Search

Transient receptor potential families play important roles in the pathology of osteoarthritis (OA) of the knee. While transient receptor potential ankyrin 1 (TRPA1) is also an essential component of the pathogenesis of various arthritic conditions, its association with pain is controversial. Thus, we researched whether TRPA1 is involved in knee OA pain by in vivo patch–clamp recordings and evaluated the behavioral responses using CatWalk gait analysis and pressure application measurement (PAM). Injection of the Trpa1 agonist, allyl isothiocyanate (AITC), into the knee joint significantly increased spontaneous excitatory synaptic current (sEPSC) frequency in the substantia gelatinosa of rats with knee OA, while injection of the Trpa1 antagonist, HC-030031, significantly decreased the sEPSC. Meanwhile, AITC did not affect the sEPSC in sham rats. In the CatWalk and PAM behavioral tests, AITC significantly decreased pain thresholds, but no difference between HC-030031 and saline injections was observed. Our results indicate that Trpa1 mediates knee OA-induced pain. We demonstrated that Trpa1 is activated in the knee joints of rats with OA, and Trpa1 activity enhanced the pain caused by knee OA.

Sexual dysfunction can be caused by impaired neurotransmission from the peripheral to the central nervous system. Therefore, it is important to evaluate the input of sensory information from the peripheral genital area and investigate the control mechanisms in the spinal cord to clarify the pathological basis of sensory abnormalities in the genital area. However, an in vivo evaluation system for the spinal cord–penile neurotransmission mechanism has not yet been developed. Here, urethane-anesthetized rats were used to evaluate neuronal firing induced by innocuous or nociceptive stimulation of the penis using extracellular recording or patch-clamp techniques in the lumbosacral spinal dorsal horn and electrophysiological evaluation in the peripheral pelvic nerves. As a result, innocuous and nociceptive stimuli-evoked neuronal firing was successfully recorded in the deep and superficial spinal dorsal horns, respectively. The innocuous stimuli-evoked nerve firing was also recorded in the pelvic nerve. These firings were suppressed by lidocaine. To the best of our knowledge, this is the first report of a successful quantitative evaluation of penile stimuli-evoked neuronal firing. This method is not only useful for analyzing the pathological basis of spinal cord–penile neurotransmission in sexual dysfunction but also provides a useful evaluation system in the search for new treatments. [ABSTRACT FROM AUTHOR]

• Chronic widespread pain like fibromyalgia (FM) is a serious medical problem. • Here we examined the spinal mechanisms using a rat model of FM. • Superficial dorsal horn (SDH) neurons were strongly sensitized in the model. • Increased excitatory postsynaptic input and decreased inhibitory drive to the SDH neurons were also evident. • These spinal mechanisms may be relevant to the nociceptive hypersensitivity in FM. Chronic widespread pain is one of the important issues to be solved in medical practice. Impaired spinal descending pain inhibitory system due to decreased monoamine neurotransmitters is assumed to cause nociceptive hypersensitivities in chronic painful conditions like that described in patients with fibromyalgia (FM). However, response behaviors and synaptic transmission of the spinal dorsal horn neurons in response to reserpine remain to be clarified. Here we examined the activities of superficial dorsal horn (SDH) neurons, as well as excitatory and inhibitory postsynaptic inputs to SDH neurons, using a putative rat model of FM that was established by injecting reserpine. Extracellular recordings in vivo revealed that SDH neurons were sensitized to mechanical stimulation applied to the neurons' receptive fields, and the mechanically sensitized neurons were spontaneously more active. The sensitizing effect was evident 1 day and 3 days after the reserpine treatment, but subsided 5 days after the treatment or later. Using patch-clamp recordings in vivo , spontaneous excitatory postsynaptic currents (sEPSCs) to SDH neurons were found to increase in the pain model, while spontaneous inhibitory postsynaptic currents (sIPSCs) to SDH neurons decreased. These results demonstrate that the SDH neurons were strongly sensitized in response to the reserpine treatment, and that increased excitatory and decreased inhibitory postsynaptic inputs could be responsible for the spinal nociceptive hypersensitivity in the putative FM model. [ABSTRACT FROM AUTHOR]

