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1 A coronal section at the level of the rostral pole of the mouse thalamus showing the structure of the cortex and the bed nucleus of stria terminalis. The photograph on the left is an AChE stained section, the diagram on the right is the corresponding drawing.
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The cells that project from the brain to the spinal cord have previously been mapped in a wide range of mammalian species, but have not been comprehensively studied in the mouse. We have mapped these cells in the mouse using retrograde tracing after large unilateral Fluoro-Gold (FG) and horseradish peroxidase (HRP) injections in the C1 and C2 spina...
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... the mouse (anatomy of mouse cerebral cortex shown in Fig I.1, 2, and 3. All sections and diagrams are from "Franklin KBJ and Paxinos G. ...
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... nucleus may be involved in conditioning related to the startle response in experimental animals (in rats: Lee and Davis 1997;Walker and Davis 1997;Gewirtz et al., 1998) and mediate fear reactions (in rats: Wallace and Rosen 2001;Fendt et al., 2002). It has a small number of spinal projecting neurons in its medial and lateral parts in the rat (anatomy of this nucleus of the mouse shown in Fig.I1). Descending fibers from this nucleus reach the lumbar cord ( Schwanzel-Fukuda et al., 1984). ...
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... projecting neurons in the midrostral portion of the paraventricular hypothalamic nucleus in the rat have collaterals to the rostroventrolateral reticular nucleus (RVL), suggesting that this nucleus plays a role in cardiovascular control (Pyner and Coote, 2000). In thoracic segments of the rat, cat, and the monkey, fibers from the paraventricular nucleus are seen to terminate on the intermediolateral cell column (anatomy of mouse spinal cord shown in FigI.15). This indicates a direct involvement of this nucleus in the modulation of the autonomic system ( Saper et al., 1976). ...
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... trigeminal nuclei encompass three subdivisions: the mesencephalic trigeminal nucleus (Me5), the principal sensory trigeminal nucleus (Pr5), and the spinal trigeminal nucleus (Sp5) (anatomy of mouse trigeminal nucleus shown in FigI.8-14). ...
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... vestibular nuclei are four: the lateral (LVe), superior (SuVe), medial (MVe), and the spinal nuclei (SpVe) (anatomy of mouse vestibular nuclei shown in FigI.9-12). Each of the subdivisions has been reported to have spinal projecting neurons and the largest is the lateral vestibular nucleus (in mice: Carretta et al., 2001; in rats: Watkins et al., 1981;Huisman et al., 1984;Nudo and Masterton, 1988;Shen et al., 1990;de Boer-van Huizen and ten Donkelaar, 1999; in cats: Kuypers and Maisky, 1975). ...
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... solitary nucleus (Sol) has spinal projecting neurons in all species studied (in mice: Auclaire et al., 1999;VanderHorst 2005;VanderHorst and Ulfhake, 2006; in rats: Norgren 1978; Leong et al., 1984a;Mtui et al., 1993;in cats: Kuypers and Maisky, 1975;Loewy and Burton, 1978;Basbaum and Fields, 1979;Rikard-Bell et al., 1984;in monkeys: Carlton et al., 1985) (anatomy of mouse Sol shown in FigI.11-14). These neurons are distributed in the ventral (SolV), ventrolateral (SolVL), intermediate (SolI) and commissural (SolC) subdivisions of the contralateral nucleus (in mice: VanderHorst 2005;VanderHorst and Ulfhake, 2006; in rats: Leong et al., 1984a; in cats: Kuypers and Maisky, 1975;Loewy and Burton, 1978). ...
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... has a large number of spinal projecting neurons with an ipsilateral predominance (in mice: VanderHorst and Ulfhake, 2006; in rats: Watkins et al., 1981;Leong et al., 1984a; in cats: Kuypers and Maisky, 1975;Basbaum and Fields, 1979;Hayes and Rustioni, 1981;Wada et al., 1993) (anatomy of mouse Gi shown in FigI.10-12). Interestingly, the dorsolateral part of this nucleus has more spinal projecting neurons on the contraltaral side than on the ipsilateral side (in rats: Leong et al., 1984a). ...
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... medullary reticular nuclei have bilateral spinal projections (in mice: VanderHorst and Ulfhake, 2006; in rats: Leichnetz et al., 1978;Watkins et al., 1981;Leong et al., 1984a;Reed et al., 2008; in cats: Basbaum and Fields, 1979;Hayes and Rustioni, 1981; in monkeys: Kneisley et al., 1978;Carlton et al., 1985) (anatomy of mouse MdD and MdV shown in FigI.13 and 14). Some of the spinal projecting neurons are glutamic acid decarboxylase (GAD) positive (in ...
