Showing papers on "Somatosensory system published in 2021"
TL;DR: In this paper, the authors show that PROKR2Cre-marked sensory neurons, which innervate the periosteum but not abdominal fascia (for example, the peritoneum), are crucial for driving the vagal-adrenal axis.
Abstract: Somatosensory autonomic reflexes allow electroacupuncture stimulation (ES) to modulate body physiology at distant sites1–6 (for example, suppressing severe systemic inflammation6–9). Since the 1970s, an emerging organizational rule about these reflexes has been the presence of body-region specificity1–6. For example, ES at the hindlimb ST36 acupoint but not the abdominal ST25 acupoint can drive the vagal–adrenal anti-inflammatory axis in mice10,11. The neuroanatomical basis of this somatotopic organization is, however, unknown. Here we show that PROKR2Cre-marked sensory neurons, which innervate the deep hindlimb fascia (for example, the periosteum) but not abdominal fascia (for example, the peritoneum), are crucial for driving the vagal–adrenal axis. Low-intensity ES at the ST36 site in mice with ablated PROKR2Cre-marked sensory neurons failed to activate hindbrain vagal efferent neurons or to drive catecholamine release from adrenal glands. As a result, ES no longer suppressed systemic inflammation induced by bacterial endotoxins. By contrast, spinal sympathetic reflexes evoked by high-intensity ES at both ST25 and ST36 sites were unaffected. We also show that optogenetic stimulation of PROKR2Cre-marked nerve terminals through the ST36 site is sufficient to drive the vagal–adrenal axis but not sympathetic reflexes. Furthermore, the distribution patterns of PROKR2Cre nerve fibres can retrospectively predict body regions at which low-intensity ES will or will not effectively produce anti-inflammatory effects. Our studies provide a neuroanatomical basis for the selectivity and specificity of acupoints in driving specific autonomic pathways. Neuroanatomical findings demonstrate why electroactupuncture at only specific acupoints can drive the vagal–adrenal axis and treat inflammation in mice.
169 citations
TL;DR: The authors used single nuclear transcriptomics to characterize transcriptomic classes of human dorsal root ganglia (DRG) neurons that detect different types of stimuli, such as pain and itch, and found that the transcriptomic features of human DRG neurons have similar features to those of mouse neurons.
Abstract: Somatosensory neurons with cell bodies in the dorsal root ganglia (DRG) project to the skin, muscles, bones, and viscera to detect touch and temperature as well as to mediate proprioception and many types of interoception. In addition, the somatosensory system conveys the clinically relevant noxious sensations of pain and itch. Here, we used single nuclear transcriptomics to characterize transcriptomic classes of human DRG neurons that detect these diverse types of stimuli. Notably, multiple types of human DRG neurons have transcriptomic features that resemble their mouse counterparts although expression of genes considered important for sensory function often differed between species. More unexpectedly, we identified several transcriptomic classes with no clear equivalent in the other species. This dataset should serve as a valuable resource for the community, for example as means of focusing translational efforts on molecules with conserved expression across species.
68 citations
TL;DR: In this article, the authors used single nuclear transcriptomics to characterize the classes of human dorsal root ganglia (DRG) neurons that detect these diverse types of stimuli and found that multiple types of human DRG neurons have transcriptomic features that resemble their mouse counterparts although expression of genes considered important for sensory function often differed between species.
Abstract: Somatosensory neurons with cell bodies in the dorsal root ganglia (DRG) project to the skin, muscles, bones, and viscera to detect touch and temperature as well as to mediate proprioception and many types of interoception. In addition, the somatosensory system conveys the clinically relevant noxious sensations of pain and itch. Here we used single nuclear transcriptomics to characterize the classes of human DRG neurons that detect these diverse types of stimuli. Notably, multiple types of human DRG neurons have transcriptomic features that resemble their mouse counterparts although expression of genes considered important for sensory function often differed between species. More unexpectedly, we demonstrated that several classes of mouse neurons have no direct equivalents in humans and human specific cell-types were also identified. This dataset should serve as a valuable resource for the community, for example as means of focusing translational efforts on molecules with conserved expression across species.
58 citations
TL;DR: In this article, the authors detect the full complement of spatially selective firing patterns similar to that reported in the hippocampal-entorhinal network, namely, place cells, head direction cells, boundary vector/border cells, grid cells and conjunctive cells, in the primary somatosensory cortex.
