Regressive changes in sizes of somatosensory cuneate nucleus after sensory loss in primates.

Neurons in the early stages of processing sensory information suffer transneuronal atrophy when deprived of their activating inputs. For over 40 y, members of our laboratory have studied the reorganization of the somatosensory cortex during and after recovering from different types of sensory loss. Here, we took advantage of the preserved histological material from these studies of the cortical effects of sensory loss to evaluate the histological consequences in the cuneate nucleus of the lower brainstem and the adjoining spinal cord. The neurons in the cuneate nucleus are activated by touch on the hand and arm, and relay this activation to the contralateral thalamus, and from the thalamus to the primary somatosensory cortex. Neurons deprived of activating inputs tend to shrink and sometimes die. We considered the effects of differences in species, type and extent of sensory loss, recovery time after injury, and age at the time of injury on the histology of the cuneate nucleus. The results indicate that all injuries that deprived part or all of the cuneate nucleus of sensory activation result in some atrophy of neurons as reflected by a decrease in nucleus size. The extent of the atrophy is greater with greater sensory loss and with longer recovery times. Based on supporting research, atrophy appears to involve a reduction in neuron size and neuropil, with little or no neuron loss. Thus, the potential exists for restoring the hand to cortex pathway with brain-machine interfaces, for bionic prosthetics, or biologically with hand replacement surgery.

Mechanical and cold polymodality coexist in tactile peripheral afferents, and it's not mediated by TRPM8.

In the mammalian somatosensory system, polymodality is defined as the competence of some neurons to respond to multiple forms of energy (e.g., mechanical and thermal). This ability is thought to be an exclusive property of nociceptive neurons (polymodal C-fiber nociceptors) and one of the pillars of nociceptive peripheral plasticity. The current study uncovered a completely different neuronal sub-population with polymodal capabilities on the opposite mechanical modality spectrum (tactile). We have observed that several tactile afferents (1/5) can respond to cold in non-nociceptive ranges. These cells' mechanical thresholds and electrical properties are similar to any low-threshold mechano-receptors (LT), conducting in a broad range of velocities (Aδ to Aß), lacking CGRP and TRPM8 receptors. Due to its density, cold-response range, speed, and response to injury (or lack thereof), we speculate on its role in controlling reflexive behaviors (wound liking and rubbing) and modulation of nociceptive spinal cord integration. Further studies are required to understand the mechanisms behind this neuron's polymodality, central architecture, and impact on pain perception.

Spatial sensorimotor mismatch between the motor command and somatosensory feedback decreases motor cortical excitability. A transcranial magnetic stimulation-virtual reality study.

Effective control of movement predominantly depends on the exchange and integration between sensory feedback received by our body and motor command. However, the precise mechanisms governing the adaptation of the motor system's response to altered somatosensory signals (i.e., discrepancies between an action performed and feedback received) following movement execution remain largely unclear. In order to address these questions, we developed a unique paradigm using virtual reality (VR) technology. This paradigm can induce spatial incongruence between the motor commands executed by a body district (i.e., moving the right hand) and the resulting somatosensory feedback received (i.e., feeling touch on the left ankle). We measured functional sensorimotor plasticity in 17 participants by assessing the effector's motor cortical excitability (right hand) before and after a 10-min VR task. The results revealed a decrease in motor cortical excitability of the movement effector following exposure to a 10-min conflict between the motor output and the somatosensory input, in comparison to the control condition where spatial congruence between the moved body part and the area of the body that received the feedback was maintained. This finding provides valuable insights into the functional plasticity resulting from spatial sensorimotor conflict arising from the discrepancy between the anticipated and received somatosensory feedback following movement execution. The cortical reorganization observed can be attributed to functional plasticity mechanisms within the sensorimotor cortex that are related to establishing a new connection between somatosensory input and motor output, guided by temporal binding and the Hebbian plasticity rule.

Somatosensory processing in long COVID fatigue and its relations with physiological and psychological factors.

