Dimitri Ryczko

The activity of neurotransmitter-based cell types in the cuneiform and pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation is not fully understood. Using fiber photometry in mice, we found cell-type specific responses to sensory stimuli. Glutamatergic and GABAergic cells responded to sound, visual looming, and air puffs, except for pedunculopontine GABAergic cells, which did not respond to visual looming. Cholinergic cells responded to air puffs. Air puffs triggered high-speed locomotion, whereas visual looming and sound stimuli evoked low-speed locomotion. During air puff–evoked locomotion, cuneiform glutamatergic neuron activity was higher than in trials without locomotion. In contrast, during locomotion evoked by visual looming or sound, activity in pedunculopontine glutamatergic neurons was higher than when no locomotion occurred. In the open-field arena, mice exhibited spontaneous low-speed locomotion during which activity increased in pedunculopontine glutamatergic cells. Activity also increased in a cell type-specific manner during grooming or rearing. Our study shows cell type-specific activity in the cuneiform or pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation. Sensory responsiveness likely has relevance in Parkinson’s disease, where sensory circuits are increasingly targeted to improve walking.

The activity of neurotransmitter-based cell types in the cuneiform and pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation is not fully understood. Using fiber photometry in mice, we found cell-type specific responses to sensory stimuli. Glutamatergic and GABAergic cells responded to sound, visual looming, and air puffs, except for pedunculopontine GABAergic cells, which did not respond to visual looming. Cholinergic cells responded to air puffs. When a stimulus triggered high-speed locomotion, activity increased in cuneiform glutamatergic neurons. Conversely, when low-speed locomotion was triggered, activity increased in pedunculopontine glutamatergic neurons. During spontaneous low-speed locomotion, activity increased in pedunculopontine glutamatergic cells. Activity also increased in a cell type-specific manner during grooming or rearing. Our study shows cell type-specific activity in the cuneiform or pedunculopontine nuclei during locomotion, non-locomotor behaviors, and following sensory stimulation. Sensory responsiveness likely has relevance in Parkinson’s disease, where sensory circuits are increasingly targeted to improve walking.

This study introduces a novel neuromechanical model employing a detailed spiking neural network to explore the role of axial proprioceptive sensory feedback in salamander locomotion. Unlike previous studies that often oversimplified the dynamics of the locomotor networks, our model includes detailed simulations of the classes of neurons that are considered responsible for generating movement patterns. The locomotor circuits, modeled as a spiking neural network of adaptive leaky integrate-and-fire neurons, are coupled to a three-dimensional mechanical model of a salamander with realistic physical parameters and simulated muscles. In open-loop simulations (i.e., without sensory feedback) the model accurately replicates locomotor patterns observed in-vitro and in-vivo for swimming and trotting gaits. Additionally, a modular architecture of the descending reticulospinal (RS) drive to the central pattern generation (CPG) network, allows to accurately control the activation, frequency and phase relationship of the different sections of the limb and axial circuits. In closed-loop simulations (i.e. with the inclusion of axial proprioceptive sensory feedback), systematic evaluations reveal that intermediate values of feedback strength significantly enhance the locomotor efficiency and robustness to disturbances during swimming. Specifically, our results show that sensory feedback increases the tail beat frequency and reduces the intersegmental phase lag, contributing to more coordinated and faster movement patterns. Moreover, the presence of feedback expanded the stability region of the closed-loop swimming network, enhancing tolerance to a wider range of external stimulations, internal parameters’ modulation and noise levels. This study provides new insights into the complex interplay between central and peripheral pattern generation mechanisms, offering potential strategies for developing advanced biomimetic robots. Additionally, this study underscores the critical role of detailed, biologically-realistic neural networks to improve our understanding of vertebrate locomotion. Author summary In this paper, we developed a computational model to investigate how salamanders move, both while swimming and walking. Unlike previous studies that often oversimplified the dynamics of these complex neural networks, our model includes detailed simulations of the classes of neurons that are considered responsible for generating movement patterns. The locomotor circuits, modeled as a spiking neural network, are coupled to a three-dimensional mechanical model of a salamander with realistic physical parameters and simulated muscles. The neural model integrates axial proprioceptive sensory feedback from the body’s movements to modulate the locomotor gaits. Our simulations suggest that this sensory feedback plays a major role in controlling the rhythm and coordination of movements. This has implications for understanding not only how salamanders move but also provides insights into the evolution of locomotion in vertebrates. By investigating how central and sensory mechanisms interact to produce efficient and adaptable movement, our work contributes to the broader field of neuroscience and robotics, offering potential strategies for designing more effective biomimetic robots.

The ability to generate and control locomotor movements depends on complex interactions between many areas of the nervous system, the musculoskeletal system, and the environment. How the nervous system manages to accomplish this task has been the subject of investigation for more than a century. In vertebrates, locomotion is generated by neural networks located in the spinal cord referred to as central pattern generators. Descending inputs from the brain stem initiate, maintain, and stop locomotion as well as control speed and direction. Sensory inputs adapt locomotor programs to the environmental conditions. This review presents a comparative and historical overview of some of the neural mechanisms underlying the control of locomotion in vertebrates. We have put an emphasis on spinal mechanisms and descending control.

