Multimodal sensory control of motor performance by glycinergic interneurons of the mouse spinal cord deep dorsal horn.

Sensory feedback is integral for contextually appropriate motor output, yet the neural circuits responsible remain elusive. Here, we pinpoint the medial deep dorsal horn of the mouse spinal cord as a convergence point for proprioceptive and cutaneous input. Within this region, we identify a population of tonically active glycinergic inhibitory neurons expressing parvalbumin. Using anatomy and electrophysiology, we demonstrate that deep dorsal horn parvalbumin-expressing interneuron (dPV) activity is shaped by convergent proprioceptive, cutaneous, and descending input. Selectively targeting spinal dPVs, we reveal their widespread ipsilateral inhibition onto pre-motor and motor networks and demonstrate their role in gating sensory-evoked muscle activity using electromyography (EMG) recordings. dPV ablation altered limb kinematics and step-cycle timing during treadmill locomotion and reduced the transitions between sub-movements during spontaneous behavior. These findings reveal a circuit basis by which sensory convergence onto dorsal horn inhibitory neurons modulates motor output to facilitate smooth movement and context-appropriate transitions.

Measuring the burden of cystic fibrosis: A scoping review.

BACKGROUND: Cystic fibrosis (CF) contributes a significant economic burden on individuals, healthcare systems, and society. Understanding the economic impact of CF is crucial for planning resource allocation. METHODS: We conducted a scoping review of literature published between 1990 and 2022 that reported the cost of illness, and/or economic burden of CF. Costs were adjusted for inflation and reported as United States dollars. RESULTS: A total of 39 studies were included. Direct healthcare costs (e.g., medications, inpatient and outpatient care) were the most frequently reported. Most studies estimated the cost of CF using a prevalence-based (n = 18, 46.2 %), bottom-up approach (n = 23, 59 %). Direct non-healthcare costs and indirect costs were seldom included. The most frequently reported direct cost components were medications (n = 34, 87.2 %), inpatient care (n = 33, 84.6 %), and outpatient care (n = 31, 79.5 %). Twenty-eight percent (n = 11) of studies reported the burden of CF from all three perspectives (healthcare system (payer), individual, and society). Indirect costs of CF were reported in approximately 20 % of studies (n = 8). The reported total cost of CF varied widely, ranging from $451 to $160,000 per person per year (2022 US$). The total cost depended on the number of domains and perspectives included in each study. CONCLUSIONS: Most studies only reported costs to the healthcare system (i.e., hospitalizations and healthcare encounters) which likely underestimates the total costs of CF. The wide range of costs reported highlights the importance of standardizing perspectives, domains and costs when estimating the economic burden of CF.

Distinct roles of spinal commissural interneurons in transmission of contralateral sensory information.

Crossed reflexes are mediated by commissural pathways transmitting sensory information to the contralateral side of the body, but the underlying network is not fully understood. Commissural pathways coordinating the activities of spinal locomotor circuits during locomotion have been characterized in mice, but their relationship to crossed reflexes is unknown. We show the involvement of two genetically distinct groups of commissural interneurons (CINs) described in mice, V0 and V3 CINs, in the crossed reflex pathways. Our data suggest that the exclusively excitatory V3 CINs are directly involved in the excitatory crossed reflexes and show that they are essential for the inhibitory crossed reflexes. In contrast, the V0 CINs, a population that includes excitatory and inhibitory CINs, are not directly involved in excitatory or inhibitory crossed reflexes but downregulate the inhibitory crossed reflexes. Our data provide insights into the spinal circuitry underlying crossed reflexes in mice, describing the roles of V0 and V3 CINs in crossed reflexes.

Distinct roles of spinal commissural interneurons in transmission of contralateral sensory information.

Crossed reflexes (CR) are mediated by commissural pathways transmitting sensory information to the contralateral side of the body, but the underlying network is not fully understood. Commissural pathways coordinating the activities of spinal locomotor circuits during locomotion have been characterized in mice, but their relationship to CR is unknown. We show the involvement of two genetically distinct groups of commissural interneurons (CINs) described in mice, V0 and V3 CINs, in the CR pathways. Our data suggest that the exclusively excitatory V3 CINs are directly involved in the excitatory CR, and show that they are essential for the inhibitory CR. In contrast, the V0 CINs, a population that includes excitatory and inhibitory CINs, are not directly involved in excitatory or inhibitory CRs but down-regulate the inhibitory CR. Our data provide insights into the spinal circuitry underlying CR in mice, describing the roles of V0 and V3 CINs in CR.

