Biased synaptopathy as a central mechanism of age-related hearing loss.
age-related hearing loss; bushy cell; innervation
Lu Y
The Journal Of Physiology
2021
2021-01-31
journalArticle
<a href="http://doi.org/10.1113/JP281348" target="_blank" rel="noreferrer noopener">10.1113/JP281348</a>
Neurotrophin-3 Ameliorates Sensory-motor Deficits In Er81-deficient Mice
afferents; Anatomy & Morphology; connections; Developmental Biology; differentiation; ER81; ETS; innervation; motor neurons; muscle spindles; muscle spindles; mutant mice; neurons; neurotrophins; NT3; rat; regeneration; sensory neurons; specification; spinal-cord; transcription factors
Two factors, the ETS transcription factor ER81 and skeletal muscle-derived neurotrophin-3 (NT3), are essential for the formation of muscle spindles and the function of spindle afferent-motoneuron synapses in the spinal cord. Spindles either degenerate completely or are abnormal, and spindle afferents fail to project to spinal motoneurons in Er81 null mice; however, the interactions between ER81 and NT3 during the processes of afferent neuron and muscle spindle development are poorly understood. To examine if overexpression of NT3 in muscle rescues spindles and afferent-motoneuron connectivity in the absence of ER81, we generated myoNT3;Er81(-/-) double-mutant mice that selectively overexpress NT3 in muscle in the absence of ER81. Spindle reflex arcs in myoNT3;Er81(-/-) mutants differed greatly from Er81 null mice. Muscle spindle densities were greater and more afferents projected into the ventral spinal cord in myoNT3;Er81(-/-) mice. Spindles of myoNT3,Er81(-/-) muscles responded normally to repetitive muscle taps, and the monosynaptic inputs from la afferents to motoneurons, grossly reduced in Er81(-/-) mutants, were restored to wild-type levels in myoNT3,Er81(-/-) mice. Thus, an excess of muscle-derived NT3 reverses deficits in spindle numbers and afferent function induced by the absence of ER81. We conclude that muscle-derived NT3 can modulate spindle density and afferent-motoneuron connectivity independently of ER81.
Li L Y; Wang Z; Sedy J; Quazi R; Walro J M; Frank E; Kucera J
Developmental Dynamics
2006
2006-11
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/dvdy.20964" target="_blank" rel="noreferrer noopener">10.1002/dvdy.20964</a>
Differential-effects Of Neonatal Denervation On Intrafusal Muscle-fibers In The Rat
afferents; Anatomy & Morphology; denervation; Developmental Biology; expression; heavy-chain isoforms; innervation; intrafusal muscle fiber; motor denervation; muscle spindles; myosin heavy chains; neonatal rat; nerve dependence; nerve growth-factor; spindle development; spindles
The response of developing muscle spindles to denervation was studied by sectioning the nerve to the medial gastrocnemius muscle of rats at birth. The denervated spindles were examined daily throughout the first postnatal week for changes in ultrastructure and expression of several isoforms of myosin heavy chain (MHC). Each of the three different types of intrafusal muscle fiber exhibited a different response to denervation. Within 5 days after the nerve section nuclear bag, fibers degenerated completely; nuclear bag1 fibers persisted, but ceased to express the 'spindle-specific' slow-tonic MHC isoform and thereby could not be differentiated from extrafusal fibers; nuclear chain fibers did not form. The capsules of spindles disassembled, hence spindles or their remnants could no longer be identified 1 week after denervation. Neonatal deefferentation has little effect on these features of developing spindles, so removal of afferent innervation is presumably the factor that induces the loss of spindles in denervated muscles. Degeneration of the bag2 fiber, but not bag1 or extrafusal fibers, reflects a greater dependence of the bag2 fiber than the bag1 fiber on afferent innervation for maintenance of its structural integrity. This difference in response of the two types of immature bag fiber to denervation might reflect an origin of the bag2 fibers from a lineage of myogenic cells distinct from that giving rise to bag1 or extrafusal fibers, or a difference in the length of contact with afferents between the two types of bag fiber prior to nerve section.