The mesencephalic locomotor region (MLR) controls locomotion in vertebrates. In humans with Parkinson disease, locomotor deficits are increasingly associated with decreased activity in the MLR. This brainstem region, commonly considered to include the cuneiform and pedunculopontine nuclei, has been explored as a target for deep brain stimulation to improve locomotor function, but the results are variable, from modest to promising. However, the MLR is a heterogeneous structure, and identification of the best cell type to target is only beginning. Here, I review the studies that uncovered the role of genetically defined MLR cell types, and I highlight the cells whose activation improves locomotor function in animal models of Parkinson disease. The promising cell types to activate comprise some glutamatergic neurons in the cuneiform and caudal pedunculopontine nuclei, as well as some cholinergic neurons of the pedunculopontine nucleus. Activation of MLR GABAergic neurons should be avoided, since they stop locomotion or evoke bouts flanked with numerous stops. MLR is also considered a potential target in spinal cord injury, supranuclear palsy, primary progressive freezing of gait, or stroke. Better targeting of the MLR cell types should be achieved through optimized deep brain stimulation protocols, pharmacotherapy, or the development of optogenetics for human use.

The transformation of visual input into motor output is essential to approach a target or avoid a predator. In salamanders, visually guided orientation behaviors have been extensively studied during prey capture. However, the neural circuitry involved is not resolved. Using salamander brain preparations, calcium imaging and tracing experiments, we describe a neural substrate through which retinal input is transformed into spinal motor output. We found that retina stimulation evoked responses in reticulospinal neurons of the middle reticular nucleus, known to control steering movements in salamanders. Microinjection of glutamatergic antagonists in the optic tectum (superior colliculus in mammals) decreased the reticulospinal responses. Using tracing, we found that retina projected to the dorsal layers of the contralateral tectum, where the dendrites of neurons projecting to the middle reticular nucleus were located. In slices, stimulation of the tectal dorsal layers evoked glutamatergic responses in deep tectal neurons retrogradely labeled from the middle reticular nucleus. We then examined how tectum activation translated into spinal motor output. Tectum stimulation evoked motoneuronal responses, which were decreased by microinjections of glutamatergic antagonists in the contralateral middle reticular nucleus. Reticulospinal fibers anterogradely labeled from tracer injection in the middle reticular nucleus were preferentially distributed in proximity with the dendrites of ipsilateral motoneurons. Our work establishes a neural substrate linking visual and motor centers in salamanders. This retino‐tecto‐reticulo‐spinal circuitry is well positioned to control orienting behaviors. Our study bridges the gap between the behavioral studies and the neural mechanisms involved in the transformation of visual input into motor output in salamanders.

A bstract: The transformation of visual input into motor output is essential to approach a target or avoid a predator. In salamanders, visually-guided orientation behaviors have been extensively studied during prey capture. However, the neural circuitry involved is not resolved. Using salamander brain preparations, calcium imaging and tracing experiments, we describe a neural substrate through which retinal input is transformed into spinal motor output. We found that retina stimulation evoked responses in reticulospinal neurons of the middle reticular nucleus, known to control steering movements in salamanders. Microinjection of glutamatergic antagonists in the optic tectum (superior colliculus in mammals) decreased the reticulospinal responses. Using tracing we found that retina projected to the dorsal layers of the contralateral tectum, where the dendrites of neurons projecting to the middle reticular nucleus were located. In slices, stimulation of the tectal dorsal layers evoked glutamatergic responses in deep tectal neurons retrogradely labelled from the middle reticular nucleus. We then examined how tectum activation translated into spinal motor output. Tectum stimulation evoked motoneuronal responses, which were decreased by microinjections of glutamatergic antagonists in the contralateral middle reticular nucleus. Reticulospinal fibers anterogradely labelled from tracer injection in the middle reticular nucleus were preferentially distributed in proximity with the dendrites of ipsilateral motoneurons. Our work establishes a neural substrate linking visual and motor centers in salamanders. This retino-tecto-reticulo-spinal circuitry is well positioned to control orienting behaviors. Our study bridges the gap between the behavioral studies and the neural mechanisms involved in the transformation of visual input into motor output in salamanders.

Significance: In Parkinson’s disease, alleviating locomotor deficits is a challenge. Clinicians are exploring the deep brain stimulation of the mesencephalic locomotor region, a brainstem region controlling locomotion, but results are mixed. However, the best target in this region in Parkinson’s disease remains unknown. Indeed, this region, which comprises the pedunculopontine and cuneiform nuclei, contains different cell types with opposing effects on locomotor output. Here, using mice in which midbrain dopaminergic cells were damaged by a neurotoxin, we demonstrate that optogenetic activation of glutamatergic neurons in the cuneiform nucleus increases locomotion, controls speed, and evokes limb movements similar to those observed during spontaneous locomotion in intact animals. Our study identifies a potentially clinically relevant target to improve locomotor function in Parkinson’s disease.