Downregulation of microRNA-199a-5p alleviated lidocaine-induced sensory dysfunction and spinal cord myelin lesions in a rat model.

Lidocaine induces neurotoxicity in the spinal cord, but the underlying mechanisms remain unclear. In this study, we evaluated the effects of miR-199a-5p on 10 % lidocaine neurotoxicity. Increased expression of miR-199a-5p in the spinal cord of rats treated with 10 % lidocaine was assessed by qRT-PCR. Furthermore, after miR-199a-5p antagomir administration, the sensory dysfunction and myelin sheath lesions (evaluated by semithin sections stained with toluidine blue, electron microscopy, g-ratios and myelin thickness) induced by 10 % lidocaine were alleviated. Myelin regulatory factor (MYRF), a key molecule of myelin sheath development, was predicted to be a target gene of miR-199a-5p by the TargetScan and miRBase databases. MYRF and its downstream factors myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG) were significantly decreased after intrathecal 10 % lidocaine administration. Moreover, these changes were reversed after miR-199a-5p antagomir administration. FISH-immunofluorescence showed coexpression of miR-199a-5p and MYRF in the spinal cord white matter of rats. A luciferase reporter assay further demonstrated the functional association between miR-199a-5p and MYRF. Overall, miR-199a-5p upregulation is involved in 10 % lidocaine-induced spinal cord toxicity through regulation of MYRF. Therefore, downregulating miR-199a-5p expression may be a potential strategy to ameliorate spinal cord neurotoxicity induced by 10 % lidocaine.

Heat shock protein 70 is a key molecule to rescue imbalance caused by low-frequency noise.

A previous study showed that people living in urban areas are generally exposed to low-frequency noise (LFN) with frequencies below 100 Hz and sound levels of 60-110 dB in daily and occupational environments. Exposure to LFN has been shown to affect balance in humans and mice. However, there is no information about prevention of LFN-mediated imbalance because of a lack of information about the target region based on health risk assessment of LFN exposure. Here, we show that acute exposure to LFN at 100 Hz, 95 dB, but not at 85 dB or 90 dB, for only 1 h caused imbalance in mice. The exposed mice also had decreased cervical vestibular-evoked myogenic potential (cVEMP) with impaired activity of vestibular hair cells. Since imbalance in the exposed mice was irreversible, morphological damage in the vestibules of the exposed mice was further examined. The exposed mice had breakage of the otoconial membrane in the vestibule. LFN-mediated imbalance and breakage of the otoconial membrane in mice were rescued by overexpression of a stress-reactive molecular chaperone, heat shock protein 70 (Hsp70), which has been shown to be induced by exposure of mice to 12 h per day of LFN at 95 dB for 5 days. Taken together, the results of this study demonstrate that acute exposure to LFN at 100 Hz, 95 dB for only 1 h caused irreversible imbalance in mice with structural damage of the otoconial membrane as the target region for LFN-mediated imbalance, which can be rescued by Hsp70.

A multidimensional concept for mercury neuronal and sensory toxicity in fish - From toxicokinetics and biochemistry to morphometry and behavior.

BACKGROUND: Neuronal and sensory toxicity of mercury (Hg) compounds has been largely investigated in humans/mammals with a focus on public health, while research in fish is less prolific and dispersed by different species. Well-established premises for mammals have been governing fish research, but some contradictory findings suggest that knowledge translation between these animal groups needs prudence [e.g. the relative higher neurotoxicity of methylmercury (MeHg) vs. inorganic Hg (iHg)]. Biochemical/physiological differences between the groups (e.g. higher brain regeneration in fish) may determine distinct patterns. This review undertakes the challenge of identifying sensitive cellular targets, Hg-driven biochemical/physiological vulnerabilities in fish, while discriminating specificities for Hg forms. SCOPE OF REVIEW: A functional neuroanatomical perspective was conceived, comprising: (i) Hg occurrence in the aquatic environment; (ii) toxicokinetics on central nervous system (CNS)/sensory organs; (iii) effects on neurotransmission; (iv) biochemical/physiological effects on CNS/sensory organs; (v) morpho-structural changes on CNS/sensory organs; (vi) behavioral effects. The literature was also analyzed to generate a multidimensional conceptualization translated into a Rubik's Cube where key factors/processes were proposed. MAJOR CONCLUSIONS: Hg neurosensory toxicity was unequivocally demonstrated. Some correspondence with toxicity mechanisms described for mammals (mainly at biochemical level) was identified. Although the research has been dispersed by numerous fish species, 29 key factors/processes were pinpointed. GENERAL SIGNIFICANCE: Future trends were identified and translated into 25 factors/processes to be addressed. Unveiling the neurosensory toxicity of Hg in fish has a major motivation of protecting ichtyopopulations and ecosystems, but can also provide fundamental knowledge to the field of human neurodevelopment.