Abstract: Spatially selective firing of place cells, grid cells, boundary vector/border cells and head direction cells constitutes the basic building blocks of a canonical spatial navigation system centered on the hippocampal-entorhinal complex. While head direction cells can be found throughout the brain, spatial tuning outside the hippocampal formation is often non-specific or conjunctive to other representations such as a reward. Although the precise mechanism of spatially selective firing activity is not understood, various studies show sensory inputs, particularly vision, heavily modulate spatial representation in the hippocampal-entorhinal circuit. To better understand the contribution of other sensory inputs in shaping spatial representation in the brain, we performed recording from the primary somatosensory cortex in foraging rats. To our surprise, we were able to detect the full complement of spatially selective firing patterns similar to that reported in the hippocampal-entorhinal network, namely, place cells, head direction cells, boundary vector/border cells, grid cells and conjunctive cells, in the somatosensory cortex. These newly identified somatosensory spatial cells form a spatial map outside the hippocampal formation and support the hypothesis that location information modulates body representation in the somatosensory cortex. Our findings provide transformative insights into our understanding of how spatial information is processed and integrated in the brain, as well as functional operations of the somatosensory cortex in the context of rehabilitation with brain-machine interfaces.
52 citations
TL;DR: An important goal for future research is to obtain a causal and mechanistic understanding of how selected aspects of tactile sensory information are processed by specific types of neurons in the synaptically connected neuronal networks of wS1 and signaled to downstream brain areas, thus contributing to sensory-guided decision-making.
Abstract: The array of whiskers on the snout provides rodents with tactile sensory information relating to the size, shape and texture of objects in their immediate environment. Rodents can use their whiskers to detect stimuli, distinguish textures, locate objects and navigate. Important aspects of whisker sensation are thought to result from neuronal computations in the whisker somatosensory cortex (wS1). Each whisker is individually represented in the somatotopic map of wS1 by an anatomical unit named a 'barrel' (hence also called barrel cortex). This allows precise investigation of sensory processing in the context of a well-defined map. Here, we first review the signaling pathways from the whiskers to wS1, and then discuss current understanding of the various types of excitatory and inhibitory neurons present within wS1. Different classes of cells can be defined according to anatomical, electrophysiological and molecular features. The synaptic connectivity of neurons within local wS1 microcircuits, as well as their long-range interactions and the impact of neuromodulators, are beginning to be understood. Recent technological progress has allowed cell-type-specific connectivity to be related to cell-type-specific activity during whisker-related behaviors. An important goal for future research is to obtain a causal and mechanistic understanding of how selected aspects of tactile sensory information are processed by specific types of neurons in the synaptically connected neuronal networks of wS1 and signaled to downstream brain areas, thus contributing to sensory-guided decision-making.
48 citations
TL;DR: In this paper, the authors compared arousal-linked behaviors with dorsal cortical activity obtained with widefield and two-photon GCaMP6s calcium imaging and electrophysiological recordings.
38 citations
TL;DR: In this article, it was shown that dendritic spines mediate most excitatory neurotransmission in the nervous system, so their function must be critical for the brain.
Abstract: Dendritic spines mediate most excitatory neurotransmission in the nervous system, so their function must be critical for the brain. Spines are biochemical compartments, but could also electrically ...
33 citations
TL;DR: In this article, the authors examined how spaceflight affects neural processing of applied vestibular stimulation and found widespread reductions in this somatosensory and visual cortical deactivation, supporting sensory compensation and reweighting with spaceflight.
Abstract: Microgravity alters vestibular signaling. In-flight adaptation to altered vestibular afferents is reflected in post-spaceflight aftereffects, evidenced by declines in vestibularly mediated behaviors (e.g., walking/standing balance), until readaptation to Earth's 1G environment occurs. Here we examine how spaceflight affects neural processing of applied vestibular stimulation. We used fMRI to measure brain activity in response to vestibular stimulation in 15 astronauts pre- and post-spaceflight. We also measured vestibularly-mediated behaviors, including balance, mobility, and rod-and-frame test performance. Data were collected twice preflight and four times postflight. As expected, vestibular stimulation at the preflight sessions elicited activation of the parietal opercular area ("vestibular cortex") and deactivation of somatosensory and visual cortices. Pre- to postflight, we found widespread reductions in this somatosensory and visual cortical deactivation, supporting sensory compensation and reweighting with spaceflight. These pre- to postflight changes in brain activity correlated with changes in eyes closed standing balance, and greater pre- to postflight reductions in deactivation of the visual cortices associated with less postflight balance decline. The observed brain changes recovered to baseline values by 3 months postflight. Together, these findings provide evidence for sensory reweighting and adaptive cortical neuroplasticity with spaceflight. These results have implications for better understanding compensation and adaptation to vestibular functional disruption.
