Skilled forelimb movements and internal copy motor circuits

Abstract

Mammalian skilled forelimb movements are remarkable in their precision, a feature that emerges from the continuous adjustment of motor output. Here we discuss recent progress in bridging the gap between theory and neural implementation in understanding the basis of forelimb motor refinement. One influential theory is that feedback from internal copy motor pathways enables fast prediction, through a forward model of the limb, an idea supported by behavioral studies that have explored how forelimb movements are corrected online and can adapt to changing conditions. In parallel, neural substrates of forelimb internal copy pathways are coming into clearer focus, in part through the use of genetically tractable animal models to isolate spinal and cerebellar circuits and explore their contributions to movement.

Figure 1. Internal copy and sensory feedback pathways for forelimb motor control

One putative model for the control of forelimb movements is an optimal feedback control scheme that incorporates internal copy feedback for forward model implementation. In this scenario, cortical and subcortical supraspinal motor centers convey feed-forward forelimb motor commands to spinal motor circuits, where these commands are further processed before modulating motor neuron (MN) activity and eliciting forelimb muscle contraction; these motor commands are subject to noise and variability. Sensory feedback from the limb conveys information about the effects of motor commands to local spinal circuits and to supraspinal sensory pathways, but is subject to peripheral and central temporal delays. To compensate for these delays, multiple motor command pathways give rise to collaterals that transmit internal copies (green arrows) to cerebellar (Cb) circuits, where they are used to generate predictions of the sensory consequences of motor commands (forward model). These forward model predictions can be combined with delayed sensory feedback to extrapolate an estimate of limb state (state estimation), a process thought to occur at least in part through communication between the cerebellum and posterior parietal cortex (PPC). State estimates are combined with an ongoing evaluation of movement cost and reward, potentially derived from basal ganglia (BG)–cortical (Ctx) pathways, to modulate motor cortex and generate motor command updates that are relevant to the current objectives of the task. In addition, by reducing the mismatch between predicted and actual movement outcome, forward models can be adapted to novel environmental conditions to refine subsequent movements [8,14,16,19].

Figure 2. Propriospinal neurons modulate forelimb movement through an internal copy feedback loop

(a) PNs receive input from descending motor command pathways. Bifurcating PN axons innervate forelimb motor neurons (MN; pre-motor branch) and the lateral reticular nucleus (LRN; internal copy branch), which projects to the cerebellum (Cb). (b) After a mechanical lesion of the PN pre-motor axon branch, cats exhibit reaching ataxia as the paw approaches a food traget located inside of a tube [65]. (c) To activate the PN internal copy branch selectively, channelrhodopsin (ChR2) was expressed in PNs via injection of conditional virus (AAV-FLEX-ChR2-YFP) into cervical spinal cord of mice that selectively express Cre recombinase in Chx10⁺ V2a interneurons (IN). Photostimulation of ChR2⁺ PN terminals in the LRN activates the PN internal copy pathway without affecting the pre-motor PN branch [69]. Motor field potential recordings, as well as intracellular motor neuron recordings (not shown), during photostimulation reveal rapid forelimb motor neuron recruitment. These effects are substantially diminished by lesioning the inferior cerebellar peduncles (ICP), which contain projections from the LRN to the cerebellum, implicating a rapid cerebellar-motor feedback loop. Photoactivation of the PN-LRN pathway disrupts reaching movements (blue traces), quantified through highresolution 3D reconstruction of mouse reaching kinematics; movements exhibited a dramatic increase in the incidence of paw direction reversals and variation in velocity and acceleration during reaching without affecting digit abduction (not shown), suggesting a selective perturbation of circuits involved in reaching behavior. (d) Schematic of putative PN pathways as they might relate to feedback control (Figure 1). A rapid subcortical PN-LRN feedback loop (green) could modulate forelimb movement by recruiting deep cerebellar nuclei (DCN), which excite reticulospinal (RS) projections to motor neurons (MN). Additional loops (brown) might engage cerebellar cortex (Cb Ctx) and cerebral cortex via thalamus (Th), where posterior parietal cortex (PPC) and motor cortex (MC) communicate bidirectionally (see text). (b) modified from [65]; (c) modified from [69].