Morphological Analysis of the Hindbrain Glucose Sensor-Hypothalamic Neural Pathway Activated by Hindbrain Glucoprivation.

Lowered glucose availability, sensed by the hindbrain, has been suggested to enhance gluconeogenesis and food intake as well as suppress reproductive function. In fact, our previous histological and in vitro studies suggest that hindbrain ependymal cells function as a glucose sensor. The present study aimed to clarify the hindbrain glucose sensor-hypothalamic neural pathway activated in response to hindbrain glucoprivation to mediate counterregulatory physiological responses. Administration of 2-deoxy-D-glucose (2DG), an inhibitor of glucose utilization, into the fourth ventricle (4V) of male rats for 0.5 hour induced messenger RNA (mRNA) expression of c-fos, a marker for cellular activation, in ependymal cells in the 4V, but not in the lateral ventricle, the third ventricle or the central canal without a significant change in blood glucose and testosterone levels. Administration of 2DG into the 4V for 1 hour significantly increased blood glucose levels, food intake, and decreased blood testosterone levels. Simultaneously, the expression of c-Fos protein was detected in the 4V ependymal cells; dopamine ß-hydroxylase-immunoreactive cells in the C1, C2, and A6 regions; neuropeptide Y (NPY) mRNA-positive cells in the C2; corticotropin-releasing hormone (CRH) mRNA-positive cells in the hypothalamic paraventricular nucleus (PVN); and NPY mRNA-positive cells in the arcuate nucleus (ARC). Taken together, these results suggest that lowered glucose availability, sensed by 4V ependymal cells, activates hindbrain catecholaminergic and/or NPY neurons followed by CRH neurons in the PVN and NPY neurons in the ARC, thereby leading to counterregulatory responses, such as an enhancement of gluconeogenesis, increased food intake, and suppression of sex steroid secretion.

The Mesencephalic Trigeminal Nucleus Controls Food Intake and Body Weight via Hindbrain POMC Projections.

The mesencephalic trigeminal nucleus (Mes5) processes oral sensory-motor information, but its role in the control of energy balance remains unexplored. Here, using fluorescent in situ hybridization, we show that the Mes5 expresses the melanocortin-4 receptor. Consistent with MC4R activation in other areas of the brain, we found that Mes5 microinjection of the MC4R agonist melanotan-II (MTII) suppresses food intake and body weight in the mouse. Furthermore, NTS POMC-projecting neurons to the Mes5 can be chemogenetically activated to drive a suppression in food intake. Taken together, these findings highlight the Mes5 as a novel target of melanocortinergic control of food intake and body weight regulation, although elucidating the endogenous role of this circuit requires future study. While we observed the sufficiency of Mes5 MC4Rs for food intake and body weight suppression, these receptors do not appear to be necessary for food intake or body weight control. Collectively, the data presented here support the functional relevance of the NTS POMC to Mes5 projection pathway as a novel circuit that can be targeted to modulate food intake and body weight.

Folic acid supplementation rescues valproic acid-induced developmental neurotoxicity and behavioral alterations in zebrafish embryos.

