Abnormalities in whisking behaviour are associated with lesions in brain stem nuclei in a mouse model of amyotrophic lateral sclerosis (original) (raw)
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Experimental Neurology, 1998
Mutations in the superoxide dismutase gene 1 (SOD-1) are found in patients with familial amyotrophic lateral sclerosis (FALS). Overexpression of a mutated human SOD-1 gene in mice results in neurodegenerative disease as result of motoneuron loss in lumbar spinal cord (10). Using this mouse model of FALS, we have established a quantitative assay utilizing the retrograde tracer Fluorogold (FG) to determine the number of motoneurons innervating one skeletal muscle in mice with ongoing disease. In adult wildtype mice, the number of ␣ motoneurons retrogradely labeled by an injection of FG into medial gastrocnemius muscle is 50 Ϯ 7 and this number remains constant from 7 to 18 weeks of age. In mutant mice, the number of ␣ motoneurons retrogradely labeled by FG is the same as in wild-type mice at 7 and 9 weeks, but then declines to 36% of that in normal mice at 18 weeks. This decline also correlates positively to severity of motor impairments in these mice as assessed by the hindlimb splay test. In contrast, the number of FGlabeled ␥ motoneurons remains relatively unchanged in both wild-type and mutant mice up to 18 weeks. At 18 weeks of age, this apparent ␣ motoneuron denervation is paralleled by an average of 55% reduction of MG-muscle mass and 40% weaker performance in the hindlimb splay test. These data suggest that ␣ motoneurons are the most vulnerable neuronal subtype in this mouse model of ALS and it is primarily their loss that leads to functional motor deficits. This quantitative bioassay also will be valuable for evaluating novel therapeutics for ALS. 1998 Academic Press
Neuroscience, 2014
Vibrissal whisking is often employed to track facial nerve regeneration in rats; however, we have observed similar degrees of whisking recovery after facial nerve transection with or without repair. We hypothesized that the source of non-facial nerve-mediated whisker movement after chronic denervation was from autonomic, cholinergic axons traveling within the infraorbital branch of the trigeminal nerve (ION). Rats underwent unilateral facial nerve transection with repair (N = 7) or resection without repair (N = 11). Post-operative whisking amplitude was measured weekly across 10 weeks, and during intraoperative stimulation of the ION and facial nerves at P18 weeks. Whisking was also measured after subsequent ION transection (N = 6) or pharmacologic blocking of the autonomic ganglia using hexamethonium (N = 3), and after snout cooling intended to elicit a vasodilation reflex (N = 3). Whisking recovered more quickly and with greater amplitude in rats that underwent facial nerve repair compared to resection (P < 0.05), but individual rats overlapped in whisking amplitude across both groups. In the resected rats, non-facial-nerve-mediated whisking was elicited by electrical stimulation of the ION, temporarily diminished following hexamethonium injection, abolished by transection of the ION, and rapidly and significantly (P < 0.05) increased by snout cooling. Moreover, fibrillation-related whisker movements decreased in all rats during the initial recovery period (indicative of reinnervation), but re-appeared in the resected rats after undergoing ION transection (indicative of motor denervation). Cholinergic, parasympathetic axons traveling within the ION innervate whisker pad vasculature, and immunohistochemistry for vasoactive intestinal peptide revealed these axons branching extensively over whisker pad muscles and contacting neuromuscular junctions after facial nerve resection. This study provides the first behavioral and anatomical evidence of spontaneous autonomic innervation of skeletal muscle after motor nerve lesion, which not only has implications for interpreting facial nerve reinnervation results, but also calls into question whether autonomic-mediated innervation of striated muscle occurs naturally in other forms of neuropathy. Ó
The loss of motorneurons corresponding to specific muscles in the wobbler mutant mouse
Neuroscience Letters, 1983
The spin',d motorneuronal pools specific to a peripheral muscular territory were studied in the wobbler mutant mouse, with the use of retrolpr~ule transport of horseradish peroxidase, which was injected into the musculo-cutaneous nerve and into the distal part of the sciatic nerve. Counts of labeled cells showed that the mean percentage of surviving motorneurons was 48.4% in the case of the nmsculo-cutaneous nerve and 83.60/0 in the case of the sciatic nerve. The cell loss was not found to be different in old compared to young mutants, suggesting that motorneuron degeneration is an early event in the course of the disease. The 'wobbler' mutant mouse displays a hereditary lower motorneuron disease which leads to progressive denervation of skeletal muscles. Affected animals, which are homozygous (wr/wr) for the gene wr derive from a C57BL/6J mouse strain. Breeding pairs of clinically normal heterozygous (:1:/wr?) mice were kindly provided by Dr. S. Averill (Dept. of Neuroscience, Children's Hospital Medical Center, Boston, MA). Mutants are identified during the fourth week' after birth. A clinical and pathological study of wobbler was performed by Duchen and Strich [4], degeneration and cell loss being observed diffusely in the ventral horn, but mainly in the cervical enlargement. The aim of the present study is a quantitative comparison between the normal and mutant motorneuron pools which are specific of a given muscular te~itory, using the technique of retrograde transport of horseradish peroxidase (HRP). Two muscular territories were considered, one including biceps brachii and brachialis muscles in a usually severely affected area [6], innervated by the musculocutaneous nerve, and the other, in a usually spared area, was composed of the distal muscles of leg and foot [4, 5], innervated by the sciatic nerve. Twenty-four mice J Author for all correspondence.
