Resting-state fMRI-based screening of deschloroclozapine in rhesus macaques predicts dosage-dependent behavioral effects

Abstract

BackgroundVirally-mediated chemogenetic techniques hold the promise of circuit-specific neuromodulation for human brain disorders. Their protracted development in primates and issues related to the specificity of the actuator drugs has significantly slowed their implementation. Here we took a multi-disciplinary approach to assessing the translational appropriateness of a newly identified actuator drug, deschloroclozapine (DCZ).MethodsResting-state functional MRI (rs-fMRI) data was acquired from seven rhesus macaques (6 males and 1 female) after administration of either vehicle, 0.1 or 0.3 mg/kg DCZ, the latter of which produce 80% and near 100% chemogenetic receptor occupancy, respectively. Seed-based comparative-connectome analysis and independent component analysis assessed dose dependent neural impact. Two subsets of subjects were tested on socio-emotional tasks (N = 4), and a probabilistic learning task (N = 3), assessing DCZ’s impact on unconditioned and conditioned affective responses, respectively.ResultsNeither vehicle nor 0.1 mg/kg DCZ changed overall functional connectivity, affective responses, or reaction times in the learning task. 0.3 mg/kg DCZ increased functional connectivity, particularly in frontal regions, and increased reaction times in the learning task. Notably, there was a positive correlation between changes in overall functional connectivity and reaction time.ConclusionsThese experiments show the utility of rs-fMRI for in-vivo drug screening and benchmarking. We found that low dose DCZ does not alter brain function or affective behavior. However, higher doses of DCZ impacts frontal connectivity and is associated with deficits in task execution. Implementation of these methods will accelerate the development of chemogenetic in primates for research and therapeutic approaches.

High-throughput sequencing of macaque basolateral amygdala projections reveals dissociable connectional motifs with frontal cortex

“…If such patterns were identifiable in FC this would indicate that the unique anatomical networks identified with MAPseq are related to and in fact shape functional networks in the brain. We analyzed a dataset of resting state fMRI scans from six rhesus monkeys 41 ( Figure 5A ), with single seed voxels in amygdala and target voxels in the same areas used in the MAPseq experiments (Extended Data Figure 6). After computing and z-transforming FC values for each amygdala voxel with each target voxel, we binarized the FC signal by setting a threshold at 70% of each voxels’ maximum connectivity.…”

“…Functional connectivity analyses were conducted on a previously published resting-state functional MRI dataset 41 . We re-analyzed a subset of the scans, including data from 6 rhesus macaques (5 males), focusing only on the control and pre-injection scans.…”