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... neurons were also seen in the secondary somatosensory cortex (S2) on the contralateral side ( FigII.1-3, 18). The barrel field (S1BF) and upper lip (S1ULp) regions of the primary somatosensory cortex contained no labeled cells. ...
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... two cases, a small number of lightly labeled neurons were seen in the central part of the extended amygdala (EAC), the medial division of the central amygloid nucleus (CeM), and the anterior basolateral amygdaloid nucleus (BLA) on the ipsilateral side ( FigII.2-3, 18). In one case, a few labeled neurons were found in the posterolateral part of the medial division of the bed nucleus of stria terminalis (STMPL). ...
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... neurons of RMC were evenly distributed from medial to lateral. In sagittal sections, more neurons were found in the caudal part than in the rostral part ( FigII.16 and 17). ...
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... the caudal SC, there were two or three labeled neurons in the deep white (DpWh) and deep gray (DpG) layers in each section on the contralateral side (FigII.6). Laterally and caudally, there were five to ten neurons labeled in the region through the rostral 1/3 of the precuneiform area (PrCnF) on the ipsilateral side ( FigII.7-8, 17). ...
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... neurons were found in all major nuclei of the vestibular complex. The lateral (LVe) and the superior (SuVe) vestibular nuclei were ipsilaterally labeled ( FigII.10 and 11). The medial vestibular nucleus (MVe) and the spinal vestibular nucleus (SpVe) were bilaterally labeled ( FigII.10-13, 16-18). ...
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... lateral (LVe) and the superior (SuVe) vestibular nuclei were ipsilaterally labeled ( FigII.10 and 11). The medial vestibular nucleus (MVe) and the spinal vestibular nucleus (SpVe) were bilaterally labeled ( FigII.10-13, 16-18). The labeled neurons were mainly large stellate cells and the labelling was intense, especially in LVe ( FigII.10-13, 16-18). ...
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... medial vestibular nucleus (MVe) and the spinal vestibular nucleus (SpVe) were bilaterally labeled ( FigII.10-13, 16-18). The labeled neurons were mainly large stellate cells and the labelling was intense, especially in LVe ( FigII.10-13, 16-18). In MVe, most of the labeled neurons were concentrated in the magnocellular part (MVeMC); only a small number of neurons were located in the parvicellular part (MVePC). ...
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... nucleus A few labeled neurons were found in the dorsomedial (Pr5DM) and ventrolateral (Pr5VL) parts of the principal sensory trigeminal nucleus on both sides. These neurons were either spindle shaped or triangular ( FigII.9-10, 18). The labeled neurons in the oral spinal trigeminal nucleus (Sp5O) and the interpolar spinal trigeminal nucleus (Sp5I) were more numerous and more densely packed than in Pr5DM and Pr5VL. ...
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... Labeled neurons in the caudal spinal trigeminal nucleus (Sp5C) were smaller and less clustered than those in Sp5O and Sp5I, and were only found in the dorsal portion of this nucleus ( FigII.15, 17-18). ...
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... of these labeled neurons appear to lie within the triangular nucleus of the lateral lemniscus (TrLL) and the medial paralemniscal nucleus (MPL) ( FigII.7-8, 18). A small cell group dorsal to the rubrospinal tract (rs) contained a small cluster of labeled neurons; we identify this group as the epirubrospinal nucleus (ERS) of Paxinos and Watson (2007). ...
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... labeled neurons were smaller than those in adjacent PnO (FigII.8). Labeled cells were present in the ventral part of pontine reticular nucleus (PnV) and they were similar to those large cells in the gigantocellular reticular nucleus (Gi) ( FigII.9 and 10). ...
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... neurons in KF were bilaterally labeled and those in MPB and LPB were mainly labeled ipsilaterally. Labeled neurons in these nuclei appeared similar in shape, but smaller than labeled neurons in Pr5 ( FigII.9 and 18). 5N (FigII.17). ...
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... neurons in these nuclei appeared similar in shape, but smaller than labeled neurons in Pr5 ( FigII.9 and 18). 5N (FigII.17). A small number of labeled neurons were observed in the contralateral A5 region (FigII.10). ...