OBJECTIVE: Fetal exposure to the anticonvulsant drug valproic acid (VPA), used to treat certain types of epilepsy, increases the risk for birth defects, including neural tube defects, as well as learning difficulties and behavioral problems. Here, we investigated neurotoxic effects of VPA exposure using zebrafish as a model organism. The capacity of folic acid (FA) supplementation to rescue the VPA-induced neuronal and behavioral perturbations was also examined. METHODS: Zebrafish embryos of different transgenic lines with neuronal green fluorescent protein expression were exposed to increasing concentrations of VPA with or without FA supplementation. Fluorescence microscopy was used to visualize alterations in brain structures and neural progenitor cells, as well as motor neurons and neurite sprouting. A twitching behavioral assay was used to examine the functional consequences of VPA and FA treatment. RESULTS: In zebrafish embryos, VPA exposure caused a decrease in the midbrain size, an increase in the midline gap of the hindbrain, and perturbed neurite sprouting of secondary motor neurons, in a concentration-dependent manner. VPA exposure also decreased the fluorescence intensity of neuronal progenitor cells in early developmental stages, indicating fewer cells. Furthermore, VPA exposure significantly altered embryonic twitching activity, causing hyperactivity in dark and hypoactivity in light. Supplementation of FA rescued the VPA-induced smaller midbrain size and hindbrain midline gap defects. FA treatment also increased the number of neuronal progenitor cells in VPA-treated embryos and salvaged neurite sprouting of the secondary motor neurons. FA rescued the VPA-induced alterations in twitching activity in light but not in dark. SIGNIFICANCE: We conclude that VPA exposure induces specific neurotoxic perturbations in developing zebrafish embryos, and that FA reversed most of the identified defects. The results demonstrate that zebrafish is a promising model to study VPA-induced teratogenesis and to screen for countermeasures.

The endocranium and trophic ecology of Velociraptor mongoliensis.

Neuroanatomical reconstructions of extinct animals have long been recognized as powerful proxies for palaeoecology, yet our understanding of the endocranial anatomy of dromaeosaur theropod dinosaurs is still incomplete. Here, we used X-ray computed microtomography (µCT) to reconstruct and describe the endocranial anatomy, including the endosseous labyrinth of the inner ear, of the small-bodied dromaeosaur, Velociraptor mongoliensis. The anatomy of the cranial endocast and ear were compared with non-avian theropods, modern birds, and other extant archosaurs to establish trends in agility, balance, and hearing thresholds in order to reconstruct the trophic ecology of the taxon. Our results indicate that V. mongoliensis could detect a wide and high range of sound frequencies (2,368-3,965 Hz), was agile, and could likely track prey items with ease. When viewed in conjunction with fossils that suggest scavenging-like behaviours in V. mongoliensis, a complex trophic ecology that mirrors modern predators becomes apparent. These data suggest that V. mongoliensis was an active predator that would likely scavenge depending on the age and health of the individual or during prolonged climatic events such as droughts.

Untangling the dorsal diencephalic conduction system: a review of structure and function of the stria medullaris, habenula and fasciculus retroflexus.

The often-overlooked dorsal diencephalic conduction system (DDCS) is a highly conserved pathway linking the basal forebrain and the monoaminergic brainstem. It consists of three key structures; the stria medullaris, the habenula and the fasciculus retroflexus. The first component of the DDCS, the stria medullaris, is a discrete bilateral tract composed of fibers from the basal forebrain that terminate in the triangular eminence of the stalk of the pineal gland, known as the habenula. The habenula acts as a relay hub where incoming signals from the stria medullaris are processed and subsequently relayed to the midbrain and hindbrain monoaminergic nuclei through the fasciculus retroflexus. As a result of its wide-ranging connections, the DDCS has recently been implicated in a wide range of behaviors related to reward processing, aversion and motivation. As such, an understanding of the structure and connections of the DDCS may help illuminate the pathophysiology of neuropsychiatric disorders such as depression, addiction and pain. This is the first review of all three components of the DDCS, the stria medullaris, the habenula and the fasciculus retroflexus, with particular focus on their anatomy, function and development.

Behavioral evolution contributes to hindbrain diversification among Lake Malawi cichlid fish.

The evolutionary diversification of animal behavior is often associated with changes in the structure and function of nervous systems. Such evolutionary changes arise either through alterations of individual neural components ("mosaically") or through scaling of the whole brain ("concertedly"). Here we show that the evolution of a courtship behavior in Malawi cichlid fish is associated with rapid, extensive, and specific diversification of orosensory, gustatory centers in the hindbrain. We find that hindbrain volume varies significantly between species that build pit (depression) compared to castle (mound) type bowers and that this trait is evolving rapidly among castle-building species. Molecular analyses of neural activity via immediate early gene expression indicate a functional role for hindbrain structures during bower building. Finally, comparisons of bower building species in neighboring Lake Tanganyika suggest parallel patterns of neural diversification to those in Lake Malawi. Our results suggest that mosaic brain evolution via alterations to individual brain structures is more extensive and predictable than previously appreciated.