Background: Volatile anesthetics suppress noxiously evoked activity in the spinal dorsal horn, which could contribute in part to analgesia, immobility. Modulation of excitatory and inhibitory synaptic transmission in substantia gelatinosa neurons could lead to the suppression of dorsal horn activity; however, this phenomenon has not yet been investigated fully. Methods: In urethane-anesthetized rats, extracellular activity of dorsal horn neurons (action potentials) and excitatory/inhibitory postsynaptic currents in substantia gelatinosa neurons were recorded using extracellular and in vivo patch-clamp techniques, respectively, to assess the spontaneous and the noxious-evoked activity. Sevoflurane or desflurane at concentrations ranging from 0.1 to 2 minimum alveolar concentration was administered by inhalation. Hot- and cold-plate tests were performed to assess nociceptive responses during the inhalation of volatile anesthetics at lower anesthetic doses (0.1–0.5 minimum alveolar concentration). Results: At anesthetic doses (1 and 2 minimum alveolar concentration), both sevoflurane and desflurane decreased the frequency of action potentials in the dorsal horn and the activities of excitatory postsynaptic currents in substantia gelatinosa neurons during pinch stimulation and decreased the activities of spontaneous and miniature excitatory postsynaptic currents. Inhibition of the frequencies was more prominent than that of amplitudes in spontaneous and miniature excitatory postsynaptic currents at these anesthetic doses. However, at subanesthetic doses (0.1 and 0.2 minimum alveolar concentration), desflurane facilitated action potentials and excitatory postsynaptic currents. Inhibitory postsynaptic currents were inhibited by both anesthetics at anesthetic doses (1 and 2 minimum alveolar concentration). Hot- or cold-plate tests showed hyperalgesic effects of desflurane at subanesthetic doses (0.1 and 0.2 minimum alveolar concentration) and a dose-dependent analgesic effect of sevoflurane. Conclusions: Sevoflurane and desflurane at anesthetic doses suppressed dorsal horn activity mainly via inhibition of excitatory postsynaptic currents in substantia gelatinosa neurons, which would contribute to their analgesic properties. Presynaptic mechanisms were likely in excitatory postsynaptic currents inhibition. Desflurane but not sevoflurane may have a hyperalgesic effect at subanesthetic doses. [ABSTRACT FROM AUTHOR]

The influence of cortical cell spiking activity on nearby cells has been studied extensively in vitro. Less is known, however, about the impact of single cell firing on local cortical networks in vivo. In a pioneering study, Kwan and Dan (Kwan and Dan, 2012) reported that in mouse layer 2/3 (L2/3), under anesthesia, stimulating a single pyramidal cell recruits ~2.1% of neighboring units. Here we employ two-photon calcium imaging in layer 2/3 of mouse V1, in conjunction with single-cell patch clamp stimulation in layer 2/3 or layer 4, to probe, in both the awake and lightly anesthetized states, how (i) activating single L2/3 pyramidal neurons recruits neighboring units within L2/3 and from layer 4 (L4) to L2/3, and whether (ii) activating single pyramidal neurons changes population activity in local circuit. To do this, it was essential to develop an algorithm capable of quantifying how sensitive the calcium signal is at detecting effectively recruited units ("followers"). This algorithm allowed us to estimate the chance of detecting a follower as a function of the probability that an epoch of stimulation elicits one extra action potential (AP) in the follower cell. Using this approach, we found only a small fraction (<0.75%) of L2/3 cells to be significantly activated within a radius of ~200µm from a stimulated neighboring L2/3 pyramidal cell. This fraction did not change significantly in the awake vs. the lightly anesthetized state, nor when stimulating L2/3 vs. underlying L4 pyramidal neurons. These numbers are in general agreement with, though lower than, the percentage of neighboring cells (2.1% pyramidal cells and interneurons combined) reported by Kwan and Dan to be activated upon stimulating single L2/3 pyramidal neurons under anesthesia (Kwan and Dan, 2012). Interestingly, despite the small number of individual units found to be reliably driven, we did observe a modest but significant elevation in aggregate population responses compared to sham stimulation. This underscores the distributed impact that single cell stimulation has on neighboring microcircuit responses, revealing only a small minority of relatively strongly connected partners. [ABSTRACT FROM AUTHOR]