The brain integrates proprioceptive information to ensure robust locomotion.

Robust locomotion relies on information from proprioceptors: sensory organs that communicate the position of body parts to the spinal cord and brain. Proprioceptive circuits in the spinal cord are known to coarsely regulate locomotion in the presence of perturbations. Yet, the regulatory importance of the brain in maintaining robust locomotion remains less clear. Here, through mouse genetic studies and in vivo electrophysiology, we examined the role of the brain in integrating proprioceptive information during perturbed locomotion. The systemic removal of proprioceptors left the mice in a constantly perturbed state, similar to that observed during mechanically perturbed locomotion in wild-type mice and characterised by longer and less accurate synergistic activation patterns. By contrast, after surgically interrupting the ascending proprioceptive projection to the brain through the dorsal column of the spinal cord, wild-type mice showed normal walking behaviour, yet lost the ability to respond to external perturbations. Our findings provide direct evidence of a pivotal role for ascending proprioceptive information in achieving robust, safe locomotion. KEY POINTS: Whether brain integration of proprioceptive feedback is crucial for coping with perturbed locomotion is not clear. We showed a crucial role of the brain for responding to external perturbations and ensure robust locomotion. We used mouse genetics to remove proprioceptors and a spinal lesion model to interrupt the flow of proprioceptive information to the brain through the dorsal column in wild-type animals. Using a custom-built treadmill, we administered sudden and random mechanical perturbations to mice during walking. External perturbations affected locomotion in wild-type mice similar to the absence of proprioceptors in genetically modified mice. Proprioceptive feedback from muscle spindles and Golgi tendon organs contributed to locomotor robustness. Wild-type mice lost the ability to respond to external perturbations after interruption of the ascending proprioceptive projection to the brainstem.

Crossed reflex responses to flexor nerve stimulation in mice.

Motor responses in one leg to sensory stimulation of the contralateral leg have been named "crossed reflexes" and are extensively investigated in cats and humans. Despite this effort, a circuit-level understanding of the crossed reflexes has remained missing. In mice, advances in molecular genetics enabled insights into the "commissural spinal circuitry" that ensures coordinated leg movements during locomotion. Despite some common features between the commissural spinal circuitry and the circuit for the crossed reflexes, the degree to which they overlap has remained obscure. Here, we describe excitatory crossed reflex responses elicited by electrically stimulating the common peroneal nerve that mainly innervates ankle flexor muscles and the skin on anterolateral aspect of the hind leg. Stimulation of the peroneal nerve with low current intensity evoked low-amplitude motor responses in the contralateral flexor and extensor muscles. At higher current strengths, stimulation of the same nerve evoked stronger and more synchronous responses in the same contralateral muscles. In addition to the excitatory crossed reflex pathway indicated by muscle activation, we demonstrate the presence of an inhibitory crossed reflex pathway, which was modulated when the motor pools were active during walking. The results are compared with the crossed reflex responses initiated by stimulating proprioceptors from extensor muscles and cutaneous afferents from the posterior part of the leg. We anticipate that these findings will be essential for future research combining the in vivo experiments presented here with mouse genetics to understand crossed reflex pathways at the network level in vivo.NEW & NOTEWORTHY Insights into the mechanisms of crossed reflexes are essential for understanding coordinated leg movements that maintain stable locomotion. Advances in mouse genetics allow for the selective manipulation of spinal interneurons and provide opportunities to understand crossed reflexes. Crossed reflexes in mice, however, are poorly described. Here, we describe crossed reflex responses in mice initiated by stimulation of the common peroneal nerve, which serves as a starting point for investigating crossed reflexes at the cellular level.

Role of DSCAM in the Development of Neural Control of Movement and Locomotion.

Locomotion results in an alternance of flexor and extensor muscles between left and right limbs generated by motoneurons that are controlled by the spinal interneuronal circuit. This spinal locomotor circuit is modulated by sensory afferents, which relay proprioceptive and cutaneous inputs that inform the spatial position of limbs in space and potential contacts with our environment respectively, but also by supraspinal descending commands of the brain that allow us to navigate in complex environments, avoid obstacles, chase prey, or flee predators. Although signaling pathways are important in the establishment and maintenance of motor circuits, the role of DSCAM, a cell adherence molecule associated with Down syndrome, has only recently been investigated in the context of motor control and locomotion in the rodent. DSCAM is known to be involved in lamination and delamination, synaptic targeting, axonal guidance, dendritic and cell tiling, axonal fasciculation and branching, programmed cell death, and synaptogenesis, all of which can impact the establishment of motor circuits during development, but also their maintenance through adulthood. We discuss herein how DSCAM is important for proper motor coordination, especially for breathing and locomotion.