Fatigue is prevalent amongst people with long COVID, but is poorly understood. The sensory attenuation framework proposes that impairments in sensory processing lead to heightened perception of effort, driving fatigue. This study aims to investigate the role of somatosensory processing impairments in long COVID fatigue and quantify how sensory processing relates to other prominent symptoms of long COVID including autonomic dysfunction, mood and illness beliefs in driving the experience of fatigue. We will recruit 44 individuals with long COVID fatigue and 44 individuals with neither long COVID nor fatigue (controls). Our primary objective is to compare baseline somatosensory processing between individuals with long COVID fatigue and controls. Additionally, we will explore the associations between somatosensory processing, fatigability and the level of fatigue induced by cognitive and physical exertion. Due to the complex nature of fatigue, we will also investigate how long COVID, state fatigue, perceived effort, mood, illness beliefs, autonomic symptoms and autonomic nervous system function interact to predict trait fatigue. This comprehensive investigation aims to elucidate how sensory processing and other prominent symptoms interact to impact the experience of fatigue.

Event-related potential evidence for tactile orientation processing in the human brain.

It is well known that information on stimulus orientation plays an important role in sensory processing. However, the neural mechanisms underlying somatosensory orientation perception are poorly understood. Adaptation has been widely used as a tool for examining sensitivity to specific features of sensory stimuli. Using the adaptation paradigm, we measured event-related potentials (ERPs) in response to tactile orientation stimuli presented pseudo-randomly to the right-hand palm in trials with all the same or different orientations. Twenty participants were asked to count the tactile orientation stimuli. The results showed that the adaptation-related N60 component was observed around contralateral central-parietal areas, possibly indicating orientation processing in the somatosensory regions. Conversely, the adaptation-related N120 component was identified bilaterally across hemispheres, suggesting the involvement of the frontoparietal circuitry in further tactile orientation processing. P300 component was found across the whole brain in all conditions and was associated with task demands, such as attention and stimulus counting. These findings help provide an understanding of the mechanisms of tactile orientation processing in the human brain.

Transfer of Tactile Learning from Trained to Untrained Body Parts Supported by Cortical Coactivation in Primary Somatosensory Cortex.

A pioneering study by Volkmann (1858) revealed that training on a tactile discrimination task improved task performance, indicative of tactile learning, and that such tactile learning transferred from trained to untrained body parts. However, the neural mechanisms underlying tactile learning and transfer of tactile learning have remained unclear. We trained groups of human subjects (female and male) in daily sessions on a tactile discrimination task either by stimulating the palm of the right hand or the sole of the right foot. Task performance before training was similar between the palm and sole. Posttraining transfer of tactile learning was greater from the trained right sole to the untrained right palm than from the trained right palm to the untrained right sole. Functional magnetic resonance imaging (fMRI) and multivariate pattern classification analysis revealed that the somatotopic representation of the right palm in contralateral primary somatosensory cortex (SI) was coactivated during tactile stimulation of the right sole. More pronounced coactivation in the cortical representation of the right palm was associated with lower tactile performance for tactile stimulation of the right sole and more pronounced subsequent transfer of tactile learning from the trained right sole to the untrained right palm. In contrast, coactivation of the cortical sole representation during tactile stimulation of the palm was less pronounced and no association with tactile performance and subsequent transfer of tactile learning was found. These results indicate that tactile learning may transfer to untrained body parts that are coactivated to support tactile learning with the trained body part.SIGNIFICANCE STATEMENT Perceptual skills such as the discrimination of tactile cues can improve by means of training, indicative of perceptual learning and sensory plasticity. However, it has remained unclear whether and if so, how such perceptual learning can occur if the training task is very difficult. Here, we show for tactile perceptual learning that the representation of the palm of the hand in primary somatosensory cortex (SI) is coactivated to support learning of a difficult tactile discrimination task with tactile stimulation of the sole of the foot. Such cortical coactivation of an untrained body part to support tactile learning with a trained body part might be critically involved in the subsequent transfer of tactile learning between the trained and untrained body parts.

Coexisting neuronal coding strategies in the barrel cortex.

During tactile sensation by rodents, whisker movements across surfaces generate complex whisker motions, including discrete, transient stick-slip events, which carry information about surface properties. The characteristics of these events and how the brain encodes this tactile information remain enigmatic. We found that cortical neurons show a mixture of synchronized and nontemporally correlated spikes in their tactile responses. Synchronous spikes convey the magnitude of stick-slip events by numerous aspects of temporal coding. These spikes show preferential selectivity for kinetic and kinematic whisker motion. By contrast, asynchronous spikes in each neuron convey the magnitude of stick-slip events by their discharge rates, response probability, and interspike intervals. We further show that the differentiation between these two types of activity is highly dependent on the magnitude of stick-slip events and stimulus and response history. These results suggest that cortical neurons transmit multiple components of tactile information through numerous coding strategies.

The influence of reduced foot dorsum cutaneous sensitivity on the vestibular control of balance.

