Increase In Spontaneous Activity Research Articles

C1ql3 knockout affects microglia activation, neuronal integrity, and spontaneous behavior in Wistar rats.

C1QL3 is widely expressed in the brain and is specifically produced by a subset of excitatory neurons. However, its function is still not clear. We established C1ql3-deficient rats to investigate the role of C1QL3 in the brain. C1ql3 knockout (KO) rats were generated using CRISPR/Cas9. C1ql3 KO was determined by polymerase chain reaction (PCR), DNA sequencing, and western blotting. Microglia morphology and cytokine expression with or without lipopolysaccharide (LPS) stimulus were analyzed using immunohistochemistry and real-time PCR. The brain structure changes in KO rats were examined using magnetic resonance imaging. Neuronal architecture alteration was analyzed by performing Golgi staining. Behavior was evaluated using the open field test, Morris water maze test, and Y maze test. C1ql3 KO significantly increased the number of ramified microglia and decreased the number of hypertrophic microglia, whereas C1ql3 KO did not influence the expression of pro-inflammatory factors and anti-inflammatory factors except IL-10. C1ql3 KO brains had more amoeboid microglia types and higher Arg-1 expression compared with the WT rats after LPS stimulation. The brain weights and HPC sizes of C1ql3 KO rats did not differ from WT rats. C1ql3 KO damaged neuronal integrity including neuron dendritic arbors and spine density. C1ql3 KO rats demonstrated an increase in spontaneous activity and an impairment in short working memory. C1ql3 KO not only interrupts the neuronal integrity but also affects the microglial activation, resulting in hyperactive behavior and impaired short memory in rats, which highlights the role of C1QL3 in the regulation of structure and function of both neuronal and microglial cells.

An increase in spontaneous activity mediates visual habituation.

SUMMARYThe cerebral cortex is spontaneously active, but the function of this ongoing activity remains unclear. To test whether spontaneous activity encodes learned experiences, we measured the response of neuronal populations in mouse primary visual cortex with chronic two-photon calcium imaging during visual habituation to a specific oriented stimulus. We find that, during habituation, spontaneous activity increases in neurons across the full range of orientation selectivity, eventually matching that of evoked levels. This increase in spontaneous activity robustly correlates with the degree of habituation. Moreover, boosting spontaneous activity with two-photon optogenetic stimulation to the levels of visually evoked activity accelerates habituation. Our study shows that cortical spontaneous activity is linked to habituation, and we propose that habituation unfolds by minimizing the difference between spontaneous and stimulus-evoked activity levels. We conclude that baseline spontaneous activity could gate incoming sensory information to the cortex based on the learned experience of the animal.

An increase in spontaneous activity mediates visual habituation

An increase in spontaneous activity mediates visual habituation

TH79. MITOCHONDRIAL DNA ALTERATIONS IN THE POSTMORTEM BRAIN OF PSYCHIATRIC DISEASES: A SYSTEMATIC REVIEW

It has previously been hypothesized that hyperactivity of central auditory neurons following exposure to intense noise is a consequence of synaptic alterations. Recent studies suggest the involvement of NMDA receptors in the induction of this hyperactive state. NMDA receptors can mediate long term changes in the excitability of neurons through their involvement in excitotoxic injury and long term potentiation and depression. In this study, we examined the effect of administering an NMDA receptor blocker on the induction of hyperactivity in the dorsal cochlear nucleus (DCN) following intense sound exposure. Our prediction was that if hyperactivity induced by intense sound exposure is dependent on NMDA receptors, then blocking these receptors by administering an NMDA receptor antagonist just before animals are exposed to intense sound should reduce the degree of hyperactivity that subsequently emerges. We compared the levels of hyperactivity that develop in the DCN after intense sound exposure to activity recorded in control animals that were not sound exposed. One group of animals to be sound exposed received intraperitoneal injection of MK-801 twenty minutes preceding the sound exposure, while the other group received injection of saline. Recordings performed in the DCN 26–28 days post-exposure revealed increased response thresholds and widespread increases in spontaneous activity in the saline-treated animals that had been sound exposed, consistent with earlier studies. The animals treated with MK-801 preceding sound exposure showed similarly elevated thresholds but an attenuation of hyperactivity in the DCN; the attenuation was most robust in the high frequency half of the DCN, but lower levels of hyperactivity were also found in the low frequency half. These findings suggest that NMDA receptors are an important component of the hyperactivity-inducing mechanism following intense sound exposure. They further suggest that blockade of NMDA receptors may offer a useful therapeutic approach to preventing induction of noise-induced hyperactivity-related hearing disorders, such as tinnitus and hyperacusis.