DSCAM Mutation Impairs Motor Cortex Network Dynamic and Voluntary Motor Functions.

While it is well known that netrin-1 and its receptors UNC5 and UNC40 family members are involved in the normal establishment of the motor cortex and its corticospinal tract, less is known about its other receptor Down syndrome cell adherence molecule (DSCAM). DSCAM is expressed in the developing motor cortex, regulates axonal outgrowth of cortical neurons, and its mutation impairs the dendritic arborization of cortical neurons, thus suggesting that it might be involved in the normal development and functioning of the motor cortex. In comparison to WT littermates, DSCAM2J mutant mice slipped and misplaced their paw while walking on the rungs of a horizontal ladder, and exhibited more difficulties in stepping over an obstacle while walking at slow speed. Anterograde tracing showed a normal pyramidal decussation and corticospinal projection, but a more dorsal distribution of their axonal terminals in the spinal gray matter. Intracortical microstimulations showed a reduced corticospinal and intracortical efficacy, whereas stimulations of the pyramidal tract revealed a normal spinal efficacy and excitability of corticospinal tract axons, thus arguing for a dysfunctional cortical development. Our study reveals impairment of the network dynamics within the motor cortex, reducing corticospinal drive and impairing voluntary locomotor functions upon DSCAM2J mutation.

Excitatory and inhibitory crossed reflex pathways in mice.

Sensory information from one leg has been known to elicit reflex responses in the contralateral leg, known as "crossed reflexes," and these have been investigated extensively in cats and humans. Furthermore, experiments with mice have shown commissural pathways in detail by using in vitro and in vivo physiological approaches combined with genetics. However, the relationship between these commissural pathways discovered in mice and crossed reflex pathways described in cats and humans is not known. In this study, we analyzed the crossed reflex in mice by using in vivo electromyographic recording techniques combined with peripheral nerve stimulation protocols to provide a detailed description of the crossed reflex pathways. We show that excitatory crossed reflexes are mediated by both proprioceptive and cutaneous afferent activation. In addition, we provide evidence for a short-latency inhibitory crossed reflex pathway likely mediated by cutaneous feedback. Furthermore, the short-latency crossed inhibition is downregulated in the knee extensor muscle and the ankle flexor muscle during locomotion. In conclusion, this article provides an analysis of excitatory and inhibitory crossed reflex pathways during resting and locomoting mice in vivo. The data presented in this article pave the way for future research aimed at understanding crossed reflexes using genetics in mice. NEW & NOTEWORTHY We describe for the first time excitatory and inhibitory crossed reflex pathways in mouse spinal cord in vivo and show that the inhibitory pathways are modulated during walking. This is a first step toward an understanding of crossed reflexes and their function during walking using in vivo recording techniques combined with mouse genetics.

Motor hypertonia and lack of locomotor coordination in mutant mice lacking DSCAM.

Down syndrome cell adherence molecule (DSCAM) contributes to the normal establishment and maintenance of neural circuits. Whereas there is abundant literature regarding the role of DSCAM in the neural patterning of the mammalian retina, less is known about motor circuits. Recently, DSCAM mutation has been shown to impair bilateral motor coordination during respiration, thus causing death at birth. DSCAM mutants that survive through adulthood display a lack of locomotor endurance and coordination in the rotarod test, thus suggesting that the DSCAM mutation impairs motor control. We investigated the motor and locomotor functions of DSCAM(2J) mutant mice through a combination of anatomical, kinematic, force, and electromyographic recordings. With respect to wild-type mice, DSCAM(2J) mice displayed a longer swing phase with a limb hyperflexion at the expense of a shorter stance phase during locomotion. Furthermore, electromyographic activity in the flexor and extensor muscles was increased and coactivated over 20% of the step cycle over a wide range of walking speeds. In contrast to wild-type mice, which used lateral walk and trot at walking speed, DSCAM(2J) mice used preferentially less coordinated gaits, such as out-of-phase walk and pace. The neuromuscular junction and the contractile properties of muscles, as well as their muscle spindles, were normal, and no signs of motor rigidity or spasticity were observed during passive limb movements. Our study demonstrates that the DSCAM mutation induces dystonic hypertonia and a disruption of locomotor gaits.