Spontaneous pauses in firing of external pallidum neurons are associated with exploratory behavior.

Spontaneous pauses in firing are the hallmark of external pallidum (GPe) neurons. However, the role of GPe pauses in the basal ganglia network remains unknown. Pupil size and saccadic eye movements have been linked to attention and exploration. Here, we recorded GPe spiking activity and the corresponding pupil sizes and eye positions in non-human primates. We show that pauses, rather than the GPe discharge rate per se, were associated with dilated pupils. In addition, following pause initiation there was a considerable increase in the rate of spontaneous saccades. These results suggest that pauses are a powerful mechanism by which the GPe may influence basal ganglia downstream structures and play a role in exploratory behavior.

Longer ß oscillatory episodes reliably identify pathological subthalamic activity in Parkinsonism.

BACKGROUND: The efficacy of deep brain stimulation (DBS) - primarily of the subthalamic nucleus (STN) - for advanced Parkinson's disease (PD) is commonly attributed to the suppression of pathological synchronous ß oscillations along the cortico-thalamo-basal ganglia network. Conventional continuous high-frequency DBS indiscriminately influences pathological and normal neural activity. The DBS protocol would therefore be more effective if stimulation was only applied when necessary (closed-loop adaptive DBS). OBJECTIVES AND METHODS: Our study aimed to identify a reliable biomarker of the pathological neuronal activity in parkinsonism that could be used as a trigger for adaptive DBS. To this end, we examined the oscillatory features of paired spiking activities recorded in three distinct nodes of the basal ganglia network of 2 African green monkeys before and after induction of parkinsonism (by MPTP intoxication). RESULTS: Parkinsonism-related basal ganglia ß oscillations consisted of synchronized time-limited episodes, rather than a continuous stretch, of ß oscillatory activity. Episodic basal ganglia ß oscillatory activity, although prolonged in parkinsonism, was not necessarily pathological given that short ß episodes could also be detected in the healthy state. Importantly, prolongation of the basal ganglia ß episodes was more pronounced than their intensification in the parkinsonian state-especially in the STN. Hence, deletion of longer ß episodes was more effective than deletion of stronger ß episodes in reducing parkinsonian STN synchronized oscillatory activity. CONCLUSIONS: Prolonged STN ß episodes are pathological in parkinsonism and can be used as optimal trigger for future adaptive DBS applications. © 2018 International Parkinson and Movement Disorder Society.

Subthalamic, not striatal, activity correlates with basal ganglia downstream activity in normal and parkinsonian monkeys.

The striatum and the subthalamic nucleus (STN) constitute the input stage of the basal ganglia (BG) network and together innervate BG downstream structures using GABA and glutamate, respectively. Comparison of the neuronal activity in BG input and downstream structures reveals that subthalamic, not striatal, activity fluctuations correlate with modulations in the increase/decrease discharge balance of BG downstream neurons during temporal discounting classical condition task. After induction of parkinsonism with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), abnormal low beta (8-15 Hz) spiking and local field potential (LFP) oscillations resonate across the BG network. Nevertheless, LFP beta oscillations entrain spiking activity of STN, striatal cholinergic interneurons and BG downstream structures, but do not entrain spiking activity of striatal projection neurons. Our results highlight the pivotal role of STN divergent projections in BG physiology and pathophysiology and may explain why STN is such an effective site for invasive treatment of advanced Parkinson's disease and other BG-related disorders.

mGluR4-containing corticostriatal terminals: synaptic interactions with direct and indirect pathway neurons in mice.

Glutamatergic afferents from the cerebral cortex are the main excitatory drive of striatal projection neurons. The metabotropic glutamate receptor 4 (mGluR4) presynaptically modulates transmission at corticostriatal synapses, and is considered as a potent drug target for Parkinson's disease and other brain disorders. To better characterize the anatomical substrate that underlies the functional effects of mGluR4 in the striatum, we undertook electron microscopic localization studies of mGluR4 expression in the mouse striatum. Our data demonstrate that more than 80 % mGluR4-immunoreactive structures are accounted for by unmyelinated axons and axon terminals, and that almost 50 % putative glutamatergic terminals (i.e. forming asymmetric synapses) express mGluR4 in the mouse striatum. Using vGluT1 as a presynaptic marker of glutamatergic corticostriatal boutons, our findings indicate: (1) all striatal mGluR4-positive terminals co-express vGluT1 immunoreactivity, (2) 44.3 % total striatal glutamatergic terminals co-express vGluT1 and mGluR4, and (3) mGluR4 is expressed in 73.4 % of total striatal vGluT1-positive terminals. To determine if mGluR4 terminals target preferentially direct vs. indirect pathway neurons, mGluR4 immunostaining was combined with D1 receptor immunoreactivity. These data showed that around 30 % mGluR4-immunoreactive glutamatergic terminals target D1 receptor-positive spines (i.e. direct pathway neurons), while almost 70 % formed synapses with D1 receptor-negative spines (i.e. putative indirect pathway neurons). Thus, these immuno-electron microscopic studies suggest that pre-synaptic mGluR4 in striatal glutamatergic terminals is expressed almost exclusively in cortical boutons to subserve regulatory influences upon a large contingent of corticostriatal terminals that preferentially target putative "indirect" pathway striatal projection neurons in mice. These observations provide a rationale for the use of mGluR4 allosteric potentiator as a potential therapy in Parkinson's disease.

Stop and Think about Basal Ganglia Functional Organization: The Pallido-Striatal "Stop" Route.

The "arkypallidal" neurons of the globus pallidus (external segment) emit feedback GABAergic projections to the striatum. In this issue of Neuron, Mallet et al. (2016) show that "arkypallidal" neurons provide a Stop signal, suppressing the development of Go-related striatal activity.

Bridging the undergraduate curriculum using an integrated course-embedded undergraduate research experience (ICURE).

The traditional undergraduate program of study incorporates a selection of classes that represent a broad spectrum of subdisciplines. Unfortunately, few curricula successfully integrate concepts in all subdisciplines, giving undergraduates the misconception that there is a lack of application or connectedness between class subjects. An integrated course-embedded research experience (ICURE) was initiated to redress this problem by bridging classes within one discipline in an effort to engage undergraduates in a long-term analysis of biodiversity. The approach was both inclusive and longitudinal: 1) the ICURE bridge brought students from different classes and levels of instruction together with faculty members in a research project with a common goal-chronicling the changing face of the local environment in biological terms; and 2) research data collected were maintained and supplemented each semester and year in an online biodiversity database. Analysis of content and attitudinal gains suggested the integrated research protocol increased student comprehension and confidence. Results are discussed in terms of future amendments to instructional design and potential research applications. Though this program was concentrated on one discipline, there is no reason to assume other disciplines could not take advantage of similar research connections.