Hypothalamic Control of Forelimb Motor Adaptation

Abstract

The ability to perform skilled arm movements is central to everyday life, as limb impairments in common neurologic disorders such as stroke demonstrate. Skilled arm movements require adaptation of motor commands based on discrepancies between desired and actual movements, called sensory errors. Studies in humans show that this involves predictive and reactive movement adaptations to the errors, and also requires a general motivation to move. How these distinct aspects map onto defined neural signals remains unclear, because of a shortage of equivalent studies in experimental animal models that permit neural-level insights. Therefore, we adapted robotic technology used in human studies to mice, enabling insights into the neural underpinnings of motivational, reactive, and predictive aspects of motor adaptation. Here, we show that forelimb motor adaptation is regulated by neurons previously implicated in motivation and arousal, but not in forelimb motor control: the hypothalamic orexin/hypocretin neurons (HONs). By studying goal-oriented mouse-robot interactions in male mice, we found distinct HON signals occur during forelimb movements and motor adaptation. Temporally-delimited optosilencing of these movement-associated HON signals impaired sensory error-based motor adaptation. Unexpectedly, optosilencing affected neither task reward or execution rates, nor motor performance in tasks that did not require adaptation, indicating that the temporally-defined HON signals studied here were distinct from signals governing general task engagement or sensorimotor control. Collectively, these results reveal a hypothalamic neural substrate regulating forelimb motor adaptation.

Anticipatory countering of motor challenges by premovement activation of orexin neurons

“…Predictive control of movement is important, since feedback control can be too slow to produce fast smooth movements ( 1 , 9 , 10 ). Thus, we suggest that premovement HON signals contribute to movement planning, as well as adaptation ( 11 ). Since the purpose of premovement HON activity was unknown, this advances our understanding of the role of this core, evolutionarily conserved, neural module in adaptive behavior.…”

Deep Brain Stimulation in the Subthalamic Nucleus Can Improve Skilled Forelimb Movements and Retune Dynamics of Striatal Networks in a Rat Stroke Model

“…There is some evidence that distinct areas of the hypothalamus may impact motor behavior. A previous study has demonstrated that hypothalamic orexin/hypocretin neurons localized in the lateral hypothalamus are involved in skilled movements and especially in error-based motor adaption [ 93 ]: After compromised or even lost motor task, the so-called “internal model”, understood as the entirety of cortical motor commands, uses the discrepancy between the desired and present movement trajectory to currently update motor command across attempts and thus reduces error [ 93 ]. In the present study, STN-HFS did not change glucose metabolism in the LH, however, resulted in a decrease of [ 18 F]FDG uptake in the VMH.…”

Eat, seek, rest? An orexin/hypocretin perspective

“…69,70 However, this HON activation did not seem to control the amount of food consumed, but instead facilitated movement patterns that ensured steady food supply over time. 69 Overall, since these studies suggest that HON activity promotes mobile behaviours that either increase or maintain the likelihood of food discovery or acquisition, we propose that HON activity can be viewed as a driver for appetitive behaviours. This is a distinct function from food intake, as discussed further below.…”

“…To answer this question, these movement patterns need to have a known goal. When complex, non‐locomotor movements (skilled pulling on a robotic handle using one forelimb) motivated by a food goal were recently examined, it was found that they were also associated with HON activation 69,70 . However, this HON activation did not seem to control the amount of food consumed, but instead facilitated movement patterns that ensured steady food supply over time 69 .…”

“…When complex, non‐locomotor movements (skilled pulling on a robotic handle using one forelimb) motivated by a food goal were recently examined, it was found that they were also associated with HON activation 69,70 . However, this HON activation did not seem to control the amount of food consumed, but instead facilitated movement patterns that ensured steady food supply over time 69 . Overall, since these studies suggest that HON activity promotes mobile behaviours that either increase or maintain the likelihood of food discovery or acquisition, we propose that HON activity can be viewed as a driver for appetitive behaviours.…”