PURPOSE: Foot sole cooling increases vestibular-evoked balance responses, but less is known about foot dorsum temperature alterations. The purpose was to determine whether decreasing cutaneous receptor sensitivity via foot dorsum cooling modulates the vestibular control of balance. METHODS: Eighteen participants (9 males; 9 females) stood quietly on a force plate with feet together, eyes closed, and head rotated leftward during 4, 90-s trials (2 control; 2 cooled) of continuous electrical vestibular stimulation (EVS). Icepacks placed on the dorsum of both feet for 15 min induced cooling and remained throughout the EVS trials. Monofilament testing was performed at multiple locations before and after cooling to determine tactile detection thresholds. T-type thermocouples monitored skin temperature over the tibialis anterior, soleus, foot dorsum and arch of the right leg. Vestibular-evoked balance responses were characterized using time (cumulant density) and frequency (coherence and gain) domain analyses to determine the relationship between the EVS input and motor output (anteroposterior force-AP force; right medial gastrocnemius electromyography-MG EMG). RESULTS: Skin temperature of the foot dorsum and arch decreased ~ 70 and 15%, respectively during cooling (p < 0.05), but was unaltered at other locations (p ≥ 0.10). Detection thresholds for the foot dorsum increased following cooling (p < 0.05). Surprisingly, cooling reduced EVS-AP force and EVS-MG EMG coherence and gain at multiple frequencies, and peak-to-peak amplitude compared to control (p < 0.05). CONCLUSION: Our results indicate that vestibular-driven balance responses are reduced following foot dorsum cooling, likely owing to alterations in cutaneous mechanoreceptor sensitivity and subsequent alterations in the transformation of vestibular cues for balance control.

Non-invasive recording of high-frequency signals from the human spinal cord.

Throughout the somatosensory system, neuronal ensembles generate high-frequency signals in the range of several hundred Hertz in response to sensory input. High-frequency signals have been related to neuronal spiking, and could thus help clarify the functional architecture of sensory processing. Recording high-frequency signals from subcortical regions, however, has been limited to clinical pathology whose treatment allows for invasive recordings. Here, we demonstrate the feasibility to record 200-1200 Hz signals from the human spinal cord non-invasively, and in healthy individuals. Using standard electroencephalography equipment in a cervical electrode montage, we observed high-frequency signals between 200 and 1200 Hz in a time window between 8 and 16 ms after electric median nerve stimulation (n = 15). These signals overlapped in latency, and, partly, in frequency, with signals obtained via invasive, epidural recordings from the spinal cord in a patient with neuropathic pain. Importantly, the observed high-frequency signals were dissociable from classic spinal evoked responses. A spatial filter that optimized the signal-to-noise ratio of high-frequency signals led to submaximal amplitudes of the evoked response, and vice versa, ruling out the possibility that high-frequency signals are merely a spectral representation of the evoked response. Furthermore, we observed spontaneous fluctuations in the amplitude of high-frequency signals over time, in the absence of any concurrent, systematic change to the evoked response. High-frequency, "spike-like" signals from the human spinal cord thus carry information that is complementary to the evoked response. The possibility to assess these signals non-invasively provides a novel window onto the neurophysiology of the human spinal cord, both in a context of top-down control over perception, as well as in pathology.

Dependence and reduced motor function in heart failure: future directions for well-being.

While patients with heart failure experience a wide range of symptoms, evidence is mounting that patients with heart failure suffer from reduced functional independence. Given that the number of patients with heart failure is rising and considering the adverse outcomes of reduced functional independence, understanding the underlying mechanisms of reduced functionality in patients with heart failure is of increasing importance. Yet, little information exists on how heart failure negatively affects functional independence, including motor function. This article summarizes reports of reduced independence and highlights its significant adverse outcomes in the patients with heart failure. Finally, this article discusses potential causes of reduced independence based on existing reports of impaired central and peripheral nervous systems in the patients with heart failure. Overall, the article provides a solid foundation for future studies investigating motor impairments in patients with heart failure. Such studies may lead to advances in treatment and prevention of reduced independence associated with heart failure, which ultimately contribute to the well-being of patients with heart failure.

Spinal Circuits for Touch, Pain, and Itch.