Transient receptor potential families play important roles in the pathology of osteoarthritis (OA) of the knee. While transient receptor potential ankyrin 1 (TRPA1) is also an essential component of the pathogenesis of various arthritic conditions, its association with pain is controversial. Thus, we researched whether TRPA1 is involved in knee OA pain by in vivo patch-clamp recordings and evaluated the behavioral responses using CatWalk gait analysis and pressure application measurement (PAM). Injection of the Trpa1 agonist, allyl isothiocyanate (AITC), into the knee joint significantly increased spontaneous excitatory synaptic current (sEPSC) frequency in the substantia gelatinosa of rats with knee OA, while injection of the Trpa1 antagonist, HC-030031, significantly decreased the sEPSC. Meanwhile, AITC did not affect the sEPSC in sham rats. In the CatWalk and PAM behavioral tests, AITC significantly decreased pain thresholds, but no difference between HC-030031 and saline injections was observed. Our results indicate that Trpa1 mediates knee OA-induced pain. We demonstrated that Trpa1 is activated in the knee joints of rats with OA, and Trpa1 activity enhanced the pain caused by knee OA., Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Hidenobu Tamai reports financial support was provided by 10.13039/501100001691Japan Society for the Promotion of Science (KAKENHI)., (© 2023 Published by Elsevier B.V.)

Introduction: Sensory processing is profoundly regulated by brain neuromodulatory systems. One of the main neuromodulators is serotonin which influences higher cognitive functions, such as different aspects of perceptual processing. Accordingly, malfunction in the serotonergic system may lead to visual illusion in psychiatric disorders, such as autism and schizophrenia. This study aims to investigate the serotonergic modulation of visual responses of neurons to stimulus orientation in the primary visual cortex., Methods: Eight-week-old naive mice were anesthetized and a craniotomy was done on the region of interest in the primary visual cortex. Spontaneous and visual-evoked activities of neurons were recorded before and during the electrical stimulation of the dorsal raphe nucleus using in vivo whole-cell patch-clamp recording. The square-wave grating of 12 orientations was presented. The data were analyzed and the Wilcoxon signed-rank test was used to compare the data of two conditions that belong to the same neurons, with or without electrical stimulation., Results: The serotonergic system changed the orientation tuning of nearly 60% of recorded neurons by decreasing the mean firing rate in two independent visual response components, namely gain and baseline response. It also increased the mean firing rate in a small number of neurons (about 20%). Additionally, it left the preferred orientation and sensitivity of neurons unchanged., Conclusion: Serotonergic modulation showed a bidirectional effect. It causes predominately divisive and subtractive decreases in the visual responses of the neurons in the primary visual cortex that can modify the balance between internal and external sensory signals and result in disorders., Highlights: The serotonergic system predominantly decreased the mean firing rate of neurons in the primary visual cortex.The serotonergic system decreased responses of visual cortical neurons by subtractive and divisive changes of orientation tuning.The serotonergic system leaves the spontaneous activity of visual cortical neurons unchanged., Plain Language Summary: Serotonin is one of the well-known neuromodulators involved in many physiological functions of the brain, such as sensory processing. It can play an essential role in producing perceptual psychotic episodes following the use of psychedelic drugs. Neural mechanisms of changes in cortical processing by the serotonergic system are not elucidated enough. In this study, we showed the electrical stimulation of the dorsal raphe nucleus as the main resource for projecting serotonergic neurons to the visual cortex, causing to decrease in visual-evoked responses of neurons in the primary visual cortex without changing the spontaneous activity. This effect may lead to an imbalance between the brain's intrinsic and stimulus-evoked activity and result in various kinds of psychiatric disorders, such as visual hallucinogenic experiences in schizophrenia and autism. Accordingly, it is crucial to understand the mechanisms by which serotonin affects the rapid and long-term activity of neocortical circuits. Such studies can be helpful in the diagnosis and treatment of disorders related to the neuromodulatory roles of the serotonergic system by providing new methods for rebalancing these intricate components., Competing Interests: The authors declared no conflict of interest., (Copyright© 2023 Iranian Neuroscience Society.)