31 citations
TL;DR: In this paper, the authors reviewed the mechanism of action surrounding PNS, the recent literature from January 2018 to January 2021, and pertinent clinical outcomes and selected 15 consensus articles were selected for in-depth review and inclusion for qualitative analysis.
Abstract: The number of applications for peripheral nerve stimulation (PNS) in the pain management field is ever-growing. With the increasing number of clinical applications for peripheral nerve stimulation, the purpose of this article is to review the mechanism of action surrounding PNS, the recent literature from January 2018 to January 2021, and pertinent clinical outcomes. The authors searched articles identified from PubMed (January 2018–January 2021), Cochrane Central Register of Controlled Trials databases (January 2018–January 2021), and Scopus (January 2018–January 2021) databases, and manually searched references of identified publications. Broad MeSH terms and Boolean operators were queried in each search, including the following terms and their respective synonyms: peripheral nerve stimulation, mechanism of action, biochemical pathway, and pain pathway. 15 consensus articles were selected for in-depth review and inclusion for qualitative analysis. PNS may activate and modulate higher central nervous system (CNS) centers, including the dorsal lateral prefrontal cortex, somatosensory cortex, anterior cingulate cortex, and parahippocampal areas. Neuromodulatory effects from PNS may also extend into the spinal columns. Also, PNS may lead to changes in endogenous neurotransmitters and affect the plasticity of NMDA pathways.
30 citations
TL;DR: In this article, the authors used single-cell RNA sequencing to profile developing and mature glia from dorsal root ganglia and auditory spiral ganglia, and found that glial precursors (GPs) in these two systems differ in their transcriptional profiles.
30 citations
TL;DR: In this paper, the authors analyzed synaptic strength from functionally relevant brain areas to diverse neuronal types in the primary somatosensory cortex (S1) and found that long-range projections from different areas preferentially engage specific sets of GABAergic neurons in S1.
TL;DR: In this paper, the authors discuss the close relationship between the cerebral cortex and peripheral nerves and discuss the role that regulating reorganization mechanisms plays in functional recovery, and conclude with a suggestion to target cortical plasticity along with therapeutic interventions to promote peripheral nerve injury recovery.
TL;DR: In this paper, the relationship between thalamic and somatosensory cortex inhibitory (gamma-aminobutyric acid, GABA) and excitatory (glutamate) neurochemicals with the intrinsic functional connectivity of those regions in 35 ASD and 35 typically developing pediatric subjects was examined.
Abstract: Sensory over-responsivity (SOR), extreme sensitivity to or avoidance of sensory stimuli (e.g., scratchy fabrics, loud sounds), is a highly prevalent and impairing feature of neurodevelopmental disorders such as autism spectrum disorders (ASD), anxiety, and ADHD. Previous studies have found overactive brain responses and reduced modulation of thalamocortical connectivity in response to mildly aversive sensory stimulation in ASD. These findings suggest altered thalamic sensory gating which could be associated with an excitatory/inhibitory neurochemical imbalance, but such thalamic neurochemistry has never been examined in relation to SOR. Here we utilized magnetic resonance spectroscopy and resting-state functional magnetic resonance imaging to examine the relationship between thalamic and somatosensory cortex inhibitory (gamma-aminobutyric acid, GABA) and excitatory (glutamate) neurochemicals with the intrinsic functional connectivity of those regions in 35 ASD and 35 typically developing pediatric subjects. Although there were no diagnostic group differences in neurochemical concentrations in either region, within the ASD group, SOR severity correlated negatively with thalamic GABA (r = -0.48, p < 0.05) and positively with somatosensory glutamate (r = 0.68, p < 0.01). Further, in the ASD group, thalamic GABA concentration predicted altered connectivity with regions previously implicated in SOR. These variations in GABA and associated network connectivity in the ASD group highlight the potential role of GABA as a mechanism underlying individual differences in SOR, a major source of phenotypic heterogeneity in ASD. In ASD, abnormalities of the thalamic neurochemical balance could interfere with the thalamic role in integrating, relaying, and inhibiting attention to sensory information. These results have implications for future research and GABA-modulating pharmacologic interventions.