Network Dynamics in the Developing Piriform Cortex of Unanesthetized Rats.

The time course of changes in functional cortical activity during early development has been extensively studied in the rodent visual system. A key period in this process is the time of eye opening, which marks the onset of patterned visual input and active vision. However, vision differs from other systems in that it receives limited patterned sensory input before eye opening, and it remains unclear how findings from vision relate to other systems. Here, we focus on the development of cortical network activity in the olfactory system-which is crucial for survival at birth-by recording field potential and spiking activity from piriform cortex of unanesthetized rat pups from birth (P0) to P21. Our results demonstrate that odors evoke stable 10-15Hz oscillations in piriform cortex from birth to P15, after which cortical responses undergo rapid changes. This transition is coincident with the emergence of gamma oscillations and fast sniffing behavior and preceded by an increase in spontaneous activity. Neonatal network oscillations and their developmental dynamics exhibit striking similarities with those previously observed in the visual, auditory, and somatosensory systems, providing insight into the network-level mechanisms underlying the development of sensory cortex in general and olfactory processing in particular.

Transient activation of spinal trigeminal neurons in a rat model of hypoxia-induced headache.

The mechanisms underlying headaches attributed to hypoxia are poorly known. The activation of spinal trigeminal neurons with meningeal afferent input is believed to be responsible for the generation of headaches. In the caudal spinal trigeminal nucleus of anaesthetized and ventilated rats, the spontaneous firing of neurons with input from the exposed parietal dura mater and the activity evoked by mechanical stimuli to the dura and the adjacent periosteum were recorded, whereas the O2 fraction of the ventilation gas was stepwise reduced by omitting O2 and adding nitrogen. The expiratory CO2 level, the arterial pressure, the pulse rate, and the peripheral O2 saturation (SpO2) were registered. The meningeal blood flow was recorded using laser Doppler flowmetry; video imaging was used to measure the diameter of dural and medullary arteries. Lowering O2 in the ventilation gas from hyperoxic to normoxic and finally hypoxic conditions was followed by an increase in spontaneous activity up to 300% of the initial activity in most neurons, whereas the activity in a minor fraction of neurons ceased. The mechanical threshold was reduced under hypoxia. Arterial pressure, pulse rate, and SpO2 fell during stepwise lowering of the O2 concentration, whereas the arteries of the dura mater and the medulla dilated. Increased neuronal activity in the spinal trigeminal nucleus following lowering of the inhaled O2 goes along with variations in cardiovascular parameters. The experiments may partly model the conditions of high altitudes and other hypoxic states as risk factors for headache generation.

Nitric oxide increases gain in the ventral cochlear nucleus of guinea pigs with tinnitus.

Previous work has led to the hypothesis that, during the production of noise-induced tinnitus, higher levels of nitric oxide (NO), in the ventral cochlear nucleus (VCN), increase the gain applied to a reduced input from the cochlea. To test this hypothesis, we noise-exposed 26 guinea pigs, identified evidence of tinnitus in 12 of them and then compared the effects of an iontophoretically applied NO donor or production inhibitor on VCN single unit activity. We confirmed that the mean driven firing rate for the tinnitus and control groups was the same while it had fallen in the non-tinnitus group. By contrast, the mean spontaneous rate had increased for the tinnitus group relative to the control group, while it remained the same for the non-tinnitus group. A greater proportion of units responded to exogenously applied NO in the tinnitus (56%) and non-tinnitus groups (71%) than a control population (24%). In the tinnitus group, endogenous NO facilitated the driven firing rate in 37% (7/19) of neurons and appeared to bring the mean driven rate back up to control levels by a mechanism involving N-methyl-D-aspartic acid (NMDA) receptors. By contrast, in the non-tinnitus group, endogenous NO only facilitated the driven firing rate in 5% (1/22) of neurons and there was no facilitation of driven rate in the control group. The effects of endogenous NO on spontaneous activity were unclear. These results suggest that NO is involved in increasing the gain applied to driven activity, but other factors are also involved in the increase in spontaneous activity.

