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Mutations in genes essential for synaptic function, such as the presynaptic adhesion molecule Neurexin1α (Nrxn1α), are strongly implicated in neuropsychiatric pathophysiology. As the input nucleus of the basal ganglia, the striatum integrates diverse excitatory projections governing cognitive and motor control, and its impairment may represent a recurrent pathway to disease. Here, we test the functional relevance of Nrxn1α in striatal circuits by employing optogenetic-mediated afferent recruitment of dorsal prefrontal cortical (dPFC) and parafascicular thalamic connections onto dorsomedial striatal (DMS) spiny projection neurons (SPNs). For dPFC-DMS circuits, we find decreased synaptic strength specifically onto indirect pathway SPNs in both Nrxn1α +/- and Nrxn1α -/- mice, driven by reductions in neurotransmitter release. In contrast, thalamic excitatory inputs to DMS exhibit relatively normal excitatory synaptic strength despite changes in synaptic N-methyl-D-aspartate receptor (NMDAR) content. These findings suggest that dysregulation of Nrxn1α modulates striatal function in an input- and target-specific manner., Competing Interests: Declaration of interests M.V.F. is a member of the Cell Reports advisory board., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

The presence of two separate afferent channels from the olfactory glomeruli to different targets in the brain is unravelled in the lamprey. The mitral-like cells send axonal projections directly to the piriform cortex in the ventral part of pallium, whereas the smaller tufted-like cells project separately and exclusively to a relay nucleus called the dorsomedial telencephalic nucleus (dmtn). This nucleus, located at the interface between the olfactory bulb and pallium, in turn projects to a circumscribed area in the anteromedial, ventral part of pallium. The tufted-like cells are activated with short latency from the olfactory nerve and terminate with mossy fibers on the dmtn cells, wherein they elicit large unitary excitatory postsynaptic potentials (EPSPs). In all synapses along this tufted-like cell pathway, there is no concurrent inhibition, in contrast to the mitral-like cell pathway. This is similar to recent findings in rodents establishing two separate exclusive projection patterns, suggesting an evolutionarily conserved organization., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

The nucleus prethalamicus (PTh) receives fibers from the optic tectum and then projects to the dorsal telencephalon in the yellowfin goby Acanthogobius flavimanus. However, it remained unclear whether the PTh is a visual relay nucleus, because the optic tectum receives not only visual but also other sensory modalities. Furthermore, precise telencephalic regions receiving prethalamic input remained unknown in the goby. We therefore investigated the full set of afferent and efferent connections of the PTh by direct tracer injections into the nucleus. Injections into the PTh labeled cells in the optic tectum, ventromedial thalamic nucleus, central and medial parts of the dorsal telencephalon, and caudal lobe of the cerebellum. We found that the somata of most tecto-prethalamic neurons are present in the stratum periventriculare. Their dendrites ascend to reach the major retinorecipient layers of the tectum. The PTh is composed of two subnuclei (medial and lateral) and topographic organization was appreciated only for tectal projections to the lateral subnucleus (PTh-l), which also receives sparse retinal projections. In contrast, the medial subnucleus receives fibers only from the medial tectum. We found that the PTh projects to nine subregions in the dorsal telencephalon and four in the ventral telencephalon. Furthermore, cerebellar injections revealed that cerebello-prethalamic fibers cross the midline twice to innervate the PTh-l on both sides. The present study is the first detailed report on the full set of the connections of PTh, which suggests that the PTh relays visual information from the optic tectum to the telencephalon., (© 2020 Wiley Periodicals, Inc.)

Injury induces synaptic, circuit, and systems reorganization. After unilateral amputation or stroke, this functional loss disrupts the interhemispheric interaction between intact and deprived somatomotor cortices to recruit deprived cortex in response to intact limb stimulation. This recruitment has been implicated in enhanced intact sensory function. In other patients, maladaptive consequences such as phantom limb pain can occur. We used unilateral whisker denervation in male and female mice to detect circuitry alterations underlying interhemispheric cortical reorganization. Enhanced synaptic strength from the intact cortex via the corpus callosum (CC) onto deep neurons in deprived primary somatosensory barrel cortex (S1BC) has previously been detected. It was hypothesized that specificity in this plasticity may depend on to which area these neurons projected. Increased connectivity to somatomotor areas such as contralateral S1BC, primary motor cortex (M1) and secondary somatosensory cortex (S2) may underlie beneficial adaptations, while increased connectivity to pain areas like anterior cingulate cortex (ACC) might underlie maladaptive pain phenotypes. Neurons from the deprived S1BC that project to intact S1BC were hyperexcitable, had stronger responses and reduced inhibitory input to CC stimulation. M1-projecting neurons also showed increases in excitability and CC input strength that was offset with enhanced inhibition. S2 and ACC-projecting neurons showed no changes in excitability or CC input. These results demonstrate that subgroups of output neurons undergo dramatic and specific plasticity after peripheral injury. The changes in S1BC-projecting neurons likely underlie enhanced reciprocal connectivity of S1BC after unilateral deprivation consistent with the model that interhemispheric takeover supports intact whisker processing. SIGNIFICANCE STATEMENT Amputation, peripheral injury, and stroke patients experience widespread alterations in neural activity after sensory loss. A hallmark of this reorganization is the recruitment of deprived cortical space which likely aids processing and thus enhances performance on intact sensory systems. Conversely, this recruitment of deprived cortical space has been hypothesized to underlie phenotypes like phantom limb pain and hinder recovery. A mouse model of unilateral denervation detected remarkable specificity in alterations in the somatomotor circuit. These changes underlie increased reciprocal connectivity between intact and deprived cortical hemispheres. This increased connectivity may help explain the enhanced intact sensory processing detected in humans., (Copyright © 2020 Petrus et al.)

The parabrachial nucleus (PBN) is one of the major targets of spinal projection neurons and plays important roles in pain. However, the architecture of the spinoparabrachial pathway underlying its functional role in nociceptive information processing remains elusive. Here, we report that the PBN directly relays nociceptive signals from the spinal cord to the intralaminar thalamic nuclei (ILN). We demonstrate that the spinal cord connects with the PBN in a bilateral manner and that the ipsilateral spinoparabrachial pathway is critical for nocifensive behavior. We identify Tacr1-expressing neurons as the major neuronal subtype in the PBN that receives direct spinal input and show that these neurons are critical for processing nociceptive information. Furthermore, PBN neurons receiving spinal input form functional monosynaptic excitatory connections with neurons in the ILN, but not the amygdala. Together, our results delineate the neural circuit underlying nocifensive behavior, providing crucial insight into the circuit mechanism underlying nociceptive information processing., Competing Interests: Declaration of Interests The authors declare no competing interests., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Taste receptor cells use multiple signaling pathways to detect chemicals in potential food items. These cells are functionally grouped into different types: Type I cells act as support cells and have glial-like properties; Type II cells detect bitter, sweet, and umami taste stimuli; and Type III cells detect sour and salty stimuli. We have identified a new population of taste cells that are broadly tuned to multiple taste stimuli including bitter, sweet, sour, and umami. The goal of this study was to characterize these broadly responsive (BR) taste cells. We used an IP3R3-KO mouse (does not release calcium (Ca2+) from internal stores in Type II cells when stimulated with bitter, sweet, or umami stimuli) to characterize the BR cells without any potentially confounding input from Type II cells. Using live cell Ca2+ imaging in isolated taste cells from the IP3R3-KO mouse, we found that BR cells are a subset of Type III cells that respond to sour stimuli but also use a PLCβ signaling pathway to respond to bitter, sweet, and umami stimuli. Unlike Type II cells, individual BR cells are broadly tuned and respond to multiple stimuli across different taste modalities. Live cell imaging in a PLCβ3-KO mouse confirmed that BR cells use this signaling pathway to respond to bitter, sweet, and umami stimuli. Short term behavioral assays revealed that BR cells make significant contributions to taste driven behaviors and found that loss of either PLCβ3 in BR cells or IP3R3 in Type II cells caused similar behavioral deficits to bitter, sweet, and umami stimuli. Analysis of c-Fos activity in the nucleus of the solitary tract (NTS) also demonstrated that functional Type II and BR cells are required for normal stimulus induced expression., Competing Interests: The authors have declared that no competing interests exist.

