Quantitative analysis of locomotor defects in neonatal mice lacking proprioceptive feedback

Abstract

Proprioceptive feedback derived from specialized receptors in skeletal muscle is critical in forming an accurate map of limb position in space, and is used by the central nervous system to plan future movements and to determine accuracy of executed movements. Knockout mouse strains for genes expressed by proprioceptive sensory neurons have been generated that result in generalized motor deficits, but these deficits have not been quantitatively characterized. Here we characterize a conditional knockout mouse model where proprioceptive sensory neuron synaptic transmission has been blocked by selective ablation of munc18-1, a synaptic vesicle associated protein required for fusion of synaptic vesicles with the plasma membrane. Proprioceptive munc18-1 conditional mutants are impaired in surface righting—a dynamic postural adjustment task—and display several specific deficits in pivoting, an early locomotor behavior. Before the emergence of forward locomotion during postnatal development, animals explore their surroundings through pivoting, or rotating the upper torso around the relatively immobile base of the hind limbs. 3-D kinematic analysis was used to quantitatively describe this pivoting behavior at postnatal days 5 and 8 in control and munc18-1 conditional mutants. Mutant animals also pivot, but demonstrate alterations in movement strategy and in postural placement of the forelimbs during pivoting when compared to controls. In addition, brief forelimb stepping movements associated with pivoting are altered in mutant animals. Step duration and step height is increased in mutant animals. These results underscore the importance of proprioceptive feedback even at early stages in postnatal development.

Role of DSCAM in the development of the spinal locomotor and sensorimotor circuits

“…In addition to this hunched posture, DSCAM 2J mice also displayed an aberrant limb hyperkinesia during treadmill locomotion, which likely results from proprioceptive deficits. Limb hyperflexion and hyperextension have been previously reported following peripheral sensory denervation or peripheral deafferentation in the free-walking cat (Bouyer and Rossignol 2003;Bretzner and Drew 2005;Wiesendanger 1964), and upon conditional deletion of proprioceptive DRGs in the neonatal mouse (Dallman and Ladle 2013). Moreover, mutant mouse models lacking muscle spindles also exhibit a similar hyperextension to DSCAM 2J mice (Andrechek et al 2002;Ernfors et al 1994;Klein et al 1994).…”

Sensorimotor training during expression of the leg extension response (LER) in 1‐day‐old rats

“…These findings add to a growing body of literature showing that motor behavior, including species‐typical action patterns, expressed by the newborn mammal is modulated by sensory feedback. This includes spontaneous limb activity (Brumley & Robinson, ), locomotor behavior (Brumley et al, ; Dallman & Ladle, ; Viala, Viala, & Fayein, ), facial wiping (Robinson & Smotherman, ; Smotherman & Robinson, ), and righting (Alberts & Ronca, ; Dallman & Ladle, ; Ronca & Alberts, ; Ronca, Fritzsch, Bruce, & Alberts, ; Walton, Harding, Anschel, Harris, & Llinas, ; Wubbels & de Jong, ).…”

“…The munc18‐1 conditional knockout mouse is a proprioceptive‐specific knockout model, and these animals lack functional proprioceptive feedback due impaired proprioceptive neuron synaptic transmission. However, it has been suggested that the infant munc18‐1 knockout mouse is able to use cutaneous feedback from the limbs to perform locomotor pivoting behavior, albeit using altered motor and postural strategies compared to controls (Dallman & Ladle, ). Thus, cutaneous stimulation may compensate for the lack of proprioceptive feedback, thus making the contribution of each form of sensory stimulation difficult to disentangle still.…”

Three-dimensional analysis of the characteristics of joint motion and gait pattern in a rodent model following spinal nerve ligation

“…Gait analysis is promising for the evaluation of neurological deficits as gait is a fundamental, physiological and unforced form of locomotion with direct clinical relevance. 3D digital gait analysis could be a useful tool for detecting the severity of neuropathic pain and the change in gait characteristics following SNL [11,[14][15][16][17][18][19][20][21][22][23][24]. Indeed, some authors claim that 2D catwalk analysis is useful for assessing animal pain [9,10,12,13], and these types of measures are relatively easy to assess [13,21].…”

“…Spontaneous withdrawal reactions are strongly affected by spinal reflex, and scientific evidence that the reactions are a specific reflex against pain is lacking [5]. In addition, the von Frey withdrawal test has some issues of test-retest reliability and interrater reliability [5,[9][10][11][12][13][14]. The test cannot reveal impaired coordination of the motions of the right-left lower limbs in rodent models following SNL or spinal cord injury [15][16][17][18][19][20][21][22][23].…”