Дифференцированная иммунотерапия в интеграционной программе реабилитации иммунокомпрометированных детей с врожденными расщелинами губы и нёба

One of the development directions of osteoimmunology is the search for new therapeutic approaches in the pathology of bone tissue, in the pathogenesis of which the interaction between the immune and bone systems plays an essential role. In children with congenital cleft lip and palate (CCLP), the physiological deficiency of the immune system (IS) and its anatomical disorders lead to intense tension in the immature mechanism for maintaining immune homeostasis, which is accompanied by clinical features of immunodeficiency in the form of recurrent viral, bacterial and fungal infectious and inflammatory diseases of the respiratory tract, ENT organs and oral cavity. Objective. To develop an integration program for the rehabilitation of children with CCLP, which includes not only traditional complex rehabilitation, but also measures aimed at restoration of the normal functioning of IS with the use of new approaches to conduct differentiated immunotherapy for each age period. Patients and methods. The study included 210 children of different ages: 150 children with CCLP and 60 conditionally healthy children without CCLP. Immunophenotyping of lymphocytes was conducted by flow cytometry; testing of phagocytic activity of neutrophilic granulocytes (NG), spontaneous and induced production of reactive oxygen species in the NBT test, determination of the level of serum IgA, IgM, IgG and sIgA in oral fluid. Results. Common for all age groups of children with CCLP, NG dysfunctions of different severity were found: defects of phagocytosis, an increase of spontaneous activity of NADPH oxidase and dysfunction of adequate response in the form of partial or complete blockade of NADPH oxidase activity during additional antigenic bacterial load in the system in vitro. Taking into account revealed defects in the functioning of IS and peculiarities of the clinical status of immunocompromised children of different ages with CCLP who suffer from a high frequency of infectious and inflammatory diseases of the respiratory tract, ENT organs and oral cavity, we have developed programs of differentiated immunotropic therapy for children of different ages with CCLP. Considering revealed defects in the functioning of IS and peculiarities of the clinical status of immunocompromised children of different ages with CCLP who suffer from a high frequency of infectious and inflammatory diseases of the respiratory tract, we have developed and used an integration program of immunorehabilitation with a positive clinical and immunological effect. Conclusion. The developed integration program for the rehabilitation of immunocompromised children with CCLP with a high frequency of infectious and inflammatory diseases of the respiratory tract, ENT organs and oral cavity, organically including differentiated immunotherapy along with methods of surgical, orthodontic and social rehabilitation and speech therapy, optimizes the treatment of patients with this pathology. The principles of differentiated immunotherapy are based on the revealed clinical and immunological peculiarities of immunodeficiency, which have both common features and differences depending on age, infectious and inflammatory manifestations and the stage of surgical treatment of children with CCLP. Key words: congenital cleft lip and palate, immunocompromised children, immunotropic therapy, rehabilitation

Epiregulin is released from intervertebral disks and induces spontaneous activity in pain pathways.