The nucleus reuniens (RE) is part of the midline thalamus and one of the major sources of thalamic inputs to the hippocampal formation and the medial prefrontal cortex. However, it not only sends strong efferents to these areas but is also heavily innervated by both brain regions. Based on its connectivity and supported by functional studies the RE has been suggested to represent a major hub in reciprocal hippocampal-prefrontal communication. Indeed, inactivation studies have demonstrated that this nucleus is particularly important for cognitive behaviors which depend on prefrontal-hippocampal communication, such as working memory or memory consolidation. However, besides its central role in mediating hippocampal-prefrontal communication, the RE is target of a multitude of other cortical and subcortical afferents, which likely modulate its function. So far, however, studies that have systematically investigated the afferents of the RE have only been performed in rats. Because of the unique role of the mouse as a genetically accessible model system for mammalian brain circuit analysis we have mapped the afferent connectivity of the mouse RE using retrograde Fluoro-Gold tracing. Comparison with similar data from rats indicated a very high level of similarity in prefrontal and hippocampal afferents but some differences in afferent connectivity with other brain regions. In particular, our results suggest interspecies differences regarding the integration of the RE in circuits of fear, aversion, and defense., (© 2019 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals, Inc.)

We studied the thalamic afferents to cortical areas in the precuneus using injections of retrograde fluorescent neuronal tracers in four male macaques (Macaca fascicularis). Six injections were within the limits of cytoarchitectural area PGm, one in area 31 and one in area PEci. Precuneate areas shared strong input from the posterior thalamus (lateral posterior nucleus and pulvinar complex) and moderate input from the medial, lateral, and intralaminar thalamic regions. Area PGm received strong connections from the subdivisions of the pulvinar linked to association and visual function (the medial and lateral nuclei), whereas areas 31 and PEci received afferents from the oral division of the pulvinar. All three cytoarchitectural areas also received input from subdivisions of the lateral thalamus linked to motor function (ventral lateral and ventral anterior nuclei), with area PEci receiving additional input from a subdivision linked to somatosensory function (ventral posterior lateral nucleus). Finally, only PGm received substantial limbic association afferents, mainly via the lateral dorsal nucleus. These results indicate that area PGm integrates information from visual association, motor and limbic regions of the thalamus, in line with a hypothesized role in spatial cognition, including navigation. By comparison, dorsal precuneate areas (31 and PEci) are more involved in sensorimotor functions, being akin to adjacent areas of the dorsal parietal cortex.

The hypothalamic neuropeptide Y (NPY) circuitry is a key regulator of feeding behavior. NPY also acts in the mesolimbic dopaminergic circuitry, where it can increase motivational aspects of feeding behavior through effects on dopamine output in the nucleus accumbens (NAc) and on neurotransmission in the ventral tegmental area (VTA). Endogenous NPY in the NAc originates from local interneurons and afferent projections from the hypothalamic arcuate nucleus (Arc). However, the origin of endogenous NPY in the VTA is unknown. We determined, in normal-weight male Wistar rats, if the source of VTA NPY is local, and/or whether it is derived from VTA-projecting neurons. Immunocytochemistry, in situ hybridization and RT-qPCR were utilized, when appropriate in combination with colchicine treatment or 24 hr fasting, to assess NPY/Npy expression locally in the VTA. Retrograde tracing using cholera toxin beta (CTB) in the VTA, fluorescent immunocytochemistry and confocal microscopy were used to determine NPY-immunoreactive afferents to the VTA. NPY in the VTA was observed in fibers, but not following colchicine pretreatment. No NPY- or Npy-expressing cell bodies were observed in the VTA. Fasting for 24 hr, which increased Npy expression in the Arc, failed to induce Npy expression in the VTA. Double-labeling with CTB and NPY was observed in the Arc and in the ventrolateral medulla. Thus, VTA NPY originates from the hypothalamic Arc and the ventrolateral medulla of the brainstem in normal-weight male Wistar rats. These afferent connections link hypothalamic and brainstem processing of physiologic state to VTA-driven motivational behavior., (© 2019 The Authors. The Journal of Comparative Neurology published by Wiley Periodicals, Inc.)

The highly mobile chin appendage of Gnathonemus petersii, the Schnauzenorgan, is used to actively probe the environment and is known to be a fovea of the electrosensory system. It receives an important innervation from both the trigeminal sensory and motor systems. However, little is known about the premotor control pathways that coordinate the movements of the Schnauzenorgan, or about central pathways originating from the trigeminal motor nucleus. The present study focuses on the central connections of the trigeminal motor system to elucidate premotor centers controlling Schnauzenorgan movements, with particular interest in the possible connections between the electrosensory and trigeminal systems. Neurotracer injections into the trigeminal motor nucleus revealed bilateral, reciprocal connections between the two trigeminal motor nuclei and between the trigeminal sensory and motor nuclei by bilateral labeling of cells and terminals. Prominent afferent input to the trigeminal motor nucleus originates from the nucleus lateralis valvulae, the nucleus dorsalis mesencephali, the cerebellar corpus C1, the reticular formation, and the Raphe nuclei. Retrogradely labeled cells were also observed in the central pretectal nucleus, the dorsal anterior pretectal nucleus, the tectum, the ventroposterior nucleus of the torus semicircularis, the gustatory sensory and motor nuclei, and in the hypothalamus. Labeled terminals, but not cell bodies, were observed in the nucleus lateralis valvulae and the reticular formation. No direct connections were found between the electrosensory system and the V motor nucleus but the central connections identified would provide several multisynaptic pathways linking these two systems, including possible efference copy and corollary discharge mechanisms., (© 2019 Wiley Periodicals, Inc.)

The ability to sense sour provides an important sensory signal to prevent the ingestion of unripe, spoiled, or fermented foods. Taste and somatosensory receptors in the oral cavity trigger aversive behaviors in response to acid stimuli. Here, we show that the ion channel Otopetrin-1, a proton-selective channel normally involved in the sensation of gravity in the vestibular system, is essential for sour sensing in the taste system. We demonstrate that knockout of Otop1 eliminates acid responses from sour-sensing taste receptor cells (TRCs). In addition, we show that mice engineered to express otopetrin-1 in sweet TRCs have sweet cells that also respond to sour stimuli. Next, we genetically identified the taste ganglion neurons mediating each of the five basic taste qualities and demonstrate that sour taste uses its own dedicated labeled line from TRCs in the tongue to finely tuned taste neurons in the brain to trigger aversive behaviors., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The corticospinal (CS) neurons projecting to the cervical cord distribute not only in motor-related cortical areas, but also in somatosensory areas, including the primary somatosensory cortex (S1). The exact functions of these widely distributed CS neurons are largely unknown, however. In this study, we injected mice with adeno-associated virus encoding membrane-binding fluorescent proteins to investigate the distribution of axons from CS neurons in different regions within a broad cortical area. We found that CS axons from the primary motor cortex (M1), the rostral part of S1 (S1r), and the caudal part of S1 (S1c) differentially project to specific compartments within the spinal gray matter of the seventh cervical cord segment: (a) M1 projects mainly to intermediate and ventral areas, (b) S1r to the mediodorsal area, and (c) S1c to the dorsolateral area. We also found that the projection from S1r, which corresponds to the forelimb area, largely overlaps the cutaneous afferent terminals from the forepaw (hand) in the dorsal horn, and we detected a similar relation between S1c and the trunk. Our findings suggest the existence of considerably fine somatotopic compartments within the dorsal horn that process somatosensation and descending information, which is provided mainly by S1 CS neurons and contribute to delicate control of sensory information in generation of movement., (© 2019 Wiley Periodicals, Inc.)

