Aging-induced microbleeds of the mouse thalamus compared to sensorimotor and memory defects.

The aim of this study is to investigate the relationship between aging and brain vasculature health. Three groups of mice, 3, 17-18, and 24 months, comparable to young adult, middle age, and old human were studied. Prussian blue histology and fast imaging with steady precession T2∗-weighted magnetic resonance imaging were used to quantify structural changes in the brain across age groups. The novel object recognition test was used to assess behavioral changes associated with anatomical changes. This study is the first to show that the thalamus is the most vulnerable brain region in the mouse model for aging-induced vascular damage. Magnetic resonance imaging data document the timeline of accumulation of thalamic damage. Histological data reveal that the majority of vascular damage accumulates in the ventroposterior nucleus and mediodorsal thalamic nucleus. Functional studies indicate that aging-induced vascular damage in the thalamus is associated with memory and sensorimotor deficits. This study points to the possibility that aging-associated vascular disease is a factor in irreversible brain damage as early as middle age.

A Structured Approach to the Diagnosis of Peripheral Nervous System Disorders.

PURPOSE OF REVIEW: Neuroanatomic localization and pattern recognition can be used to diagnose both focal lesions and generalized disorders of the peripheral nervous system. This article describes the nature and pattern of sensory and motor deficits associated with lesions of specific spinal nerve roots, plexus, or peripheral nerves. It also describes the patterns of sensory and motor deficits that suggest multifocal or generalized disorders of the motor neurons, sensory neurons, and peripheral nerves. RECENT FINDINGS: The pattern of sensory and motor deficits may be used to distinguish lesions of the peripheral nervous system from those of the central nervous system. The spinal roots, nerve plexus, and peripheral nerves supply specific muscles and receive sensory input from distinctive cutaneous regions. Focal lesions of these structures therefore produce characteristic patterns of sensory and motor deficits. Multifocal or generalized disorders of the peripheral nervous system may be distinguished by categorizing their sensory and motor involvement, proximal and distal predominance, and degree of symmetry. Serum tests, CSF analysis, electrodiagnostic studies, MRI, ultrasound, nerve biopsy, and skin biopsy have unique roles in the diagnosis of suspected neuromuscular disorders. SUMMARY: A structured approach to the diagnosis of nerve and motor neuron disorders can lead to hypothesis-driven diagnostic testing. Ancillary tests should be reserved for cases in which confirming or refuting a diagnosis will change patient management.

Impairment of intermediate somatosensory function in corticobasal syndrome.

Corticobasal syndrome (CBS) is characterized by unilateral atrophy of the brain. New diagnostic criteria for CBS include intermediate somatosensory dysfunction. Here, we aimed to carefully examine intermediate somatosensory function to identify tests which can assess impairment in CBS patients. Using voxel-based morphometry (VBM), we also aimed to show the anatomical bases of these impairments. Subjects included 14 patients diagnosed with CBS and 14 patients with Parkinson's disease (PD). Patients were evaluated using intermediate somatosensory tests and neuropsychological assessments. VBM was used to analyze differences in gray matter volumes between CBS and PD patients. In the PD group, no tests showed a significant difference between the dominant-side onset and the non-dominant-side onset. In the CBS group, all tests showed worse scores on the affected side. For detecting intermediate somatosensory dysfunction in CBS, two tests are recommended: tactile object naming and 2-point discrimination. VBM analysis showed that the volume of the left post- and pre-central gyrus, and both sides of the supplementary motor area were significantly decreased in the CBS group compared to the PD group. Although CBS remains untreatable, early and correct diagnosis is possible by performing close examination of intermediate somatosensory function.

CMT2Q-causing mutation in the Dhtkd1 gene lead to sensory defects, mitochondrial accumulation and altered metabolism in a knock-in mouse model.