Introduction:Lumbar radicular pain after disk herniation is associated with local release of many inflammatory molecules from nucleus pulposus (NP) cells leaking out of the intervertebral disk. Here, we have used a rat model to investigate the role of epiregulin (EREG), a member of the epidermal growth factor (EGF) family, in this process.Methods:A protein immunoassay was chosen to confirm the release of EREG from the NP tissue. Single unit recordings were used to demonstrate the effect of recombinant EREG applied onto the dorsal nerve roots in vivo. Intracellular responses induced by recombinant EREG were studied in cultured dorsal root ganglion (DRG) cells by phosphoprotein assay. Changes in EGF receptor expression induced by NP in the DRG were examined by quantitative polymerase chain reaction.Results:The protein immunoassay showed that EREG was released from the NP tissue. Moreover, application of EREG onto the spinal dorsal nerve roots induced a decrease in the evoked responses, but an increase in spontaneous activity in the dorsal horn neurons. Interestingly, the EREG activated the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in the DRG, a pathway previously linked to cellular growth, proliferation, and tissue regeneration. An NP-induced upregulation of the EGF receptor HER3 in the DRG was also revealed.Conclusion:Taken together, the present observations indicate that EREG may induce changes in the DRG and spontaneous activity in the pain pathways. We suggest that EREG signaling may be involved in the pathophysiological process leading to sensory deficits and neuropathic pain in patients after disk herniation.

Cholinergic Homeostatic Synaptic Plasticity Drives the Progression of Aβ-Induced Changes in Neural Activity

Homeostatic synaptic plasticity (HSP) is the ability of neurons to exert compensatory changes in response to altered neural activity. How pathologically induced activity changes are intertwined with HSP mechanisms is unclear. We show that, in cholinergic neurons from Drosophila, beta-amyloid (Aβ) peptides Aβ40 and Aβ42 both induce an increase in spontaneous activity. In a transgenic line expressing Aβ42, we observe that this early increase in spontaneous activity is followed by a dramatic reduction in spontaneous events, a progression that has been suggested to occur in cholinergic brain regions of mammalian models of Alzheimer's disease. We present evidence that the early enhancement in synaptic activity is mediated by the Drosophila α7 nicotinic acetylcholine receptor (nAChR) and that, later, Aβ42-induced inhibition of synaptic events is a consequence of Dα7-dependent HSP mechanisms induced by earlier hyperactivity. Thus, while HSP may initially be an adaptive response, it may also drive maladaptive changes and downstream pathologies.

Increased spontaneous firing rates in auditory midbrain following noise exposure are specifically abolished by a Kv3 channel modulator

Noise exposure has been shown to produce long-lasting increases in spontaneous activity in central auditory structures in animal models, and similar pathologies are thought to contribute to clinical phenomena such as hyperacusis or tinnitus in humans. Here we demonstrate that multi-unit spontaneous neuronal activity in the inferior colliculus (IC) of mice is significantly elevated four weeks following noise exposure at recording sites with frequency tuning within or near the noise exposure band, and this selective central auditory pathology can be normalised through administration of a novel compound that modulates activity of Kv3 voltage-gated ion channels. The compound had no statistically significant effect on IC spontaneous activity without noise exposure, nor on thresholds or frequency tuning of tone-evoked responses either with or without noise exposure. Administration of the compound produced some reduction in the magnitude of evoked responses to a broadband noise, but unlike effects on spontaneous rates, these effects on evoked responses were not specific to recording sites with frequency tuning within the noise exposure band. Thus, the results suggest that modulators of Kv3 channels can selectively counteract increases in spontaneous activity in the auditory midbrain associated with noise exposure.

AT1aR Dependent GABAa Inhibition in the MnPO Following Chronic Intermittent Hypoxia