Area 10, located in the frontal pole, is a unique specialization of the primate cortex. We studied the cortical connections of area 10 in the New World Cebus monkey, using injections of retrograde tracers in different parts of this area. We found that injections throughout area 10 labeled neurons in a consistent set of areas in the dorsolateral, ventrolateral, orbital, and medial parts of the frontal cortex, superior temporal association cortex, and posterior cingulate/retrosplenial region. However, sites on the midline surface of area 10 received more substantial projections from the temporal lobe, including clear auditory connections, whereas those in more lateral parts received >90% of their afferents from other frontal areas. This difference in anatomical connectivity reflects functional connectivity findings in the human brain. The pattern of connections in Cebus is very similar to that observed in the Old World macaque monkey, despite >40 million years of evolutionary separation, but lacks some of the connections reported in the more closely related but smaller marmoset monkey. These findings suggest that the clearer segregation observed in the human frontal pole reflects regional differences already present in early simian primates, and that overall brain mass influences the pattern of cortico-cortical connectivity., (© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The current model, based on rodent data, proposes that thalamocortical afferents (TCA) innervate the subplate towards the end of cortical neurogenesis. This implies that the laminar identity of cortical neurons is specified by intrinsic instructions rather than information of thalamic origin. In order to determine whether this mechanism is conserved in the primates, we examined the growth of thalamocortical (TCA) and corticofugal afferents in early human and monkey fetal development. In the human, TCA, identified by secretagogin, calbindin, and ROBO1 immunoreactivity, were observed in the internal capsule of the ventral telencephalon as early as 7-7.5 PCW, crossing the pallial/subpallial boundary (PSB) by 8 PCW before the calretinin immunoreactive corticofugal fibers do. Furthermore, TCA were observed to be passing through the intermediate zone and innervating the presubplate of the dorsolateral cortex, and already by 10-12 PCW TCAs were occupying much of the cortex. Observations at equivalent stages in the marmoset confirmed that this pattern is conserved across primates. Therefore, our results demonstrate that in primates, TCAs innervate the cortical presubplate at earlier stages than previously demonstrated by acetylcholinesterase histochemistry, suggesting that pioneer thalamic afferents may contribute to early cortical circuitry that can participate in defining cortical neuron phenotypes., (© The Author(s) 2019. Published by Oxford University Press.)

The neuromodulation of the greater occipital nerve (GON) has proved effective to treat chronic refractory neurovascular headaches, in particular migraine and cluster headache. Moreover, animal studies have shown convergence of cervical and trigeminal afferents on the same territories of the upper cervical and lower medullary dorsal horn (DH), the so-called trigeminocervical complex (TCC), and recent studies in rat models of migraine and craniofacial neuropathy have shown that GON block or stimulation alter nociceptive processing in TCC. The present study examines in detail the anatomy of GON and its central projections in the rat applying different tracers to the nerve and quantifying its ultrastructure, the ganglion neurons subserving GON, and their innervation territories in the spinal cord and brainstem. With considerable intersubject variability in size, GON contains on average 900 myelinated and 3,300 unmyelinated axons, more than 90% of which emerge from C 2 ganglion neurons. Unmyelinated afferents from GON innervates exclusively laminae I-II of the lateral DH, mostly extending along segments C 2-3 . Myelinated fibers distribute mainly in laminae I and III-V of the lateral DH between C 1 and C 6 and, with different terminal patterns, in medial parts of the DH at upper cervical segments, and ventrolateral rostral cuneate, paratrigeminal, and marginal part of the spinal caudal and interpolar nuclei. Sparse projections also appear in other locations nearby. These findings will help to better understand the bases of sensory convergence on spinomedullary systems, a critical pathophysiological factor for pain referral and spread in severe painful craniofacial disorders., (© 2018 Wiley Periodicals, Inc.)

Functionally important regions of sensory maps are overrepresented in the sensory pathways and cortex, but the underlying developmental mechanisms are not clear. In the spinal cord dorsal horn (DH), we recently showed that paw innervating Mrgprd + nonpeptidergic nociceptors display distinctive central arbor morphologies that well correlate with increased synapse transmission efficiency and heightened sensitivity of distal limb skin. Given that peripheral and central arbor formation of Mrgprd + neurons co-occurs around the time of birth, we tested whether peripheral cues from different skin areas and/or postnatal reorganization mechanisms could instruct this somatotopic difference among central arbors. We found that, while terminal outgrowth/refinement occurs during early postnatal development in both the skin and the DH, postnatal refinement of central terminals precedes that of peripheral terminals. Furthermore, we used single-cell ablation of Ret to genetically disrupt epidermal innervation of Mrgprd + neurons and revealed that the somatotopic difference among their central arbors was unaffected by this manipulation. Finally, we saw that region-specific Mrgprd + central terminal arbors are present from the earliest postnatal stages, before skin terminals are evident. In summary, we find that region-specific organization of Mrgprd + neuron central arbors is present shortly after initial central terminal formation, which likely develops independently of peripheral target innervation. Our data suggest that either cell-intrinsic and/or DH prepatterning mechanisms are likely to establish this somatotopic difference., (© 2018 Wiley Periodicals, Inc.)

GAD67-EGFP mice were used in a series of experiments to provide anatomical evidence for the role of the reduction in myelinated primary afferent input to GABA spinal neurons in the production of neuropathic pain following peripheral L5 nerve injury. First, we confirmed that L5 injury in these mice produced mechanical and thermal hyperalgesia in the ipsilateral foot. Second, we injected a mixture of cholera toxin subunit-B (CTb) and isolectin B4 (IB4) in the sciatic nerve to selectively label its myelinated and unmyelinated primary afferents. Results showed that primary afferents of sciatic nerve extend from L2-L6 spinal segments. Third, we determined the central terminations of myelinated primary afferents of L4 and L5 spinal nerves following CTb injection in either nerve. The myelinated primary afferents of both nerves terminated in the corresponding and two to three rostral spinal segments with some fibers descending to terminate in the segment caudal to the level at which they entered indicating an intermingling of their terminals at the dorsal horn of the spinal cord. Fourthly, we injected CTb in L5 nerve and CTb HRP-conjugate in L4 nerve. Confocal microscopy and subsequent image analyses showed that individual EGFP-labeled neurons in L4 segment receive myelinated primary afferent contacts from both L4 and L5 nerves. Eliminating inputs from L5 nerve following its injury would result in less involvement of spinal GABA neurons which would very likely initiate neuronal sensitization in L4 segment. This could lead to the development of hyperalgesia in response to the stimulation of the adjacent uninjured L4 nerve., (© 2018 Wiley Periodicals, Inc.)

The entorhinal cortex is a prominent structure of the medial temporal lobe, which plays a pivotal role in the interaction between the neocortex and the hippocampal formation in support of declarative and spatial memory functions. We implemented design-based stereological techniques to provide estimates of neuron numbers, neuronal soma size, and volume of different layers and subdivisions of the entorhinal cortex in adult rhesus monkeys (Macaca mulatta; 5-9 years of age). These data corroborate the structural differences between different subdivisions of the entorhinal cortex, which were shown in previous connectional and cytoarchitectonic studies. In particular, differences in the number of neurons contributing to distinct afferent and efferent hippocampal pathways suggest not only that different types of information may be more or less segregated between caudal and rostral subdivisions, but also, and perhaps most importantly, that the nature of the interaction between the entorhinal cortex and the rest of the hippocampal formation may vary between different subdivisions. We compare our quantitative data in monkeys with previously published stereological data for the rat and human, in order to provide a perspective on the relative development and structural organization of the main subdivisions of the entorhinal cortex in two model organisms widely used to decipher the basic functional principles of the human medial temporal lobe memory system. Altogether, these data provide fundamental information on the number of functional units that comprise the entorhinal-hippocampal circuits and should be considered in order to build realistic models of the medial temporal lobe memory system., (© 2018 Wiley Periodicals, Inc.)