Charcot-Marie-Tooth disease (CMT) is a group of inherited neurological disorders of the peripheral nervous system. CMT is subdivided into two main types: a demyelinating form, known as CMT1, and an axonal form, known as CMT2. Nearly 30 genes have been identified as a cause of CMT2. One of these is the 'dehydrogenase E1 and transketolase domain containing 1' (DHTKD1) gene. We previously demonstrated that a nonsense mutation [c.1455 T > G (p.Y485*)] in exon 8 of DHTKD1 is one of the disease-causing mutations in CMT2Q (MIM 615025). The aim of the current study was to investigate whether human disease-causing mutations in the Dhtkd1 gene cause CMT2Q phenotypes in a mouse model in order to investigate the physiological function and pathogenic mechanisms associated with mutations in the Dhtkd1 gene in vivo. Therefore, we generated a knock-in mouse model with the Dhtkd1Y486* point mutation. We observed that the Dhtkd1 expression level in sciatic nerve of knock-in mice was significantly lower than in wild-type mice. Moreover, a histopathological phenotype was observed, reminiscent of a peripheral neuropathy, including reduced large axon diameter and abnormal myelination in peripheral nerves. The knock-in mice also displayed clear sensory defects, while no abnormalities in the motor performance were observed. In addition, accumulation of mitochondria and an elevated energy metabolic state was observed in the knock-in mice. Taken together, our study indicates that the Dhtkd1Y486* knock-in mice partially recapitulate the clinical phenotypes of CMT2Q patients and we hypothesize that there might be a compensatory effect from the elevated metabolic state in the knock-in mice that enables them to maintain their normal locomotor function.

Sensorimotor and pain-related alterations of the gray matter and white matter in Type 2 diabetic patients with peripheral neuropathy.

Although diabetic peripheral neuropathy (DPN) has long been considered a disease of the peripheral nervous system, recent neuroimaging studies have shown that alterations in the central nervous system may play a crucial role in its pathogenesis. Here, we used surface-based morphometry (SBM) and tract-based spatial statistics (TBSS) to investigate gray matter (GM) and white matter (WM) differences between patients with DPN (n = 67, 44 painless and 23 painful) and healthy controls (HCs; n = 88). Compared with HCs, patients with DPN exhibited GM abnormalities in the pre- and postcentral gyrus and in several deep GM nuclei (caudate, putamen, medial pallidum, thalamus, and ventral nuclear). They also exhibited altered WM tracts (corticospinal tract, spinothalamic tract, and thalamocortical projecting fibers). These findings suggest impaired motor and somatosensory pathways in DPN. Further, patients with DPN (particularly painful DPN) exhibited morphological differences in the cingulate, insula, prefrontal cortex, and thalamus, as well as impaired WM integrity in periaqueductal WM and internal and external capsules. This suggests pain-perception/modulation pathways are altered in painful DPN. Intermodal correlation analyses found that the morphological indices of the brain regions identified by the SBM analysis were significantly correlated with the fractional anisotropy of brain regions identified by the TBSS analysis, suggesting that the GM and WM alterations were tightly coupled. Overall, our study showed sensorimotor and pain-related GM and WM alterations in patients with DPN, which might be involved in the development of DPN.

Functional connectivity impairment of postcentral gyrus in relapsing-remitting multiple sclerosis with somatosensory disorder.

PURPOSE: To characterize the spatial patterns of functional connectivity(FC) changes of whole brain in RRMS with somatosensory disorder(RRMS-SS) and to investigate the correlation between abnormal FC and clinical scores. METHODS: Twenty-six RRMS-SS patients and 23 healthy controls(HC) underwent resting-state functional magnetic resonance imaging(RS-fMRI) scanning. The clinical scores were collected including Expanded Disability Status Scores(EDSS), Disease Duration and Somatosensory Evaluation by the Fugl-Meyer sensory score(FMSS). With the voxel-wise methods, RS-fMRI data were analyzed using REST software, to assess the FC of the postcentral gyrus(PoCG). Correlation between clinical variables and the strength of FC was analyzed. RESULTS: Compared with HC, the left postcentral-based FC showed decreased FC of the right cerebellum_8, lingual lobe and Rolandic operculum gyrus, and increased FC of the left middle frontal lobe. The right postcentral-based FC revealed decreased FC with the right Heschl's gyrus lobule, and increased FC with bilateral middle frontal lobe (p <  0.001, AlphaSim corrected). Correlation analysis revealed that the FC of altered brain regions was associated with FMSS, EDSS and disease duration. CONCLUSION: The functional connectivity of PoCG at RS-fMRI has multi-network changes in patients with RRMS-SS. This suggests a complex pattern of abnormal connections between the somatosensory network regions and the whole brain. Moreover, the correlation between the FC and the FMSS, such as the left middle frontal lobe and the right PoCG, indicate that these two brain regions play an important role in RRMS-SS.

Stabbing Injury of the Cervical Spinal Cord Resulting in Complete Loss of Bilateral Proprioception.