TL;DR: A review of the diversity of mammalian dorsal root ganglia (DRG) neuron subtypes and the intrinsic and extrinsic mechanisms that control their development is given in this paper.
TL;DR: In this article, the authors examined whether motor planning, in addition to changing the neural state of primary motor cortex (M1), changes the neural states of S1, preparing it for the sensory feedback that arises during action.
Abstract: Recent data and motor control theory argues that movement planning involves preparing the neural state of primary motor cortex (M1) for forthcoming action execution. Theories related to internal models, feedback control, and predictive coding also emphasize the importance of sensory prediction (and processing) prior to (and during) the movement itself, explaining why motor-related deficits can arise from damage to primary somatosensory cortex (S1). Motivated by this work, here we examined whether motor planning, in addition to changing the neural state of M1, changes the neural state of S1, preparing it for the sensory feedback that arises during action. We tested this idea in two human functional MRI studies (N=31, 16 female) involving delayed object manipulation tasks, focusing our analysis on pre-movement activity patterns in M1 and S1. We found that the motor effector to be used in the upcoming action could be decoded, well before movement, from neural activity in M1 in both studies. Critically, we found that this effector information was also present, well before movement, in S1. In particular, we found that the encoding of effector information in area 3b (S1 proper) was linked to the contralateral hand, similarly to that found in M1, whereas in areas 1 and 2 this encoding was present in both the contralateral and ipsilateral hemispheres. Together, these findings suggest that motor planning not only prepares the motor system for movement, but also changes the neural state of the somatosensory system, presumably allowing it to anticipate the sensory information received during movement.SIGNIFICANCE STATEMENT:Whereas recent work on motor cortex has emphasized the critical role of movement planning in preparing neural activity for movement generation, it has not investigated the extent to which planning also modulates the activity in adjacent primary somatosensory cortex (S1). This reflects a key gap in knowledge, given that recent motor control theories emphasize the importance of sensory feedback processing in effective movement generation. Here we find, through a convergence of experiments and analyses, that the planning of object manipulation tasks, in addition to modulating the activity in motor cortex, changes the state of neural activity in different subfields of human S1. We suggest that this modulation prepares S1 for the sensory information it will receive during action execution.
TL;DR: In this article, the authors show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit.
Abstract: Peripheral nerve injury-induced mechanical allodynia is often accompanied by abnormalities in the higher cortical regions, yet the mechanisms underlying such maladaptive cortical plasticity remain unclear. Here, we show that in male mice, structural and functional changes in the primary somatosensory cortex (S1) caused by peripheral nerve injury require neuron-microglial signaling within the local circuit. Following peripheral nerve injury, microglia in the S1 maintain ramified morphology and normal density but up-regulate the mRNA expression of brain-derived neurotrophic factor (BDNF). Using in vivo two-photon imaging and Cx3cr1CreER;Bdnfflox mice, we show that conditional knockout of BDNF from microglia prevents nerve injury-induced synaptic remodeling and pyramidal neuron hyperactivity in the S1, as well as pain hypersensitivity in mice. Importantly, S1-targeted removal of microglial BDNF largely recapitulates the beneficial effects of systemic BDNF depletion on cortical plasticity and allodynia. Together, these findings reveal a pivotal role of cerebral microglial BDNF in somatosensory cortical plasticity and pain hypersensitivity.
TL;DR: In this paper, the authors found that increasing the frequency evoked more intense percepts on some electrodes but evoked less-intense percepts at other electrodes, which supported the idea that stimulation frequency directly controls tactile perception.