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... few spindle shaped neurons were observed in the parvicellular reticular nucleus (PCRt) and the intermediate reticular nucleus (IRt) on both sides (FigII.10-18). In the caudal hindbrain, labeled neurons were concentrated in the caudal part of IRt between the dorsal (MdD) and ventral (MdV) parts of the medullary reticular nuclei, and were mainly in the ipsilateral IRt ( FigII.13-15, 17). At the same level, a large number of labeled neurons were found in MdD and MdV with an ipsilateral predominance ( FigII.14-17). ...
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... the caudal hindbrain, labeled neurons were concentrated in the caudal part of IRt between the dorsal (MdD) and ventral (MdV) parts of the medullary reticular nuclei, and were mainly in the ipsilateral IRt ( FigII.13-15, 17). At the same level, a large number of labeled neurons were found in MdD and MdV with an ipsilateral predominance ( FigII.14-17). Medial to MdV, a small number of neurons was labeled in the paramedian reticular nucleus (PMn) (FigII.14). ...
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... the same level, a large number of labeled neurons were found in MdD and MdV with an ipsilateral predominance ( FigII.14-17). Medial to MdV, a small number of neurons was labeled in the paramedian reticular nucleus (PMn) (FigII.14). At the level of the abducens nucleus (6N), a large number of labeled neurons were observed in Gi, the lateral paragigantocellular reticular nucleus (LPGi), the alpha part of the gigantocellular reticular nucleus (GiA), and the ventral part of the gigantocellular reticular nucleus (GiV). ...
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... the level of the abducens nucleus (6N), a large number of labeled neurons were observed in Gi, the lateral paragigantocellular reticular nucleus (LPGi), the alpha part of the gigantocellular reticular nucleus (GiA), and the ventral part of the gigantocellular reticular nucleus (GiV). There were more labeled neurons on the ipsilateral side than the contralateral side ( FigII.11-13, 16-17). In GiA and GiV, labeled neurons formed an arch on the ipsilateral side covering the pyramidal tract (py) and the medial lemniscus (ml). ...
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... contralateral (FigII.11-12). Ventral to LPGi, a small number of labeled neurons were observed in the parapyramidal nucleus (PPy) bilaterally (FigII.11). In some cases, a few labeled neurons also were found in the area ventral to the facial nucleus (7N), which is likely to correspond to the retrotrapezoid nucleus (RTz) ( Smith et al. 1989) (FigII. 11). FigII.9 In this diagram of a coronal section through the caudal hindbrain at the level of the rostral pole of LC, labeled neurons were mainly present in the ipsilateral MPB, LPB. Labeled neurons were present in bilateral Pr5VL, Su5, SubCD, and SubCV with an ipsilateral predominance. Labeled neurons were present in bilateral PnC but ...
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... the raphe, labeled neurons were found in the raphe magnus nucleus (RMg), raphe interpositus nucleus (RIP), raphe obscurus nucleus (ROb), and the raphe pallidus nucleus (RPa) ( FigII.9-13). These labeled neurons were mostly oriented horizontally in coronal sections. ...
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... labeled neurons were observed in the contralateral anterior interposed cerebellar nucleus (IntA), posterior interposed cerebellar nucleus (IntP), and medial cerebellar nucleus (Med), including the dorsal lateral protuberance (MedDL) (FigII.11-12, 16-18). The intensity of labeling was similar to that in ...
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... cervical injections, small clusters of neurons were labeled in the PrCnF (FigIII.1a, ...
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... the rostralmost part of the PrCnF, there were 17.6 ± 1.6 labeled neurons per section (based After upper thoracic injections, there were 15.3 ± 1.5 and 6.7 ± 2.1 labeled cells in total on the ipsi-and contralateral side of the PrCnF, respectively (on the basis of 24 sections from 3 animals; FigIII.1c, d). In terms of their size (20.07 ± 5.14 μm × 13.29 ± 3.37 μm) and shape, the labeled neurons situated in the PrCnF were similar to those seen after cervical injections (FigIII.1d). After upper lumbar injections, labeled cells were not found in the PrCnF, but were still seen in the LPAG adjacent to the PrCnF (data not ...
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The central nucleus of the amygdala (CEA) and lateral bed nucleus of stria terminalis (BST) are highly interconnected limbic forebrain regions that share similar connectivity with other brain regions that coordinate behavioral and physiological responses to internal and environmental stressors. Their similar connectivity is frequently referred to w...
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... We also excluded subjects that had mCherry labeled cell bodies in supramammillary nucleus. But we did not exclude mice with spread to red nucleus or IPN because these regions are not known to project to NAc, PFC, VP, or LHb (Liang et al., 2011;McLaughlin et al., 2017). were incubated at 33°C for 25-30 min in a holding chamber containing NMDG-aCSF saturated with carbogen. ...