BACKGROUND: Direct penetrating trauma to the spinal cord as a result of stabbing is rare. The vertebral column is strongly suited to protecting the vital neural structures underneath, especially in the midline. CASE DESCRIPTION: A 25-year-old woman experienced a direct stabbing injury to her spinal cord, through the midline structures, resulting in bilateral dorsal column injury. She remained intact with regard to motor function despite bilateral sensory and proprioception loss. CONCLUSIONS: Owing to the strength of the protective elements of the osseous structures surrounding the spinal cord, direct stabbing injuries usually result in incomplete neurologic deficits. This is generally manifested as a Brown-Sequard syndrome because of the midline ligamentous structures and spinous processes deflecting injuries laterally. Our patient experienced a direct midline puncture, resulting in a unique case of bilateral dorsal column injury. These injuries are generally treated conservatively, in the absence of a retained foreign body. Spinal cord stabbing injuries are a rare entity with interesting clinical and anatomic correlations.

Hyperactivation of proprioceptors induces microglia-mediated long-lasting pain in a rat model of chronic fatigue syndrome.

BACKGROUND: Patients diagnosed with chronic fatigue syndrome (CFS) or fibromyalgia experience chronic pain. Concomitantly, the rat model of CFS exhibits microglial activation in the lumbar spinal cord and pain behavior without peripheral tissue damage and/or inflammation. The present study addressed the mechanism underlying the association between pain and chronic stress using this rat model. METHODS: Chronic or continuous stress-loading (CS) model rats, housed in a cage with a thin level of water (1.5 cm in depth), were used. The von Frey test and pressure pain test were employed to measure pain behavior. The neuronal and microglial activations were immunohistochemically demonstrated with antibodies against ATF3 and Iba1. Electromyography was used to evaluate muscle activity. RESULTS: The expression of ATF3, a marker of neuronal hyperactivity or injury, was first observed in the lumbar dorsal root ganglion (DRG) neurons 2 days after CS initiation. More than 50% of ATF3-positive neurons simultaneously expressed the proprioceptor markers TrkC or VGluT1, whereas the co-expression rates for TrkA, TrkB, IB4, and CGRP were lower than 20%. Retrograde labeling using fluorogold showed that ATF3-positive proprioceptive DRG neurons mainly projected to the soleus. Substantial microglial accumulation was observed in the medial part of the dorsal horn on the fifth CS day. Microglial accumulation was observed around a subset of motor neurons in the dorsal part of the ventral horn on the sixth CS day. The motor neurons surrounded by microglia were ATF3-positive and mainly projected to the soleus. Electromyographic activity in the soleus was two to three times higher in the CS group than in the control group. These results suggest that chronic proprioceptor activation induces the sequential activation of neurons along the spinal reflex arc, and the neuronal activation further activates microglia along the arc. Proprioceptor suppression by ankle joint immobilization significantly suppressed the accumulation of microglia in the spinal cord, as well as the pain behavior. CONCLUSION: Our results indicate that proprioceptor-induced microglial activation may be a key player in the initiation and maintenance of abnormal pain in patients with CFS.

Abnormal cerebellar processing of the neck proprioceptive information drives dysfunctions in cervical dystonia.

The cerebellum can influence the responsiveness of the primary motor cortex (M1) to undergo spike timing-dependent plastic changes through a complex mechanism involving multiple relays in the cerebello-thalamo-cortical pathway. Previous TMS studies showed that cerebellar cortex excitation can block the increase in M1 excitability induced by a paired-associative stimulation (PAS), while cerebellar cortex inhibition would enhance it. Since cerebellum is known to be affected in many types of dystonia, this bidirectional modulation was assessed in 22 patients with cervical dystonia and 23 healthy controls. Exactly opposite effects were found in patients: cerebellar inhibition suppressed the effects of PAS, while cerebellar excitation enhanced them. Another experiment comparing healthy subjects maintaining the head straight with subjects maintaining the head turned as the patients found that turning the head is enough to invert the cerebellar modulation of M1 plasticity. A third control experiment in healthy subjects showed that proprioceptive perturbation of the sterno-cleido-mastoid muscle had the same effects as turning the head. We discuss these finding in the light of the recent model of a mesencephalic head integrator. We also suggest that abnormal cerebellar processing of the neck proprioceptive information drives dysfunctions of the integrator in cervical dystonia.

Microneedles: A versatile strategy for transdermal delivery of biological molecules.