Abstract: Microstimulation in the somatosensory cortex can evoke artificial tactile percepts and can be incorporated into bidirectional brain-computer interfaces (BCIs) to restore function after injury or disease. However, little is known about how stimulation parameters themselves affect perception. Here, we stimulated through microelectrode arrays implanted in the somatosensory cortex of two human participants with cervical spinal cord injury and varied the stimulus amplitude, frequency, and train duration. Increasing the amplitude and train duration increased the perceived intensity on all tested electrodes. Surprisingly, we found that increasing the frequency evoked more intense percepts on some electrodes but evoked less-intense percepts on other electrodes. These different frequency-intensity relationships were divided into three groups, which also evoked distinct percept qualities at different stimulus frequencies. Neighboring electrode sites were more likely to belong to the same group. These results support the idea that stimulation frequency directly controls tactile perception and that these different percepts may be related to the organization of somatosensory cortex, which will facilitate principled development of stimulation strategies for bidirectional BCIs.
TL;DR: In this paper, the role of inhibitory and excitatory activity was examined using multimodal approaches: electrophysiological recording, 15.2 T fMRI, optical intrinsic signal imaging, and modeling.
Abstract: The BOLD fMRI response in the cortex is often assumed to reflect changes in excitatory neural activity. However, the contribution of inhibitory neurons to BOLD fMRI is unclear. Here, the role of inhibitory and excitatory activity was examined using multimodal approaches: electrophysiological recording, 15.2 T fMRI, optical intrinsic signal imaging, and modeling. Inhibitory and excitatory neuronal activity in the somatosensory cortex were selectively modulated by 20-s optogenetic stimulation of VGAT-ChR2 and CaMKII-ChR2 mice, respectively. Somatosensory stimulation and optogenetic stimulation of excitatory neurons induced positive BOLD responses in the somatosensory network, whereas stimulation of inhibitory neurons produced biphasic responses at the stimulation site, initial positive and later negative BOLD signals, and negative BOLD responses at downstream sites. When the stimulation duration was reduced to 5 s, the hemodynamic response of VGAT-ChR2 mice to optogenetic stimulation was only positive. Lastly, modeling performed from neuronal and hemodynamic data shows that the hemodynamic response function (HRF) of excitatory neurons is similar across different conditions, whereas the HRF of inhibitory neurons is highly sensitive to stimulation frequency and peaks earlier than that of excitatory neurons. Our study provides insights into the neurovascular coupling of excitatory and inhibitory neurons and the interpretation of BOLD fMRI signals.
TL;DR: This paper investigated the early development of S1 and M1 as a sensory processing unit and found that S1-M1 independently develop somatotopy before establishing the interactive relationship that typifies their functionality in adults.
Abstract: It is generally supposed that primary motor cortex (M1) receives somatosensory input predominantly via primary somatosensory cortex (S1). However, a growing body of evidence indicates that M1 also receives direct sensory input from the thalamus, independent of S1; such direct input is particularly evident at early ages before M1 contributes to motor control. Here, recording extracellularly from the forelimb regions of S1 and M1 in unanesthetized rats at postnatal day (P)8 and P12, we compared S1 and M1 responses to self-generated (i.e., reafferent) forelimb movements during active sleep and wake, and to other-generated (i.e., exafferent) forelimb movements. At both ages, reafferent responses were processed in parallel by S1 and M1; in contrast, exafferent responses were processed in parallel at P8 but serially, from S1 to M1, at P12. To further assess this developmental difference in processing, we compared exafferent responses to proprioceptive and tactile stimulation. At both P8 and P12, proprioceptive stimulation evoked parallel responses in S1 and M1, whereas tactile stimulation evoked parallel responses at P8 and serial responses at P12. Independent of the submodality of exafferent stimulation, pairs of S1-M1 units exhibited greater coactivation during active sleep than wake. These results indicate that S1 and M1 independently develop somatotopy before establishing the interactive relationship that typifies their functionality in adults.SIGNIFICANCE STATEMENT Learning any new motor task depends on the ability to use sensory information to update motor outflow. Thus, to understand motor learning, we must also understand how animals process sensory input. Primary somatosensory cortex (S1) and primary motor cortex (M1) are two interdependent structures that process sensory input throughout life. In adults, the functional relationship between S1 and M1 is well established; however, little is known about how S1 and M1 begin to transmit or process sensory information in early life. In this study, we investigate the early development of S1 and M1 as a sensory processing unit. Our findings provide new insights into the fundamental principles of sensory processing and the development of functional connectivity between these important sensorimotor structures.
TL;DR: In this article, the authors performed ultra-high spatiotemporal resolution fMRI at 15.2 T of the mouse somatosensory network during forepaw somato-ensory stimulation and optogenetic stimulation of the primary motor cortex (M1).