Title : Dynamic neuromuscular remodeling precedes motor-unit loss in a mouse 1 model of ALS 2
Affiliations: 4 1 Département de neurosciences, Université de Montréal, PO box 6128, Station centre-ville, 5 Montréal, Québec, Canada, H3C 3J7. 6 2 Groupe de recherche sur le système nerveux central, Université de Montréal. 7 3 Centre de recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), 900 Saint 8 Denis Street, Montréal, Québec, Canada, H2X 0A9. 9 *To whom correspondence should be addressed: richard.robitaille@umontreal.ca; Phone 10 number: 1-514-343-6111 ext 1946; Fax: 1-514-343-7972. 11 12
Morphological and functional changes in innervation of a fast forelimb muscle in SOD1-G85R mice
Neurobiology of Disease, 2012
Muscle endplates become denervated in mice that express mutations of human superoxide dismutase 1 (hSOD1), models of familial amyotrophic lateral sclerosis. This denervation is especially marked in fast limb muscles, and precedes death of motor neuron somata. This study used mice that expressed yellow fluorescent protein (YFP) in neurons to investigate changes in the morphology and function of axons and motor terminals innervating a fast forelimb muscle (epitrochleoanconeus, ETA) in presymptomatic and symptomatic hSOD1-G85R mice, compared to those in mice that express wild-type (wt) hSOD1. The percentage of endplates (identified using fluorescently-labeled α-bungarotoxin) innervated by motor terminals remained high in presymptomatic SOD1-G85R mice, but fell to~50% in symptomatic mice. The number of large diameter (≥ 4 μm) axons in the ETA nerve also decreased as mice became symptomatic, and endplate innervation correlated best with the number of large diameter axons. Motor terminal function was assessed using changes in terminal YFP fluorescence evoked by trains of action potentials; different components of the pH-dependent YFP signals reflect stimulation-induced Ca 2+ entry and vesicular exo/endocytosis. Most visible motor terminals (>90%) remained capable of responding to nerve stimulation in both pre-and symptomatic hSOD1-G85R mice, but with functional alterations. Responses in presymptomatic terminals suggested reduced acidification and increased vesicular release, whereas symptomatic terminals exhibited increased acidification and reduced vesicular release. The fact that most remaining terminals were able to respond to nerve stimulation suggests that motor terminal-protective therapies might contribute to preserving neuromuscular function in fALS mice.
Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis
The Journal of Physiology, 2008
The present study investigated motor unit (MU) loss in a murine model of familial amyotrophic lateral sclerosis (ALS). The fast-twitch tibialis anterior (TA) and medial gastrocnemius (MG) muscles of transgenic SOD1 G93A and SOD1 WT mice were studied during the presymptomatic phase of disease progression at 60 days of age. Whole muscle maximum isometric twitch and tetanic forces were 80% lower (P < 0.01) in the TA muscles of SOD1 G93A compared to SOD1 WT mice. Enumeration of total MU numbers within TA muscles showed a 60% reduction (P < 0.01) within SOD1 G93A mice (38 ± 7) compared with SOD1 WT controls (95 ± 12); this was attributed to a lower proportion of the most forceful fast-fatigable (FF) MU in SOD1 G93A mice, as seen by a significant (P < 0.01) leftward shift in the cumulative frequency histogram of single MU forces. Similar patterns of MU loss and corresponding decreases in isometric twitch force were observed in the MG. Immunocytochemical analyses of the entire cross-sectional area (CSA) of serial sections of TA muscles stained with anti-neural cell adhesion molecule (NCAM) and various monoclonal antibodies for myosin heavy chain (MHC) isoforms showed respective 65% (P < 0.01) and 28% (P < 0.05) decreases in the number of innervated IIB and IID/X muscle fibres in SOD1 G93A , which paralleled the 60% decrease (P < 0.01) in the force generating capacity of individual fibres. The loss of fast MUs was partially compensated by activity-dependent fast-to-slower fibre type transitions, as determined by increases (P < 0.04) in the CSA and proportion of IIA fibres (from 4% to 14%) and IID/X fibres (from 31% to 39%), and decreases (P < 0.001) in the CSA and proportion of type IIB fibres (from 65% to 44%). We conclude that preferential loss of IIB fibres is incomplete at 60 days of age, and is consistent with a selective albeit gradual loss of FF MUs that is not fully compensated by sprouting of the remaining motoneurons that innervate type IIA or IID/X muscle fibres. Our findings indicate that disease progression in fast-twitch muscles of SOD1 G93A mice involves parallel processes: (1) gradual selective motor axon die-back of the FF motor units that contain large type IIB muscle fibres, and of fatigue-intermediate motor units that innervate type IID/X muscle fibres, and (2) activity-dependent conversion of motor units to those innervated by smaller motor axons innervating type IIA fatigue-resistant muscle fibres.