Kucera J; Walro J M; Reichler J
Anatomy and Embryology
1993
1993-04
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/bf00185898" target="_blank" rel="noreferrer noopener">10.1007/bf00185898</a>
Expression Of Type-specific Mhc Isoforms In Rat Intrafusal Muscle-fibers
cat; Cell Biology; differentiation; fiber types; histochemistry; identification; immunocytochemistry; innervation; intrafusal; monoclonal antimyosin antibodies; monoclonal-antibody; motor; muscle fiber typing; muscle spindles; myosin heavy-chain; rat skeletal muscle; skeletal-muscle; spindles
Myosin heavy chain (MHC) expression by intrafusal fibers was studied by immunocytochemistry to determine how closely it parallels MHC expression by extrafusal fibers in the soleus and tibialis anterior muscles of the rat. Among the MHC isoforms expressed in extrafusal fibers, only the slow-twitch MHC of Type 1 extrafusal fibers was expressed along much of the fibers. Monoclonal antibodies (MAb) specific for this MHC bound to the entire length of bag2 fibers and the extracapsular region of bag1 fibers. The fast-twitch MHC isoform strongly expressed by bag2 and chain fibers had an epitope not recognized by MAb to the MHC isoforms characteristic of developing muscle fibers or the three subtypes (2A, 2B, 2X) of Type 2 extrafusal fibers. Therefore, intrafusal fibers may express a fast-twitch MHC that is not expressed by extrafusal fibers. Unlike extrafusal fibers, all three intrafusal fiber types bound MAb generated against mammalian heart and chicken limb muscles. The similarity of the fast-twitch MHC of bag2 and chain fibers and the slow-tonic MHC of bag1 and bag2 fibers to the MHC isoforms expressed in avian extrafusal fibers suggests that phylogenetically primitive MHCs might persist in intrafusal fibers. Data are discussed relative to the origin and regional regulation of MHC isoforms in intrafusal and extrafusal fibers of rat hindlimb muscles.
Kucera J; Walro J M; Gorza L
Journal of Histochemistry & Cytochemistry
1992
1992-02
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1177/40.2.1552171" target="_blank" rel="noreferrer noopener">10.1177/40.2.1552171</a>
Fusimotor-free Spindles In Reinnervated Muscles Of Neonatal Rats Treated With Nerve Growth-factor
crush; fibers; hindlimb muscles; injury; innervation; Neurosciences & Neurology; sensory neurons; survival
Crushing the nerve to the medial gastrocnemius muscle in newborn rats and administering nerve growth factor afterwards results in a reinnervated muscle containing supernumerary muscle spindles. The structure and innervation of 88 spindles in the reinnervated muscles were reconstructed from serial thick and thin transverse sections at 30 35 days after the nerve crush, and compared to those of five control spindles. The spindles consisted of one to four small-diameter encapsulated fibers with features of nuclear chain intrafusal fibers, or infrequently a nuclear bag intrafusal fiber. Some of the spindles were located within a capsule that also contained an extrafusal fiber. Each spindle was innervated by an afferent with features of the primary afferent. The density of secondary afferents was lower in reinnervated muscles than in controls. Endplates were observed on extrafusal fibers in the experimental muscles. attesting to restoration of skeletomotor (alpha) innervation after the nerve crush. However, 78% of the experimental spindles were entirely devoid of efferent innervation. The remainder received either one or two fusimotor (gamma) axons or a skeletofusimotor (beta) axon, compared to the six to eight motor axons that innervated control spindles. The presence of supernumerary spindles composed of fibers that resemble normal intrafusal fibers in the absence of motor innervation suggests that afferents alone can induce the formation and subsequent differentiation of intrafusal fibers in nerve-crushed muscles of neonatal rats. In addition, the paucity of gamma innervation in nerve-crushed muscles suggests that immature gamma neurons are more susceptible than spindle afferents or alpha efferents to cell death after axotomy at birth.