Abstract: Blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging (fMRI) has been widely used to localize brain functions. To further advance understanding of brain functions, it is critical to understand the direction of information flow, such as thalamocortical versus corticothalamic projections. For this work, we performed ultrahigh spatiotemporal resolution fMRI at 15.2 T of the mouse somatosensory network during forepaw somatosensory stimulation and optogenetic stimulation of the primary motor cortex (M1). Somatosensory stimulation induced the earliest BOLD response in the ventral posterolateral nucleus (VPL), followed by the primary somatosensory cortex (S1) and then M1 and posterior thalamic nucleus. Optogenetic stimulation of excitatory neurons in M1 induced the earliest BOLD response in M1, followed by S1 and then VPL. Within S1, the middle cortical layers responded to somatosensory stimulation earlier than the upper or lower layers, whereas the upper cortical layers responded earlier than the other two layers to optogenetic stimulation in M1. The order of early BOLD responses was consistent with the canonical understanding of somatosensory network connections and cannot be explained by regional variabilities in the hemodynamic response functions measured using hypercapnic stimulation. Our data demonstrate that early BOLD responses reflect the information flow in the mouse somatosensory network, suggesting that high-field fMRI can be used for systems-level network analyses.
TL;DR: In this paper, the authors analyzed healthy human tongue and hard palate and found that the hard palate is equipped with a rich repertoire of sensory neurons for pressure sensing and spatial localization of mechanical inputs.
Abstract: The oral somatosensory system relays essential information about mechanical stimuli to enable oral functions such as feeding and speech The neurochemical and anatomical diversity of sensory neurons across oral cavity sites have not been systematically compared To address this gap, we analyzed healthy human tongue and hard-palate innervation Biopsies were collected from 12 volunteers and underwent fluorescent immunohistochemistry (≥2 specimens per marker/structure) Afferents were analyzed for markers of neurons (βIII tubulin), myelinated afferents (neurofilament heavy, NFH), and Merkel cells and taste cells (keratin 20, K20) Hard-palate innervation included Meissner corpuscles, glomerular endings, Merkel cell-neurite complexes, and free nerve endings The organization of these somatosensory endings is reminiscent of fingertips, suggesting that the hard palate is equipped with a rich repertoire of sensory neurons for pressure sensing and spatial localization of mechanical inputs, which are essential for speech production and feeding Likewise, the tongue is innervated by afferents that impart it with exquisite acuity and detection of moving stimuli that support flavor construction and speech Filiform papillae contained end bulbs of Krause, as well as endings that have not been previously reported, including subepithelial neuronal densities, and NFH+ neurons innervating basal epithelia Fungiform papillae had Meissner corpuscles and densities of NFH+ intraepithelial neurons surrounding taste buds The differing compositions of sensory endings within filiform and fungiform papillae suggest that these structures have distinct roles in mechanosensation Collectively, this study has identified previously undescribed neuronal endings in human oral tissues and provides an anatomical framework for understanding oral mechanosensory functions
TL;DR: In this paper, the authors describe how advances in our understanding of brain function, along with the development of neural interfaces that allow for the monitoring and activation of neurons, have paved the way for brain machine interferences.
Abstract: Advances in our understanding of brain function, along with the development of neural interfaces that allow for the monitoring and activation of neurons, have paved the way for brain machine interf...
TL;DR: In this paper, the authors used mouse genetic manipulations to investigate the contributions of peripheral mechanoreceptor subtypes to cortical responses to touch, and found that cortical neuron responses reflect subcortical mixing of signals from both rapidly adapting and slowly adapting low-threshold mechanoreceptors.
