CE37 - Neurosciences intégratives et cognitives

New Roles of the External Globus Pallidus in Decision-Making Neural Networks: Function and Dysfunction – Demake

Submission summary

Basal ganglia (BG) are a set of interconnected subcortical nuclei involved in decision-making and their malfunction is responsible for decision-making deficits observed in patients suffering from Parkinson’s disease (PD). The external globus pallidus (GPe) is a major component of the BG circuitry and crucial in the orchestration of BG activity and in BG information processing. However, the neural mechanisms and computations of decision-making in the BG network are still elusive and do not satisfactorily reflect the neuronal complexity and heterogeneity of the GPe. Indeed, GPe can be divided into ventral and dorsal GPe (VP and DP, respectively) and very little is known about how these two distinct pallidal regions integrate motor, cognitive and limbic information required during decision-making processes in healthy and pathological (i.e., parkinsonian) states. Moreover, despite no debate regarding the existence of different (at least two) neuronal populations in the GPe, we do not know yet whether this dichotomous organization is held in the different pallidal regions of the GPe and what is the distinct physiological actions of the different neuronal populations of the GPe.
To fill this gap, we propose to i) untangle the neural mechanisms underlying decision-making in the ventral and dorsal regions of the GPe, ii) characterize their dysfunction in parkinsonism and iii) identify the consequences on decision-making capabilities. First, we will induce transient and reversible chemogenetic (DREADD-based) inactivation in both the VP and DP of monkeys making choices and dissect the consequences on monkey’s decision-making capabilities. Secondly, we will record and examine the spontaneous and event-related activity in the two pallidal regions of the behaving monkeys before and after induction of parkinsonism with MPTP toxin. Using such multidisciplinary approach combining a large range of methods from behavior to chemogenetics, electrophysiology, pharmacology and immunohistochemistry, we will determine the causal contribution of the VP and DP in decision-making and shed light on the role of the neuronal heterogeneity of the GPe. Moreover, we will uncover how the VP and DP neurons encode (in term of discharge rate, pattern and neuronal synchronization) the motor, cognitive and limbic information required during decision-making. Finally, we will characterize the pathological parkinsonism-related mechanisms that emerge in both the VP and DP and correlate them with specific decision-making deficits.
The proposed research will decipher the neural mechanisms and computations in the VP and DP during decision-making and will force us to revise the role of the GPe in the decision-making neural networks. Moreover, it will allow us to gain a better understanding of the consequences of BG dysfunction in PD on decision-making capabilities and will identify PD biomarkers that are related to decision-making deficits. Importantly, the unique value of the non-human primate model in translational research will help to translate our results to human. Therefore, this project will provide new insight into BG physiology and pathophysiology that will be extremely useful for the development of innovative therapeutic approaches aiming at restoring normal BG functioning in order to alleviate both the motor and non-motor (e.g., decision-making deficits) parkinsonian symptoms while minimizing the emergence of side-effects.

Project coordination

Marc DEFFAINS (Institut des Maladies Neurodégénératives)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IMN Institut des Maladies Neurodégénératives

Help of the ANR 353,039 euros
Beginning and duration of the scientific project: November 2021 - 48 Months

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