The exteroceptive somatosensory system is important for reflexive and adaptive behaviors and for the dynamic control of movement in response to external stimuli. This review outlines recent efforts using genetic approaches in the mouse to map the spinal cord circuits that transmit and gate the cutaneous somatosensory modalities of touch, pain, and itch. Recent studies have revealed an underlying modular architecture in which nociceptive, pruritic, and innocuous stimuli are processed by distinct molecularly defined interneuron cell types. These include excitatory populations that transmit information about both innocuous and painful touch and inhibitory populations that serve as a gate to prevent innocuous stimuli from activating the nociceptive and pruritic transmission pathways. By dissecting the cellular composition of dorsal-horn networks, studies are beginning to elucidate the intricate computational logic of somatosensory transformation in health and disease.

Circuit-Specific Plasticity of Callosal Inputs Underlies Cortical Takeover.

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.

Feedforward and feedback pathways of nociceptive and tactile processing in human somatosensory system: A study of dynamic causal modeling of fMRI data.

Nociceptive and tactile information is processed in the somatosensory system via reciprocal (i.e., feedforward and feedback) projections between the thalamus, the primary (S1) and secondary (S2) somatosensory cortices. The exact hierarchy of nociceptive and tactile information processing within this 'thalamus-S1-S2' network and whether the processing hierarchy differs between the two somatosensory submodalities remains unclear. In particular, two questions related to the ascending and descending pathways have not been addressed. For the ascending pathways, whether tactile or nociceptive information is processed in parallel (i.e., 'thalamus-S1' and 'thalamus-S2') or in serial (i.e., 'thalamus-S1-S2') remains controversial. For the descending pathways, how corticothalamic feedback regulates nociceptive and tactile processing also remains elusive. Here, we aimed to investigate the hierarchical organization for the processing of nociceptive and tactile information in the 'thalamus-S1-S2' network using dynamic causal modeling (DCM) combined with high-temporal-resolution fMRI. We found that, for both nociceptive and tactile information processing, both S1 and S2 received inputs from thalamus, indicating a parallel structure of ascending pathways for nociceptive and tactile information processing. Furthermore, we observed distinct corticothalamic feedback regulations from S1 and S2, showing that S1 generally exerts inhibitory feedback regulation independent of external stimulation whereas S2 provides additional inhibition to the thalamic activity during nociceptive and tactile information processing in humans. These findings revealed that nociceptive and tactile information processing have similar hierarchical organization within the somatosensory system in the human brain.

Defective Somatosensory Inhibition and Plasticity Are Not Required to Develop Dystonia.

BACKGROUND: Dystonia may have different neuroanatomical substrates and pathophysiology. This is supported by studies on the motor system showing, for instance, that plasticity is abnormal in idiopathic dystonia, but not in dystonia secondary to basal ganglia lesions. OBJECTIVE: The aim of this study was to test whether somatosensory inhibition and plasticity abnormalities reported in patients with idiopathic dystonia also occur in patients with dystonia caused by basal ganglia damage. METHODS: Ten patients with acquired dystonia as a result of basal ganglia lesions and 12 healthy control subjects were recruited. They underwent electrophysiological testing at baseline and after a single 45-minute session of high-frequency repetitive somatosensory stimulation. Electrophysiological testing consisted of somatosensory temporal discrimination, somatosensory-evoked potentials (including measurement of early and late high-frequency oscillations and the spatial inhibition ratio of N20/25 and P14 components), the recovery cycle of paired-pulse somatosensory-evoked potentials, and primary motor cortex short-interval intracortical inhibition. RESULTS: Unlike previous reports of patients with idiopathic dystonia, patients with acquired dystonia did not differ from healthy control subjects in any of the electrophysiological measures either before or after high-frequency repetitive somatosensory stimulation, except for short-interval intracortical inhibition, which was reduced at baseline in patients compared to control subjects. CONCLUSIONS: The data show that reduced somatosensory inhibition and enhanced cortical plasticity are not required for the clinical expression of dystonia, and that the abnormalities reported in idiopathic dystonia are not necessarily linked to basal ganglia damage. © 2020 International Parkinson and Movement Disorder Society.

Psychophysical evaluation of somatosensory function in oro-facial pain: achievements and challenges.

