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Current Topics in Developmental Biology 2021Commissural axons have been a key model system for identifying axon guidance signals in vertebrates. This review summarizes the current thinking about the molecular and... (Review)
Review
Commissural axons have been a key model system for identifying axon guidance signals in vertebrates. This review summarizes the current thinking about the molecular and cellular mechanisms that establish a specific commissural neural circuit: the dI1 neurons in the developing spinal cord. We assess the contribution of long- and short-range signaling while sequentially following the developmental timeline from the birth of dI1 neurons, to the extension of commissural axons first circumferentially and then contralaterally into the ventral funiculus.
Topics: Animals; Axon Guidance; Axons; Neurons; Spinal Cord
PubMed: 33706918
DOI: 10.1016/bs.ctdb.2020.10.009 -
Veterinary Pathology Jan 2023This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of...
This report describes 2 events of degenerative myelopathy in 4- to 27-day-old piglets, with mortality rates reaching 40%. Sows were fed rations containing low levels of pantothenic acid. Piglets presented with severe depression, weakness, ataxia, and paresis, which were more pronounced in the pelvic limbs. No significant gross lesions were observed. Histologically, there were degeneration and necrosis of neurons in the spinal cord, primarily in the thoracic nucleus in the thoracic and lumbar segments, and motor neurons in nucleus IX of the ventral horn in the cervical and lumbar intumescence. Minimal-to-moderate axonal and myelin degeneration was observed in the dorsal funiculus of the spinal cord and in the dorsal and ventral nerve roots. Immunohistochemistry demonstrated depletion of acetylcholine neurotransmitters in motor neurons and accumulation of neurofilaments in the perikaryon of neurons in the thoracic nucleus and motor neurons. Ultrastructurally, the thoracic nucleus neurons and motor neurons showed dissolution of Nissl granulation. The topographical distribution of the lesions indicates damage to the second-order neurons of the spinocerebellar tract, first-order axon cuneocerebellar tract, and dorsal column-medial lemniscus pathway as the cause of the conscious and unconscious proprioceptive deficit, and damage to the alpha motor neuron as the cause of the motor deficit. Clinical signs reversed and no new cases occurred after pantothenic acid levels were corrected in the ration, and piglets received parenteral administration of pantothenic acid. This study highlights the important and practical use of detailed neuropathological analysis to refine differential diagnosis.
Topics: Animals; Swine; Female; Pantothenic Acid; Spinal Cord; Neurons; Medulla Oblongata; Spinal Cord Diseases; Swine Diseases
PubMed: 36250539
DOI: 10.1177/03009858221128920 -
The Journal of Neuroscience : the... Aug 2023Axon fasciculation is thought to be a critical step in neural circuit formation and function. Recent studies have revealed various molecular mechanisms that underlie...
Axon fasciculation is thought to be a critical step in neural circuit formation and function. Recent studies have revealed various molecular mechanisms that underlie axon fasciculation; however, the impacts of axon fasciculation, and its corollary, defasciculation, on neural circuit wiring remain unclear. Corticospinal (CS) neurons in the sensorimotor cortex project axons to the spinal cord to control skilled movements. In rodents, the axons remain tightly fasciculated in the brain and traverse the dorsal funiculus of the spinal cord. Here we show that plexinA1 (PlexA1) and plexinA3 (PlexA3) receptors are expressed by CS neurons, whereas their ligands, semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B) are expressed in the medulla at the decussation site of CS axons to inhibit premature defasciculation of these axons. In the absence of Sema5A/5B-PlexA1/A3 signaling, some CS axons are prematurely defasciculated in the medulla of the brainstem, and those defasciculated CS axons aberrantly transverse in the spinal gray matter instead of the spinal dorsal funiculus. In the absence of Sema5A/Sema5B-PlexA1/A3 signaling, CS axons, which would normally innervate the lumbar spinal cord, are unbundled in the spinal gray matter, and prematurely innervate the cervical gray matter with reduced innervation of the lumbar gray matter. In both and mutant mice (both sexes), stimulation of the hindlimb motor cortex aberrantly evokes robust forelimb muscle activation. Finally, and mutant mice show deficits in skilled movements. These results suggest that proper fasciculation of CS axons is required for appropriate neural circuit wiring and ultimately affect the ability to perform skilled movements. Axon fasciculation is believed to be essential for neural circuit formation and function. However, whether and how defects in axon fasciculation affect the formation and function of neural circuits remain unclear. Here we examine whether the transmembrane proteins semaphorin-5A (Sema5A) and semaphorin-5B (Sema5B), and their receptors, plexinA1 (PlexA1) and plexinA3 (PlexA3) play roles in the development of corticospinal circuits. We find that Sema5A/Sema5B and PlexA1/A3 are required for proper axon fasciculation of corticospinal neurons. Furthermore, and mutant mice show marked deficits in skilled motor behaviors. Therefore, these results strongly suggest that proper corticospinal axon fasciculation is required for the appropriate formation and functioning of corticospinal circuits in mice.