Kucera J; Walro J M; Gao Y
Neuroscience
1993
1993-01
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1016/0306-4522(93)90194-k" target="_blank" rel="noreferrer noopener">10.1016/0306-4522(93)90194-k</a>
Slow-tonic Mhc Expression In Paralyzed Hindlimbs Of Fetal Rats
Cell Biology; heavy-chain isoforms; innervation; intrafusal muscle-fibers; numbers; spindles
Whether nerve activity and active contraction of myotubes are essential for the assembly and initial differentiation of muscle spindles was investigated by paralyzing fetal rats with tetrodotoxin (TTX) from embryonic day 16 (E16) to E21, prior to and during the period when spindles typically form. TTX-treated soleus muscles were examined by light and electron microscopy for the presence of spindles and expression of myosin heavy chain (MHC) isoforms by the intrafusal fibers. Treatment with TTX did not inhibit the formation of a spindle capsule or the expression of a slow-tonic MHC isoform characteristic of intrafusal fibers, but did retard development of spindles. Spindles of TTX-treated E21 muscles usually consisted of one intrafusal fiber (bag2) only rather than two fibers (bag1 and bag2) typically present in untreated (control) E21 spindles. Intrafusal fibers of TTX-treated spindles also had only one sensory region supplied by multiple afferents, and were devoid of motor innervation. These features are characteristic of spindles in normal E18-E19 muscles. Thus, nerve and/or muscle activity is not essential for the assembly of muscle spindles, formation of a spindle capsule, and transformation of undifferentiated myotubes into the intrafusal fibers containing spindle-specific myosin isoforms. However, activity may promote the maturation of intrafusal bundles, as well as the maturation of afferent and efferent nerve supplies to intrafusal fibers.
Kucera J; Walro J M
Histochemistry
1991
1991
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/bf00266761" target="_blank" rel="noreferrer noopener">10.1007/bf00266761</a>
Sequences Of Intrafusal Fiber Formation Are Muscle-dependent In Rat Hindlimbs
Anatomy & Morphology; cat; development; Developmental Biology; embryonic-development; expression; innervation; intrafusal fibers; motor; muscle; muscle spindles; myosin heavy chains; myosin heavy-chain; neonatal rats; skeletal-muscle; slow myosin; spindles; tenuissimus muscles
A rat muscle spindle typically contains four intrafusal fibers - one nuclear bag(2), one nuclear bag, and two nuclear chain fibers. We compared the sequence of formation of the three intrafusal fiber types among the tibialis anterior (TA), soleus (SOL) and medial gastrocnemius (RIG) muscles using immunocytochemistry of spindle-specific myosin heavy chain isoforms. Spindles of the TA began to differentiate earlier and acquired the full complement of intrafusal fibers sooner than spindles of the SOL or MG muscles. At the onset of spindle assembly, the intrafusal myotubes expressed myosin heavy chains similar to those expressed by extrafusal myotubes. The first intrafusal myotube then differentiated into the bag, fiber regardless of the muscle. However, the fate of the second-forming intrafusal myotube varied among the muscles studied. It usually differentiated into a chain fiber in the TA, into a bag(1) fiber in the SOL, and into either a bag(1) or a chain in the MG. The fate of the third-forminge was reciprocal to that of the second; i.e. in those spindles in which the bag(1) fiber was second to form, a chain was third, and vice versa. The fourth and last intrafusal myotube gave rise to a chain fiber. The inter- and intramuscular variability in the fate of intrafusal myotubes of the second and third generation argues against the existence of a program intrinsic to the myotubes that would mandate their differentiation along specific paths. Rather, an extrinsic regulatory factor, probably associated with the primary afferent neuron, may govern differentiation of pluripotential myotubes into particular types of intrafusal fiber. The fate of the intrafusal myotubes might then depend on the timing of the regulatory effect of afferents relative to the stage of development of the intrafusal bundle.
Kucera J; Walro J M
Anatomy and Embryology
1994
1994-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/bf00234305" target="_blank" rel="noreferrer noopener">10.1007/bf00234305</a>
Aggregation Of Myonuclei And The Spread Of Slow-tonic Myosin Immunoreactivity In Developing Muscle-spindles
Cell Biology; expression; fibers; heavy-chain isoforms; innervation; motor; rat; skeletal-muscle
The pattern of regional expression of a slowtonic myosin heavy chain (MHC) isoform was studied in developing rat soleus intrafusal muscle fibers. Binding of the slow-tonic antibody (ATO) began at the equator of prenatal intrafusal fibers where sensory nerve endings are located, and spread into the polar regions of nuclear bag2 and bag1 fibers but not nuclear chain fibers during ontogeny. The onset of the ATO reactivity coincided with the appearance of equatorial clusters of myonuclei (nuclear bag formations) in bag1 and bag2 fibers. Moreover, the intensity of the ATO reaction was strongest in the region of equatorial myonuclei and decreased with increasing distance from the equator of bag1 and bag2 fibers at all stages of prenatal and postnatal development. The polar expansion of ATO reactivity continued throughout the postnatal development of bag1 fibers, but ceased shortly after birth in bag2 fiber coincident with innervation by motor axons. Thus, afferents that innervate the equator might induce the slow-tonic MHC isoform in bag2 and bag1 fibers by regulating the myosin gene expression by equatorial myonuclei, and efferents or twitch contractile activity might inhibit the spread of the slow-tonic MHC isoform into the poles of bag2 but not bag1 fibers. Absence of ATO binding in chain fibers suggests that chain myotubes may not be as susceptible to the effect of afferents as are myotubes that develop into bag2 and bag1 fibers. The different patterns of slow-tonic MHC expression in the three types of intrafusal fiber may therefore result from the interaction of three elements: sensory neurons, motor neurons, and intrafusal myotubes.