Generation of the squamous epithelial roof of the 4th ventricle.

We use the transparency of zebrafish embryos to reveal the de novo generation of a simple squamous epithelium and identify the cellular architecture in the epithelial transition zone that ties this squamous epithelium to the columnar neuroepithelium within the embryo's brain. The simple squamous epithelium of the rhombencephalic roof plate is pioneered by distinct mesenchymal cells at the dorsal midline of the neural tube. Subsequently, a progenitor zone is established at the interface between columnar epithelium of the rhombic lip and the expanding squamous epithelium of the roof plate. Surprisingly, this interface consists of a single progenitor cell type that we have named the veil cell. Veil cells express gdf6a and constitute a lineage restricted stem zone that generates the squamous roof plate by direct transformation and asymmetrically fated divisions. Experimental restriction of roof plate expansion leads to extrusion of veil cell daughters and squamous cells, suggesting veil cell fate is regulated by the space available for roof plate growth.

The Postmigratory Alar Topography of Visceral Cranial Nerve Efferents Challenges the Classical Model of Hindbrain Columns.

The classic columnar model of cranial nerve central representation assumes that all motor and sensory hindbrain neurons develop within four radial migration domains, held to be separated by a sulcal alar-basal boundary (sulcus limitans). This essay reviews a number of developmental data that challenge these concepts. These results are interpreted within the framework of present day neuromeric conception of the brainstem (the prosomeric model). Advances in dorsoventral patterning of the spinal cord and hindbrain now show that there exist up to eight alar microzones and five basal microzones (molecularly and histogenetically distinct longitudinal progenitor domains). This reveals that the classic tetracolumnar model is excessively simplistic. There is both older and recent data revealing that the visceral efferent neurons of the cranial nerves (preganglionic and branchiomotor neurons) are generated next to the floor plate and later migrate dorsalwards before adopting their final topography in the mantle, contrary to the purely radial migration assumed in the classic model. Moreover, various results support the conclusion that at least the branchiomotor neurons end their migration and mature within the alar region of the mantle. Evidence on this point obtained in chick embryos is reviewed in detail, and novel evidence in mouse embryos is presented. Anat Rec, 302:485-504, 2019. © 2018 Wiley Periodicals, Inc.

Hindbrain morphometry and choroid plexus position in differential diagnosis of posterior fossa cystic malformations.

OBJECTIVE: To assess the differential diagnostic significance of a series of quantitative and qualitative variables of the cerebellar vermis in fetuses with posterior fossa cystic malformation, including Dandy-Walker malformation (DWM), vermian hypoplasia (VH) and Blake's pouch cyst (BPC). METHODS: This was a retrospective study of confirmed cases of DWM, VH and BPC, diagnosed at the Fetal Medicine and Surgery Unit of the Federico II University between January 2005 and June 2013 or the Fetal Medicine and Surgery Unit of G. Gaslini Hospital between July 2013 and September 2017. All included cases had good-quality three-dimensional (3D) volume datasets of the posterior fossa, acquired by transvaginal ultrasound through the posterior fontanelle. The midsagittal view of the posterior fossa was the reference view for the study. We assessed brainstem-tentorium angle and brainstem-vermis angle (BVA), as well as craniocaudal (CCVD) and anteroposterior (APVD) vermian diameters and vermian area (VA), which were normalized by biparietal diameter (BPD) to take into account gestational age (CCVD/BPD × 100, APVD/BPD × 100 and VA/BPD × 100, respectively). Finally, the position of the fourth ventricular choroid plexus (4VCP) was defined as normal ('up') or abnormal ('down'), relative to the roof/cyst inlet of the fourth ventricle. RESULTS: We analyzed 67 fetuses with posterior fossa malformations (24 cases of DWM, 13 of VH and 30 of BPC). The mean gestational age at diagnosis was 23.6 weeks. Regardless of gestational age, the BVA differed significantly between the three groups, and the VA/BPD was able to differentiate between VH and BPC. In differentiating between VH and BPC, the greatest areas under the receiver-operating characteristics curve were those for VA/BPD ratio. The 4VCP position was down in all cases of DWM and VH, while it was up in all cases of BPC. CONCLUSIONS: Our data support the concept that VA/BPD ratio and 4VCP position may be used to differentiate between DWM, VH and BPC in the fetus. In our series, the position of the 4VCP had the highest accuracy, but a larger number of VH cases should be evaluated to confirm that an up position of the 4VCP indicates BPC while a down position indicates DWM or VH. Copyright © 2018 ISUOG. Published by John Wiley & Sons Ltd.