Although bone is continually being remodeled and ultimately declines with aging, little is known whether similar changes occur in the sensory and sympathetic nerve fibers that innervate bone. Here, immunohistochemistry and confocal microscopy were used to examine changes in the sensory and sympathetic nerve fibers that innervate the young (10 days post-partum), adult (3 months) and aging (24 months) C57Bl/6 mouse femur. In all three ages examined, the periosteum was the most densely innervated bone compartment. With aging, the total number of sensory and sympathetic nerve fibers clearly declines as the cambium layer of the periosteum dramatically thins. Yet even in the aging femur, there remains a dense sensory and sympathetic innervation of the periosteum. In cortical bone, sensory and sympathetic nerve fibers are largely confined to vascularized Haversian canals and while there is no significant decline in the density of sensory fibers, there was a 75% reduction in sympathetic nerve fibers in the aging vs. adult cortical bone. In contrast, in the bone marrow the overall density/unit area of both sensory and sympathetic nerve fibers appeared to remain largely unchanged across the lifespan. The preferential preservation of sensory nerve fibers suggests that even as bone itself undergoes a marked decline with age, the nociceptors that detect injury and signal skeletal pain remain relatively intact., (Copyright © 2018 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Dual visual pathways reaching the telencephalon appear to be an ancient vertebrate trait, but some teleost fish seem to possess only one pathway via the optic tectum. We undertook the present study to determine if and when this loss occurred during evolution. Tracer injection experiments to the optic nerve, the optic tectum, and the dorsal telencephalon were performed in the present study, to investigate ascending visual pathways to the dorsal telencephalon in an acanthopterygian teleost, the yellowfin goby Acanthogobius flavimanus (Temminck & Schlegel, 1845). We confirmed the presence of a nucleus prethalamicus (PTh) in the goby, which has been convincingly identified only in holocentrids, suggesting that this nucleus is present in other acanthopterygians. We found that the optic tectum projects to the PTh bilaterally. The PTh projects in turn to the dorsal telencephalon, ipsilaterally. These results suggest that the yellowfin goby possesses only an extrageniculate-like pathway, while a geniculate-like pathway could not be identified. This situation is common with that of holocentrids and may be a character common in acanthopterygians. It is possible that a geniculate-like system was lost in the common ancestor of acanthopterygians, although the scenario for the evolution of ascending visual systems in actinopterygians remains uncertain due to the lack of precise knowledge in a number of actinopterygian taxons., (© 2018 Wiley Periodicals, Inc.)

The lateral-line neuromast of the zebrafish displays a restricted, consistent pattern of innervation that facilitates the comparison of microcircuits across individuals, developmental stages, and genotypes. We used serial blockface scanning electron microscopy to determine from multiple specimens the neuromast connectome, a comprehensive set of connections between hair cells and afferent and efferent nerve fibers. This analysis delineated a complex but consistent wiring pattern with three striking characteristics: each nerve terminal is highly specific in receiving innervation from hair cells of a single directional sensitivity; the innervation is redundant; and the terminals manifest a hierarchy of dominance. Mutation of the canonical planar-cell-polarity gene vangl2 , which decouples the asymmetric phenotypes of sibling hair-cell pairs, results in randomly positioned, randomly oriented sibling cells that nonetheless retain specific wiring. Because larvae that overexpress Notch exhibit uniformly oriented, uniformly innervating hair-cell siblings, wiring specificity is mediated by the Notch signaling pathway., Competing Interests: ED, AJ, SH, KS, AH No competing interests declared, (© 2018, Dow et al.)

Aim: The mechanisms underlying detection and transmission of sensory signals arising from visceral organs, such as the urethra, are poorly understood. Recently, specialized ACh-expressing cells embedded in the urethral epithelium have been proposed as chemosensory sentinels for detection of bacterial infection. Here, we examined the morphology and potential role in sensory signalling of a different class of specialized cells that express serotonin (5-HT), termed paraneurones., Methods: Urethrae, dorsal root ganglia neurones and spinal cords were isolated from adult female mice and used for immunohistochemistry and calcium imaging. Visceromotor reflexes (VMRs) were recorded in vivo., Results: We identified two morphologically distinct groups of 5-HT + cells with distinct regional locations: bipolar-like cells predominant in the mid-urethra and multipolar-like cells predominant in the proximal and distal urethra. Sensory nerve fibres positive for calcitonin gene-related peptide, substance P, and TRPV1 were found in close proximity to 5-HT + paraneurones. In vitro 5-HT (1 μm) stimulation of urethral primary afferent neurones, mimicking 5-HT release from paraneurones, elicited changes in the intracellular calcium concentration ([Ca 2+ ] i ) mediated by 5-HT 2 and 5-HT 3 receptors. Approximately 50% of 5-HT responding cells also responded to capsaicin with changes in the [Ca 2+ ] i . In vivo intra-urethral 5-HT application increased VMRs induced by urethral distention and activated pERK in lumbosacral spinal cord neurones., Conclusion: These morphological and functional findings provide insights into a putative paraneurone-neural network within the urethra that utilizes 5-HT signalling, presumably from paraneurones, to modulate primary sensory pathways carrying nociceptive and non-nociceptive (mechano-sensitive) information to the central nervous system., (© 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.)

GPR151 is a G-protein coupled receptor for which the endogenous ligand remains unknown. In the nervous system of vertebrates, its expression is enriched in specific diencephalic structures, where the highest levels are observed in the habenular area. The habenula has been implicated in a range of different functions including behavioral flexibility, decision making, inhibitory control, and pain processing, which makes it a promising target for treating psychiatric and neurological disease. This study aimed to further characterize neurons expressing the Gpr151 gene, by tracing the afferent connectivity of this diencephalic cell population. Using pseudotyped rabies virus in a transgenic Gpr151-Cre mouse line, monosynaptic afferents of habenular and thalamic Gpr151-expressing neuronal populations could be visualized. The habenular and thalamic Gpr151 systems displayed both shared and distinct connectivity patterns. The habenular neurons primarily received input from basal forebrain structures, the bed nucleus of stria terminalis, the lateral preoptic area, the entopeduncular nucleus, and the lateral hypothalamic area. The Gpr151-expressing neurons in the paraventricular nucleus of the thalamus was primarily contacted by medial hypothalamic areas as well as the zona incerta and projected to specific forebrain areas such as the prelimbic cortex and the accumbens nucleus. Gpr151 mRNA was also detected at low levels in the lateral posterior thalamic nucleus which received input from areas associated with visual processing, including the superior colliculus, zona incerta, and the visual and retrosplenial cortices. Knowledge about the connectivity of Gpr151-expressing neurons will facilitate the interpretation of future functional studies of this receptor., (© 2017 The Authors The Journal of Comparative Neurology Published by Wiley Periodicals, Inc.)

Introduction Within superficial trigeminal nucleus caudalis (Sp5C) (laminae I/II), meningeal primary afferents project exclusively to lamina I, whereas nociceptive cutaneous ones distribute in both lamina I and outer lamina II. Whether such a relative absence of meningeal inputs to lamina II represents a fundamental difference from cutaneous pathways in the central processing of sensory information is still unknown. Methods We recorded extracellular field potentials in the superficial Sp5C of anesthetised rats evoked by electrically stimulating the dura mater, to selectively assess the synaptic transmission between meningeal primary afferents and second-order Sp5C neurons, the first synapse in trigeminovascular pathways. We tested the effect of systemic morphine and local glycinergic and GABA A ergic disinhibition. Results Meningeal stimulation evokes two negative field potentials in superficial Sp5C. The conduction velocities of the activated primary afferents are within the Aδ- and C-fibre ranges. Systemic morphine specifically suppresses meningeal C-fibre-evoked field potentials, and this effect is reversed by systemic naloxone. Segmental glycinergic or GABA A ergic disinhibition strongly potentiates meningeal C-fibre-evoked field potentials but not Aδ-fibre ones. Interestingly, the same segmental disinhibition conversely potentiates cutaneous Aδ-fibre-evoked field potentials and suppresses C-fibre ones. Conclusion These findings reveal that the different anatomical organization of meningeal and cutaneous inputs into superficial Sp5C is associated with a different central processing of meningeal and cutaneous pain information within Sp5C. Moreover, they suggest that the potentiation upon local disinhibition of the first synapse in trigeminovascular pathways may contribute to the generation of headache pain.