Kucera J; Walro J M
Histochemistry
1991
1991
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1007/bf00315994" target="_blank" rel="noreferrer noopener">10.1007/bf00315994</a>
Formation Of Supernumerary Muscle Spindles At The Expense Of Golgi Tendon Organs In Er81-deficient Mice
Anatomy & Morphology; Developmental Biology; ETS transcription factors; expression; Golgi tendon organs; group; ia afferents; innervation; motor neurons; muscle spindles; mutant mice; myosin heavy-chain; neonatal rats; nerve growth-factor; neurotrophin-3; primary sensory neurons; proprioceptive afferents; transcription factors
ER81, a member of the ETS family of transcription factors, is essential for the formation of connections between sensory and motor neurons in the spinal cord. Mice lacking Er81 genes exhibit reduced monosynaptic sensory-motoneuron connectivity in response to muscle nerve stimulation. Proximal muscle nerve stimulation elicits fewer monosynaptic potentials than stimulation of distal nerves in hind-limbs, a deficit that is paralleled by a paucity of muscle spindles in proximal muscles (Arber et al., 2000). We examined whether a presence of spindles innervated by afferents in distal muscles correlated with the increased preservation of monosynaptic sensory-motor potentials in distal muscle nerves. Not only were spindles and Ia afferents present, but also they were supernumerary in distal muscles such as the soleus, medial gastrocnemius, and extensor hallucis longus. Concomitantly, a deficiency of Golgi tendon organs (GTOs) and Ib afferents was observed in distal muscles, as if supernumerary spindles formed at the expense of tendon organs in the absence of Er81. Thus, ER81 may be involved in mechanisms that regulate acquisition of the Ia and Ib phenotypes by subsets of proprioceptive muscle afferents. Segmental differences in muscle spindle and GTO dependence on ER81 suggest that more than one ETS transcription factor may participate in the regulation of limb proprioceptive system assembly in the mouse. (C) 2002 Wiley-Liss, Inc.
Kucera J; Cooney W; Que A; Szeder V; Stancz-Szeder H; Walro J
Developmental Dynamics
2002
2002-03
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1002/dvdy.10066" target="_blank" rel="noreferrer noopener">10.1002/dvdy.10066</a>
Effects Of Topical Brinzolamide On Infantile Nystagmus Syndrome Waveforms: Eyedrops For Nystagmus
amaurosis; carbonic-anhydrase activity; congenital nystagmus; gene transfer; innervation; muscle; Neurosciences & Neurology; ocular motor system; Ophthalmology; rat; Surgery; tenotomy
Dell'Osso L F; Hertle R W; Leigh R J; Jacobs J B; King S; Yaniglos S
Journal of Neuro-Ophthalmology
2011
2011-09
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1097/WNO.0b013e3182236427" target="_blank" rel="noreferrer noopener">10.1097/WNO.0b013e3182236427</a>
Management of iatrogenic injury to the spinal accessory nerve
anatomy; Surgery; palsy; innervation; radical neck-dissection; trapezius muscle
Spinal accessory nerve injury results in a debilitating shoulder dysfunction. The trapezius is a major suspensory muscle of the shoulder girdle, and paralysis results in chronic pain and debility from disruption of synchronous scapulohumeral rhythm. This injury usually follows a simple posterior triangle lymph node biopsy and is treatable if appropriate measures are taken in a timely fashion. A major pitfall in early management is either failure to recognize or acknowledge the injury or hoping that it will resolve with conservative treatment. Variation of innervation of the trapezius alters clinical presentation and can make diagnosis difficult. We present a series of six patients with iatrogenic spinal accessory nerve injury following a neck node biopsy. Pain was the most common presenting symptom, and a loss of sustained abduction was the most common physical sign. Three patients had a primary nerve repair and the other three patients had nerve grafting. Maximum recovery time ranged from 4 to 10 months. All patients had varying degrees of recovery of motor function, and all six patients were 100 percent painfree. An algorithm for the management of this distressing condition emphasizes the importance of early referral and highlights the pitfalls in making an accurate diagnosis. Whereas conservative therapy is less predictable and needs careful selection, it also runs the risk of delaying a more effective surgical management. Early operative intervention is more definitive and has the best functional results. Prevention is key and is best achieved by avoiding unnecessary biopsies of the posterior triangle lymph node. When operating, knowledge of posterior neck anatomy and judicious use of the bipolar cautery and magnifying loupes arc essential in preventing this problem.