The ventral tegmental area (VTA) contains projection neurons that release the neurotransmitters dopamine, GABA, and/or glutamate from distal synapses. VTA also contains GABA neurons that synapse locally on to VTA dopamine neurons, synapses widely credited to a population of so-called VTA interneurons. Interneurons in cortex, striatum, and elsewhere have well-defined morphological features, physiological properties, and molecular markers, but such features have not been clearly described in VTA. Indeed, there is scant evidence that local and distal synapses originate from separate populations of VTA GABA neurons. In this study we tested whether several markers expressed in non-dopamine VTA neurons are selective markers of interneurons, defined as neurons that synapse locally but not distally. Challenging previous assumptions, we found that VTA neurons genetically defined by expression of parvalbumin, somatostatin, neurotensin, or mu-opioid receptor project to known VTA targets including nucleus accumbens, ventral pallidum, lateral habenula, and prefrontal cortex. Moreover, we provide evidence that VTA GABA and glutamate projection neurons make functional inhibitory or excitatory synapses locally within VTA. These findings suggest that local collaterals of VTA projection neurons could mediate functions prior attributed to VTA interneurons. This study underscores the need for a refined understanding of VTA connectivity to explain how heterogeneous VTA circuits mediate diverse functions related to reward, motivation, or addiction.
Significance statement
GABA neurons in VTA are key regulators of VTA dopamine neurons and considered central to the mechanisms of by which opioids and other drugs of abuse can induce addiction. Conventionally, these VTA GABA neurons are considered interneurons, but GABA projection neurons are also abundant in VTA, and it is unclear if these represent separate populations. We found that several markers enriched in non-dopamine neurons of VTA, including Mu-opioid receptor, are also expressed in projection neurons, and thus are not selective interneuron markers. Moreover, we found that VTA GABA and glutamate projection neurons collateralize within VTA where they make local synapses. These data challenge the notion of a VTA interneuron that synapses only within VTA and suggest that inhibitory projection neurons can serve functions previously attributed to VTA interneurons.
... These brain areas included the contralateral motor cortices, ipsilateral primary somatosensory cortex, barrel area, contralateral p1 reticular formation, magnocellular and parvicellular parts of the red nucleus (RMC and RPC), ipsilateral oral and caudal part of the pontine reticular nucleus, and bilateral gigantocellular vestibular nucleus. Previous unilateral retrograde tracing from the cervical 1 and 2 segments in mouse shows a similar tracing pattern as observed in our tracing experiment (Liang et al., 2011). The RMC and reticular formations are related to analgesic functions (Prado et al., 1984;Martins and Tavares, 2017;Basile et al., 2021) and the RMC, RPC, and pontine reticular nucleus to motor functions (Morales et al., 1987;Kennedy, 1990;Basile et al., 2021). ...
Glycinergic neurons regulate nociceptive and pruriceptive signaling in the spinal cord, and the identity and role of the glycine-regulated neurons are not fully known. Herein, we have characterized spinal glycine receptor alpha 3 ( Glra3 ) subunit-expressing neurons in Glra3 -Cre female and male mice. Glra3 -Cre(+) neurons express Glra3 , are located mainly in laminae III‒VI, and respond to glycine. Chemogenetic activation of spinal Glra3 -Cre(+) neurons induced biting/licking, stomping, and guarding behaviors, indicative of both a nociceptive and pruriceptive role for this population. Chemogenetic inhibition did not affect mechanical or thermal responses, but reduced behaviors evoked by compound 48/80 and chloroquine, revealing a pruriceptive role for these neurons. Spinal cells activated by compound 48/80 or chloroquine express Glra3 , further supporting the phenotype. Retrograde tracing revealed that spinal Glra3 -Cre(+) neurons receive input from afferents associated with pain and itch, and dorsal root stimulation validated the monosynaptic input. In conclusion, these results show that spinal Glra3 (+) neurons contribute to acute communication of compound 48/80- and chloroquine-induced itch in hairy skin.
Significance Statement Spinal glycinergic neurons regulate itch (pruriception), suggesting that components of the glycinergic system have great potential as drug targets to treat pruritus. Nonetheless, thus far, the pruriceptive roles of any of the glycine receptor (GLR) subunits have not been evaluated. Here, we successfully linked the Glra3 -Cre populations to a pro-pruriceptive role in itch, indicating that GLRA3-expressing neurons may be a potential novel target for itch treatment. The spontaneous stomping and guarding behaviors observed from activating the Glra3 -Cre populations are indicative of a role in sensory hypersensitivity and hence, raises questions regarding the hypersensitivity involvement of these populations for future investigations.