Newly formed ectopic hair-cell-like cells (EHCLCs) induced by overexpression of atonal homolog 1 (Atoh1) in vitro were found to possess features of endogenous hair cells (HCs) in previous reports and in the present study. However, limited information is available regarding whether EHCLCs and native spiral ganglion neurons (SGNs) form afferent synapses, which are important for the restoration of hearing. In the current study, we focused on the afferent synaptogenesis between EHCLCs and SGN-derived dendrites. Cochlear explants of auditory epithelia with native SGNs retained were cultured in vitro, and human adenovirus serotype 5 (Ad5) vectors encoding Atoh1 were used to overexpress Atoh1 and induce EHCLCs. We observed that the neurites of the original SGNs extended toward the lesser epithelial ridge (LER) and innervated the EHCLCs. Immunohistochemical analyses revealed the expression of presynaptic ribbon C-terminal-binding protein 2 (CtBP2) and postsynaptic density protein (PSD)-95 in the nerve endings of SGN-derived neurons adjacent to EHCLCs. PSD-95 was located directly opposite CtBP2-positive puncta in the terminals of branches of SGNs, demonstrating that the neurites of SGNs formed afferent-like synaptic connections with EHCLCs. However, the expression of glutamate receptor type 2 (GluR2) could not be detected in the terminals of branches of SGNs surrounding EHCLCs. In addition, we found that the presynaptic ribbon (CtBP2) formation in EHCLCs preceded neural innervation. Furthermore, CtBP2-positive puncta increased and then decreased in EHCLCs, similar to the changes observed in endogenous HCs in terms of their number and distribution. Our finding of the generation of cochlear afferent synapses between EHCLCs and original SGNs will lay the foundation for regenerative approaches to restoring hearing after hair cell loss., (Copyright © 2017. Published by Elsevier Ltd.)

Sensory processing of deep somatic tissue constitutes an important component of the nociceptive system, yet associated central processing pathways remain poorly understood. Here, we provide a novel electrophysiological characterization and immunohistochemical analysis of neural activation in the lateral spinal nucleus (LSN). These neurons show evoked activity to deep, but not cutaneous, stimulation. The evoked responses of neurons in the LSN can be sensitized to somatosensory stimulation following intramuscular hypertonic saline, an acute model of muscle pain, suggesting this is an important spinal relay site for the processing of deep tissue nociceptive inputs. Neurons of the thalamic ventrobasal complex (VBC) mediate both cutaneous and deep tissue sensory processing, but in contrast to the lateral spinal nucleus our electrophysiological studies do not suggest the existence of a subgroup of cells that selectively process deep tissue inputs. The sensitization of polymodal and thermospecific VBC neurons to mechanical somatosensory stimulation following acute muscle stimulation with hypertonic saline suggests differential roles of thalamic subpopulations in mediating cutaneous and deep tissue nociception in pathological states. Overall, our studies at both the spinal (lateral spinal nucleus) and supraspinal (thalamic ventrobasal complex) levels suggest a convergence of cutaneous and deep somatosensory inputs onto spinothalamic pathways, which are unmasked by activation of muscle nociceptive afferents to produce consequent phenotypic alterations in spinal and thalamic neural coding of somatosensory stimulation. A better understanding of the sensory pathways involved in deep tissue nociception, as well as the degree of labeled line and convergent pathways for cutaneous and deep somatosensory inputs, is fundamental to developing targeted analgesic therapies for deep pain syndromes., (© 2017 University College London. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

The habenula is an epithalamic structure differentiated into two nuclear complexes, medial (MHb) and lateral habenula (LHb). Recently, MHb together with its primary target, the interpeduncular nucleus (IP), have been identified as major players in mediating the aversive effects of nicotine. However, structures downstream of the MHb-IP axis, including the median (MnR) and caudal dorsal raphe nucleus (DRC), may contribute to the behavioral effects of nicotine. The afferent and efferent connections of the IP have hitherto not been systematically investigated with sensitive tracers. Thus, we placed injections of retrograde or anterograde tracers into different IP subdivisions or the MnR and additionally examined the transmitter phenotype of major IP and MnR afferents by combining retrograde tract tracing with immunofluorescence and in situ hybridization techniques. Besides receiving inputs from MHb and also LHb, we found that IP is reciprocally interconnected mainly with midline structures, including the MnR/DRC, nucleus incertus, supramammillary nucleus, septum, and laterodorsal tegmental nucleus. The bidirectional connections between IP and MnR proved to be primarily GABAergic. Regarding a possible topography of IP outputs, all IP subnuclei gave rise to descending projections, whereas major ascending projections, including focal projections to ventral hippocampus, ventrolateral septum, and LHb originated from the dorsocaudal IP. Our findings indicate that IP is closely associated to a distributed network of midline structures that modulate hippocampal theta activity and forms a node linking MHb and LHb with this network, and the hippocampus. Moreover, they support a cardinal role of GABAergic IP/MnR interconnections in the behavioral response to nicotine., (© 2017 Wiley Periodicals, Inc.)

Presympathetic neurons in the rostral ventrolateral medulla (RVLM) including the adrenergic cell groups play a major role in the modulation of several reflexes required for the control of sympathetic vasomotor tone and blood pressure (BP). Moreover, sympathetic vasomotor drive to the kidneys influence natriuresis and diuresis by inhibiting the cAMP/PKA pathway and redistributing the Na + /H + exchanger isoform 3 (NHE3) to the body of the microvilli in the proximal tubules. In this study we aimed to evaluate the effects of renal afferents stimulation on (1) the neurochemical phenotype of Fos expressing neurons in the medulla oblongata and (2) the level of abundance and phosphorylation of NHE3 in the renal cortex. We found that electrical stimulation of renal afferents increased heart rate and BP transiently and caused activation of tyrosine hydroxylase (TH)-containing neurons in the RVLM and non-TH neurons in the NTS. Additionally, activation of the inhibitory renorenal reflex over a 30-min period resulted in increased natriuresis and diuresis associated with increased phosphorylation of NHE3 at serine 552, a surrogate for reduced activity of this exchanger, in the contralateral kidney. This effect was not dependent of BP changes considering that no effects on natriuresis or diuresis were found in the ipsilateral-stimulated kidney. Therefore, our data show that renal afferents leads to activation of catecholaminergic and non-catecholaminergic neurons in the medulla oblongata. When renorenal reflex is induced, NHE3 exchanger activity appears to be decreased, resulting in decreased sodium and water reabsorption in the contralateral kidney., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In some patients, renal nerve denervation has been reported to be an effective treatment for essential hypertension. Considerable evidence suggests that afferent renal nerves (ARN) and sodium balance play important roles in the development and maintenance of high blood pressure. ARN are sensitive to sodium concentrations in the renal pelvis. To better understand the role of ARN, we infused isotonic or hypertonic NaCl (308 or 500mOsm) into the left renal pelvis of conscious rats for two 2hours while recording arterial pressure and heart rate. Subsequently, brain tissue was analyzed for immunohistochemical detection of the protein Fos, a marker for neuronal activation. Fos-immunoreactive neurons were identified in numerous sites in the forebrain and brainstem. These areas included the nucleus tractus solitarius (NTS), the lateral parabrachial nucleus, the paraventricular nucleus of the hypothalamus (PVH) and the supraoptic nucleus (SON). The most effective stimulus was 500mOsm NaCl. Activation of these sites was attenuated or prevented by administration of benzamil (1μM) or amiloride (10μM) into the renal pelvis concomitantly with hypertonic saline. In anesthetized rats, infusion of hypertonic saline but not isotonic saline into the renal pelvis elevated ARN activity and this increase was attenuated by simultaneous infusion of benzamil or amiloride. We propose that renal pelvic epithelial sodium channels (ENaCs) play a role in activation of ARN and, via central visceral afferent circuits, this system modulates fluid volume and peripheral blood pressure. These pathways may contribute to the development of hypertension., (Copyright © 2016 Elsevier B.V. All rights reserved.)

