Selective striatal fast-spiking interneuron inhibition induces cortical seizure.

Whether striatal fast-spiking interneurons are involved in cortical synchronization remains elusive. We performed acute microinjections of a selective FSI-AMPA receptor antagonist into the sensorimotor striatum of non-human primates to verify whether selective FSI inhibition within the sensorimotor striatum could potentially modify cortical excitability, thereby triggering focal seizures. Experiments were performed on three fascicularis monkeys. During each experimental session, low volumes of IEM-1460 (4-8 µL) were injected slowly at 1 µL/min. Spontaneous behavioral changes were classified according to the Racine scale modified for primates. These induced motor behaviors were correlated with electroencephalographic (EEG and EMG) measures. Power spectrum and time-frequency analysis were performed and compared between each period of interest. Pharmacological selective inhibition of striatal fast-spiking INs induced focal motor seizures. Back averaging confirmed that myoclonic activity was closely linked to cortical spikes-and-waves epileptic activity, with a significant increase in cortical EEG power in all studied frequency bands (p < .0001). Thus, striatal FSIs likely play a role in controlling cortical excitability through the cortico-striato-thalamo-cortical pathway. They may contribute to the pathophysiology of focal motor epilepsies by modulating the threshold at which focal motor seizures are triggered.

In vivo electrophysiological validation of DREADD-based modulation of pallidal neurons in the non-human primate.

Designer receptors exclusively activated by designer drugs (DREADDs) are widely used in rodents to manipulate neuronal activity and establish causal links between structure and function. Their utilization in non-human primates (NHPs) is, however, limited and their efficacy still debated. Here, we recorded and examined the neuronal activity in the hM4Di DREADD-transduced and hM4Di DREADD-free GPe of two anesthetized animals following local intra-GPe microinjection of clozapine-N-oxide (CNO). Our results revealed that the neuronal activity of the well-isolated units recorded in the hM4Di DREADD-transduced GPe exhibited diverse patterns in timing and polarity (increase/decrease) of firing rate modulations following CNO injection. Nevertheless, significant decreases in activity were more frequent (and more pronounced) than significant increases in activity during CNO injection (6/18 vs. 3/18 units) and were exclusive after CNO Injection (8/18 units). In contrast, only one of the 8 well-isolated units recorded in hM4Di DREADD-free GPe exhibited a significant increase in activity after CNO injection. Overall, the number of units exhibiting a significant period-related decrease following CNO injection was significantly larger in hM4Di DREADD-transduced GPe than in the hM4Di DREADD-free GPe (8/18 [44.4%] vs. 0/8 [0%]). Moreover, postmortem histochemical analysis revealed that hM4Di DREADDs were expressed at high level in the GPe neurons located in the vicinity of the viral vector injection sites. Our results therefore show in vivo hM4Di DREADD-based inhibition of pallidal neurons in the NHP model and reinforce the view that DREADD technology can be effective in NHPs.

Acute Striato-Cortical Synchronization Induces Focal Motor Seizures in Primates.

OBJECTIVE: Whether the basal ganglia are involved in the cortical synchronization during focal seizures is still an open question. In the present study, we proposed to synchronize cortico-striatal activities acutely inducing striatal disinhibition, performing GABA-antagonist injections within the putamen in primates. METHOD: Experiments were performed on three fascicularis monkeys. During each experimental session, low volumes of bicuculline (0.5-4 µL) were injected at a slow rate of 1 µL/min. Spontaneous behavioral changes were classified according to Racine's scale modified for primates. These induced motor behaviors were correlated with electromyographic, electroencephalographic, and putaminal and pallidal local field potentials changes in activity. RESULTS: acute striatal desinhibition induced focal motor seizures. Seizures were closely linked to cortical epileptic activity synchronized with a striatal paroxysmal activity. These changes in striatal activity preceded the cortical epileptic activity and the induced myoclonia, and both cortical and subcortical activities were coherently synchronized during generalized seizures. INTERPRETATION: Our results strongly suggest the role of the sensorimotor striatum in the regulation and synchronization of cortical excitability. These dramatic changes in the activity of this "gating" pathway might influence seizure susceptibility by modulating the threshold for the initiation of focal motor seizures.

Checking behavior in rhesus monkeys is related to anxiety and frontal activity.

When facing doubt, humans can go back over a performed action in order to optimize subsequent performance. The present study aimed to establish and characterize physiological doubt and checking behavior in non-human primates (NHP). We trained two rhesus monkeys (Macaca mulatta) in a newly designed "Check-or-Go" task that allows the animal to repeatedly check and change the availability of a reward before making the final decision towards obtaining that reward. By manipulating the ambiguity of a visual cue in which the reward status is embedded, we successfully modulated animal certainty and created doubt that led the animals to check. This voluntary checking behavior was further characterized by making EEG recordings and measuring correlated changes in salivary cortisol. Our data show that monkeys have the metacognitive ability to express voluntary checking behavior similar to that observed in humans, which depends on uncertainty monitoring, relates to anxiety and involves brain frontal areas.

Easy rider: monkeys learn to drive a wheelchair to navigate through a complex maze.

The neurological bases of spatial navigation are mainly investigated in rodents and seldom in primates. The few studies led on spatial navigation in both human and non-human primates are performed in virtual, not in real environments. This is mostly because of methodological difficulties inherent in conducting research on freely-moving monkeys in real world environments. There is some incertitude, however, regarding the extrapolation of rodent spatial navigation strategies to primates. Here we present an entirely new platform for investigating real spatial navigation in rhesus monkeys. We showed that monkeys can learn a pathway by using different strategies. In these experiments three monkeys learned to drive the wheelchair and to follow a specified route through a real maze. After learning the route, probe tests revealed that animals successively use three distinct navigation strategies based on i) the place of the reward, ii) the direction taken to obtain reward or iii) a cue indicating reward location. The strategy used depended of the options proposed and the duration of learning. This study reveals that monkeys, like rodents and humans, switch between different spatial navigation strategies with extended practice, implying well-conserved brain learning systems across different species. This new task with freely driving monkeys provides a good support for the electrophysiological and pharmacological investigation of spatial navigation in the real world by making possible electrophysiological and pharmacological investigations.