Chemogenetic inactivation reveals the inhibitory control function of the prefronto-striatal pathway in the macaque brain

Mineki Oguchi,Kazuto Kobayashi,Xiaochuan Pan,Masamichi Sakagami,Keiko Moriya-Ito,Shingo Tanaka,Shigeki Kato,Takefumi Kikusui

doi:10.1038/s42003-021-02623-y

Abstract

The lateral prefrontal cortex (LPFC) has a strong monosynaptic connection with the caudate nucleus (CdN) of the striatum. Previous human MRI studies have suggested that this LPFC-CdN pathway plays an important role in inhibitory control and working memory. We aimed to validate the function of this pathway at a causal level by pathway-selective manipulation of neural activity in non-human primates. To this end, we trained macaque monkeys on a delayed oculomotor response task with reward asymmetry and expressed an inhibitory type of chemogenetic receptors selectively to LPFC neurons that project to the CdN. Ligand administration reduced the inhibitory control of impulsive behavior, as well as the task-related neuronal responses observed in the local field potentials from the LPFC and CdN. These results show that we successfully suppressed pathway-selective neural activity in the macaque brain, and the resulting behavioral changes suggest that the LPFC-CdN pathway is involved in inhibitory control.

Highlights

The lateral prefrontal cortex (LPFC) has a strong monosynaptic connection with the caudate nucleus (CdN) of the striatum
To selectively suppress the activity of LPFC neurons projecting to the CdN, we used inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) targeting the bilateral LPFC-CdN pathway in two macaque monkeys (Monkeys W and S)
AAV5-hSyn-DIO-hM4Di-mCherry was used as a local vector for the LPFC, and fusion glycoprotein type E (FuG-E)(NeuRet)-nls/Cre2A-enhanced green fluorescent protein (eGFP) was used as a retrograde vector for the CdN (Fig. 1a)

Summary

Introduction

The lateral prefrontal cortex (LPFC) has a strong monosynaptic connection with the caudate nucleus (CdN) of the striatum. We aimed to validate the function of this pathway at a causal level by pathway-selective manipulation of neural activity in non-human primates To this end, we trained macaque monkeys on a delayed oculomotor response task with reward asymmetry and expressed an inhibitory type of chemogenetic receptors selectively to LPFC neurons that project to the CdN. In order to better understand the function of the LPFC-CdN pathway, it is necessary to study non-human primate models, especially macaque monkeys, using techniques that selectively regulate neural activity of a specific pathway Such physiological investigations to elucidate circuit function at a causal level have not been carried out until very recently due to the lack of appropriate technology applicable to the macaque brain. This study achieves the successful regulation of neural activity using pathwayselective chemogenetic suppression in the macaque prefrontal network and reports changes both in behavior and neural activity, representing an important step forward in elucidating various neural circuit functions using non-human primates

Objectives

Methods

Results

Conclusion