Muscle & Nerve, 2012
Introduction-Rodent whisking behavior is supported by the buccal and mandibular branches of the facial nerve, a description of how these branches converge and contribute to whisker movement is lacking. Methods-Eight rats underwent isolated transection of either the buccal or mandibular branch and subsequent opposite branch transection. Whisking function was analyzed following both transections. Anatomical measurements, and video recording of stimulation to individual branches, were taken from both facial nerves in 10 rats. Results-Normal to near-normal whisking was demonstrated after isolated branch transection. Following transection of both branches whisking was eliminated. The buccal and mandibular branches form a convergence just proximal to the whisker-pad, named the "distal pes." Distal to this convergence, we identified consistent anatomy that demonstrated cross-innervation. Conclusion-The overlap of efferent supply to the whisker pad must be considered when studying facial nerve regeneration in the rat facial nerve model.
Frontiers in Molecular Neuroscience, 2023
Introduction: The ultimate deficit in amyotrophic lateral sclerosis (ALS) is neuromuscular junction (NMJ) loss, producing permanent paralysis, ultimately in respiratory muscles. However, understanding the functional and structural deficits at NMJs prior to this loss is crucial for therapeutic strategy design. Should early interventions focus on reversing denervation, or supporting largely intact NMJs that are functionally impaired? We therefore determined when functional and structural deficits appeared in diaphragmatic NMJs relative to the onset of hindlimb tremor (the first overt motor symptoms) in vivo in the SOD1-G93A mouse model of ALS. Materials and methods: We employed electrophysiological recording of NMJ postsynaptic potentials for spontaneous and nerve stimulation-evoked responses. This was correlated with fluorescent imaging microscopy of the postsynaptic acetylcholine receptor (AChR) distribution throughout the postnatal developmental timecourse from 2 weeks to early symptomatic ages. Results: Significant reduction in the amplitudes of spontaneous miniature endplate potentials (mEPPs) and evoked EPPs emerged only at early symptomatic ages (in our colony, 18-22 weeks). Reductions in mEPP frequency, number of vesicles per EPP, and EPP rise time were seen earlier, at 16weeks, but this reversed by early symptomatic ages. However, the earliest and most striking impairment was an inability to maintain EPP amplitude during a 20 Hz stimulus train, which appeared 6 weeks before overt in vivo motor symptoms. Despite this, fluorescent α-bungarotoxin labelling revealed no systematic, progressive changes in 11 comprehensive NMJ morphological parameters (area, shape, compactness, number of acetylcholine receptor, AChR, regions, etc.) with disease progression. Rather, while NMJs were largely normally-shaped, from 16 weeks there was a progressive and substantial disruption in AChR concentration and distribution within the NMJ footprint. Discussion: Thus, NMJ functional deficits appear at least 6 weeks before motor symptoms in vivo, while structural deficits occur 4 weeks later, and predominantly within NMJs. These data suggest initial therapies focused on rectifying suboptimal NMJ function could produce effective relief of symptoms of weakness.
Whisker Movements Evoked by Stimulation of Single Motor Neurons in the Facial Nucleus of the Rat
Journal of Neurophysiology, 2008
The lateral facial nucleus is the sole output structure whose neuronal activity leads to whisker movements. To understand how single facial nucleus neurons contribute to whisker movement we combined single-cell stimulation and high-precision whisker tracking. Half of the 44 stimulated neurons gave rise to fast whisker protraction or retraction movement, whereas no stimulation-evoked movements could be detected for the remainder. Direction, speed, and amplitude of evoked movements varied across neurons. Protraction movements were more common than retraction movements ( n = 16 vs. n = 4), had larger amplitudes (1.8 vs. 0.3° for single spike events), and most protraction movements involved only a single whisker, whereas most retraction movements involved multiple whiskers. We found a large range in the amplitude of single spike-evoked whisker movements (0.06–5.6°). Onset of the movement occurred at 7.6 (SD 2.5) ms after the spike and the time to peak deflection was 18.2 (SD 4.3) ms. Ea...