Enhanced Sensory-Cognitive Processing by Activation of Nicotinic Acetylcholine Receptors.

Activation of nicotinic acetylcholine receptors (nAChRs) enhances sensory-cognitive function in human subjects and animal models, yet the neural mechanisms are not fully understood. This review summarizes recent studies on nicotinic regulation of neural processing in the cerebral cortex that point to potential mechanisms underlying enhanced cognitive function. Studies from our laboratory focus on nicotinic regulation of auditory cortex and implications for auditory-cognitive processing, but relevant emerging insights from multiple brain regions are discussed. Although the major contributions of the predominant nAChRs containing α7 (homomeric receptors) or α4 and ß2 (heteromeric) subunits are well recognized, recent results point to additional, potentially critical contributions from α2 subunits that are relatively sparse in cortex. Ongoing studies aim to elucidate the specific contributions to cognitive and cortical function of diverse nAChRs. IMPLICATIONS: This review highlights the therapeutic potential of activating nAChRs in the cerebral cortex to enhance cognitive function. Future work also must determine the contributions of relatively rare but important nAChR subtypes, potentially to develop more selective treatments for cognitive deficits.

Voltage-gated Sodium Channels in Sensory Information Processing.

Objective & Background: Voltage-gated sodium channels (VGSCs) and potassium channels are critical in the generation of action potentials in the nervous system. VGSCs and potassium channels play important roles in the five fundamental senses of vision, audition, olfaction, taste and touch. Dysfunctional VGSCs are associated with clinical sensory symptoms, such as hyperpselaphesia, parosphresia, and so on. Conclusion: This short review highlights the recent advances in the study of VGSCs in sensory information processing and discusses the potential role of VGSCs to serve as pharmacological targets for the treatment of sensory system diseases.

Variable sensory perception in autism.

Autism is associated with sensory and cognitive abnormalities. Individuals with autism generally show normal or superior early sensory processing abilities compared to healthy controls, but deficits in complex sensory processing. In the current opinion paper, it will be argued that sensory abnormalities impact cognition by limiting the amount of signal that can be used to interpret and interact with environment. There is a growing body of literature showing that individuals with autism exhibit greater trial-to-trial variability in behavioural and cortical sensory responses. If multiple sensory signals that are highly variable are added together to process more complex sensory stimuli, then this might destabilise later perception and impair cognition. Methods to improve sensory processing have shown improvements in more general cognition. Studies that specifically investigate differences in sensory trial-to-trial variability in autism, and the potential changes in variability before and after treatment, could ascertain if trial-to-trial variability is a good mechanism to target for treatment in autism.

A Hypothesis and Pilot Study of Age-Related Sensory Innervation of the Hard Palate: Sensory Disorder After Nasopalatine Nerve Division.