Chronic intermittent hypoxia (CIH) is an animal model that simulates the hypoxemia seen in obstructive sleep apnea (OSA). Rats exposed to CIH exhibit an increase in sympathetic tone and reactivity and a persistent elevation in blood pressure during periods of normoxia, similar to that observed in patients with OSA. The median preoptic nucleus (MnPO) exhibits increases in Angiotensin type 1a receptor (AT1aR) mRNA following CIH and blocking this increase in AT1aR mRNA prevents the sustained increase in blood pressure. Our lab has previously reported that AT1aR activation influences GABAa mediated inhibition within the MnPO. Here we investigate the role of Angiotensin II (Ang II) signaling via the AT1a receptor in the MnPO and its influence on excitatory/inhibitory balance in rats subjected to CIH. Under isoflurane (2–3%) anesthesia, male Sprague‐Dawley rats (250–350 g) received microinfusions (0.4 μL) of recombinant AAV construct containing GFP reporter and shRNA against AT1aR (AT1a KD) or an AAV construct containing the GFP reporter and a shRNA scramble (Scr) targeted to the MnPO. After recovery, rats were subjected to 7 days of CIH (0800–1600 hrs). The CIH protocol consisted of 6 min cycles (3 min 21% O2, 3 min 10% O2) repeated 10×/hr for 8 consecutive hrs (during the normal inactive/sleep phase) on 7 consecutive days. After 7 days CIH, the rats were anesthetized with isoflurane (2–3%) and coronal slices (300 μm) containing the MnPO were cut using standard in vitro slice procedures. Loose patch recordings were obtained from GFP labeled neurons using borosilicate glass micropipettes containing aCSF as the internal solution (1–3 MΩ). Spontaneous action potential firing was recorded in response to focal application of Ang II (100 nM, 30s) or muscimol (100 uM, 30s). Brief focal application of Ang II produced a transient increase in spontaneous action potential frequency of MnPO neurons from both CIH/Scr (n = 11) and normoxic/Scr (n = 9) rats. The Ang II dependent increase in activity was blocked in neurons from AT1a KD rats from both CIH (n = 12) and normoxic (n = 10) groups. The GABAa agonist muscimol decreased action potential activity (n = 10) of neurons from normoxic/Scr rats. This GABAa mediated inhibition was blunted in neurons from CIH/Scr (n = 13) and normoxic/AT1a KD (n = 10) rats. However, GABAa activation from neurons in the CIH/AT1a KD (n = 15) group produced an increase in spontaneous activity. The current study shows AT1aR KD mediated reduction in GABAa inhibition is exacerbated to the point where GABAa activation is excitatory following CIH. Future studies will address the influence of reduced AT1a signaling combined with reduced GABAa mediated inhibition on downstream targets of the MnPO in AT1aKD from both normoxic and CIH rats.Support or Funding InformationSupported by P01 HL088052This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Attenuation of noise-induced hyperactivity in the dorsal cochlear nucleus by pre-treatment with MK-801

It has previously been hypothesized that hyperactivity of central auditory neurons following exposure to intense noise is a consequence of synaptic alterations. Recent studies suggest the involvement of NMDA receptors in the induction of this hyperactive state. NMDA receptors can mediate long term changes in the excitability of neurons through their involvement in excitotoxic injury and long term potentiation and depression. In this study, we examined the effect of administering an NMDA receptor blocker on the induction of hyperactivity in the dorsal cochlear nucleus (DCN) following intense sound exposure. Our prediction was that if hyperactivity induced by intense sound exposure is dependent on NMDA receptors, then blocking these receptors by administering an NMDA receptor antagonist just before animals are exposed to intense sound should reduce the degree of hyperactivity that subsequently emerges. We compared the levels of hyperactivity that develop in the DCN after intense sound exposure to activity recorded in control animals that were not sound exposed. One group of animals to be sound exposed received intraperitoneal injection of MK-801 twenty minutes preceding the sound exposure, while the other group received injection of saline. Recordings performed in the DCN 26–28 days post-exposure revealed increased response thresholds and widespread increases in spontaneous activity in the saline-treated animals that had been sound exposed, consistent with earlier studies. The animals treated with MK-801 preceding sound exposure showed similarly elevated thresholds but an attenuation of hyperactivity in the DCN; the attenuation was most robust in the high frequency half of the DCN, but lower levels of hyperactivity were also found in the low frequency half. These findings suggest that NMDA receptors are an important component of the hyperactivity-inducing mechanism following intense sound exposure. They further suggest that blockade of NMDA receptors may offer a useful therapeutic approach to preventing induction of noise-induced hyperactivity-related hearing disorders, such as tinnitus and hyperacusis.

