Explore the vast range of titles available.

Historically, the creation of the parasympathetic division of the autonomic nervous system of the vertebrates is inextricably linked to the unification of the cranial and sacral autonomic outflows. There is an intriguing disproportion between the entrenchment of the notion of a ‘cranio-sacral’ pathway, which informs every textbook schematic of the autonomic nervous system since the early XX th century, and the wobbliness of its two roots: an anatomical detail overinterpreted by Walter Holbrook Gaskell (the ‘gap’ between the lumbar and sacral outflows), on which John Newport Langley grafted a piece of physiology (a supposed antagonism of these two outflows on external genitals), repeatedly questioned since, to little avail. I retrace the birth of a flawed scientific concept (the cranio-sacral outflow) and the way in which it ossified instead of dissipated. Then, I suggest that the critique of the ‘cranio-sacral outflow’ invites, in turn, a radical deconstruction of the very notion of a ‘parasympathetic’ outflow, and a more realistic description of the autonomic nervous system.

Most of the enteric nervous system derives from the “vagal” neural crest, lying at the level of somites 1–7, which invades the digestive tract rostro-caudally from the foregut to the hindgut. Little is known about the initial phase of this colonization, which brings enteric precursors into the foregut. Here we show that the “vagal crest” subsumes two populations of enteric precursors with contrasted origins, initial modes of migration, and destinations. Crest cells adjacent to somites 1 and 2 produce Schwann cell precursors that colonize the vagus nerve, which in turn guides them into the esophagus and stomach. Crest cells adjacent to somites 3–7 belong to the crest streams contributing to sympathetic chains: they migrate ventrally, seed the sympathetic chains, and colonize the entire digestive tract thence. Accordingly, enteric ganglia, like sympathetic ones, are atrophic when deprived of signaling through the tyrosine kinase receptor ErbB3, while half of the esophageal ganglia require, like parasympathetic ones, the nerve-associated form of the ErbB3 ligand, Neuregulin-1. These dependencies might bear relevance to Hirschsprung disease, with which alleles of Neuregulin-1 are associated.

Introduction A pilot study provided preliminary evidence indicating that peri‐lesional adult autologous neural cell ecosystem transplantation (so‐called ANCE) can enhance the functional recovery of manual dexterity in macaque monkeys following a unilateral lesion of the hand representation in the primary motor cortex (M1). As compared to five untreated control animals subjected to M1 lesions, the improvement of functional recovery was observed in our pilot study in two ANCE‐treated monkeys (also M1 lesioned). To strengthen these promising preliminary results, the present study aimed at introducing two additional ANCE monkeys, as well as one new control monkey, all subjected to M1 lesion. Methods Manual dexterity was assessed based on the modified Brinkman board task, performed with the contralesional hand to retrieve small food pellets from slots using the precision grip (opposition of thumb and index finger). Results As with the two pilot ANCE‐treated monkeys, the two new ANCE‐treated monkeys exhibited a rebound of functional recovery (a second plateau) associated to the treatment (after approximately 2–3 months delay post‐treatment), following a first plateau of spontaneous recovery. In contrast, all control monkeys (n = 6) exhibited a single plateau of functional recovery. Conclusion The present study confirms that ANCE treatment significantly improves functional recovery from motor cortex lesions in adult macaques, with performance gains ranging from 20% to 40%. These findings support a possible future initiative to initiate clinical trials based on ANCE therapy. Together, an earlier pilot study and the current confirmatory study show that an autologous cellular therapy promotes beneficial, significant enhancement of manual dexterity recovery after lesion of the primary motor cortex.

It has been known for more than a century that, in adult vertebrates, the maintenance of taste buds depends on their afferent nerves. However, the initial formation of taste buds is proposed to be nerve-independent in amphibians, and evidence to the contrary in mammals has been endlessly debated, mostly due to indirect and incomplete means to impede innervation during the protracted perinatal period of taste bud differentiation. Here, by genetically ablating, in mice, all somatic (i.e. touch) or visceral (i.e. taste) neurons for the oral cavity, we show that the latter but not the former are absolutely required for the proper formation of their target organs, the taste buds.

Taste and most sensory inputs required for the feedback regulation of digestive, respiratory, and cardiovascular organs are conveyed to the central nervous system by so-called \"visceral\" sensory neurons located in three cranial ganglia (geniculate, petrosal, and nodose) and integrated in the hindbrain by relay sensory neurons located in the nucleus of the solitary tract. Visceral sensory ganglia and the nucleus of the solitary tract all depend for their formation on the pan-visceral homeodomain transcription factor Phox2b, also required in efferent neurons to the viscera. We show here, by genetically tracing Phox2b+ cells, that in the absence of the protein, many visceral sensory neurons (first- and second-order) survive. However, they adopt a fate—including molecular signature, cell positions, and axonal projections—akin to that of somatic sensory neurons (first- and second-order), located in the trigeminal, superior, and jugular ganglia and the trigeminal sensory nuclei, that convey touch and pain sensation from the oro-facial region. Thus, the cranial sensory pathways, somatic and visceral, are related, and Phox2b serves as a developmental switch from the former to the latter.