Human skin is made up of multiple layers and is designed to protect the human body. The stratum corneum (SC), specifically, is a keratinized layer of skin through which molecules heavier than 500 Da cannot penetrate. Traditional methods of transdermal drug delivery through the SC, such as hypodermic needles, are less than ideal because their size and appearance can cause fear and pain, creating hesitation, limiting self-administration, and preventing their use in some patients altogether. A new technology has been developed to address these limitations, in which an array of needles, each microns in diameter and length, called microneedles, are able to pierce the skin's SC to deliver therapeutic agents without stimulating the proprioceptive pain nerves. These needles provide a strong advantage because they are capable of being incorporated into patches that can be conveniently self-administered by patients, while also offering the same bioabsorption and bioavailability currently provided by hypodermic needles. There have been many advancements in microneedle fabrication, and there are currently many variations of microneedle technology. Therefore, the purpose of this review is to provide a broad, introductory summary of current microneedle technology.

Neuroanatomy of pain-deficiency and cross-modal activation in calcium channel subunit (CACN) α2δ3 knockout mice.

The phenotype of calcium channel subunit (CACN) α2δ3 knockout (KO) mice includes sensory cross-activation and deficient pain perception. Sensory cross-activation defines the activation of a sensory cortical region by input from another modality due to reorganization in the brain such as after sensory loss. To obtain mechanistic insight into both phenomena, we employed a comprehensive battery of neuroanatomical techniques. While CACNα2δ3 was ubiquitously expressed in wild-type mice, it was absent in α2δ3 KO animals. Immunostaining of α1A, α1B, and α1E revealed upregulation of N-type and R-type, but not P/Q-type Cav2 channels in cortical neurons of CACNα2δ3 KO mice. Compared to wild-type mice, axonal processes in somatosensory cortex were enhanced, and dendritic processes reduced, in CACNα2δ3 KO mice. Immunohistochemical and MRI analyses, investigating morphology, thalamocortical and intra-/intercortical trajectories, revealed a disparity between projection and commissural fibers with reduction of the number of spatial specificity of thalamocortical projections. L1cam staining revealed wide-ranging projections of thalamocortical fibers reaching both somatosensory/motor and visual cortical areas. Activation (c-fos+) of excitatory and inhibitory neurons suggested that deficient pain perception in α2δ3 KO mice is unlikely to result from cortical disinhibition. Collectively, our data demonstrate that knock out of CACN α2δ3 results in some structural abnormalities whose functional implications converge to dedifferentiation of sensory activation.

The intense desire for healthy limb amputation: A dis-proprioceptive neuropsychiatric disorder.

BACKGROUND: The first mention of a condition in which apparently nonpsychotic individuals have a strong, unrelenting desire to amputate ≥1 of their healthy limbs was published nearly 4 decades ago. Once dismissed as a paraphilia, the condition in recent years has been re-investigated with neurologic testing and imaging, yielding evidence suggesting it may be attributable to a neuroanatomical anomaly. METHODS: A literature review of data was conducted of recently published studies with pinprick testing, magnetic resonance imaging (MRI)/functional MRI imaging, magnetoencephalography, and interviews of individuals with a desire for limb amputation. RESULTS: Published literature on this condition features studies with a limited number of participants. However, the results indicate that affected individuals predominantly desire amputation of the left lower limb, and correspondingly, usually have changes in cortical thickness in the right parietal lobe. CONCLUSIONS: Further investigation of this condition is warranted, particularly, more research into the precise nature of the anomalous neuroanatomy, biopsychosocial background of those with the condition, and longitudinal perspective of the childhood onset and evolution of symptoms. Large sample studies involving a collaborative effort across multiple sites are required.

Pins and Needles From Fingers to Toes: High-Resolution MRI of Peripheral Sensory Mononeuropathies.

OBJECTIVE: The purpose of this article is to review advanced MRI techniques and describe the MRI findings of pure sensory mononeuropathy with relevant clinical and anatomic correlation. CONCLUSION: Peripheral sensory mononeuropathy can be challenging to evaluate with MRI because of the small caliber of pure sensory nerves and the lack of changes in secondary muscular denervation. Advances in MRI afford the necessary signal-intensity contrast and resolution for adequate evaluation of many of these small peripheral nerves.

NT-3 promotes proprioceptive axon regeneration when combined with activation of the mTor intrinsic growth pathway but not with reduction of myelin extrinsic inhibitors.