Segmental Analysis of the Vestibular Nerve and the Efferents of the Vestibular Complex.

Use of a segmental approach in the study of vestibular centers in the hindbrain improves morphological and functional understanding of this region controlled by Hox genes, among other molecular determinants. Here, we review accrued data about segmental organization of vestibular afferents and efferents. Inner ear-originated vestibular fibers enter the hindbrain, together with auditory ones, through the alar plate of rhombomere 4, then branch into descending and ascending branches to reach appropriate vestibular nuclei along the vestibular column. Classical vestibular nuclei (superior, lateral, medial, and inferior) originate in eight successive rhombomeric segments, which suggests internal subdivisions correlated with distinct connections and functions. The vestibular projection neurons identified for various targets aggregate in discrete groups, which correlate topographically either with rhombomeric units, or with internal subdivisions within them. Each vestibular projection system (e.g., vestibulo-spinal, vestibulo-ocular, vestibulocerebellar) has a characteristic ipsilateral/contralateral organization. Comparing them as a connective mosaic in different species shows that various aspects of this segmental connective organization are conserved throughout evolution in vertebrates. Furthermore, certain genes that control the development of the rhombomeric units in the hindbrain may determine, among other aspects, the specific properties of the different neuronal subpopulations related to their axonal navigation and synaptogenesis. Anat Rec, 302:472-484, 2019. © 2018 Wiley Periodicals, Inc.

Features of the structure, development, and activity of the zebrafish noradrenergic system explored in new CRISPR transgenic lines.

The noradrenergic (NA) system of vertebrates is implicated in learning, memory, arousal, and neuroinflammatory responses, but is difficult to access experimentally. Small and optically transparent, larval zebrafish offer the prospect of exploration of NA structure and function in an intact animal. We made multiple transgenic zebrafish lines using the CRISPR/Cas9 system to insert fluorescent reporters upstream of slc6a2, the norepinephrine transporter gene. These lines faithfully express reporters in NA cell populations, including the locus coeruleus (LC), which contains only about 14 total neurons. We used the lines in combination with two-photon microscopy to explore the structure and projections of the NA system in the context of the columnar organization of cell types in the zebrafish hindbrain. We found robust alignment of NA projections with glutamatergic neurotransmitter stripes in some hindbrain segments, suggesting orderly relations to neuronal cell types early in life. We also quantified neurite density in the rostral spinal cord in individual larvae with as much as 100% difference in the number of LC neurons, and found no correlation between neuronal number in the LC and projection density in the rostral spinal cord. Finally, using light sheet microscopy, we performed bilateral calcium imaging of the entire LC. We found that large-amplitude calcium responses were evident in all LC neurons and showed bilateral synchrony, whereas small-amplitude events were more likely to show interhemispheric asynchrony, supporting the potential for targeted LC neuromodulation. Our observations and new transgenic lines set the stage for a deeper understanding of the NA system.

