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

Background: Virally-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). Methods: Resting-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. Results: Neither 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. Conclusions: These 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.

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Cortical silencing results in paradoxical fMRI overconnectivity

10.1101/2020.08.05.237958 ◽

2020 ◽

Cited By ~ 2

Author(s):

Carola Canella ◽

Federico Rocchi ◽

Shahryar Noei ◽

Daniel Gutierrez-Barragan ◽

Ludovico Coletta ◽

...

Keyword(s):

Prefrontal Cortex ◽

Functional Connectivity ◽

Resting State ◽

Resting State Fmri ◽

Gamma Activity ◽

Functional Coupling ◽

Cortical Region ◽

Delta Band ◽

Slow Rhythm

ABSTRACTfMRI-based measurements of functional connectivity are commonly interpreted as an index of anatomical coupling and direct interareal communication. However, causal testing of this hypothesis has been lacking. Here we combine neural silencing, resting-state fMRI and in vivo electrophysiology to causally probe how inactivation of a cortical region affects brain-wide functional coupling. We find that chronic silencing of the prefrontal cortex (PFC) via overexpression of a potassium channel paradoxically increases rsfMRI connectivity between the silenced area and its thalamo-cortical terminals. Acute chemogenetic silencing of the PFC reproduces analogous patterns of overconnectivity, an effect associated with over-synchronous fMRI coupling between polymodal thalamic regions and widespread cortical districts. Notably, multielectrode recordings revealed that chemogenetic inactivation of the PFC attenuates gamma activity and increases delta power in the silenced area, resulting in robustly increased delta band coherence between functionally overconnected regions. The observation of enhanced rsfMRI coupling between chemogenetically silenced areas challenges prevailing interpretations of functional connectivity as a monotonic index of direct axonal communication, and points at a critical contribution of slow rhythm generators to the establishment of brain-wide functional coupling.

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Changes in visual and sensory-motor resting-state functional connectivity support motor learning by observing

Journal of Neurophysiology ◽

10.1152/jn.00286.2015 ◽

2015 ◽

Vol 114 (1) ◽

pp. 677-688 ◽

Cited By ~ 20

Author(s):

Heather R. McGregor ◽

Paul L. Gribble

Keyword(s):

Functional Connectivity ◽

Motor Learning ◽

Resting State ◽

Action Observation ◽

Resting State Fmri ◽

Learning Task ◽

Brain Regions ◽

Neural Systems ◽

Resting State Functional Connectivity ◽

Somatosensory Cortices

Motor learning occurs not only through direct first-hand experience but also through observation (Mattar AA, Gribble PL. Neuron 46: 153–160, 2005). When observing the actions of others, we activate many of the same brain regions involved in performing those actions ourselves (Malfait N, Valyear KF, Culham JC, Anton JL, Brown LE, Gribble PL. J Cogn Neurosci 22: 1493–1503, 2010). Links between neural systems for vision and action have been reported in neurophysiological (Strafella AP, Paus T. Neuroreport 11: 2289–2292, 2000; Watkins KE, Strafella AP, Paus T. Neuropsychologia 41: 989–994, 2003), brain imaging (Buccino G, Binkofski F, Fink GR, Fadiga L, Fogassi L, Gallese V, Seitz RJ, Zilles K, Rizzolatti G, Freund HJ. Eur J Neurosci 13: 400–404, 2001; Iacoboni M, Woods RP, Brass M, Bekkering H, Mazziotta JC, Rizzolatti G. Science 286: 2526–2528, 1999), and eye tracking (Flanagan JR, Johansson RS. Nature 424: 769–771, 2003) studies. Here we used a force field learning paradigm coupled with resting-state fMRI to investigate the brain areas involved in motor learning by observing. We examined changes in resting-state functional connectivity (FC) after an observational learning task and found a network consisting of V5/MT, cerebellum, and primary motor and somatosensory cortices in which changes in FC were correlated with the amount of motor learning achieved through observation, as assessed behaviorally after resting-state fMRI scans. The observed FC changes in this network are not due to visual attention to motion or observation of movement errors but rather are specifically linked to motor learning. These results support the idea that brain networks linking action observation and motor control also facilitate motor learning.

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