Management of tinnitus patient

General tinnitus knowledge: What is tinnitus? Involuntary sound perception originating in the head Tinnitus can be caused by: Hearing loss Exposure to loud sounds Extreme stress or trauma Acoustic neuroma Injury to ears, neck or head and heart disease Neurophysiological models indicate the mechanism of tinnitus in an increase in spontaneous activity in the absence of acoustic stimuli. General notes on Tinnitus: 1- Any Tinnitus treatment must be used in connection with counseling and possible other treatment. 2- Tinnitus is a perception of involuntary sound. It must be audible to the person, it originates in the head (McFadden 1982). 3- It is most commonly referred to as ringing in the ears. 4- Produced centrally, with peripheral influences (e.g. Cochlear damage). Exact mechanism(s), or epidemiology is unknown. 5- Noise type can vary from pure tones over modulated noise to crackling sounds that varies significantly with time & Large intensity variations. 6- Not a ‘phantom’ perception for the patient, it is real 7- Tinnitus can be described in many different forms, for example: Ringing, Chirping, Clicking, Pulsating, Continuous, Sudden A-Geriatric tinnitus Presby tinnitus, defined as tinnitus that accompanies the progressive hearing loss of presbycusis; is classified as: type 1 (normal aging affecting the cochlea), and type II (preexistent sensorineural hearing loss accompanied by multiple systemic complaints, especially of sensory ones). B-Pediatric tinnitus has an incidence of 13% in children who passed an audio metric screening test, and 23-60% in those with hearing loss, 44% in secretory otitis media, but only 3% complain spontaneously because that the child considers tinnitus to be a normal event. There is no significant difference between children with tinnitus and those without in terms of hearing level, age, gender, or etiology of the deafness. Despite the fact that often children do not mention it, tinnitus may incite behavioral problems.

Non-Monotonic Relation between Noise Exposure Severity and Neuronal Hyperactivity in the Auditory Midbrain.

The occurrence of tinnitus can be linked to hearing loss in the majority of cases, but there is nevertheless a large degree of unexplained heterogeneity in the relation between hearing loss and tinnitus. Part of the problem might be that hearing loss is usually quantified in terms of increased hearing thresholds, which only provides limited information about the underlying cochlear damage. Moreover, noise exposure that does not cause hearing threshold loss can still lead to “hidden hearing loss” (HHL), i.e., functional deafferentation of auditory nerve fibers (ANFs) through loss of synaptic ribbons in inner hair cells. While it is known that increased hearing thresholds can trigger increases in spontaneous neural activity in the central auditory system, i.e., a putative neural correlate of tinnitus, the central effects of HHL have not yet been investigated. Here, we exposed mice to octave-band noise at 100 and 105 dB SPL to generate HHL and permanent increases of hearing thresholds, respectively. Deafferentation of ANFs was confirmed through measurement of auditory brainstem responses and cochlear immunohistochemistry. Acute extracellular recordings from the auditory midbrain (inferior colliculus) demonstrated increases in spontaneous neuronal activity (a putative neural correlate of tinnitus) in both groups. Surprisingly, the increase in spontaneous activity was most pronounced in the mice with HHL, suggesting that the relation between hearing loss and neuronal hyperactivity might be more complex than currently understood. Our computational model indicated that these differences in neuronal hyperactivity could arise from different degrees of deafferentation of low-threshold ANFs in the two exposure groups. Our results demonstrate that HHL is sufficient to induce changes in central auditory processing, and they also indicate a non-monotonic relationship between cochlear damage and neuronal hyperactivity, suggesting an explanation for why tinnitus might occur without obvious hearing loss and conversely why hearing loss does not always lead to tinnitus.