Topics: Female; Male; Mice; Animals; Semaphorins; Axon Fasciculation; Neurons; Axons; Spinal Cord
PubMed: 37344234
DOI: 10.1523/JNEUROSCI.0073-22.2023 -
The Journal of Physiology Feb 2016Inflammatory kinins are released following spinal cord injury or neurotrauma. The effects of these kinins on ongoing locomotor activity of central pattern generator...
KEY POINTS
Inflammatory kinins are released following spinal cord injury or neurotrauma. The effects of these kinins on ongoing locomotor activity of central pattern generator networks are unknown. In the present study, kinins were shown to have short- and long-term effects on motor networks. The short-term effects included direct depolarization of interneurons and motoneurons in the ventral horn accompanied by modulation of transient receptor potential vanilloid 1-sensitive nociceptors in the dorsal horn. Over the long-term, we observed a bradykinin-mediated effect on promoting plasticity in the spinal cord. In a model of spinal cord injury, we observed an increase in microglia numbers in both the dorsal and ventral horn and, in a microglia cell culture model, we observed bradykinin-induced expression of glial-derived neurotrophic factor.
ABSTRACT
The expression and function of inflammatory mediators in the developing spinal cord remain poorly characterized. We discovered novel, short and long-term roles for the inflammatory nonapeptide bradykinin (BK) and its receptor bradykinin receptor B2 (B2R) in the neuromodulation of developing sensorimotor networks following a spinal cord injury (SCI), suggesting that BK participates in an excitotoxic cascade. Functional expression of B2R was confirmed by a transient disruptive action of BK on fictive locomotion generated by a combination of NMDA, 5-HT and dopamine. The role of BK in the dorsal horn nociceptive afferents was tested using spinal cord attached to one-hind-limb (HL) preparations. In the HL preparations, BK at a subthreshold concentration induced transient disruption of fictive locomotion only in the presence of: (1) noxious heat applied to the hind paw and (2) the heat sensing ion channel transient receptor potential vanilloid 1 (TRPV1), known to be restricted to nociceptors in the superficial dorsal horn. BK directly depolarized motoneurons and ascending interneurons in the ventrolateral funiculus. We found a key mechanism for BK in promoting long-term plasticity within the spinal cord. Using a model of neonatal SCI and a microglial cell culture model, we examined the role of BK in inducing activation of microglia and expression of glial-derived neurotrophic factor (GDNF). In the neonatal SCI model, we observed an increase in microglia numbers and increased GDNF expression restricted to microglia. In the microglia cell culture model, we observed a BK-induced increased expression of GDNF via B2R, suggesting a novel mechanism for BK spinal-mediated plasticity.
Topics: Animals; Anterior Horn Cells; Bradykinin; Cells, Cultured; Central Pattern Generators; Glial Cell Line-Derived Neurotrophic Factor; Interneurons; Locomotion; Mice; Microglia; Nerve Net; Neuronal Plasticity; Nociception; Posterior Horn Cells; Receptors, Bradykinin; Spinal Cord Injuries; TRPV Cation Channels
PubMed: 26634895
DOI: 10.1113/JP271152 -
International Journal of Molecular... Sep 2021This study aimed to reveal functional and morphological changes in the corticospinal tract, a pathway shown to be susceptible to diabetes. Type 1 diabetes was induced in...
This study aimed to reveal functional and morphological changes in the corticospinal tract, a pathway shown to be susceptible to diabetes. Type 1 diabetes was induced in 13-week-old male Wistar rats administered streptozotocin. Twenty-three weeks after streptozotocin injection, diabetic animals and age-matched control animals were used to demonstrate the conduction velocity of the corticospinal tract. Other animals were used for morphometric analyses of the base of the dorsal funiculus of the corticospinal tract in the spinal cord using both optical and electron microscopy. The conduction velocity of the corticospinal tract decreased in the lumbar spinal cord in the diabetic animal, although it did not decrease in the cervical spinal cord. Furthermore, atrophy of the fibers of the base of the dorsal funiculus was observed along their entire length, with an increase in the g-ratio in the lumbar spinal cord in the diabetic animal. This study indicates that the corticospinal tract fibers projecting to the lumbar spinal cord experience a decrease in conduction velocity at the lumbar spinal cord of these axons in diabetic animals, likely caused by a combination of axonal atrophy and an increased g-ratio due to thinning of the myelin sheath.