Endocranial Casts of Pre-Mammalian Therapsids Reveal an Unexpected Neurological Diversity at the Deep Evolutionary Root of Mammals.

The origin and evolution of the mammalian brain has long been the focus of scientific enquiry. Conversely, little research has focused on the palaeoneurology of the stem group of Mammaliaformes, the Permian and Triassic non-mammaliaform Therapsida (NMT). This is because the majority of the NMT have a non-ossified braincase, making the study of their endocranial cast (sometimes called the "fossil brain") problematic. Thus, descriptions of the morphology and size of NMT endocranial casts have been based largely on approximations rather than reliable determination. Accordingly, here we use micro-CT scans of the skulls of 1 Dinocephalia and 3 Biarmosuchia, which are NMT with a fully ossified braincase and thus a complete endocast. For the first time, our work enables the accurate determination of endocranial shape and size in NMT. This study suggests that NMT brain size falls in the upper range of the reptilian and amphibian variation. Brain size in the dicynodont Kawingasaurus is equivalent to that of early Mammaliaformes, whereas the Dinocephalia show evidence of a secondary reduction of brain size. In addition, unlike other NMT in which the endocast has a tubular shape and its parts are arranged in a linear manner, the biarmosuchian endocast is strongly flexed at the level of the midbrain, creating a near right angle between the fore- and hindbrain. These data highlight an unexpected diversity of endocranial size and morphology in NMT, features that are usually considered conservative in this group.

A circuit motif in the zebrafish hindbrain for a two alternative behavioral choice to turn left or right.

Animals collect sensory information from the world and make adaptive choices about how to respond to it. Here, we reveal a network motif in the brain for one of the most fundamental behavioral choices made by bilaterally symmetric animals: whether to respond to a sensory stimulus by moving to the left or to the right. We define network connectivity in the hindbrain important for the lateralized escape behavior of zebrafish and then test the role of neurons by using laser ablations and behavioral studies. Key inhibitory neurons in the circuit lie in a column of morphologically similar cells that is one of a series of such columns that form a developmental and functional ground plan for building hindbrain networks. Repetition within the columns of the network motif we defined may therefore lie at the foundation of other lateralized behavioral choices.

Connectivity-based segmentation of the periaqueductal gray matter in human with brainstem optimized diffusion MRI.

The periaqueductal gray matter (PAG) is a midbrain structure, involved in key homeostatic neurobiological functions, such as pain modulation and cardiorespiratory control. Animal research has identified four subdivisional columns that differ in both connectivity and function. Until now these findings have not been replicated in humans. This study used high-resolution brainstem optimized diffusion magnetic resonance imaging and probabilistic tractography to segment the human PAG into four subdivisions, based on voxel connectivity profiles. We identified four distinct subdivisions demonstrating high spatial concordance with the columns of the animal model. The resolution of these subdivisions for individual subjects permitted detailed examination of their structural connectivity without the requirement of an a priori starting location. Interestingly patterns of forebrain connectivity appear to be different to those found in nonhuman studies, whereas midbrain and hindbrain connectivity appears to be maintained. Although there are similarities in the columnar structure of the PAG subdivisions between humans and nonhuman animals, there appears to be different patterns of cortical connectivity. This suggests that the functional organization of the PAG may be different between species, and as a consequence, functional studies in nonhumans may not be directly translatable to humans. This highlights the need for focused functional studies in humans.

Evolution of Courtship Songs in Xenopus : Vocal Pattern Generation and Sound Production.

The extant species of African clawed frogs (Xenopus and Silurana) provide an opportunity to link the evolution of vocal characters to changes in the responsible cellular and molecular mechanisms. In this review, we integrate several robust lines of research: evolutionary trajectories of Xenopus vocalizations, cellular and circuit-level mechanisms of vocalization in selected Xenopus model species, and Xenopus evolutionary history and speciation mechanisms. Integrating recent findings allows us to generate and test specific hypotheses about the evolution of Xenopus vocal circuits. We propose that reduced vocal sex differences in some Xenopus species result from species-specific losses of sexually differentiated neural and neuromuscular features. Modification of sex-hormone-regulated developmental mechanisms is a strong candidate mechanism for reduced vocal sex differences.