Chandawarkar R Y; Cervino A L; Pennington G A
Plastic and Reconstructive Surgery
2003
2003-02
Journal Article or Conference Abstract Publication
<a href="http://doi.org/10.1097/01.prs.0000041943.47622.eb" target="_blank" rel="noreferrer noopener">10.1097/01.prs.0000041943.47622.eb</a>
MORPHOMETRIC ANALYSIS OF COATED VESICLES IN DEVELOPING RAT MUSCLE-SPINDLES
acetylcholine-receptors; cells; coated vesicles; development; innervation; intrafusal fibers; membrane; morphometry; motor; muscle spindle; Physiology; rat
The incidence of coated vesicles under sarcolemmal surfaces of equatorial, juxtaequatorial and polar regions in developing and adult spindles of the rat soleus muscle was examined by quantitative morphometry of transverse ultrathin sections. Coated vesicles were more numerous: 1) under primary sensory endings than under other types of neuromuscular contacts; 2) under the appositional sarcolemma between neighbouring intrafusal fibres than under free surfaces of the sarcolemma; and 3) in developing than in mature spindles. Factors such as location and age of the animal often interacted to produce an additive effect on the incidence of coated vesicles. Although there was a high incidence of coated vesicles at the postsynaptic surface under sensory terminals of bag2 fibres in 18 and 19 day gestational embryonic rats, it peaked in 4 day postnatal animals. The high incidence of coated vesicles at sensory endings supports the view that coated vesicles mediate neurotrophic interactions between afferents and intrafusal fibres during the critical late gestation and early postnatal time period, as sensory axons first contact their target fibres and exert a maximal directing influence on the differentiation of intrafusal fibre types. In addition, the preferential localization of coated vesicles under appositional rather than free surfaces of developing intrafusal fibres in 0-4 day rats suggests that they play a role in the transport of active substances among intrafusal fibres exhibiting different stages of maturity.
Stephens H; Walro J M; Kucera J
Physiological Research
1992
1992
Journal Article
n/a
SELECTIVE SUBREGIONAL DOPAMINE DEPLETIONS IN THE RAT CAUDATE-PUTAMEN FOLLOWING NIGROSTRIATAL LESIONS
heterogeneity; innervation; Neurosciences & Neurology; nucleus-accumbens; projection; striatum; substantia-nigra
Previous work has demonstrated a complex neurochemical and neuroanatomical heterogeneity of the striatum in normal brains. The present research investigated whether the heterogeneous distribution of dopamine would be altered following unilateral injections of the neurotoxin 6-hydroxydopamine into the substantia nigra of the rat. Four weeks following injection, the nucleus accumbens and subregions of the caudate-putamen and substantia nigra were dissected and analyzed by HPLC with electrochemical detection for dopamine, 5-hydroxytryptamine, and their respective metabolites. Levels of dopamine and its metabolites in the anterodorsolateral caudate-putamen were depleted more than medial, posterior, and ventral, striatal areas in partially lesioned animals (< 90% dopamine depletion). This resulted in an alteration of striatal heterogeneity such that a mediolateral gradient of dopamine tissue content was now superimposed on the normal rostrocaudal gradient observed in controls. Paralleling these findings, dopamine was more depleted in the lateral, as opposed to the medial, substantia nigra. These results indicate that the nigrostriatal dopamine system degenerates in a heterogeneous fashion following 6-hydroxydopamine administration. It is speculated that the differential loss of dopamine neurons observed in the nigra of Parkinson's patients may be due to a differential sensitivity to toxins within the nigra.
Pehek E A; Crock R; Yamamoto B K
Synapse
1992
1992-04
Journal Article
<a href="http://doi.org/10.1002/syn.890100406" target="_blank" rel="noreferrer noopener">10.1002/syn.890100406</a>