ABSTRACT The hippocampus plays a key role in learning and memory. Previous studies suggested that the main types of principal neurons, dentate gyrus granule cells (GCs), CA3 pyramidal neurons, and CA1 pyramidal neurons, differ in their activity pattern, with sparse firing in GCs and more frequent firing in CA3 and CA1 pyramidal neurons. It has been assumed but never shown that such different activity may be caused by differential synaptic excitation. To test this hypothesis, we performed high-resolution whole-cell patch-clamp recordings in anesthetized rats in vivo. In contrast to previous in vitro data, both CA3 and CA1 pyramidal neurons fired action potentials spontaneously, with a frequency of ∼3-6 Hz, whereas GCs were silent. Furthermore, both CA3 and CA1 cells primarily fired in bursts. To determine the underlying mechanisms, we quantitatively assessed the frequency of spontaneous excitatory synaptic input, the passive membrane properties, and the active membrane characteristics. Surprisingly, GCs showed comparable synaptic excitation to CA3 and CA1 cells and the highest ratio of excitation versus hyperpolarizing inhibition. Thus, differential synaptic excitation is not responsible for differences in firing. Moreover, the three types of hippocampal neurons markedly differed in their passive properties. While GCs showed the most negative membrane potential, CA3 pyramidal neurons had the highest input resistance and the slowest membrane time constant. The three types of neurons also differed in the active membrane characteristics. GCs showed the highest action potential threshold, but displayed the largest gain of the input-output curves. In conclusion, our results reveal that differential firing of the three main types of hippocampal principal neurons in vivo is not primarily caused by differences in the characteristics of the synaptic input, but by the distinct properties of synaptic integration and input-output transformation. © 2015 The Authors Hippocampus Published by Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Summary Cross-modality interaction in sensory perception is advantageous for animals’ survival. How cortical sensory processing is cross-modally modulated and what are the underlying neural circuits remain poorly understood. In mouse primary visual cortex (V1), we discovered that orientation selectivity of layer (L)2/3, but not L4, excitatory neurons was sharpened in the presence of sound or optogenetic activation of projections from primary auditory cortex (A1) to V1. The effect was manifested by decreased average visual responses yet increased responses at the preferred orientation. It was more pronounced at lower visual contrast and was diminished by suppressing L1 activity. L1 neurons were strongly innervated by A1-V1 axons and excited by sound, while visual responses of L2/L3 vasoactive intestinal peptide (VIP) neurons were suppressed by sound, both preferentially at the cell’s preferred orientation. These results suggest that the cross-modality modulation is achieved primarily through L1 neuron- and L2/L3 VIP-cell-mediated inhibitory and disinhibitory circuits. [ABSTRACT FROM AUTHOR]

Rat primary somatosensory (barrel) cortex (SI) contains a detailed representation of the whiskers on the face. The somatosensory information is transferred to the SI from whiskers via the ventroposteromedial nucleus (VPM) of the thalamus. To investigate detailed synaptic activities of cortical neurons receiving input from the thalamus, we have applied the in vivo whole-cell patch clamp recording technique to rat SI. Male Sprague–Dawley rats were anesthetized with urethane (1.2 g/kg, i.p.). Recording pipettes were filled with a standard solution containing 0.2% neurobiotin. Rats were then perfused for the morphological studies. Most recorded neurons exhibited spontaneous excitatory postsynaptic currents (EPSCs) at a holding potential (Vh) of -70 mV and spontaneous IPSCs (Vh=0 mV). Deflection of contralateral whiskers elicited increased EPSCs in both frequency and amplitude. Some neurons exhibited membrane current fluctuation (oscillation). Application of CNQX (100 μM) to the surface of the cortex abolished the oscillatory current, indicating that the oscillation consisted of the summated EPSCs. Whisker stimulation distorted the regularity of the oscillation indicating that oscillation could be related to neural processing in a silent period of sensory input. A single pulse delivered to the VPM via bipolar electrode induced an EPSC with short latency (2 ms), as well as EPSCs with long latency (120 ms) in the cortical neurons. This stimulation also suppressed the oscillations suggesting that thalamic activities could regulate oscillation. [Copyright &y& Elsevier]