They used the DigiGait imaging system to quantify posture and kinematics following a sciatic nerve crush in wild type and αBC null (αBC -/-) mice. After 28 day, αBC-/- mice displayed gait abnormalities that were indicative of enhanced pain sensitivity, abnormal mobility, and a decrease in strength and stability.αBC-/- mice had slower conduction velocity and thinner myelin sheaths than did wild-type mice at the end of the study. We are proud that the DigiGait instrumentation was able to assist these researchers in showing for the first time that αBC is important for peripheral nerve regeneration.
Video 1. DigiGait view of a rat following nerve crush. Note the change in the posture of the paw of the injured right limb. The injury not only influences the posture and kinematics of the injured hind limb but also affects the kinematics of the contralateral forelimb, potentially to help stabilize the gait. Numerous metrics are affected, including the Sciatic Functional Index (SFI).
- In utero hypoxia-ischemia and inflammation results in complex white matter abnormalities and gait deficits in young adult rats
The central feature of cerebral palsy (CP) is an abnormality of movement. CP is often not diagnosed until the infant starts to mobilize, when preferential use of limbs, motor assymetries, or motor skills development delay are identified. Preterm birth is a leading cause of infant death. Infants born preterm commonly suffer from a combination of hypoxia-ischemia (HI) and infectious perinatal inflammatory insults that lead to CP.Lauren Jantzie and Shenandoah Robinson from Children’s Hospital / Harvard Medical School present a novel rat model of combined late gestation HI and lipopolysaccharide (LPS)-induced inflammation to test whether inflammation from transient HI (TSHI) and LPS differentially impact white matter development and motor impairment during the first postnatal month.
Pups were reared by their dams that had undergone laparotomy on embryonic day 18 and TSHI and/or intra-amniotic LPS injection. Expression of myelin basic protein, a marker of myelination, was most reduced in the combination injury on post natal day 15. The DigiGait Imaging System was used to detect and analyze deficits in gait in the pups on post-natal day 28. The injury groups (TSHI, LPS and TSHI+LPS) were ataxic with deficits in stride, paw placement, gait consistency and coordination (p<0.001). A recent publication from these authors further reported that TSHI and TSHI + LPS pups exhibited evidence of toe walking consistent with spastic gait reflected by significantly decreased paw area at peak stance. Similar to children with spasticity from prematurity, the hind limbs were more greatly affected than the forelimbs. The presence of TSHI, with or without LPS, produced more gait abnormalities.
We are quite proud to have provided the DigiGait instrumentation to aid these researchers in characterizing their novel clinically relevant rat model of perinatal brain injury.
Video 1: Neonatal mouse pup walking on DigiGait treadmill. Mouse pups develop the capacity for treadmill locomotion at about post-natal day 14. Their posture and gait patterns are adult-like by about post-natal day 28.
- 6-hydroxydopamine striatal lesions in creatine transporter deficient mice results in heightened parkinsonian symptoms
Gait disturbances in patients with Parkinson’s disease (PD) are well described, with shorter stride length, increased stride frequency, and increased gait variability being cardinal features. Many preclinical PD animal model studies have not included gait analysis because of the challenges associated with the variable behavior of lab animals walking different speeds overground, leaving only a few, often ambiguous, paw prints behind. The DigiGait Ventral Plane Imaging technology, however, is providing the opportunity for researchers such as Zuhair Abdulla and colleagues from Cincinnati to apply state of the gait analysis to their animal models of PD in order to better identify and quantify gait disturbances. These researchers were interested whether creatine (Cr), which has important established anti-oxidative properties, might provide neuroprotection in a mouse model of PD. To test this, they administered unilateral striatal injections of the dopaminergic neurotoxin 6-hydroxydopamine (6-OHDA) to Cr Transporter (CrT) knockout mice (CrT-/y), which lack Cr in the brain, and wild-type mice (CrT+/y).
In normal healthy subjects, there is good symmetry in the posture and kinematics of the hind limbs of humans, rats, and mice. The foot or paw placement angle in normal mice, for example, is nearly the same for the right and left hind limbs. DigiGait indicated no differences in paw placement angle prior to surgery. Following 6-OHDA administration, however, a significant increase in the paw placement angle of the unaffected limb of CrT-/y mice was noted, potentially indicating a compensatory mechanism for impaired gait, not observed in CrT+/y mice. Similar observations were reported by Andreas Kottmann’s team who applied DigiGait to their model of progressive PD via conditional ablation of sonic hedgehog from dopaminergic neurons.
We are proud that the DigiGait instrumentation was able to help these researchers show that the loss of Cr exacerbates the motor defects from DA depletion and highlights the important role of Cr in PD etiology.
Figure 1. Stride time variability in a PD mouse (top, treated with the neurotoxin MPTP), a Huntington’s disease mouse (middle, treated with the neurotoxin 3-nitroproprionic acid, 3NP), and normal B6 saline-treated mice (bottom panel). Note the increased variability in step-to-step stride time in the animal models of basal ganglia disease, in hind limbs and forelimbs. One key advantage of the DigiGait treadmill is the opportunity to thoroughly explore gait variability metrics because of the numerous strides available for analyses.
- Autonomic nervous system function – alive and well
Two entirely different disorders, one studied in mice and one in man, share a common denominator that is increasingly being recognized as an important factor in many human maladies: autonomic nervous system (ANS) dysfunction. Two entirely different SFN presentations, one that studied heart rate in a mouse model of Huntington’s disease [HD], and one that studied heart rate in humans with spinal cord injury (SCI), help to make this point.
Heramb Chadchankar and colleagues from Finland report on ANS abnormalities in two HD mouse models (zQ175 knock-in and R6/2 transgenic), having recorded ECG over a three-month period after surgical implantation of radiotransmitters in the HD mice. The HD mice exhibited a sizeable increase in heart rate (HR) compared to wild-type, becoming more noticeable with age. The R6/2 mice also exhibited evidence of arrhythmia. In both HD lines of mice, time domain and frequency domain metrics of heart rate variability (HRV) were reduced, suggesting sympathetic and parasympathetic disturbances contributing to autonomic dysfunction. The reduced core body temperature (CBT) they measured in HD mice makes the HR increase more intriguing since usually HR decreases ~25 bpm for each 1 ºC decrease in CBT in mice.
Consistent with these observations, the non-invasive ECGenie reports higher HR and reduced HRV in R6/2 mice, as well as in animal models of muscular dystrophy and spinal muscular atrophy. The ECGenie non-invasively reports the complete ECG in awake animals from day 1 of life, without the stresses of anesthetic, surgery, pain, possible infection, and recovery associated with implantation of radiotransmitters. Aberrant autonomic signaling is being increasingly recognized as an important symptom in a variety of clinically defined neuromuscular disorders during development, making the ECGenie convenient instrumentation for this research.
So what did Gonzalo Varas and his colleagues from Chile discover in humans with SCI? They are following the premise that the ANS, through vagal tone activity and activity of the prefrontal cortex, improves the interactions of a subject with its environments through an inhibitory effect on the sino-atrial node. They measured HR in healthy people and individuals with SCI, diagnosed with paraplegia, “who were pursuing a period of adaptation and socio-labor integration”. Their observations confirm a positive correlation between limitations in autonomic flexibility and worse performance in social cognition tasks. Interestingly, alterations in social behavior in HD mice are well described. Potentially we can appreciate a link between the ANS and social cognition in a variety of disorders. Perhaps a key to getting along with others is a flexible ANS.