Topics: Action Potentials; Animals; Blood Glucose; Body Weight; Diabetes Mellitus, Experimental; Male; Motor Neurons; Neural Conduction; Pyramidal Tracts; Rats, Wistar; Spinal Cord; Streptozocin; Rats
PubMed: 34576288
DOI: 10.3390/ijms221810123 -
Enhanced Network in Corticospinal Tracts after Infused Mesenchymal Stem Cells in Spinal Cord Injury.Journal of Neurotrauma Dec 2022Although limited spontaneous recovery occurs after spinal cord injury (SCI), current knowledge reveals that multiple forms of axon growth in spared axons can lead to...
Although limited spontaneous recovery occurs after spinal cord injury (SCI), current knowledge reveals that multiple forms of axon growth in spared axons can lead to circuit reorganization and a detour or relay pathways. This hypothesis has been derived mainly from studies of the corticospinal tract (CST), which is the primary descending motor pathway in mammals. The major CST is the dorsal CST (dCST), being the major projection from cortex to spinal cord. Two other components often called "minor" pathways are the ventral and the dorsal lateral CSTs, which may play an important role in spontaneous recovery. Intravenous infusion of mesenchymal stem cells (MSCs) provides functional improvement after SCI with an enhancement of axonal sprouting of CSTs. Detailed morphological changes of CST pathways, however, have not been fully elucidated. The primary objective was to evaluate detailed changes in descending CST projections in SCI after MSC infusion. The MSCs were infused intravenously one day after SCI. A combination of adeno-associated viral vector (AAV), which is an anterograde and non-transsynaptic axonal tracer, was injected 14 days after SCI induction. The AAV with advanced tissue clearing techniques were used to visualize the distribution pattern and high-resolution features of the individual axons coursing from above to below the lesion. The results demonstrated increased observable axonal connections between the dCST and axons in the lateral funiculus, both rostral and caudal to the lesion core, and an increase in observable axons in the dCST below the lesion. This increased axonal network could contribute to functional recovery by providing greater input to the spinal cord below the lesion.
Topics: Animals; Pyramidal Tracts; Spinal Cord Injuries; Recovery of Function; Axons; Spinal Cord; Mesenchymal Stem Cells; Nerve Regeneration; Mammals
PubMed: 35611987
DOI: 10.1089/neu.2022.0106 -
The Journal of Clinical Investigation Oct 2015Primary pain and touch sensory neurons not only detect internal and external sensory stimuli, but also receive inputs from other neurons. However, the neuronal derived...
Primary pain and touch sensory neurons not only detect internal and external sensory stimuli, but also receive inputs from other neurons. However, the neuronal derived inputs for primary neurons have not been systematically identified. Using a monosynaptic rabies viruses-based transneuronal tracing method combined with sensory-specific Cre-drivers, we found that sensory neurons receive intraganglion, intraspinal, and supraspinal inputs, the latter of which are mainly derived from the rostroventral medulla (RVM). The viral-traced central neurons were largely inhibitory but also consisted of some glutamatergic neurons in the spinal cord and serotonergic neurons in the RVM. The majority of RVM-derived descending inputs were dual GABAergic and enkephalinergic (opioidergic). These inputs projected through the dorsolateral funiculus and primarily innervated layers I, II, and V of the dorsal horn, where pain-sensory afferents terminate. Silencing or activation of the dual GABA/enkephalinergic RVM neurons in adult animals substantially increased or decreased behavioral sensitivity, respectively, to heat and mechanical stimuli. These results are consistent with the fact that both GABA and enkephalin can exert presynaptic inhibition of the sensory afferents. Taken together, this work provides a systematic view of and a set of tools for examining peri- and extrasynaptic regulations of pain-afferent transmission.