... These pathways in mammals play vital roles in the initiation of movements of the limbs and trunk, including grasping, walking and posture maintenance. More than twenty brain regions have been identified giving rise to the descending tracts by using retrograde tracing methods (e.g., adeno-associated virus or dyes) in previous research 8,9 , in which the descending tracts arising from the cerebral cortex 1,2,10,11 , red nucleus 12,13 , hindbrain reticular formation 14,15 , and vestibular nuclei 16 have been studied extensively. However, several other descending nuclei, such as the medial and interposed cerebellar nuclei (Med and Int) 5,17 , the superior colliculus 18,19 , and the spinal trigeminal nucleus 20,21 are less well understood. ...
... In our studies, we detected rare neurons in the superior colliculus through retrograde labelling by virus injection into the spinal cord ( Fig. 1E, Supplementary Fig S1). The results suggested that the superior colliculus neurons barely projected to the spinal cord in mouse, which was consistent with previous findings 8 . We further confirmed the observation by imaging the cleared spinal cords of mice labelling the SC neurons through virus injection. ...
Descending tracts carry motor signals from the brain to spinal cord. However, few previous studies show the full view of the long tracts from a 3D perspective. In this study, we have followed five less well-known tracts that project from midbrain, hindbrain, and cerebellum to the mouse spinal cord, using the tissue clearing method in combination with tiling light sheet microscopy. By tracing axons in spinal cord, we found several notable features: among the five tracts the collateral "sister" branches occurred only in the axons originating from the cerebellospinal tracts; the axons from the spinal trigeminal nucleus crossed the midline of spinal cord to the contralateral side; those arising in the medullary reticular formation ventral part gave many branches in both cervical and lumbar segments; the axons from superior colliculus terminated only at upper cervical but with abundant branches in the hindbrain. Furthermore, we investigated the monosynaptic connections between the tracts and motor neurons in the spinal cord through hydrogel-based tissue expansion, and found several monosynaptic connections between the medullary reticular formation ventral part axons and spinal motor neurons. We believe that this is the first study to show the full 3D scope of the projection patterns and axonal morphologies of these five descending tracts to the mouse spinal cord. In addition, we have developed a new method for future study of descending tracts by three-dimensional imaging.
... These are thought to engage motor systems principally by driving central pattern generators (CPGs), neurons or neuronal circuits that produce periodic bursts in the absence of a bursting input, to generate rhythmic appendage and body movements (Fig. 1, teal) (10). Descending neurons may also modulate reflexes and directly influence lower motor neurons (11). CPG-based control is capable of coordinating very different modes of locomotion, including swimming and walking (12). ...
Robotics and neuroscience are sister disciplines that both aim to understand how agile, efficient, and robust locomotion can be achieved in autonomous agents. Robotics has already benefitted from neuromechanical principles discovered by investigating animals. These include the use of high-level commands to control low-level central pattern generator-like controllers, which, in turn, are informed by sensory feedback. Reciprocally, neuroscience has benefited from tools and intuitions in robotics to reveal how embodiment, physical interactions with the environment, and sensory feedback help sculpt animal behavior. We illustrate and discuss exemplar studies of this dialog between robotics and neuroscience. We also reveal how the increasing biorealism of simulations and robots is driving these two disciplines together, forging an integrative science of autonomous behavioral control with many exciting future opportunities.
... In CaMKIIα-GFP mice, we determined that a high proportion of motor cortex neurons are GFP + (Fig. 1), consistent with previous reports (Wang et al., 2013). GFP fluorescence in the corticospinal tract, suggested that CaMKIIα may be driving hTDP-43 expression in descending axons that terminate in either lamina X to control motor pathways or the dorsal horn to modulate sensory pathways (Liang et al., 2011;Steward et al., 2021). GFP was also expressed by cell bodies in the spinal cord grey matter, specifically the dorsal horn (Fig. 1), placing them outside of the direct motor circuit (Nimmagadda et al., 2013). ...
