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BioRxiv : the Preprint Server For... Apr 2024The dorsal funiculus in the spinal cord relays somatosensory information to the brain. It is made of T-shaped bifurcation of dorsal root ganglion (DRG) sensory axons....
The dorsal funiculus in the spinal cord relays somatosensory information to the brain. It is made of T-shaped bifurcation of dorsal root ganglion (DRG) sensory axons. Our previous study has shown that Slit signaling is required for proper guidance during bifurcation, but loss of Slit does not affect all DRG axons. Here, we examined the role of the extracellular molecule Netrin-1 (Ntn1). Using wholemount staining with tissue clearing, we showed that mice lacking Ntn1 have axons escaping from the dorsal funiculus at the time of bifurcation. Genetic labeling confirmed that these misprojecting axons come from DRG neurons. Single axon analysis showed that loss of Ntn1 does not affect bifurcation but rather alters turning angles. To distinguish their guidance functions, we examined mice with triple deletion of Ntn1, Slit1, and Slit2 and found a completely disorganized dorsal funiculus. Comparing mice with different genotypes using immunolabeling and single axon tracing revealed additive guidance errors, demonstrating the independent roles of Ntn1 and Slit. Moreover, the same defects were observed in embryos lacking their cognate receptors. These studies thus demonstrate the presence of multi-factorial guidance mechanisms that ensure proper formation of a common branched axonal structure during spinal cord development.
PubMed: 38014092
DOI: 10.1101/2023.11.17.567638 -
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 -
Temperature (Austin, Tex.) 2023Thermoregulatory behaviors are powerful effectors for core body temperature (T) regulation. We evaluated the involvement of afferent fibers ascending through the dorsal...
Selection of preferred thermal environment and cold-avoidance responses in rats rely on signals transduced by the dorsal portion of the lateral funiculus of the spinal cord.
Thermoregulatory behaviors are powerful effectors for core body temperature (T) regulation. We evaluated the involvement of afferent fibers ascending through the dorsal portion of the lateral funiculus (DLF) of the spinal cord in "spontaneous" thermal preference and thermoregulatory behaviors induced by thermal and pharmacological stimuli in a thermogradient apparatus. In adult Wistar rats, the DLF was surgically severed at the first cervical vertebra bilaterally. The functional effectiveness of funiculotomy was verified by the increased latency of tail-flick responses to noxious cold (-18°C) and heat (50°C). In the thermogradient apparatus, funiculotomized rats showed a higher variability of their preferred ambient temperature (T) and, consequently, increased T fluctuations, as compared to sham-operated rats. The cold-avoidance (warmth-seeking) response to moderate cold (whole-body exposure to ~17°C) or epidermal menthol (an agonist of the cold-sensitive TRPM8 channel) was attenuated in funiculotomized rats, as compared to sham-operated rats, and so was the T (hyperthermic) response to menthol. In contrast, the warmth-avoidance (cold-seeking) and T responses of funiculotomized rats to mild heat (exposure to ~28°C) or intravenous RN-1747 (an agonist of the warmth-sensitive TRPV4; 100 μg/kg) were unaffected. We conclude that DLF-mediated signals contribute to driving spontaneous thermal preference, and that attenuation of these signals is associated with decreased precision of T regulation. We further conclude that thermally and pharmacologically induced changes in thermal preference rely on neural, presumably afferent, signals that travel in the spinal cord within the DLF. Signals conveyed by the DLF are important for cold-avoidance behaviors but make little contribution to heat-avoidance responses.
PubMed: 37187830
DOI: 10.1080/23328940.2023.2191378 -
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 Comparative Neurology Dec 2022Our knowledge about the detailed wiring of neuronal circuits in the spinal dorsal horn (DH), where initial sensory processing takes place, is still very sparse. While a...
Quantitative spatial analysis reveals that the local axons of lamina I projection neurons and interneurons exhibit distributions that predict distinct roles in spinal sensory processing.
