There is growing evidence that the basal ganglia (BG) participate in multiple segregated """"""""loops"""""""" with a wide variety of cortical areas including regions of motor, prefrontal, posterior parietal and inferotemporal cortex. These circuits could provide the BG with the neural substrate to influence motor, cognitive, emotional and perceptual domains of behavior. We and others have argued that abnormal activity in BG loops with the cerebral cortex could lead not only to motor disorders, but also to non-motor symptoms like those associated with Obsessive-Compulsive Disorder (OCD) and Tourette Syndrome (TS). The overall goal of our experiments is to link some of the non-motor symptoms associated with BG dysfunction to the cortical areas that are responsible for their expression. The basal ganglia have been subdivided into 3 general territories: sensorimotor, associative and limbic. These subdivisions are based on anatomical connections and immunohistochemical staining patterns. This application will focus on the limbic territory. Prior studies have shown that micro-injections of the GABA antagonist, Bicuculline (Bic) into the limbic territory of the external segment of the Globus Pallidus (GPe) evoke abnormal behaviors including excessive grooming, nail biting, and communicative gestures. We will use transneuronal transport of rabies virus to identify the cortical areas that are interconnected with sites in GPe where Bic produces these behaviors. We propose two sets of experiments. First, we will behaviorally define specific sites in the limbic territory of GPe using Bic microinjections. Then, we will inject rabies virus in GPe and allow retrograde transneuronal transport to 2nd order neurons in the cerebral cortex. This approach will identify cortical neurons that provide input to the limbic territory in GPe. In a second set of experiments, we will again use Bic injections to define specific sites in the limbic territory of GPe. These sites with be marked by micro- lesions. Then, we will inject rabies virus into sites of interest in the cerebral cortex. These sites will be the sites that contained the highest density of labeled neurons in the first set of experiments. We will allow retrograde transneuronal transport to 3rd order neurons in GPe. We will compare the location of these GPe neurons to the marking lesions at GPe sites. This approach will identify cortical regions that are the targets of output from the limbic territory in GPe. Together these experiments should provide new insights into the cortical areas that are responsible for the non-motor symptoms of basal ganglia dysfunction. This information may result in new avenues for treatment of complex disorders like OCD and TS. ? ? ?
| Gittis, Aryn H; Berke, Joshua D; Bevan, Mark D et al. (2014) New roles for the external globus pallidus in basal ganglia circuits and behavior. J Neurosci 34:15178-83 |