Alterations in upper motor neuron excitability are one of the earliest phenomena clinically detected in ALS, and in 97% of cases, the RNA/DNA binding protein, TDP-43, is mislocalised in upper and lower motor neurons. While these are two major pathological hallmarks in disease, our understanding of where disease pathology begins, and how it spreads through the corticomotor system, is incomplete. This project used a model where mislocalised TDP-43 was expressed in the motor cortex, to determine if localised cortical pathology could result in widespread corticomotor system degeneration. Mislocalised TDP-43 caused layer V excitatory neurons in the motor cortex to become hyperexcitable after 20 days of expression. Following cortical hyperexcitability, a spread of pathogenic changes through the corticomotor system was observed. By 30 days expression, there was a significant decrease in lower motor neuron number in the lumbar spinal cord. However, cell loss occurred selectively, with a significant loss in lumbar regions 1-3, and not lumbar regions 4-6. This regional vulnerability was associated with alterations in pre-synaptic excitatory and inhibitory proteins. Excitatory inputs (VGluT2) were increased in all lumbar regions, while inhibitory inputs (GAD65/67) were increased in lumbar regions 4-6 only. This data indicates that mislocalised TDP-43 in upper motor neurons can cause lower motor neuron degeneration. Furthermore, cortical pathology increased excitatory inputs to the spinal cord, to which local circuitry compensated with an upregulation of inhibition. These findings reveal how TDP-43 mediated pathology may spread through corticofugal tracts in ALS and identify a potential pathway for therapeutic intervention.
... The neuronal networks from dPVN, LC and DR to L5 spinal dorsal horn was confirmed using a retrograde tracer, consistent with results from previous studies 36,37 . OT innervation was more prominent between L4 and L6 in the superficial layers (laminae I-II). ...
Oxytocin is involved in pain transmission, although the detailed mechanism is not fully understood. Here, we generate a transgenic rat line that expresses human muscarinic acetylcholine receptors (hM3Dq) and mCherry in oxytocin neurons. We report that clozapine-N-oxide (CNO) treatment of our oxytocin-hM3Dq-mCherry rats exclusively activates oxytocin neurons within the supraoptic and paraventricular nuclei, leading to activation of neurons in the locus coeruleus (LC) and dorsal raphe nucleus (DR), and differential gene expression in GABA-ergic neurons in the L5 spinal dorsal horn. Hyperalgesia, which is robustly exacerbated in experimental pain models, is significantly attenuated after CNO injection. The analgesic effects of CNO are ablated by co-treatment with oxytocin receptor antagonist. Endogenous oxytocin also exerts anti-inflammatory effects via activation of the hypothalamus-pituitary-adrenal axis. Moreover, inhibition of mast cell degranulation is found to be involved in the response. Taken together, our results suggest that oxytocin may exert anti-nociceptive and anti-inflammatory effects via both neuronal and humoral pathways.
... Extensive work spanning more than a century has employed orthograde degeneration, electrical stimulation, and axonal transport-tracing methods to characterize the location and function of specific supraspinal neurons in various animals, providing a base of knowledge to understand supraspinal control (Nudo and Masterton, 1988;Kuypers and Martin, 1982;Hoff, 1932;Glees, 1946;ten Donkelaar, 2000). Several efforts in rodents have provided more global information by performing retrograde tracing from selected spinal levels, followed by tissue sectioning and manual assignment of labeled cell bodies to regions within the brain (Lakke, 1997;Leong et al., 1984;Liang et al., 1997 ). Significant challenges, however, impede the distribution of this foundational knowledge and its application to the study of disease and injury-based disruptions. ...
... This attention is justified as these regions serve important motor functions and comprise a majority of descending input (Lemon, 2008). On the other hand, dozens of additional brain regions also project to the spinal cord, many of which carry essential motor and autonomic commands (Liang et al., 1997). Without tools to easily monitor the totality of the supraspinal connectome, researchers lack even basic information regarding their sensitivity to injury, innate plasticity, or potentially disparate responses to potential pro-regenerative therapies. ...
... This region contains spinally projecting neurons that may initiate locomotion, as well as the ventral rostral medullary group that regulates blood pressure (Capelli et al., 2017;Van Bockstaele et al., 1989;Opris et al., 2019). A cluster of labeled nuclei was also located dorsally in the caudal medulla, within and near the solitary nucleus, as supraspinal region implicated in visceral input to respiration and cardiovascular tone (Leong et al., 1984;Liang et al., 1997;Mtui et al., 1995 ;Figure 1-figure supplement 4B3). ...