Abstract: Current models to explain how signals emanating from cutaneous mechanoreceptors generate representations of touch are based on comparisons of the tactile responses of mechanoreceptor subtypes and neurons in somatosensory cortex1–8. Here we used mouse genetic manipulations to investigate the contributions of peripheral mechanoreceptor subtypes to cortical responses to touch. Cortical neurons exhibited remarkably homogeneous and transient responses to skin indentation that resembled rapidly adapting (RA) low-threshold mechanoreceptor (LTMR) responses. Concurrent disruption of signals from both Aβ RA-LTMRs and Aβ slowly adapting (SA)-LTMRs eliminated cortical responses to light indentation forces. However, disruption of either LTMR subtype alone caused opposite shifts in cortical sensitivity but otherwise largely unaltered tactile responses, indicating that both subtypes contribute to normal cortical responses. Selective optogenetic activation of single action potentials in Aβ RA-LTMRs or Aβ SA-LTMRs drove low-latency responses in most mechanically sensitive cortical neurons. Similarly, most somatosensory thalamic neurons were also driven by activation of Aβ RA-LTMRs or Aβ SA-LTMRs. These findings support a model in which signals from physiologically distinct mechanoreceptor subtypes are extensively integrated and transformed within the subcortical somatosensory system to generate cortical representations of touch. Genetic manipulation of skin peripheral sensory neurons in mice shows that cortical neuron responses to touch reflect subcortical mixing of signals from both rapidly adapting and slowly adapting low-threshold mechanoreceptors.
TL;DR: In this paper, the Hcn1M294L mouse was engineered to explore the disease mechanism underlying an HCN1 developmental and epileptic encephalopathy, including spontaneous seizures and a learning deficit.
Abstract: Pathogenic variants in HCN1 are associated with developmental and epileptic encephalopathies. The recurrent de novo HCN1 M305L pathogenic variant is associated with severe developmental impairment and drug-resistant epilepsy. We engineered the homologue Hcn1 M294L heterozygous knock-in (Hcn1M294L) mouse to explore the disease mechanism underlying an HCN1 developmental and epileptic encephalopathy. The Hcn1M294L mouse recapitulated the phenotypic features of patients with the HCN1 M305L variant, including spontaneous seizures and a learning deficit. Active epileptiform spiking on the electrocorticogram and morphological markers typical of rodent seizure models were observed in the Hcn1M294L mouse. Lamotrigine exacerbated seizures and increased spiking, whereas sodium valproate reduced spiking, mirroring drug responses reported in a patient with this variant. Functional analysis in Xenopus laevis oocytes and layer V somatosensory cortical pyramidal neurons in ex vivo tissue revealed a loss of voltage dependence for the disease variant resulting in a constitutively open channel that allowed for cation 'leak' at depolarized membrane potentials. Consequently, Hcn1M294L layer V somatosensory cortical pyramidal neurons were significantly depolarized at rest. These neurons adapted through a depolarizing shift in action potential threshold. Despite this compensation, layer V somatosensory cortical pyramidal neurons fired action potentials more readily from rest. A similar depolarized resting potential and left-shift in rheobase was observed for CA1 hippocampal pyramidal neurons. The Hcn1M294L mouse provides insight into the pathological mechanisms underlying hyperexcitability in HCN1 developmental and epileptic encephalopathy, as well as being a preclinical model with strong construct and face validity, on which potential treatments can be tested.
TL;DR: It is reported that the neuromodulator oxytocin differentially shapes spontaneous activity patterns across sensory cortices and decreases the excitatory/inhibitory (E/I) ratio by recruiting SST+ interneurons and modulates specific features of V1 spontaneousactivity patterns that are crucial for the wiring and refining of developing sensory circuits.
TL;DR: The roles of purinergic signalling in physiological and pathological pain processing are complex and remain an ever-expanding field of research.
Abstract: Purinergic signalling plays important roles in somatosensory and nociceptive transmission in the dorsal horn of the spinal cord under physiological and pathophysiological conditions. Physiologically, ATP mediates excitatory postsynaptic responses in nociceptive transmission in the superficial dorsal horn, and in transmission of innocuous primary afferent inputs in the deep dorsal horn. Additionally, extracellular conversion of ATP to adenosine mediates inhibitory postsynaptic responses from Pacinian corpuscle afferents, and is implicated in analgesia caused by transcutaneous electrical nerve stimulation in humans. In terms of pathological pain, P2X4 receptors de novo expressed on dorsal horn microglia are implicated in pain hypersensitivity following peripheral nerve injury. There is evidence that involvement of such P2X4 receptors is sexually dimorphic, occurring in males but not in females. Thus, the roles of purinergic signalling in physiological and pathological pain processing are complex and remain an ever-expanding field of research.
TL;DR: In this article, high-resolution structural MRI (sMRI) and magnetoencephalographic (MEG) imaging of neural oscillatory activity was used to compute response amplitude, sensory gating metrics, and spontaneous cortical activity power.