Although previous studies have identified several strategies to stimulate regeneration of CNS axons, extensive regeneration and functional recovery have remained a major challenge, particularly for large diameter myelinated axons. Within the CNS, myelin is thought to inhibit axon regeneration, while modulating activity of the mTOR pathway promotes regeneration of injured axons. In this study, we examined NT-3 mediated regeneration of sensory axons through the dorsal root entry zone in a triple knockout of myelin inhibitory proteins or after activation of mTOR using a constitutively active (ca) Rheb in DRG neurons to determine the influence of environmental inhibitory or activation of intrinsic growth pathways could enhance NT-3-mediate regeneration. Loss of myelin inhibitory proteins showed modest enhancement of sensory axon regeneration. In mTOR studies, we found a dramatic age related decrease in the mTOR activation as determined by phosphorylation of the downstream marker S6 ribosomal subunit. Expression of caRheb within adult DRG neurons in vitro increased S6 phosphorylation and doubled the overall length of neurite outgrowth, which was reversed in the presence of rapamycin. In adult female rats, combined expression of caRheb in DRG neurons and NT-3 within the spinal cord increased regeneration of sensory axons almost 3 fold when compared to NT-3 alone. Proprioceptive assessment using a grid runway indicates functionally significant regeneration of large-diameter myelinated sensory afferents. Our results indicate that caRheb-induced increase in mTOR activation enhances neurotrophin-3 induced regeneration of large-diameter myelinated axons.

Involvement of sensory innervation in the skin of SOD1(G93A) ALS mice.

Sensory alterations have been described in both amyotrophic lateral sclerosis (ALS) patients and mouse models. While involvement of intraepidermal and subepidermal axons has been shown in skin biopsies of ALS patients, it is unclear if the SOD1(G93A) mouse presents similar alterations. We analyzed the epidermal and dermal innervation, based on PGP9.5 immunostaining, of SOD1(G93A) mice at different stages. The results showed a marked reduction of intraepidermal nerve fibers, Meissner's corpuscles, and subepidermal nerve density already at 4 weeks. This loss of innervation progressed over time. Dermal axonal density decreased at a later stage of the disease. There was a gradient of axonal loss, with a more severe decline in the epidermis compared with deeper structures, indicating a distal axonal neuropathy as the mechanism of degeneration. These findings suggest that the analysis of the cutaneous sensory innervation may be an accessible and useful tool to assess the neurodegeneration process in motoneuron diseases.

Neglect and extinction in kinesthesia and thesesthesia: understanding proprioceptive inattention.

This paper describes a new observation of neglect and extinction of kinesthesia and thesesthesia (movement and position imperception), jointly reflecting proprioceptive inattention, in a series of patients with parietal lesions. A prototypical case is discussed in detail and unaddressed aspects of proprioceptive inattention are discussed through findings from four additional cases. Thesesthetic and kinesthetic extinction were tested through simultaneous antidromic vertical displacement of index fingers, while having patients report on finger proprioceptive perception with eyes closed. Patients had variable degrees of proprioceptive inattention affecting a specific limb, but without pallesthetic inattention or somatoagnosia, whereas symptoms often resolved with visual feedback or active limb movements. Findings support that kinesthesia and thesesthesia (a) are subserved by near-identical brain networks, (b) relate more to tactile perception than pallesthesia in higher order cortical areas, and (c) have a somatotopic cortical organization even in association brain areas. Furthermore, proprioceptive extinction and neglect involve (i) "attention network" structures, (ii) either hemisphere, (iii) gray or subcortical white matter damage, (iv) defective vigilance mechanisms possibly through premature habituation of spatiotemporally saturated neural capacitor circuits, and (v) are not the result of somatoagnosia, while (vi) their resolution is observed through reafferent motor-sensory or visual feedback.

Neonatal Restriction of Tactile Inputs Leads to Long-Lasting Impairments of Cross-Modal Processing.

Optimal behavior relies on the combination of inputs from multiple senses through complex interactions within neocortical networks. The ontogeny of this multisensory interplay is still unknown. Here, we identify critical factors that control the development of visual-tactile processing by combining in vivo electrophysiology with anatomical/functional assessment of cortico-cortical communication and behavioral investigation of pigmented rats. We demonstrate that the transient reduction of unimodal (tactile) inputs during a short period of neonatal development prior to the first cross-modal experience affects feed-forward subcortico-cortical interactions by attenuating the cross-modal enhancement of evoked responses in the adult primary somatosensory cortex. Moreover, the neonatal manipulation alters cortico-cortical interactions by decreasing the cross-modal synchrony and directionality in line with the sparsification of direct projections between primary somatosensory and visual cortices. At the behavioral level, these functional and structural deficits resulted in lower cross-modal matching abilities. Thus, neonatal unimodal experience during defined developmental stages is necessary for setting up the neuronal networks of multisensory processing.

