Dovero, S. | Search bioRxiv

bioRxiv2020

In vivo electrophysiological validation of DREADD-based inhibition 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 tested DREADD expression in the NHP external globus pallidus (GPe) and electrophysiologically validated DREADD-based inhibition of GPe neurons in the anesthetized monkey.To do so, we performed intracerebral injections of viral construct expressing hM4Di receptor under a neuron-specific promoter into the GPe. Then, we recorded the neuronal activity in the DREADD-transduced (test condition) and DREADD-free (control condition) GPe of two anesthetized animals following local intra-GPe microinjection of clozapine-N-oxide (CNO). In total, 19 and 8 well-isolated and stable units were recorded in the DREADD-transduced and DREADD-free GPe, respectively. Overall, we found that almost half (9/19) of the units modulated their activity following CNO injection in DREADD-transduced GPe. Surprisingly, neuronal activity of the GPe units exhibited diverse patterns in timing and polarity (increase/decrease) of firing rate modulations during and after CNO injection. Nevertheless, decreases were exclusive and stronger after CNO injection. In contrast, only one unit modulated its activity after CNO injection in DREADD-free GPe. Moreover, post-mortem histochemical analysis revealed that hM4Di DREADDs were expressed at high level in the GPe neurons located in the vicinity of the viral construct injection sites. Our results therefore show in vivo DREADD-based inhibition of pallidal neurons in the NHP model and reinforce the view that DREADD technology can be effective in NHPs.

neuroscience↗

bioRxiv2019

Identification of distinct pathological signatures induced by patient-derived α-synuclein structures in non-human primates

AO_SCPLOWBSTRACTC_SCPLOWDopaminergic neuronal cell death, associated with intracellular -synuclein (-syn)-rich protein aggregates (termed Lewy bodies), is a well-established characteristic of Parkinsons disease. Much evidence, accumulated from multiple experimental models has suggested that -syn plays a role in PD pathogenesis, not only as a trigger of pathology but also as a mediator of disease progression through pathological spreading. Here we have used a machine learning-based approach to identify unique signatures of neurodegeneration in monkeys induced by distinct -syn pathogenic structures derived from PD patients. Unexpectedly, our results show that, in non-human primates, a small amount of singular -syn aggregates is as toxic as larger amyloid fibrils present in the LBs, thus reinforcing the need for preclinical research in this species. Furthermore, our results provide evidence supporting the true multifactorial nature of PD as multiple causes can induce similar outcome regarding dopaminergic neurodegeneration.

neuroscience↗