Fujimoto, S. H. | Search bioRxiv

bioRxiv2023

The neural basis of resting-state fMRI functional connectivity in fronto-limbic circuits revealed by chemogenetic manipulation

Measures of fMRI resting-state functional connectivity (rs-FC) are an essential tool for basic and clinical investigations of fronto-limbic circuits. Understanding the relationship between rs-FC and neural activity in these circuits is therefore vital. Here we introduced inhibitory designer receptors exclusively activated by designer drugs (DREADDs) into the macaque amygdala and activated them with a highly selective and potent DREADD agonist, deschloroclozapine. We evaluated the causal effect of activating the DREADD receptors on rs-FC and neural activity within circuits connecting amygdala and frontal cortex. Interestingly, activating the inhibitory DREADD increased rs-FC between amygdala and ventrolateral prefrontal cortex. Neurophysiological recordings revealed that the DREADD-induced increase in fMRI rs-FC was associated with increased local field potential coherency in the alpha band (6.5-14.5Hz) between amygdala and ventrolateral prefrontal cortex. Thus, our multi-disciplinary approach reveals the specific signature of neuronal activity that underlies rs-FC in fronto-limbic circuits.

neuroscience↗

bioRxiv2021

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

Chemogenetic techniques such as Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) enable transient, reversible, and minimally invasive manipulation of neural activity in vivo. Their development in non-human primates is essential for uncovering neural circuits contributing to cognitive functions and their translation to humans. One key issue that has delayed the development of chemogenetic techniques in primates is the lack of an accessible drug-screening method. Here, we utilize resting-state functional MRI (rs-fMRI), a non-invasive neuroimaging tool, to assess the impact of deschloroclozapine (DCZ) on brain-wide resting-state functional connectivity in seven rhesus macaques without DREADDs. We found that systemic administration of 0.1 mg/kg DCZ did not alter the resting-state functional connectivity. Conversely, 0.3 mg/kg of DCZ was associated with a prominent increase in functional connectivity that was mainly confined to the connections of frontal regions. Additional behavioral tests confirmed a negligible impact of 0.1 mg/kg DCZ on socio-emotional behaviors as well as on reaction time in a probabilistic learning task. 0.3 mg/kg DCZ did, however, slow responses in the probabilistic learning task, suggesting attentional or motivational deficits associated with hyperconnectivity in fronto-temporo-parietal networks. Our study highlights both the excellent selectivity of DCZ as a DREADD actuator, and the side-effects of its excess dosage. The results demonstrate the translational value of rs-fMRI as a drug-screening tool to accelerate the development of chemogenetics in primates.

neuroscience↗