Pain and temperature processing in dementia: a clinical and neuroanatomical analysis.

Symptoms suggesting altered processing of pain and temperature have been described in dementia diseases and may contribute importantly to clinical phenotypes, particularly in the frontotemporal lobar degeneration spectrum, but the basis for these symptoms has not been characterized in detail. Here we analysed pain and temperature symptoms using a semi-structured caregiver questionnaire recording altered behavioural responsiveness to pain or temperature for a cohort of patients with frontotemporal lobar degeneration (n = 58, 25 female, aged 52-84 years, representing the major clinical syndromes and representative pathogenic mutations in the C9orf72 and MAPT genes) and a comparison cohort of patients with amnestic Alzheimer's disease (n = 20, eight female, aged 53-74 years). Neuroanatomical associations were assessed using blinded visual rating and voxel-based morphometry of patients' brain magnetic resonance images. Certain syndromic signatures were identified: pain and temperature symptoms were particularly prevalent in behavioural variant frontotemporal dementia (71% of cases) and semantic dementia (65% of cases) and in association with C9orf72 mutations (6/6 cases), but also developed in Alzheimer's disease (45% of cases) and progressive non-fluent aphasia (25% of cases). While altered temperature responsiveness was more common than altered pain responsiveness across syndromes, blunted responsiveness to pain and temperature was particularly associated with behavioural variant frontotemporal dementia (40% of symptomatic cases) and heightened responsiveness with semantic dementia (73% of symptomatic cases) and Alzheimer's disease (78% of symptomatic cases). In the voxel-based morphometry analysis of the frontotemporal lobar degeneration cohort, pain and temperature symptoms were associated with grey matter loss in a right-lateralized network including insula (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest) and anterior temporal cortex (P < 0.001 uncorrected over whole brain) previously implicated in processing homeostatic signals. Pain and temperature symptoms accompanying C9orf72 mutations were specifically associated with posterior thalamic atrophy (P < 0.05 corrected for multiple voxel-wise comparisons within the prespecified anatomical region of interest). Together the findings suggest candidate cognitive and neuroanatomical bases for these salient but under-appreciated phenotypic features of the dementias, with wider implications for the homeostatic pathophysiology and clinical management of neurodegenerative diseases.

Acute heat-evoked temperature sensation is impaired but not abolished in mice lacking TRPV1 and TRPV3 channels.

The discovery of heat-sensitive Transient Receptor Potential Vanilloid ion channels (ThermoTRPVs) greatly advanced our molecular understanding of acute and injury-evoked heat temperature sensation. ThermoTRPV channels are activated by partially overlapping temperatures ranging from warm to supra-threshold noxious heat. TRPV1 is activated by noxious heat temperature whereas TRPV3 can be activated by warm as well as noxious heat temperatures. Loss-of-function studies in single TRPV1 and TRPV3 knock-out mice have shown that heat temperature sensation is not completely abolished suggesting functional redundancies among these two channels and highlighting the need of a detailed analysis of TRPV1::TRPV3 double knock-out mice (V1V3dKO) which is hampered by the close proximity of the loci expressing the two channels. Here we describe the generation of a novel mouse model in which trpv1 and trpv3 genes have been inactivated using bacterial artificial chromosome (BAC)-based homologous recombination in embryonic stem cells. In these mice, using classical thermosensory tests such hot plate, tail flick and the thermotaxis gradient paradigms, we confirm that TRPV1 is the master channel for sensing noxious heat temperatures and identify a cooperative role of TRPV1 and TRPV3 for sensing a well-defined window of acute moderate heat temperature. Using the dynamic hot plate assay, we unravel an intriguing and unexpected pronounced escape behavior in TRPV1 knock-out mice that was attenuated in the V1V3dKO. Together, and in agreement with the temperature activation overlap between TRPV1 and TRPV3 channels, our data provide in vivo evidence of a cooperative role between skin-derived TRPV3 and primary sensory neurons-enriched TRPV1 in modulation of moderate and noxious heat temperature sensation and suggest that other mechanisms are required for heat temperature sensation.