The Order and Place of Neuronal Differentiation Establish the Topography of Sensory Projections and the Entry Points within the Hindbrain.

Establishing topographical maps of the external world is an important but still poorly understood feature of the vertebrate sensory system. To study the selective innervation of hindbrain regions by sensory afferents in the zebrafish embryo, we mapped the fine-grained topographical representation of sensory projections at the central level by specific photoconversion of sensory neurons. Sensory ganglia located anteriorly project more medially than do ganglia located posteriorly, and this relates to the order of sensory ganglion differentiation. By single-plane illumination microscopy (SPIM) in vivo imaging, we show that (1) the sequence of arrival of cranial ganglion inputs predicts the topography of central projections, and (2) delaminated neuroblasts differentiate in close contact with the neural tube, and they never loose contact with the neural ectoderm. Afferent entrance points are established by plasma membrane interactions between primary differentiated peripheral sensory neurons and neural tube border cells with the cooperation of neural crest cells. These first contacts remain during ensuing morphological growth to establish pioneer axons. Neural crest cells and repulsive slit1/robo2 signals then guide axons from later-differentiating neurons toward the neural tube. Thus, this study proposes a new model by which the topographical representation of cranial sensory ganglia is established by entrance order, with the entry points determined by cell contact between the sensory ganglion cell bodies and the hindbrain.

More a finger than a nose: the trigeminal motor and sensory innervation of the Schnauzenorgan in the elephant-nose fish Gnathonemus petersii.

The weakly electric fish Gnathonemus petersii uses its electric sense to actively probe the environment. Its highly mobile chin appendage, the Schnauzenorgan, is rich in electroreceptors. Physical measurements have demonstrated the importance of the position of the Schnauzenorgan in funneling the fish's self-generated electric field. The present study focuses on the trigeminal motor pathway that controls Schnauzenorgan movement and on its trigeminal sensory innervation and central representation. The nerves entering the Schnauzenorgan are very large and contain both motor and sensory trigeminal components as well as an electrosensory pathway. With the use of neurotracer techniques, labeled Schnauzenorgan motoneurons were found throughout the ventral main body of the trigeminal motor nucleus but not among the population of larger motoneurons in its rostrodorsal region. The Schnauzenorgan receives no motor or sensory innervation from the facial nerve. There are many anastomoses between the peripheral electrosensory and trigeminal nerves, but these senses remain separate in the sensory ganglia and in their first central relays. Schnauzenorgan trigeminal primary afferent projections extend throughout the descending trigeminal sensory nuclei, and a few fibers enter the facial lobe. Although no labeled neurons could be identified in the brain as the trigeminal mesencephalic root, some Schnauzenorgan trigeminal afferents terminated in the trigeminal motor nucleus, suggesting a monosynaptic, possibly proprioceptive, pathway. In this first step toward understanding multimodal central representation of the Schnauzenorgan, no direct interconnections were found between the trigeminal sensory and electromotor command system, or the electrosensory and trigeminal motor command. The pathways linking perception to action remain to be studied.

Control of food intake and energy expenditure by Nos1 neurons of the paraventricular hypothalamus.