Our knowledge about the detailed wiring of neuronal circuits in the spinal dorsal horn (DH), where initial sensory processing takes place, is still very sparse. While a substantial amount of data is available on the somatodendritic morphology of DH neurons, the laminar and segmental distribution patterns and consequential function of individual axons are much less characterized. In the present study, we fully reconstructed the axonal and dendritic processes of 10 projection neurons (PNs) and 15 interneurons (INs) in lamina I of the rat, to reveal quantitative differences in their distribution. We also performed whole-cell patch-clamp recordings to test the predicted function of certain axon collaterals. In line with our earlier qualitative description, we found that lamina I INs in the lateral aspect of the superficial DH send axon collaterals toward the medial part and occupy mostly laminae I-III, providing anatomical basis for a lateromedial flow of information within the DH. Local axon collaterals of PNs were more extensively distributed including dorsal commissural axon collaterals that might refer to those reported earlier linking the lateral aspect of the left and right DHs. PN collaterals dominated the dorsolateral funiculus and laminae IV-VI, suggesting propriospinal and ventral connections. Indeed, patch-clamp recordings confirmed the existence of a dorsoventral excitatory drive upon activation of neurokinin-1 receptors that, although being expressed in various lamina I neurons, are specifically enriched in PNs. In summary, lamina I PNs and INs have almost identical dendritic input fields, while their segmental axon collateral distribution patterns are distinct. INs, whose somata reside in lamina I, establish local connections, may show asymmetry, and contribute to bridging the medial and lateral halves of the DH. PNs, on the other hand, preferably relay their integrated dendritic input to deeper laminae of the spinal gray matter where it might be linked to other ascending pathways or the premotor network, resulting in a putative direct contribution to the nociceptive withdrawal reflex.
Topics: Rats; Animals; Receptors, Neurokinin-1; Spinal Cord; Axons; Interneurons; Posterior Horn Cells; Neurons; Spatial Analysis; Perception
PubMed: 36094014
DOI: 10.1002/cne.25413 -
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 -
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 -
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 -
Neuroscience Insights 2020The highly interconnected somatosensory and motor systems are subjected to connectivity changes at close or remote locations following a central nervous system injury....
Cutaneous Inputs to Dorsal Column Nuclei in Adult Macaque Monkeys Subjected to Unilateral Lesion of the Primary Motor Cortex or of the Cervical Spinal Cord and Treatments Promoting Axonal Growth.
The highly interconnected somatosensory and motor systems are subjected to connectivity changes at close or remote locations following a central nervous system injury. What is the impact of unilateral injury of the primary motor cortex (hand area; MCI) or of the cervical cord (hemisection at C7-C8 level; SCI) on the primary somatosensory (cutaneous) inputs to the dorsal column nuclei (DCN) in adult macaque monkeys? The effects of treatments promoting axonal growth were assessed. In the SCI group (n = 4), 1 monkey received a control antibody and 3 monkeys a combination treatment of anti-Nogo-A antibody and brain-derived neurotrophic factor (BDNF). In the MCI group (n = 4), 2 monkeys were untreated and 2 were treated with the anti-Nogo-A antibody. Using trans-ganglionic transport of cholera toxin B subunit injected in the first 2 fingers and toes on both sides, the areas of axonal terminal fields in the cuneate and gracile nuclei were bilaterally compared. Unilateral SCI at C7-C8 level, encroaching partially on the dorsal funiculus, resulted in an ipsilesional lower extent of the inputs from the toes in the gracile nuclei, not modified by the combined treatment. SCI at C7-C8 level did not affect the bilateral balance of primary inputs to the cuneate nuclei, neither in absence nor in presence of the combined treatment. MCI targeted to the hand area did not impact on the primary inputs to the cuneate nuclei in 2 untreated monkeys. After MCI, the administration of anti-Nogo-A antibody resulted in a slight bilateral asymmetrical extent of cutaneous inputs to the cuneate nuclei, with a larger extent ipsilesionally. Overall, remote effects following MCI or SCI have not been observed at the DCN level, except possibly after MCI and anti-Nogo-A antibody treatment.
PubMed: 33283186
DOI: 10.1177/2633105520973991