Chemogenetic dissection of the primate prefronto-subcortical pathways for working memory and decision-making

Abstract

The primate prefrontal cortex (PFC) is situated at the core of higher brain functions by linking and cooperating with the caudate nucleus (CD) and mediodorsal thalamus (MD) via neural circuits. However, the distinctive roles of these prefronto-subcortical pathways remain elusive. Combining in vivo neuronal projection mapping with chemogenetic synaptic silencing, we reversibly dissected key pathways from PFC to the CD and MD individually in single monkeys. We found that silencing the bilateral PFC-MD projections, but not the PFC-CD projections, impaired performance in a spatial working memory task. Conversely, silencing the unilateral PFC-CD projection, but not the PFC-MD projection, altered preference in a free-choice task. These results revealed dissociable roles of the prefronto-subcortical pathways in working memory and decision-making, representing the technical advantage of imaging-guided pathway-selective chemogenetic manipulation for dissecting neural circuits underlying cognitive functions in primates.

Chemogenetic sensory fMRI reveals behaviorally relevant bidirectional changes in primate somatosensory network

“…In contrast to the DREADD-expressing SI D2 , sensoryevoked activity of the SI foot sole region in the same hemisphere was not attenuated following DCZ administration, but rather unexpectedly augmented as compared to the vehicle control condition (Figure 5A, bottom middle). PET analysis revealed that DREADD expression could not be detected within the SI foot sole region even at a lower threshold, where the DREADD at the axon terminal of the SI D2 neurons was observed in other cortical and subcortical regions (Figure S5B) (Nagai et al, 2020;Oyama et al, 2021). This result was histologically confirmed as well (data not shown).…”

“…To estimate the expression level of transduced DREADD in vivo, the specific binding of [ 11 C]DCZ was calculated as regional binding potential relative to nondisplaceable radioligand (BP ND ) using PMOD with an original multilinear reference tissue model (MRTMo) (Nagai et al, 2020). Since the signal in the BP ND image of [ 11 C]DCZ reflects both DREADD expression and background tracer binding (i.e., noise) (Yan et al, 2021), we removed the background noise by subtracting the BP ND value obtained with the control data of the same individual in which DREADD was not expressed (Oyama et al, 2021). The control data was obtained before AAV injection for monkey 2.…”

Chronic behavioral manipulation via orally delivered chemogenetic actuator in macaques

“…We examined the behavioral effects of two oral DCZ doses (300 and 1,000 μg/kg) and an intramuscular DCZ dose (100 μg/kg) for comparison. Consistent with previous studies [17,21], intramuscular 100 μg/kg DCZ administration resulted in a delay-dependent decrease in the task performance for 1-2 h following administration (Fig. 3c).…”

“…Three monkeys (#226, #229, and #245) were tested with a spatial delayed response task. The protocol was almost the same as of our previous study [21].…”

“…Our previous studies have shown that chemogenetic silencing of the dlPFC via intramuscular DCZ administration (100 μg/kg) in these monkeys impaired performance in the spatial delayed response task (Fig. 3b), in which spatial working memory is essentially involved [17,21]. c-e, Effects of oral administration of 300 μg/kg (orange) and 1,000 μg/kg (magenta), and intramuscular administration of 100 μg/kg (green) of DCZ on task performance.…”