Topics: Afferent Pathways; Animals; Defective Viruses; Efferent Pathways; Enkephalins; Forelimb; GABAergic Neurons; Ganglia, Spinal; Hyperalgesia; Interneurons; Nerve Net; Nerve Tissue Proteins; Neural Conduction; Neurons, Afferent; Neurons, Efferent; Nociception; Nociceptors; Posterior Horn Cells; Presynaptic Terminals; Rabies virus; Sensory Receptor Cells; Skin; Spinal Cord Dorsal Horn; Virus Replication; gamma-Aminobutyric Acid
PubMed: 26426077
DOI: 10.1172/JCI81156 -
Journal of Neurotrauma Feb 2015Deficits in bladder function are complications following spinal cord injury (SCI), severely affecting quality of life. Normal voiding function requires coordinated...
Deficits in bladder function are complications following spinal cord injury (SCI), severely affecting quality of life. Normal voiding function requires coordinated contraction of bladder and urethral sphincter muscles dependent upon intact lumbosacral reflex arcs and integration of descending and ascending spinal pathways. We previously reported, in electrophysiological recordings, that segmental reflex circuit neurons in anesthetized male rats were modulated by a bilateral spino-bulbo-spinal pathway in the mid-thoracic lateral funiculus. In the present study, behavioral measures of bladder voiding reflexes and hematuria (hemorrhagic cystitis) were obtained to assess the correlation of plasticity-dependent recovery to the degree of lateral funiculus sparing and mid-thoracic lesion level. Adult rats received mid-thoracic-level lesions at one of the following severities: complete spinal transection; bilateral dorsal column lesion; unilateral hemisection; bilateral dorsal hemisection; a bilateral lesion of the lateral funiculi and dorsal columns; or a severe contusion. Voiding function and hematuria were evaluated by determining whether the bladder was areflexic (requiring manual expression, i.e., "crede maneuver"), reflexive (voiding initiated by perineal stroking), or "automatic" (spontaneous voiding without caretaker assistance). Rats with one or both lateral funiculi spared (i.e., bilateral dorsal column lesion or unilateral hemisection) recovered significantly faster than animals with bilateral lateral funiculus lesions, severe contusion, or complete transection. Bladder reflex recovery time was significantly slower the closer a transection lesion was to T10, suggesting that proximity to the segmental sensory and sympathetic innervation of the upper urinary tract (kidney, ureter) should be avoided in the choice of lesion level for SCI studies of micturition pathways. In addition, hematuria duration was significantly longer in males, compared to females, despite similar bladder reflex onset times. We conclude that the sparing of the mid-thoracic lateral funiculus on one side is required for early recovery of bladder reflex voiding function and resolution of hematuria.
Topics: Animals; Disease Models, Animal; Female; Hematuria; Male; Rats; Rats, Wistar; Recovery of Function; Reflex; Spinal Cord Injuries; Urinary Bladder; Urination
PubMed: 25137571
DOI: 10.1089/neu.2013.3247 -
Frontiers in Neural Circuits 2014We aimed to explore the cerebellar cortical inputs from two spinocerebellar pathways, the spinal border cell-component of the ventral spinocerebellar tract (SBC-VSCT)...
We aimed to explore the cerebellar cortical inputs from two spinocerebellar pathways, the spinal border cell-component of the ventral spinocerebellar tract (SBC-VSCT) and the dorsal spinocerebellar tract (DSCT), respectively, in the sublobule C1 of the cerebellar posterior lobe. The two pathways were activated by electrical stimulation of the contralateral lateral funiculus (coLF) and the ipsilateral LF (iLF) at lower thoracic levels. Most granule cells in sublobule C1 did not respond at all but part of the granule cell population displayed high-intensity responses to either coLF or iLF stimulation. As a rule, Golgi cells and Purkinje cell simple spikes responded to input from both LFs, although Golgi cells could be more selective. In addition, a small population of granule cells responded to input from both the coLF and the iLF. However, in these cases, similarities in the temporal topography and magnitude of the responses suggested that the same axons were stimulated from the two LFs, i.e., that the axons of individual spinocerebellar neurons could be present in both funiculi. This was also confirmed for a population of spinal neurons located within known locations of SBC-VSCT neurons and dorsal horn (dh) DSCT neurons. We conclude that bilateral spinocerebellar responses can occur in cerebellar granule cells, but the VSCT and DSCT systems that provide the input can also be organized bilaterally. The implications for the traditional functional separation of VSCT and DSCT systems and the issue whether granule cells primarily integrate functionally similar information or not are discussed.
Topics: Action Potentials; Animals; Biophysics; Cats; Cerebellar Cortex; Electric Stimulation; Electroencephalography; Functional Laterality; Nerve Net; Neurons; Spinal Cord; Spinocerebellar Tracts
PubMed: 25386122
DOI: 10.3389/fncir.2014.00128