Evidence of activity-dependent plasticity in the dorsal cochlear nucleus, in vivo, induced by brief sound exposure

The purpose of the present study was to investigate the immediate effects of acute exposure to intense sound on spontaneous and stimulus-driven activity in the dorsal cochlear nucleus (DCN). We examined the levels of multi- and single-unit spontaneous activity before and immediately following brief exposure (2 min) to tones at levels of either 109 or 85 dB SPL. Exposure frequency was selected to either correspond to the units' best frequency (BF) or fall within the borders of its inhibitory side band. The results demonstrate that these exposure conditions caused significant alterations in spontaneous activity and responses to BF tones. The induced changes have a fast onset (minutes) and are persistent for durations of at least 20 min. The directions of the change were found to depend on the frequency of exposure relative to BF. Transient decreases followed by more sustained increases in spontaneous activity were induced when the exposure frequency was at or near the units’ BF, while sustained decreases of activity resulted when the exposure frequency fell inside the inhibitory side band. Follow-up studies at the single unit level revealed that the observed activity changes were found on unit types having properties which have previously been found to represent fusiform cells. The changes in spontaneous activity occurred despite only minor changes in response thresholds. Noteworthy changes also occurred in the strength of responses to BF tones, although these changes tended to be in the direction opposite those of the spontaneous rate changes. We discuss the possible role of activity-dependent plasticity as a mechanism underlying the rapid emergence of increased spontaneous activity after tone exposure and suggest that these changes may represent a neural correlate of acute noise-induced tinnitus.

Noise-induced hearing loss: Neuropathic pain via Ntrk1 signaling.

Severe noise-induced damage to the inner ear leads to auditory nerve fiber degeneration thereby reducing the neural input to the cochlear nucleus (CN). Paradoxically, this leads to a significant increase in spontaneous activity in the CN which has been linked to tinnitus, hyperacusis and ear pain. The biological mechanisms that lead to an increased spontaneous activity are largely unknown, but could arise from changes in glutamatergic or GABAergic neurotransmission or neuroinflammation. To test this hypothesis, we unilaterally exposed rats for 2h to a 126dB SPL narrow band noise centered at 12kHz. Hearing loss measured by auditory brainstem responses exceeded 55dB from 6 to 32kHz. The mRNA from the exposed CN was harvested at 14 or 28days post-exposure and qRT-PCR analysis was performed on 168 genes involved in neural inflammation, neuropathic pain and glutamatergic or GABAergic neurotransmission. Expression levels of mRNA of Slc17a6 and Gabrg3, involved in excitation and inhibition respectively, were significantly increased at 28days post-exposure, suggesting a possible role in the CN spontaneous hyperactivity associated with tinnitus and hyperacusis. In the pain and inflammatory array, noise exposure upregulated mRNA expression levels of four pain/inflammatory genes, Tlr2, Oprd1, Kcnq3 and Ntrk1 and decreased mRNA expression levels of two more genes, Ccl12 and Il1β. Pain/inflammatory gene expression changes via Ntrk1 signaling may induce sterile inflammation, neuropathic pain, microglial activation and migration of nerve fibers from the trigeminal, cuneate and vestibular nuclei into the CN. These changes could contribute to somatic tinnitus, hyperacusis and otalgia.

Effects of different predator stress on vulnerability to predation and the underlying physiological and behavioral mechanisms of this vulnerability in juvenile qingbo (Spinibarbus sinensis)

Differences in the early life history would have a profound influence on the survival of the animal during the later life stages. We aimed to examine the effect of predator stress on vulnerability to predation in fish and the possible underlying behavioral and physiological mechanisms of this vulnerability. For this, we selected juvenile qingbo (Spinibarbus sinensis) as the prey and its natural predator, the southern catfish (Silurus meridionalis), as the predator. The juvenile qingbo were reared together with free predators (lethal group), caged predators (non-lethal group), and without predators (control group) for 4weeks at 25±0.5°C. After predator acclimation, predation mortality was evaluated to understand the potential difference in vulnerability to predation among these treatments when prey fish from each treatment group was cultured together with the predator. To investigate the possible physiological and behavioral mechanisms of this vulnerability, we measured the following parameters under the same environmental conditions: metabolic response parameters such as routine metabolic rate (RMR), maximum metabolic rate (MMR), and metabolic scope (MS=MMR−MS); routine activity level determined by measuring the total movement distance, percentage of time spent moving or hiding, and average velocity while moving; fast-start escape performance determined by measuring the response latency, maximum swimming speed (Vmax), and maximum acceleration (Amax). Both the lethal and non-lethal group fish exhibited significantly lower predation mortality, greater boldness (as suggested by the percentage of time spent hiding), and shorter response latency of fast-start response compared to those of the control group. Furthermore, the lethal group exhibited higher activity level, as evidenced by the increased amount of time spent moving at higher average speed and higher RMR. However, neither the fast-start parameters (Vmax and Amax) nor the maximum metabolic capacity (MMR and MS) of the two predator-stress groups differed from those of the control group. These results suggest that the S. sinensis cultured under predation stress was less vulnerable to predators because of shorter response latency and more explorative routine activities. However, the increase in spontaneous activity and enhanced alertness resulted in further energy expenditure in qingbo. Thus, the plasticity in physiology and behavior in qingbo may be one of the main anti-predator strategies that can increase the survival rate of this fish species under predator stress conditions.