The central connections of the gustatory/general visceral system of the adult zebrafish (Danio rerio) were examined by means of carbocyanine dye tracing. Main primary gustatory centers (facial and vagal lobes) received sensory projections from the facial and vagal nerves, respectively. The vagal nerve also projects to the commissural nucleus of Cajal, a general visceral sensory center. These primary centers mainly project on a prominent secondary gustatory and general visceral nucleus (SGN/V) located in the isthmic region. Secondary projections on the SGN/V were topographically organized, those of the facial lobe mainly ending medially to those of the vagal lobe, and those from the commissural nucleus ventrolaterally. Descending facial lobe projections to the medial funicular nucleus were also noted. Ascending fibers originating from the SGN/V mainly projected to the posterior thalamic nucleus and the lateral hypothalamus (lateral torus, lateral recess nucleus, hypothalamic inferior lobe diffuse nucleus) and an intermediate cell- and fiber-rich region termed here the tertiary gustatory nucleus proper, but not to a nucleus formerly considered as the zebrafish tertiary gustatory nucleus. The posterior thalamic nucleus, tertiary gustatory nucleus proper, and nucleus of the lateral recess gave rise to descending projections to the SGN/V and the vagal lobe. The connectivity between diencephalic gustatory centers and the telencephalon was also investigated. The present results showed that the gustatory connections of the adult zebrafish are rather similar to those reported in other cyprinids, excepting the tertiary gustatory nucleus. Similarities between the gustatory systems of zebrafish and other fishes are also discussed. J. Comp. Neurol. 525:333-362, 2017. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Individual striatal neurons integrate somatosensory information from both sides of the body, however, the afferent pathways mediating these bilateral responses are unclear. Whereas ipsilateral corticostriatal projections are prevalent throughout the neocortex, contralateral projections provide sparse input from primary sensory cortices, in contrast to the dense innervation from motor and frontal regions. There is, therefore, an apparent discrepancy between the observed anatomical pathways and the recorded striatal responses. We used simultaneous in vivo whole-cell and extracellular recordings combined with focal cortical silencing, to dissect the afferent pathways underlying bilateral sensory integration in the mouse striatum. We show that unlike direct corticostriatal projections mediating responses to contralateral whisker deflection, responses to ipsilateral stimuli are mediated mainly by intracortical projections from the contralateral somatosensory cortex (S1). The dominant pathway is the callosal projection from contralateral to ipsilateral S1. Our results suggest a functional difference between the cortico-basal ganglia pathways underlying bilateral sensory and motor processes., (© The Author 2016. Published by Oxford University Press.)

Neurons of the globus pallidus receive massive inputs from the striatum and the subthalamic nucleus, but their activity, as well as those of their striatal and subthalamic inputs, are modulated by brainstem afferents. These include serotonin (5-HT) projections from the dorsal raphe nucleus, cholinergic (ACh) inputs from the pedunculopontine tegmental nucleus, and dopamine (DA) afferents from the substantia nigra pars compacta. This review summarizes our recent findings on the distribution, quantitative and ultrastructural aspects of pallidal 5-HT, ACh and DA innervations. These results have led to the elaboration of a new model of the pallidal neuron based on a precise knowledge of the hierarchy and chemical features of the various synaptic inputs. The dense 5-HT, ACh and DA innervations disclosed in the associative and limbic pallidal territories suggest that these brainstem inputs contribute principally to the planification of motor behaviors and the regulation of attention and mood. Although 5-HT, ACh and DA inputs were found to modulate pallidal neurons and their afferents mainly through asynaptic (volume) transmission, genuine synaptic contacts occur between these chemospecific axon varicosities and pallidal dendrites, revealing that these brainstem projections have a direct access to pallidal neurons, in addition to their indirect input through the striatum and subthalamic nucleus. Altogether, these findings reveal that the brainstem 5-HT, ACh and DA pallidal afferents act in concert with the more robust GABAergic inhibitory striatopallidal and glutamatergic excitatory subthalamopallidal inputs. We hypothesize that a fragile equilibrium between forebrain and brainstem pallidal afferents plays a key role in the functional organization of the primate basal ganglia, in both health and disease.

The axonal projections and synaptic input of the C1 adrenergic neurons of the rostral ventrolateral medulla (VLM) were examined using transgenic dopamine-beta hydroxylase Cre mice and modified rabies virus. Cre-dependent viral vectors expressing TVA (receptor for envelopeA) and rabies glycoprotein were injected into the left VLM. EnvelopeA-pseudotyped rabies-EGFP glycoprotein-deficient virus (rabies-EGFP) was injected 4-6 weeks later in either thoracic spinal cord (SC) or hypothalamus. TVA immunoreactivity was detected almost exclusively (95 %) in VLM C1 neurons. In mice with SC injections of rabies-EGFP, starter cells (expressing TVA + EGFP) were found at the rostral end of the VLM; in mice with hypothalamic injections starter C1 cells were located more caudally. C1 neurons innervating SC or hypothalamus had other terminal fields in common (e.g., dorsal vagal complex, locus coeruleus, raphe pallidus and periaqueductal gray matter). Putative inputs to C1 cells with SC or hypothalamic projections originated from the same brain regions, especially the lower brainstem reticular core from spinomedullary border to rostral pons. Putative input neurons to C1 cells were also observed in the nucleus of the solitary tract, caudal VLM, caudal spinal trigeminal nucleus, cerebellum, periaqueductal gray matter and inferior and superior colliculi. In sum, regardless of whether they innervate SC or hypothalamus, VLM C1 neurons receive input from the same general brain regions. One interpretation is that many types of somatic or internal stimuli recruit these neurons en bloc to produce a stereotyped acute stress response with sympathetic, parasympathetic, vigilance and neuroendocrine components.

In visceral organs of mammals, most noxious (painful) stimuli as well as innocuous stimuli are detected by spinal afferent neurons, whose cell bodies lie in dorsal root ganglia (DRGs). One of the major unresolved questions is the location, morphology, and neurochemistry of the nerve endings of spinal afferents that actually detect these stimuli in the viscera. In the upper gastrointestinal (GI) tract, there have been many anterograde tracing studies of vagal afferent endings, but none on spinal afferent endings. Recently, we developed a technique that now provides selective labeling of only spinal afferents. We used this approach to identify spinal afferent nerve endings in the upper GI tract of mice. Animals were anesthetized, and injections of dextran-amine were made into thoracic DRGs (T8-T12). Seven days post surgery, mice were euthanized, and the stomach and esophagus were removed, fixed, and stained for calcitonin gene-related peptide (CGRP). Spinal afferent axons were identified that ramified extensively through many rows of myenteric ganglia and formed nerve endings in discrete anatomical layers. Most commonly, intraganglionic varicose endings (IGVEs) were identified in myenteric ganglia of the stomach and varicose simple-type endings in the circular muscle and mucosa. Less commonly, nerve endings were identified in internodal strands, blood vessels, submucosal ganglia, and longitudinal muscle. In the esophagus, only IGVEs were identified in myenteric ganglia. No intraganglionic lamellar endings (IGLEs) were identified in the stomach or esophagus. We present the first identification of spinal afferent endings in the upper GI tract. Eight distinct types of spinal afferent endings were identified in the stomach, and most of them were CGRP immunoreactive. J. Comp. Neurol. 524:3064-3083, 2016. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Modality-specific sensory inputs from individual sense organs are processed in parallel in distinct areas of the neocortex. For each sensory modality, input follows a cortico-thalamo-cortical loop in which a 'first-order' exteroceptive thalamic nucleus sends peripheral input to the primary sensory cortex, which projects back to a 'higher order' thalamic nucleus that targets a secondary sensory cortex. This conserved circuit motif raises the possibility that shared genetic programs exist across sensory modalities. Here we report that, despite their association with distinct sensory modalities, first-order nuclei in mice are genetically homologous across somatosensory, visual, and auditory pathways, as are higher order nuclei. We further reveal peripheral input-dependent control over the transcriptional identity and connectivity of first-order nuclei by showing that input ablation leads to induction of higher-order-type transcriptional programs and rewiring of higher-order-directed descending cortical input to deprived first-order nuclei. These findings uncover an input-dependent genetic logic for the design and plasticity of sensory pathways, in which conserved developmental programs lead to conserved circuit motifs across sensory modalities.

