Identification of a direct GABAergic pallidocortical pathway in rodents

Abstract

The basal ganglia, interacting with the cortex, play a critical role in a range of behaviors. Output from the basal ganglia to the cortex is thought to relay through the thalamus, yet an intriguing alternative is that the basal ganglia may directly project to, and communicate with, the cortex. We explored an efferent projection from the globus pallidus externa (GPe), a key hub in the basal ganglia system, to the cortex of rats and mice. Anterograde and retrograde tracing revealed projections to the frontal premotor cortex, especially the deep projecting layers, originating from GPe neurons that receive axonal inputs from the dorsal striatum. Cre-dependent anterograde tracing in GPe Vgat-ires-cre mice confirmed that the pallidocortical projection is GABAergic, and in vitro optogenetic stimulation in the cortex of these projections produced a fast inhibitory postsynaptic current in targeted cells that was abolished by bicucculine. The pallidocortical projections targeted GABAergic interneurons and, to a lesser extent, pyramidal neurons. This GABAergic pallidocortical pathway directly links the basal ganglia and cortex and may play a key role in behavior and cognition in normal and disease states.

Deep brain stimulation in the globus pallidus externa promotes sleep

“…For example, dopamine from the SNc acting on D 2 receptors in the striatum enhances GPe activity and promotes sleep (Qiu et al, 2014). We propose that pallidocortical projections regulate sleep (Chen et al, 2015). …”

“…The GPe is a key basal ganglia hub and also directly interacts with the cortex, and we hypothesize that DBS in the GPi and STN may act through the GPe for the regulation of sleep and motor behavior (Qiu et al, 2010, Qiu et al, 2014, Chen et al, 2015). GPe lesions can produce or exacerbate both motor and non-motor symptoms of Parkinson’s disease, including sleep dysfunction, while lesions to other basal ganglia output pathways like the SNr or thalamus have minimal effects on sleep in rats (Zhang et al, 2006, Qiu et al, 2010, Fuller et al, 2011).…”

“…The GPe is a major basal ganglia hub that has the most extensive efferent connections of basal ganglia structures, including a unique direct projection to the frontal cortex (Chen et al, 2015, Saunders et al, 2015). The interconnectivity of major DBS target sites and the GPe raises the possibility that direct GPe stimulation with DBS may also be an effective treatment for sleep dysfunction in Parkinson’s disease.…”

Functional circuit mapping of striatal output nuclei using simultaneous deep brain stimulation and fMRI

“…Although evidence continues to support the notion of functional antagonism between these pathways (Freeze et al, 2013; Kravitz et al, 2010; Schmidt et al, 2013), additional anatomical and functional studies have identified unanticipated circuit connectivity in both the SNr and GPe (among other basal ganglia nuclei). Recent examples in the GPe include the identification of a pallidocortical projection that entirely bypasses thalamic relays to modulate frontal cortex (Chen et al, 2015; Saunders et al, 2015), as well as pallidostriatal innervation by so-called “arkypallidal” GPe neurons (Abdi et al, 2015; Mallet et al, 2012). The SNr, generally conceptualized as an inhibitory nucleus, contains a subset of glutamatergic neurons recently mapped to innervate and excite the reticular thalamus, a higher-order non-relay region (Dunn et al, 2009).…”

Early GABAergic transmission defects in the external globus pallidus and rest/activity rhythm alteration in a mouse model of Huntington’s disease

“…The GPe projects to virtually all of the basal ganglia components, including the striatum (Mallet et al, 2012). Interestingly, direct GABAergic connections with the cortex have been recently described (Chen et al, 2015;Saunders et al, 2015). Therefore, the GPe may play an integrative role coordinating neuronal activity across the basal ganglia with direct links with the cortex.…”