motivational deficit of D2R-OEdev mice, as previously hypothesized.
In the third and final study, my original aim was to determine whether the motivational deficit of D2R-OEdev mice, induced by upregulation of D2Rs in the striatum, could be reversed by acutely activating Gαi-coupled signaling in the indirect pathway in these animals. I found that this manipulation increased motivation in D2R-OEdev mice but also in control littermates. This effect was due to energized behavioral performance, which, however, came at the cost of goal-directed efficiency. Moreover, selective manipulation of MSNs in either the DMS or NA core showed that both striatal regions contribute to this effect on motivation. Further investigation aimed at understanding how Gαi-coupled signaling affects striatal circuit function revealed that activating a Gαi-coupled receptor did not lead to a significant change in somatic MSN activity in vivo or to a change in neuronal excitability in vitro. In contrast, the GPe, which receives monosynaptic inhibition from the indirect pathway, showed disinhibited activity when Gαi signaling was activated in striatal iMSNs. In addition, as drug therapies for psychiatric diseases are not usually given acutely but involve long-term, continuous administrations, I also studied how chronically decreasing function of iMSNs would affect behavior. I showed that chronically activating a Gαi-coupled receptor in iMSNs does not lead to a measurable effect on locomotion or motivation, a behavioral desensitization response that can be recovered within 48 h and may be due to receptor desensitization to the drug or circuit-level compensation to a chronic decrease in iMSN function.
Finally, I conclude this dissertation with a general discussion addressing how the findings from each study can be related to each other to provide a more complete understanding of how basal ganglia function regulate behavior, how disruption in the basal ganglia can underlie neuropsychiatric disease, and how strategies to target basal ganglia function should be employed to treat disorders of motivation. I conclude this dissertation by proposing new avenues of research for further exploring my findings.
| Identifer | oai:union.ndltd.org:columbia.edu/oai:academiccommons.columbia.edu:10.7916/D89Z94QZ |
| Date | January 2016 |
| Creators | Poyraz, Fernanda Carvalho |
| Source Sets | Columbia University |
| Language | English |
| Detected Language | English |
| Type | Theses |
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