In this study the subcortical afferents for the rat PER areas 35 and 36, POR, and the lateral and medial entorhinal areas (LEA and MEA) were characterized. We analyzed 33 retrograde tract-tracing experiments distributed across the five regions. For each experiment, we estimated the total numbers, percentages, and densities of labeled cells in 36 subcortical structures and nuclei distributed across septum, basal ganglia, claustrum, amygdala, olfactory structures, thalamus, and hypothalamus. We found that the complement of subcortical inputs differs across the five regions, especially the PER and POR. The PER receives input from the reuniens, suprageniculate, and medial geniculate thalamic nuclei as well as the amygdala. Overall, the subcortical inputs to the PER were consistent with a role in perception, multimodal processing, and the formation of associations that include the motivational significance of individual items and objects. Subcortical inputs to the POR were dominated by the dorsal thalamus, particularly the lateral posterior nucleus, a region implicated in visuospatial attention. The complement of subcortical inputs to the POR is consistent with a role in representing and monitoring the local spatial context. We also report that, in addition to the PER, the LEA and the medial band of the MEA also receive strong amygdala input. In contrast, subcortical input to the POR and the MEA lateral band includes much less amygdala input and is dominated by dorsal thalamic nuclei, particularly nuclei involved in spatial information processing. Thus, some subcortical inputs are consistent with the view that there is functional differentiation along the septotemporal axis of the hippocampus, but others provide considerable integration. Overall, we conclude that the patterns of subcortical inputs to the PER, POR, and the entorhinal LEA and MEA provide further evidence for functional differentiation in the medial temporal lobe. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Animal models of relapse reveal that the motivation to seek drug is regulated by enduring morphological and physiological changes in the nucleus accumbens, as well as transient synaptic potentiation in the accumbens core (NAcore) that parallels drug-seeking behavior. The current study sought to examine the link between the behavioral and synaptic consequences of cue-induced cocaine seeking by optically silencing glutamatergic afferents to the NAcore from the prelimbic cortex (PL). Adeno-associated virus coding for the inhibitory opsin archaerhodopsin was microinjected into PL, and optical fibers were targeted to NAcore. Animals were trained to self-administer cocaine followed by extinction training, and then underwent cue-induced reinstatement in the presence or absence of 15 min of optically induced inhibition of PL fibers in NAcore. Inhibiting the PL-to-NAcore projection blocked reinstated behavior and was paralleled by decreased dendritic spine head diameter and AMPA/NMDA ratio relative to sham-laser control rats. Interestingly, while spine density was elevated after extinction training, no further effects were observed by cued reinstatement or optical inhibition. These findings validate the critical role for PL afferents to the NAcore in simultaneously regulating both reinstated behavior and the associated transient synaptic potentiation.

The hypoglossal motor nucleus is one of the efferent components of the neural network underlying the tongue prehension behavior of Ranid frogs. Although the appropriate pattern of the motor activity is determined by motor pattern generators, sensory inputs can modify the ongoing motor execution. Combination of fluorescent tracers were applied to investigate whether there are direct contacts between the afferent fibers of the trigeminal, facial, vestibular, glossopharyngeal-vagal, hypoglossal, second cervical spinal nerves and the hypoglossal motoneurons. Using confocal laser scanning microscope, we detected different number of close contacts from various sensory fibers, which were distributed unequally between the motoneurons innervating the protractor, retractor and inner muscles of the tongue. Based on the highest number of contacts and their closest location to the perikaryon, the glossopharyngeal-vagal nerves can exert the strongest effect on hypoglossal motoneurons and in agreement with earlier physiological results, they influence the protraction of the tongue. The second largest number of close appositions was provided by the hypoglossal and second cervical spinal afferents and they were located mostly on the proximal and middle parts of the dendrites of retractor motoneurons. Due to their small number and distal location, the trigeminal and vestibular terminals seem to have minor effects on direct activation of the hypoglossal motoneurons. We concluded that direct contacts between primary afferent terminals and hypoglossal motoneurons provide one of the possible morphological substrates of very quick feedback and feedforward modulation of the motor program during various stages of prey-catching behavior.

To identify and interact with moving objects, including other members of the same species, an animal's nervous system must correctly interpret patterns of contrast in the physical signals (such as light or sound) that it receives from the environment. In weakly electric fish, the motion of objects in the environment and social interactions with other fish create complex patterns of contrast in the electric fields that they produce and detect. These contrast patterns can extend widely over space and time and represent a multitude of relevant features, as is also true for other sensory systems. Mounting evidence suggests that the computational principles underlying contrast coding in electrosensory neural networks are conserved elements of spatiotemporal processing that show strong parallels with the vertebrate visual system.

Proprioception, the sense of limb and body position, is essential for generating proper movement. Unconscious proprioceptive information travels through cerebellar-projecting neurons in the spinal cord and medulla. The progenitor domain defined by the basic-helix-loop-helix (bHLH) transcription factor, ATOH1, has been implicated in forming these cerebellar-projecting neurons; however, their precise contribution to proprioceptive tracts and motor behavior is unknown. Significantly, we demonstrate that Atoh1-lineage neurons in the spinal cord reside outside Clarke's column (CC), a main contributor of neurons relaying hindlimb proprioception, despite giving rise to the anatomical and functional correlate of CC in the medulla, the external cuneate nucleus (ECu), which mediates forelimb proprioception. Elimination of caudal Atoh1-lineages results in mice with relatively normal locomotion but unable to perform coordinated motor tasks. Altogether, we reveal that proprioceptive nuclei in the spinal cord and medulla develop from more than one progenitor source, suggesting an avenue to uncover distinct proprioceptive functions., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

The V0 interneuronal population is derived from Dbx1 expressing progenitors. Initial studies on these interneurons in the mouse spinal cord demonstrated that they project commissural axons and are involved in coordinating left-right alternation during locomotion. Subsequent work has indicated that the V0 population can be divided into genetically distinct ventral (V0V) and dorsal (V0D) subpopulations, and experimental evidence suggests that each is responsible for left-right alternation at different locomotor speeds. In this study, we perform a series of experiments to probe the location and connectivity of these subpopulations in neonatal mice and demonstrate that they are more diverse than previously predicted. While the distribution of either subpopulation remains consistent along the extent of the lumbar spinal cord, a cluster of V0D cells lateral to the central canal receive substantial input from primary afferents. Retrograde tracing and activity dependent labeling experiments demonstrate that a group of V0 interneurons located in this same region preferentially project axons towards contralateral motoneurons via an oligosynaptic pathway, and are active during fictive locomotion. Our results suggest that this subset of V0 interneurons may be primarily responsible for coordination of left-right alternation during locomotion. Furthermore these experiments indicate that while genetic identity is one determinant of the function of a neuron during locomotion, the specific position in which the cell is located may also play a key role., (© 2015 Wiley Periodicals, Inc.)

Complex sensations accompany the activation of sensory neurons within the respiratory system, yet little is known about the organization of sensory pathways in the brain that mediate these sensations. In the present study, we employ anterograde viral neuroanatomical tract tracing with isogenic self-reporting recombinants of HSV-1 strain H129 to map the higher brain regions in receipt of vagal sensory neurons arising from the trachea versus the lungs, and single-cell PCR to characterize the phenotype of sensory neurons arising from these two divisions of the respiratory tree. The results suggest that the upper and lower airways are predominantly innervated by sensory neurons derived from the somatic jugular and visceral nodose cranial ganglia, respectively. This coincides with central circuitry that is predominately somatic-like, arising from the trachea, and visceral-like, arising from the lungs. Although some convergence of sensory pathways was noted in preautonomic cell groups, this was notably absent in thalamic and cortical regions. These data support the notion that distinct afferent subtypes, via distinct central circuits, subserve sensations arising from the upper versus lower airways. The findings may explain why sensations arising from different levels of the respiratory tree are qualitatively and quantitatively unique.