AIM: This critical review describes key methodological aspects for a successful oro-facial psychophysical evaluation of the somatosensory system and highlights the diagnostic value of somatosensory assessment and management perspectives based on somatosensory profiling. METHODS: This topical review was based on a non-systematic search for studies about somatosensory evaluation in oro-facial pain in PubMed and Embase. RESULTS: The recent progress regarding the psychophysical evaluation of somatosensory function was largely possible due to the development and application of valid, reliable and standardised psychophysical methods. Qualitative sensory testing may be useful as a screening tool to rule out relevant somatosensory abnormalities. Nevertheless, the patient should preferably be referred to a more comprehensive assessment with the quantitative sensory testing battery if confirmation of somatosensory abnormalities is necessary. Moreover, the identification of relevant somatosensory alterations in chronic pain disorders that do not fulfil the current criteria to be regarded as neuropathic has also increased the usefulness of somatosensory evaluation as a feasible method to better characterise the patients and perhaps elucidate some underpinnings of the so-called 'nociplastic' pain disorders. Finally, an additional benefit of oro-facial pain treatment based on somatosensory profiling still needs to be demonstrated and convincing evidence of somatosensory findings as predictors of treatment efficacy in chronic oro-facial pain awaits further studies. CONCLUSION: Psychophysical evaluation of somatosensory function in oro-facial pain is still in its infancy but with a clear potential to continue to improve the assessment, diagnosis and management of oro-facial pain patients.

[Rheumatic diseases and neuropathic pain : Diagnosis and treatment]. / Rheumatische Erkrankungen und neuropathischer Schmerz : Diagnose und Therapie.

Pain is a leading symptom in inflammatory rheumatic diseases. For a long time it has been assumed that this pain is of nociceptive origin; however, in about one fifth of all patients the pain remains despite successful anti-inflammatory treatment and is not typically described as nociceptive by those affected. Recent studies indicate that some patients with rheumatoid arthritis (RA) experience pain with a neuropathic pain component. The treatment of neuropathic pain with damage to the somatosensory system differs markedly from the treatment of nociceptive pain in which the pain processing system is intact. Thus, the recognition and, above all, the more precise differentiation of the pain symptoms of affected patients make a decisive contribution to a successful treatment. With the help of a few points in the history and a physical examination, the assumption of the diagnosis neuropathic pain can often be rejected or substantiated. Pain with a neuropathic component does not adequately respond to typical analgesics. Instead, the high efficacy of co-analgesics, such as anticonvulsants and antidepressants, has been repeatedly proven.

Primary culture of the rat spinal dorsal horn: a tool to investigate the effects of inflammatory stimulation on the afferent somatosensory system.

One maladaptive consequence of inflammatory stimulation of the afferent somatosensory system is the manifestation of inflammatory pain. We established and characterized a neuroglial primary culture of the rat superficial dorsal horn (SDH) of the spinal cord to test responses of this structure to neurochemical, somatosensory, or inflammatory stimulation. Primary cultures of the rat SDH consist of neurons (43%), oligodendrocytes (35%), astrocytes (13%), and microglial cells (9%). Neurons of the SDH responded to cooling (7%), heating (18%), glutamate (80%), substance P (43%), prostaglandin E2 (8%), and KCl (100%) with transient increases in the intracellular calcium [Ca2+]i. Short-term stimulation of SDH primary cultures with LPS (10 µg/ml, 2 h) caused increased expression of pro-inflammatory cytokines, inflammatory transcription factors, and inducible enzymes responsible for inflammatory prostaglandin E2 synthesis. At the protein level, increased concentrations of tumor necrosis factor-α (TNFα) and interleukin-6 (IL-6) were measured in the supernatants of LPS-stimulated SDH cultures and enhanced TNFα and IL-6 immunoreactivity was observed specifically in microglial cells. LPS-exposed microglial cells further showed increased nuclear immunoreactivity for the inflammatory transcription factors NFκB, NF-IL6, and pCREB, indicative of their activation. The short-term exposure to LPS further caused a reduction in the strength of substance P as opposed to glutamate-evoked Ca2+-signals in SDH neurons. However, long-term stimulation with a low dose of LPS (0.01 µg/ml, 24 h) resulted in a significant enhancement of glutamate-induced Ca2+ transients in SDH neurons, while substance P-evoked Ca2+ signals were not influenced. Our data suggest a critical role for microglial cells in the initiation of inflammatory processes within the SDH of the spinal cord, which are accompanied by a modulation of neuronal responses.

Effects of aging on rapid grip force responses during bimanual manipulation of an active object.