The supraspinal connectome is essential for normal behavior and homeostasis and consists of numerous sensory, motor, and autonomic projections from brain to spinal cord. Study of supraspinal control and its restoration after damage has focused mostly on a handful of major populations that carry motor commands, with only limited consideration of dozens more that provide autonomic or crucial motor modulation. Here we assemble an experimental workflow to rapidly profile the entire supraspinal mesoconnectome in adult mice and disseminate the output in a web-based resource. Optimized viral labeling, 3D imaging, and registration to a mouse digital neuroanatomical atlas assigned tens of thousands of supraspinal neurons to 69 identified regions. We demonstrate the ability of this approach to clarify essential points of topographic mapping between spinal levels, to measure population-specific sensitivity to spinal injury, and to test relationships between region-specific neuronal sparing and variability in functional recovery. This work will spur progress by broadening understanding of essential but understudied supraspinal populations.
... Approximately 0.93 million people worldwide suffer from spinal cord injury (SCI) with severe sequelae each year, justifying the intense research on treatments for SCI (Asboth et al., 2018;Shinozaki et al., 2021). The descending pathway originates from various brain nuclei and finally converges into specific areas in the spinal cord (Lemon, 2008;Liang et al., 2011). Supraspinal inputs are necessary movement commands that regulate normal activities mediated by the corresponding descending tracts, including the corticospinal tract (CST), the rubrospinal tract (RST), and the reticulospinal tract (RtST) (Engmann et al., 2020;Wang et al., 2017;Williams & Martin, 2015). ...
The supraspinal inputs play a major role in tuning the hindlimb locomotion function. While most research on spinal cord injury (SCI) with rodents is based on thoracic segments, the difference in connectivity of the supraspinal centers to the thoracic and lumbar cord is still unknown. Here, we combined retrograde tracing and 3D imaging to map the connectivity of supraspinal neurons projecting to thoracic (T9‐vertebral) and lumbar (T13‐vertebral) spinal levels in adult female mice. We dissected the difference in connections of corticospinal neurons (CSNs), rubrospinal neurons, and reticulospinal neurons projecting to thoracic and lumbar cords. The ratio of double‐labeled neurons is higher in T13‐vertebral projection CSNs and parvocellular part of the red nucleus (RPC) than in T9‐vertebral projection. Using the Cre‐DIO system, we precisely targeted CSNs projecting to T9‐vertebral or T13‐vertebral. We found that abundant axon branches communicated with the red nucleus and reticular formation and distributed from cervical gray matter to the lumbar cord. Their collateral branches showed a distinct innervation pattern in thoracic and lumbar gray matters and a similar distribution pattern in the cervical spinal cord. These results revealed the difference in connectivity between the thoracic and lumbar projection supraspinal centers and clarified the collateralization of thoracic/lumbar projection CSNs throughout the brain and spinal cord. This study highlights brain‐spinal cord neural networks and the complexity of the axon terminals of spinal projection CSNs, which could contribute to the development of targeted therapeutic strategies connecting CST fibers and hindlimb function recovery. image
Cover Image for this issue: https://doi.org/10.1111/jnc.15414
... que llegan a regiones torácicas dejan colaterales en regiones cervicales, no obstante, las que llegan a regiones lumbares no presentaron colaterales en cervicales (Shinoda et. al., 1996). En general, la distribución de las neuronas cortico-espinales mostrada en el presente estudio marcadas es similar a lo que se ha descrito previamente en roedores (Liang et. al., 2011;Moreno-López et. al., 2016;Olivares-Moreno et. al., 2017;Wang et. al., 2017;Ueno et. al., 2018;Steward et. al., 2021); sin embargo, la existencia y distribución de estas proyecciones colaterales cortico-espinales a nivel de la médula espinal en la rata, así como sus implicaciones funcionales, queda por ser explorada. ...
Nowadays, the study in vivo of neuronal circuits is of great interest, based on anatomical and functional analysis to determine the connections established between diverse types of neurons. Contemporary neurosciences have focused on studying different populations of neurons, in addition to observing how this population activity determines animal behavior. Knowledge about how these different circuits are organized and interact is essential to understand how neuronal activity participates in different aspects of sensorimotor control, as well as in the execution of complex cognitive processes such as perception and behavior. To study these phenomena, the pyramidal system is an excellent model, since it modulates an important diversity of functions related to sensorimotor control through direct and indirect actions on interneurons and motoneurons, as well as modulating the information flow at different levels (Olivares- Moreno et. al., 2017; Ueno et. al., 2018).