The paraventricular nucleus of the hypothalamus (PVH) contains a heterogeneous cluster of Sim1-expressing cell types that comprise a major autonomic output nucleus and play critical roles in the control of food intake and energy homeostasis. The roles of specific PVH neuronal subtypes in energy balance have yet to be defined, however. The PVH contains nitric oxide synthase-1 (Nos1)-expressing (Nos1(PVH)) neurons of unknown function; these represent a subset of the larger population of Sim1-expressing PVH (Sim1(PVH)) neurons. To determine the role of Nos1(PVH) neurons in energy balance, we used Cre-dependent viral vectors to both map their efferent projections and test their functional output in mice. Here we show that Nos1(PVH) neurons project to hindbrain and spinal cord regions important for food intake and energy expenditure control. Moreover, pharmacogenetic activation of Nos1(PVH) neurons suppresses feeding to a similar extent as Sim1(PVH) neurons, and increases energy expenditure and activity. Furthermore, we found that oxytocin-expressing PVH neurons (OXT(PVH)) are a subset of Nos1(PVH) neurons. OXT(PVH) cells project to preganglionic, sympathetic neurons in the thoracic spinal cord and increase energy expenditure upon activation, though not to the same extent as Nos1(PVH) neurons; their activation fails to alter feeding, however. Thus, Nos1(PVH) neurons promote negative energy balance through changes in feeding and energy expenditure, whereas OXT(PVH) neurons regulate energy expenditure alone, suggesting a crucial role for non-OXT Nos1(PVH) neurons in feeding regulation.

Molecular events directing the patterning and specification of the cerebellum

The vertebrate brain is a remarkably complex anatomical structure which contains diverse subdivisions and neuronal subtypes with specific synaptic connections that contribute to the complexity of its function. The neural tube (the primordial brain) has to be progressively regionalized by means of precise control of the spatial and temporal arrangement of an orchestrated cocktail of genes. These will regulate inter- and intracellular signals driving a proper molecular patterning and specification of the distinct brain subdivisions, and thus will generate the structural basis of complexity and cellular diversity which characterize the brain. The present revision focuses on the main molecules involved during early development of the vertebrate cerebellum, the most rostral and dorsal structure of the hindbrain. We will survey the literature related to the early molecular mechanisms arising from the isthmus to pattern the caudal midbrain and rostral hindbrain primordia. The isthmus retains morphogenetic properties to further refining these subdivisions. Once the patterning of the cerebellar anlage is established, further molecular events (coming from the ventricular side and the rhombic lip) will specify the diverse neural cell population and the fine-tuning of the stereotyped morphology and layers of the cerebellum. Finally, we will discuss the combination of molecular genetics (gene expression pattern maps) and modern neuroanatomy (based on immunohistochemistry and highly sensitive neuroimaging), which have led to an increased interest in describing the neurodevelopment mechanisms underlying structural disorders and intellectual discapacities that we currently observe in congenital anomalies of the human cerebellum

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Organotopic organization of the primary Infrared Sensitive Nucleus (LTTD) in the western diamondback rattlesnake (Crotalus atrox).

Pit vipers (Crotalinae) have a specific sensory system that detects infrared radiation with bilateral pit organs in the upper jaw. Each pit organ consists of a thin membrane, innervated by three trigeminal nerve branches that project to a specific nucleus in the dorsal hindbrain. The known topographic organization of infrared signals in the optic tectum prompted us to test the implementation of spatiotopically aligned sensory maps through hierarchical neuronal levels from the peripheral epithelium to the first central site in the hindbrain, the nucleus of the lateral descending trigeminal tract (LTTD). The spatial organization of the anatomical connections was revealed in a novel in vitro whole-brain preparation of the western diamondback rattlesnake (Crotalus atrox) that allowed specific application of multiple neuronal tracers to identified pit-organ-supplying trigeminal nerve branches. After adequate survival times, the entire peripheral and central projections of fibers within the pit membrane and the LTTD became visible. This approach revealed a morphological partition of the pit membrane into three well-defined sensory areas with largely separated innervations by the three main branches. The peripheral segregation of infrared afferents in the sensory epithelium was matched by a differential termination of the afferents within different areas of the LTTD, with little overlap. This result demonstrates a topographic organizational principle of the snake infrared system that is implemented by maintaining spatially aligned representations of environmental infrared cues on the sensory epithelium through specific neuronal projections at the level of the first central processing stage, comparable to the visual system.