Rapid grip force responses to unexpected pulling loads on the fingertips are deteriorated in older adults due to, in part, age-related declines in somatosensory function. Such reports are limited to one-hand conditions despite the higher frequency of using two hands together in daily living activities of older adults. Unexpected perturbations during bimanual movements elicit goal-oriented and cortically-meditated bilateral rapid motor responses. Since aging is associated with declined somatosensory and cognitive functions, we hypothesized that bilateral rapid motor responses differ between young and older adults, such that older adults exert stronger grip forces following perturbation and the unperturbed hand is more involved in stabilizing the object in older adults. We tested our hypothesis by comparing the rapid grip force responses of both hands in young and older adults. A total of 13 right-handed young individuals (24.2 ± 4.0 years old, 5 men) and 13 right-handed older individuals (68.7 ± 7.1 years old, 5 men) were recruited. Tactile detection threshold, fingertip friction, and the rapid grip force responses of both hands triggered by unpredicted pulling loads during grip-lift movements were assessed. Older adults had higher tactile detection thresholds and lower fingertip friction compared to young adults. Regardless of age, rapid motor responses were found in both the perturbed (right) hand and the indirectly perturbed (left) hand at 73 ms and 135 ms after the perturbation, respectively, while magnitudes of the responses depended on perturbation magnitudes. Higher values in maximum grip force and maximum grip force rate were found in older adults as compared to young adults. In older adults, the indirectly perturbed (left) hand was more involved in stabilizing the object as compared to young healthy adults. The current study suggests that age-related changes in the peripheral and central nervous systems contribute to the greater involvement of the indirectly perturbed hand in older adults.

Critical role of the pore domain in the cold response of TRPM8 channels identified by ortholog functional comparison.

In mammals, the main molecular entity involved in innocuous cold transduction is TRPM8. This polymodal ion channel is activated by cold, cooling compounds such as menthol and voltage. Despite its relevance, the molecular determinants involved in its activation by cold remain elusive. In this study we explored the use of TRPM8 orthologs with different cold responses as a strategy to identify new molecular determinants related with their thermosensitivity. We focused on mouse TRPM8 (mTRPM8) and chicken TRPM8 (cTRPM8), which present complementary thermosensitive and chemosensitive phenotypes. Although mTRPM8 displays larger responses to cold than cTRPM8 does, the avian ortholog shows a higher sensitivity to menthol compared with the mouse channel, in both HEK293 cells and primary somatosensory neurons. We took advantage of these differences to build multiple functional chimeras between these orthologs, to identify the regions that account for these discrepancies. Using a combination of calcium imaging and patch clamping, we identified a region encompassing positions 526-556 in the N terminus, whose replacement by the cTRPM8 homolog sequence potentiated its response to agonists. More importantly, we found that the characteristic cold response of these orthologs is due to nonconserved residues located within the pore loop, suggesting that TRPM8 has evolved by increasing the magnitude of its cold response through changes in this region. Our results reveal that these structural domains are critically involved in cold sensitivity and functional modulation of TRPM8, and support the idea that the pore domain is a key molecular determinant in temperature responses of this thermo-transient receptor potential (TRP) channel.

Sensorimotor integration in the whisker somatosensory brain stem trigeminal loop.

The rodent's vibrissal system is a useful model system for studying sensorimotor integration in perception. This integration determines the way in which sensory information is acquired by sensory organs and the motor commands that control them. The initial instance of sensorimotor integration in the whisker somatosensory system is implemented in the brain stem loop and may be essential to the way rodents explore and sense their environment. To examine the nature of these sensorimotor interactions, we recorded from lightly anesthetized rats in vivo and brain stem slices in vitro and isolated specific parts of this loop. We found that motor feedback to the vibrissal pad serves as a dynamic gain controller that controls the response of first-order sensory neurons by increasing and decreasing sensitivity to lower and higher tactile stimulus magnitudes, respectively. This delicate mechanism is mediated through tactile stimulus magnitude-dependent motor feedback. Conversely, tactile inputs affect the motor whisking output through influences on the rhythmic whisking circuitry, thus changing whisking kinetics. Similarly, tactile influences also modify the whisking amplitude through synaptic and intrinsic neuronal interaction in the facial nucleus, resulting in facilitation or suppression of whisking amplitude. These results point to the vast range of mechanisms underlying sensorimotor integration in the brain stem loop.NEW & NOTEWORTHY Sensorimotor integration is a process in which sensory and motor information is combined to control the flow of sensory information, as well as to adjust the motor system output. We found in the rodent's whisker somatosensory system mutual influences between tactile inputs and motor output, in which motor neurons control the flow of sensory information depending on their magnitude. Conversely, sensory information can control the magnitude and kinetics of whisker movement.