The prey-catching behavior of the frog is a complex, well-timed sequence of stimulus response chain of movements. After visual analysis of the prey, a size dependent program is selected in the motor pattern generator of the brainstem. Besides this predetermined feeding program, various direct and indirect sensory inputs provide flexible adjustment for the optimal contraction of the executive muscles. The aim of the present study was to investigate whether trigeminal primary afferents establish direct contacts with the jaw opening motoneurons innervated by the facial nerve. The experiments were carried out on Rana esculenta (Pelophylax esculentus), where the trigeminal and facial nerves were labeled simultaneously with different fluorescent dyes. Using a confocal laser scanning microscope, close appositions were detected between trigeminal afferent fibers and somatodendritic components of the facial motoneurons. Quantitative analysis revealed that the majority of close contacts were encountered on the dendrites of facial motoneurons and approximately 10% of them were located on the perikarya. We suggest that the identified contacts between the trigeminal afferents and facial motoneurons presented here may be one of the morphological substrate in the feedback and feedforward modulation of the rapidly changing activity of the jaw opening muscle during the prey-catching behavior., (Copyright © 2015 Elsevier Inc. All rights reserved.)

People with cocaine addiction retain some degree of prefrontal cortex (PFC) inhibitory control of cocaine craving, a brain capacity that may underlie the efficacy of cognitive behavioral therapy for addiction. Similar findings were recently found in rats after extended access to and escalation of cocaine self-administration. Rats' inhibitory control of cocaine seeking was flexible, sufficiently strong to suppress cocaine-primed reinstatement and depended, at least in part, on neuronal activity within the prelimbic (PL) PFC. Here, we used a large-scale and high-resolution Fos mapping approach to identify, beyond the PL PFC, how top-down and/or bottom-up PFC-subcortical circuits are recruited during inhibition of cocaine seeking. Overall, we found that effective inhibitory control of cocaine seeking is associated with the coordinated recruitment of different top-down cortical-striatal circuits originating from different PFC territories, and of different bottom-up dopamine (DA) and serotonin (5-HT) midbrain subsystems that normally modulate activity in these circuits. This integrated brain response suggests that rats concomitantly engage and experience intricate cognitive and affective processes when they have to inhibit intense cocaine seeking. Thus, even after extended drug use, rats can be successfully trained to engage whole-brain inhibitory control mechanisms to suppress cocaine seeking., (© The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Recent research into local-circuit GABAergic inhibitory interneurons of the mammalian central nervous system has provided unprecedented insight into the mechanics of neuronal circuitry and its dysfunction. Inhibitory interneurons consist of a broad array of anatomically and neurochemically diverse cell types, and this suggests that each occupies an equally diverse functional role. Although neurogliaform cells were observed by Cajal over a century ago, our understanding of the functional role of this class of interneurons is in its infancy. However, it is rapidly becoming clear that this cell type operates under a distinct repertoire of rules to provide novel forms of inhibitory control of numerous afferent pathways.

While μ-opioid receptor (MOR) agonists remain the most powerful analgesics for the treatment of severe pain, serious adverse side effects that are secondary to their central nervous system actions pose substantial barriers to therapeutic use. Preclinical and clinical evidence suggest that peripheral MORs play an important role in opioid analgesia, particularly under inflammatory conditions. However, the mechanisms of peripheral MOR signaling in primary afferent pain fibres remain to be established. We have recently introduced a novel ex vivo optical imaging approach that, for the first time, allows the study of physiological functioning within individual peripheral nociceptive fibre free nerve endings in mice. In the present study, we found that MOR activation in selectively identified, primary afferent CGRP nociceptive terminals caused inhibition of N-type Ca(2+) channel signaling and suppression of action potential-evoked Ca(2+) fluorescent transients mediated by 'big conductance' Ca(2+)-activated K(+) channels (BKCa). In the live animal, we showed that the peripherally acting MOR agonist HS-731 produced analgesia and that BKCa channels were the major effectors of the peripheral MOR signaling. We have identified two key molecular transducers of MOR activation that mediate significant inhibition of nociceptive signaling in primary afferent terminals. Understanding the mechanisms of peripheral MOR signaling may promote the development of pathway selective μ-opioid drugs that offer improved therapeutic profiles for achieving potent analgesia while avoiding serious adverse central side effects., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Not only inhibitory afferent-dominant zone (IZ) of the ventral anterior-ventral lateral thalamic complex (VA-VL) but also the ventral medial nucleus (VM) is known to receive strong inputs from the basal ganglia and send axons to motor areas. We previously reported differences in axonal arborization between IZ neurons and the other VA-VL neurons in rats by single-neuron tracing with viral vectors. In the present study, the axonal arborization of single VM neurons was visualized by the same method, and compared with that of IZ neurons. VM neurons formed fewer axon collaterals in the striatum, but sent axon fibers more widely and more preferentially (79% of fibers) to layer 1 of cortical areas than IZ neurons. Furthermore, the VM seemed to contain at least 2 types of neurons; a major population of VM neurons sent axon fibers principally to motor-associated areas as VA-VL neurons did, and the other population projected mainly to orbital or cingulate areas. Although both VM and IZ neurons receive strong basal ganglia inputs, these results suggest that VM neurons, at a single neuron level, innervate the apical dendrites of cortical pyramidal neurons more intensely and more widely than IZ neurons., (© The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

The cerebral hemispheres of amphibians display paired dorsal and ventral striatum (commonly referred to as striatum proper and nucleus accumbens, respectively). Each striatal region is proposed to be closely associated with a pallidal structure located caudal to it to form a striatopallidal system. In the present study, afferents to the dorsal and ventral striatopallidal systems of the fire-bellied toad (Bombina orientalis) were investigated using the neuronal tracer biocytin. A quantitative analysis of the topographical distribution of afferent neurons from the thalamus and posterior tubercle/ventral tegmentum was emphasised. The main results show that inputs to the two striatopallidal systems originate from distinct dorsal thalamic nuclei, with dorsal and ventral striatopallidal afferent neurons favouring strongly the lateral/central and anterior thalamic nuclei, respectively. However, afferent neuron distribution in the dorsal thalamus does not differ in the rostrocaudal axis of the brain. Afferent neurons from the posterior tubercle and ventral tegmentum, on the other hand, are organised topographically along the rostrocaudal axis. About 85 % of afferent neurons to the dorsal striatopallidal system are located rostrally in the posterior tubercle, while 75 % of afferent neurons to the ventral striatopallidal system are found more caudally in the ventral tegmentum. This difference is statistically significant and confirms the presence of distinct mesostriatal pathways in an amphibian. These findings demonstrate that an amphibian brain displays striatopallidal systems integrating parallel streams of sensory information potentially under the influence of distinct ascending mesostriatal pathways.

We examined the substrates for ocular nociception in adult male Sprague-Dawley rats. Capsaicin application to the ocular surface in awake rats evoked nocifensive responses and suppressed spontaneous grooming responses. Thus, peripheral capsaicin was able to activate the central pathways encoding ocular nociception. Our capsaicin stimulus evoked c-Fos expression in a select population of neurons within rostral trigeminal nucleus caudalis in anesthetized rats. These activated neurons also received direct contacts from corneal afferent fibers traced with cholera toxin B from the corneal surface. However, the central terminals of the corneal afferents that contacted capsaicin-activated trigeminal neurons did not contain TRPV1. To determine if TRPV1 expression had been altered by capsaicin stimulation, we examined TRPV1 content of corneal afferents in animals that did not receive capsaicin stimulation. These studies confirmed that while TRPV1 was present in 30% of CTb-labeled corneal afferent neurons within the trigeminal ganglion, TRPV1 was only detected in 2% of the central terminals of these corneal afferents within the trigeminal nucleus caudalis. Other TRP channels were also present in low proportions of central corneal afferent terminals in unstimulated animals (TRPM8, 2%; TRPA1, 10%). These findings indicate that a pathway from the cornea to rostral trigeminal nucleus caudalis is involved in corneal nociceptive transmission, but that central TRP channel expression is unrelated to the type of stimulus transduced by the peripheral nociceptive endings., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Sensorimotor integration is crucial to perception and motor control. How and where this process takes place in the brain is still largely unknown. Here we analyze the cerebellar contribution to sensorimotor integration in the whisker system of mice. We identify an area in the cerebellum where cortical sensory and motor inputs converge at the cellular level. Optogenetic stimulation of this area affects thalamic and motor cortex activity, alters parameters of ongoing movements and thereby modifies qualitatively and quantitatively touch events against surrounding objects. These results shed light on the cerebellum as an active component of sensorimotor circuits and show the importance of sensorimotor cortico-cerebellar loops in the fine control of voluntary movements.