Abstract: HIV-infection has been associated with widespread alterations in brain structure and function, although few studies have examined whether such aberrations are co-localized and the degree to which clinical and cognitive metrics are related. We examine this question in the somatosensory system using high-resolution structural MRI (sMRI) and magnetoencephalographic (MEG) imaging of neural oscillatory activity. Forty-four participants with HIV (PWH) and 55 demographically-matched uninfected controls completed a paired-pulse somatosensory stimulation paradigm during MEG and underwent 3T sMRI. MEG data were transformed into the time-frequency domain; significant sensor level responses were imaged using a beamformer. Virtual sensor time series were derived from the peak responses. These data were used to compute response amplitude, sensory gating metrics, and spontaneous cortical activity power. The T1-weighted sMRI data were processed using morphological methods to derive cortical thickness values across the brain. From these, the cortical thickness of the tissue coinciding with the peak response was estimated. Our findings indicated both PWH and control exhibit somatosensory gating, and that spontaneous cortical activity was significantly stronger in PWH within the left postcentral gyrus. Interestingly, within the same tissue, PWH also had significantly reduced cortical thickness relative to controls. Follow-up analyses indicated that the reduction in cortical thickness was significantly correlated with CD4 nadir and mediated the relationship between HIV and spontaneous cortical activity within the left postcentral gyrus. These data indicate that PWH have abnormally strong spontaneous cortical activity in the left postcentral gyrus and such elevated activity is driven by locally reduced cortical gray matter thickness.
TL;DR: In this paper, the role of subcortical circuits in shaping the multisensory properties of cortical neurons is investigated and it is shown that stimulation of the whiskers causes widespread suppression of sound-evoked activity in mouse primary auditory cortex (A1) and this suppression depends on the primary somatosensory cortex (S1), and is implemented through a descending circuit that links S1 via the auditory midbrain, with thalamic neurons that project to A1.
Abstract: Integration of information across the senses is critical for perception and is a common property of neurons in the cerebral cortex, where it is thought to arise primarily from corticocortical connections. Much less is known about the role of subcortical circuits in shaping the multisensory properties of cortical neurons. We show that stimulation of the whiskers causes widespread suppression of sound-evoked activity in mouse primary auditory cortex (A1). This suppression depends on the primary somatosensory cortex (S1), and is implemented through a descending circuit that links S1, via the auditory midbrain, with thalamic neurons that project to A1. Furthermore, a direct pathway from S1 has a facilitatory effect on auditory responses in higher-order thalamic nuclei that project to other brain areas. Crossmodal corticofugal projections to the auditory midbrain and thalamus therefore play a pivotal role in integrating multisensory signals and in enabling communication between different sensory cortical areas.
TL;DR: In this paper, a detailed wiring diagram for the hand/forelimb-related transcortical circuit is presented, delineating a basic but complex set of cell-type-specific feedforward excitatory connections that selectively and extensively engage diverse intratelencephalic projection neurons, thereby polysynaptically linking subcortical input to cortical motor output to spinal cord.
Abstract: Sensory-guided limb control relies on communication across sensorimotor loops. For active touch with the hand, the longest loop is the transcortical continuation of ascending pathways, particularly the lemnisco-cortical and corticocortical pathways carrying tactile signals via the cuneate nucleus, ventral posterior lateral (VPL) thalamus, and primary somatosensory (S1) and motor (M1) cortices to reach corticospinal neurons and influence descending activity. We characterized excitatory connectivity along this pathway in the mouse. In the lemnisco-cortical leg, disynaptic cuneate→VPL→S1 connections excited mainly layer (L) 4 neurons. In the corticocortical leg, S1→M1 connections from L2/3 and L5A neurons mainly excited downstream L2/3 neurons, which excite corticospinal neurons. The findings provide a detailed new wiring diagram for the hand/forelimb-related transcortical circuit, delineating a basic but complex set of cell-type-specific feedforward excitatory connections that selectively and extensively engage diverse intratelencephalic projection neurons, thereby polysynaptically linking subcortical somatosensory input to cortical motor output to spinal cord.
TL;DR: In this article, the authors compared the perceived intensity, somatosensory evoked potentials, and alpha-band desynchronization for self-generated, other-generated and embodied-fake-hand-generated stimuli.