Genetic dissection of the circuit for hand dexterity in primates

A new double-infection technique with viral vectors is used to interrupt transmission through the propriospinal neurons (PNs) in macaque monkeys, and this is found to impair reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Primate neural circuits within grasp Direct connections between the motor cortex — the part of the brain that controls movement — and neurons in the spine are required for dexterous hand movement in primates. Here, Tadashi Isa and colleagues establish a role for a conserved, 'evolutionarily older' indirect pathway involving spinal interneurons in hand dexterity in higher primates. The technique used in this study, involving pathway-selective and reversible blockade of synaptic transmission by double infection of viral vectors controlling the expression of GFP-tagged tetanus neurotoxin, should be generally applicable for dissecting circuit function in primates. It is generally accepted that the direct connection from the motor cortex to spinal motor neurons is responsible for dexterous hand movements in primates 1 , 2 , 3 . However, the role of the ‘phylogenetically older’ indirect pathways from the motor cortex to motor neurons, mediated by spinal interneurons, remains elusive. Here we used a novel double-infection technique to interrupt the transmission through the propriospinal neurons (PNs) 4 , 5 , 6 , which act as a relay of the indirect pathway in macaque monkeys ( Macaca fuscata and Macaca mulatta ). The PNs were double infected by injection of a highly efficient retrograde gene-transfer vector into their target area and subsequent injection of adeno-associated viral vector at the location of cell somata. This method enabled reversible expression of green fluorescent protein (GFP)-tagged tetanus neurotoxin, thereby permitting the selective and temporal blockade of the motor cortex–PN–motor neuron pathway. This treatment impaired reach and grasp movements, revealing a critical role for the PN-mediated pathway in the control of hand dexterity. Anti-GFP immunohistochemistry visualized the cell bodies and axonal trajectories of the blocked PNs, which confirmed their anatomical connection to motor neurons. This pathway-selective and reversible technique for blocking neural transmission does not depend on cell-specific promoters or transgenic techniques, and is a new and powerful tool for functional dissection in system-level neuroscience studies.