The pyramidal system consists of a variety of neuronal groups located in layer 5a and 5b of the cerebral cortex, which receive lots of inputs from other structures of the nervous system, such as the thalamus and other cortical areas, and it is the main output of information from the cortex (Hattox & Nelson, 2007; Kim et. al., 2015). Sensorimotor processes are modulated through the descending projections formed by pyramidal tract neurons, since these neuronal pathways participate in the execution of volitional movements and sensory modulation either through direct projections to the spinal cord or indirect projections to different subcortical structures such as the red nucleus, the pontine nucleus, the striatum, the thalamus, the reticular formation, the pons, among others (Akintude & Buxton, 1992; Molyneaux et. al., 2007; Moreno-López et. al., 2013, 2016; Rojas-Piloni et. al., 2017; Olivares-Moreno et. al., 2019). At the same time, the cortex modulates the selection of ascending information generated by the movement itself and coordinates the activity of other descending and ascending systems related to sensorimotor integration processes (Canedo, 2003).
Pyramidal system neurons are partially segregated into functionally heterogeneous populations, according to their projection site (Rojas-Piloni et. al., 2017; Ecónomo et. al., 2018; Olivares-Moreno et. al., 2019). There is evidence that movement generation involves the coordinated activity of multiple projections of the cortex that modulate distinct phases of movement; for example, forelimb motor control is controlled by different tracts, including the cortico-spinal in conjunction with other tracts such as the cortico-rubral (Kuypers & Martin,
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1982; Lemon, 2008; Wang et. al., 2017). Even though the cortico-spinal tract has been very well studied independently, little is known about the existing functional interactions with other tracts, as well as the hierarchy and organization of the intracortical circuits that allow the regulation of sensory inputs and execution of movements. There are few anatomical and functional studies related to the cortico-rubral tract and most of them date from before the 2000’s (Pubmed, 2022), the study of this projection pathway is just being reconsidered, which is why it is important to have more evidence on its distribution in the cortex and thus providing an anatomical background so that future functional studies can begin to identify the interactions between cortico-rubral and cortico-spinal populations and thereby more specifically determine their role in sensorimotor control.
In this project, distribution and density profiles were carried out for the location of two populations of projection neurons: cortico-rubral and cortico-spinal, whose axons project to the red nucleus and the spinal cord, respectively. To carry out the reconstructions, double injections of retrograde neuronal tracers were used, which were injected stereotaxically into Wistar rats. Subsequently, histological and large-scale microscopy analyzes were performed to locate the neurons marked with said tracers. Finally, using the specialized AMIRA software, the photomicrographs were aligned to structural magnetic resonance images and the neurons were marked to build the different profiles.
... In addition to the abovementioned cerebellar efferent pathways to other brain regions associated with motor control, it has been long known that the cerebellum also sends direct projections to the spinal cord [e.g. (Thomas et al., 1956;Fukushima et al., 1977;Matsushita and Hosoya, 1978;Asanuma et al., 1980;Liang et al., 2011;Wang et al., 2018)]. A study using retrograde labeling further characterized the cerebellospinal pathways, demonstrating that distinct populations of DCN neurons in the anterior IPN send ipsilateral projections to the cervical, thoracic, and lumbar cords, whereas contralateral connections from the posterior IPN and FN are limited to the cervical cord (Sathyamurthy et al., 2020). ...
The cerebellum has a long history in terms of research on its network structures and motor functions, yet our understanding of them has further advanced in recent years owing to technical developments, such as viral tracers, optogenetic and chemogenetic manipulation, and single cell gene expression analyses. Specifically, it is now widely accepted that the cerebellum is also involved in non-motor functions, such as cognitive and psychological functions, mainly from studies that have clarified neuronal pathways from the cerebellum to other brain regions that are relevant to these functions. The techniques to manipulate specific neuronal pathways were effectively utilized to demonstrate the involvement of the cerebellum and its pathways in specific brain functions, without altering motor activity. In particular, the cerebellar efferent pathways that have recently gained attention are not only monosynaptic connections to other brain regions, including the periaqueductal gray and ventral tegmental area, but also polysynaptic connections to other brain regions, including the non-primary motor cortex and hippocampus. Besides these efferent pathways associated with non-motor functions, recent studies using sophisticated experimental techniques further characterized the historically studied efferent pathways that are primarily associated with motor functions. Nevertheless, to our knowledge, there are no articles that comprehensively describe various cerebellar efferent pathways, although there are many interesting review articles focusing on specific functions or pathways. Here, we summarize the recent findings on neuronal networks projecting from the cerebellum to several brain regions. We also introduce various techniques that have enabled us to advance our understanding of the cerebellar efferent pathways, and further discuss possible directions for future research regarding these efferent pathways and their functions.