Upregulation of the sodium channel NaVβ4 subunit and its contributions to mechanical hypersensitivity and neuronal hyperexcitability in a rat model of radicular pain induced by local dorsal root ganglion inflammation

High-frequency spontaneous firing in myelinated sensory neurons plays a key role in initiating pain behaviors in several different models, including the radicular pain model in which the rat lumbar dorsal root ganglia (DRG) are locally inflamed. The sodium channel isoform NaV1.6 contributes to pain behaviors and spontaneous activity in this model. Among all isoforms in adult DRG, NaV1.6 is the main carrier of tetrodotoxin-sensitive resurgent Na currents that allow high-frequency firing. Resurgent currents flow after a depolarization or action potential, as a blocking particle exits the pore. In most neurons, the regulatory β4 subunit is potentially the endogenous blocker. We used in vivo siRNA-mediated knockdown of NaVβ4 to examine its role in the DRG inflammation model. NaVβ4 but not control siRNA almost completely blocked mechanical hypersensitivity induced by DRG inflammation. Microelectrode recordings in isolated whole DRG showed that NaVβ4 siRNA blocked the inflammation-induced increase in spontaneous activity of Aβ neurons and reduced repetitive firing and other measures of excitability. NaVβ4 was preferentially expressed in larger diameter cells; DRG inflammation increased its expression, and this was reversed by NaVβ4 siRNA, based on immunohistochemistry and Western blotting. NaVβ4 siRNA also reduced immunohistochemical NaV1.6 expression. Patch-clamp recordings of tetrodotoxin-sensitive Na currents in acutely cultured medium diameter DRG neurons showed that DRG inflammation increased transient and especially resurgent current, effects blocked by NaVβ4 siRNA. NaVβ4 may represent a more specific target for pain conditions that depend on myelinated neurons expressing NaV1.6.

Glutamatergic Excitation of Cortical Neurons Depending on the Point of Origin on the Membrane and Cholinergic Regulation in Hypothermia

Experiments on guinea pig sensorimotor cortex slices with cooling of the incubation medium from 34°C to 21–22°C showed that hypothermia had no effect on evoked spike responses to application of glutamate to cell bodies, while application of glutamate to dendritic loci induced spike responses in the body with a short latent period with a hypothermic increase in the level of spontaneous activity and a longer latent period with a hypothermic decrease. Low-frequency neurons mainly showed increases in spontaneous activity on cooling, while high-frequency neurons (activity greater than 4 spikes/sec) responded with decreases in spike activity. The level of spontaneous sensorimotor cortex neuron activity started to change when the temperature dropped below 30°C. At this temperature, responses to iontophoretic delivery of acetylcholine to nerve cells decreased and there was a reduction in spike amplitude, which became greater with increasing cooling. These data provide evidence that hypothermic changes in the level of spontaneous activity evoked by altered influences on cell bodies of glutamatergic excitation of the dendrites, along with impairment to ion homeostasis, leading to decreases in spike amplitude are associated with temperature-dependent limiting of the rate of the M-cholinergic process over the temperature range 27–29°C. Neurons with different functional properties had different sensitivities to hypothermia.