Breathing is maintained and controlled by a network of neurons in the brainstem that generate respiratory rhythm and provide regulatory input. Central chemoreception, the mechanism for CO₂ detection that provides an essential stimulatory input, is thought to involve neurons located near the medullary surface, whose nature is controversial. Good candidates are serotonergic medullary neurons and glutamatergic neurons in the parafacial region. Here, we show that mice bearing a mutation in Phox2b that causes congenital central hypoventilation syndrome in humans breathe irregularly, do not respond to an increase in CO₂, and die soon after birth from central apnea. They specifically lack Phox2b-expressing glutamatergic neurons located in the parafacial region, whereas other sites known or supposed to be involved in the control of breathing are anatomically normal. These data provide genetic evidence for the essential role of a specific population of medullary interneurons in driving proper breathing at birth and will be instrumental in understanding the etiopathology of congenital central hypoventilation syndrome.

The most common forms of neurocristopathy in the autonomic nervous system are Hirschsprung disease (HSCR), resulting in congenital loss of enteric ganglia, and neuroblastoma (NB), childhood tumors originating from the sympathetic ganglia and adrenal medulla. The risk for these diseases dramatically increases in patients with congenital central hypoventilation syndrome (CCHS) harboring a nonpolyalanine repeat expansion mutation of the Paired-like homeobox 2b (PHOX2B) gene, but the molecular mechanism of pathogenesis remains unknown. We found that introducing nonpolyalanine repeat expansion mutation of the PHOX2B into the mouse Phox2b locus recapitulates the clinical features of the CCHS associated with HSCR and NB. In mutant embryos, enteric and sympathetic ganglion progenitors showed sustained sex-determining region Y (SRY) box10 (Sox10) expression, with impaired proliferation and biased differentiation toward the glial lineage. Nonpolyalanine repeat expansion mutation of PHOX2B reduced transactivation of wild-type PHOX2B on its known target, dopamine β-hydroxylase (DBH), in a dominant-negative fashion. Moreover, the introduced mutation converted the transcriptional effect of PHOX2B on a Sox10 enhancer from repression to transactivation. Collectively, these data reveal that nonpolyalanine repeat expansion mutation of PHOX2B is both a dominant-negative and gain-of-function mutation. Our results also demonstrate that Sox10 regulation by PHOX2B is pivotal for the development and pathogenesis of the autonomic ganglia.

We recently defined genetic traits that distinguish sympathetic from parasympathetic neurons, both preganglionic and ganglionic (Espinosa-Medina et al., Science 354:893–897, 2016). By this set of criteria, we found that the sacral autonomic outflow is sympathetic, not parasympathetic as has been thought for more than a century. Proposing such a belated shift in perspective begs the question why the new criterion (cell types defined by their genetic make-up and dependencies) should be favored over the anatomical, physiological and pharmacological considerations of long ago that inspired the “parasympathetic” classification. After a brief reminder of the former, we expound the weaknesses of the latter and argue that the novel genetic definition helps integrating neglected anatomical and physiological observations and clearing the path for future research.

Aquaporin 4 (AQP4) is a water channel involved in water movements across the cell membrane and is spatially organized on the cell surface in orthogonal array particles (OAPs). Its role in edema formation or resolution after stroke onset has been studied mainly at late time points. We have shown recently that its expression is rapidly induced after ischemia coinciding in time with an early swelling of the ischemic hemisphere. There are two isoforms of AQP4: AQP4-M1 and AQP4-M23. The ratio of these isoforms influences the size of the OAPs but the functional impact is not known. The role of the early induction of AQP4 is not yet known. Thrombin preconditioning in mice provides a useful model to study endogenous protective mechanisms. Using this model, we provide evidence for the first time that the early induction of AQP4 may contribute to limit the formation of edema and that the AQP4-M1 isoform is predominantly induced in the ischemic tissue at this time point. Although it prevents edema formation, the early induction of the AQP4 expression does not prevent the blood—brain barrier disruption, suggesting an effect limited to the prevention of edema formation possibly by removing of water from the tissue.

The respiratory rhythm is generated by the preBötzinger complex in the medulla oblongata, and is modulated by neurons in the retrotrapezoid nucleus (RTN), which are essential for accelerating respiration in response to high CO₂. Here we identify a LBX1 frameshift (LBX1FS ) mutation in patients with congenital central hypoventilation. The mutation alters the C-terminal but not the DNA-binding domain of LBX1. Mice with the analogous mutation recapitulate the breathing deficits found in humans. Furthermore, the mutation only interferes with a small subset of Lbx1 functions, and in particular with development of RTN neurons that coexpress Lbx1 and Phox2b. Genome-wide analyses in a cell culture model show that Lbx1FS and wild-type Lbx1 proteins are mostly bound to similar sites, but that Lbx1FS is unable to cooperate with Phox2b. Thus, our analyses on Lbx1FS (dys)function reveals an unusual pathomechanism; that is, a mutation that selectively interferes with the ability of Lbx1 to cooperate with Phox2b, and thus impairs the development of a small subpopulation of neurons essential for respiratory control.