BACKGROUND The nasopalatine nerve may be injured during extraction of teeth embedded in the anterior hard palate. The neural recovery process and its impact on sensation in the anterior hard palatal region are controversial. In our clinical practice, we noticed a distinct recovery process in children compared with adolescents or adults after surgery. We hypothesized that the sensory innervations of the anterior palate might shift during later childhood and pre-adolescence, which is due to the development of the nasopalatine nerve along with the maxillary growth and permanent teeth eruption. MATERIAL AND METHODS Forty patients (20 females and 20 males, mean age 11.8±2.2) with impacted supernumerary teeth in anterior palatine area were included into our study, and were divided into 3 groups according to their age. A 24-week follow-up was conducted and the sensation in the anterior hard palate region was examined at every check point. All the data were collected and analyzed by Kaplan-Meier analysis. RESULTS Fourteen children did not complain of any numbness immediately after anesthetization, and other children with sensory disorders had shorter healing periods compared to adolescent/adult patients. CONCLUSIONS The results indicated that the dominant nerve of the anterior hard palate region was dramatically changed from the greater palatine nerve to the nasopalatine nerve, which is important in deciding when to operate and in selection of anesthesia method.

Sensitive skin.

Sensitive skin is a clinical condition defined by the self-reported facial presence of different sensory perceptions, including tightness, stinging, burning, tingling, pain and pruritus. Sensitive skin may occur in individuals with normal skin, with skin barrier disturbance, or as a part of the symptoms associated with facial dermatoses such as rosacea, atopic dermatitis and psoriasis. Although experimental studies are still pending, the symptoms of sensitive skin suggest the involvement of cutaneous nerve fibres and neuronal, as well as epidermal, thermochannels. Many individuals with sensitive skin report worsening symptoms due to environmental factors. It is thought that this might be attributed to the thermochannel TRPV1, as it typically responds to exogenous, endogenous, physical and chemical stimuli. Barrier disruptions and immune mechanisms may also be involved. This review summarizes current knowledge on the epidemiology, potential mechanisms, clinics and therapy of sensitive skin.

The G protein-coupled receptor-transient receptor potential channel axis: molecular insights for targeting disorders of sensation and inflammation.

Sensory nerves are equipped with receptors and ion channels that allow them to detect and respond to diverse chemical, mechanical, and thermal stimuli. These sensory proteins include G protein-coupled receptors (GPCRs) and transient receptor potential (TRP) ion channels. A subclass of peptidergic sensory nerves express GPCRs and TRP channels that detect noxious, irritant, and inflammatory stimuli. Activation of these nerves triggers protective mechanisms that lead to withdrawal from danger (pain), removal of irritants (itch, cough), and resolution of infection (neurogenic inflammation). The GPCR-TRP axis is central to these mechanisms. Signals that emanate from the GPCR superfamily converge on the small TRP family, leading to channel sensitization and activation, which amplify pain, itch, cough, and neurogenic inflammation. Herein we discuss how GPCRs and TRP channels function independently and synergistically to excite sensory nerves that mediate noxious and irritant responses and inflammation in the skin and the gastrointestinal and respiratory systems. We discuss the signaling mechanisms that underlie the GPCR-TRP axis and evaluate how new information about the structure of GPCRs and TRP channels provides insights into their functional interactions. We propose that a deeper understanding of the GPCR-TRP axis may facilitate the development of more selective and effective therapies to treat dysregulated processes that underlie chronic pain, itch, cough, and inflammation.

Hallucinogen persisting perception disorder and the serotonergic system: a comprehensive review including new MDMA-related clinical cases.

Hallucinogen persisting perception disorder (HPPD) is a drug-induced condition associated with inaccurate visual representations. Since the underlying mechanism(s) are largely unknown, this review aims to uncover aspects underlying its etiology. Available evidence on HPPD and drug-related altered visual processing was reviewed and the majority of HPPD cases were attributed to drugs with agonistic effects on serotonergic 5-HT2A receptors. Moreover, we present 31 new HPPD cases that link HPPD to the use of ecstasy (MDMA), which is known to reverse serotonin reuptake and acts as agonist on 5-HT2A receptors. The available evidence suggests that HPPD symptoms may be a result from a misbalance of inhibitory-excitatory activity in low-level visual processing and GABA-releasing inhibitory interneurons may be involved. However, high co-morbidities with anxiety, attention problems and derealization symptoms add complexity to the etiology of HPPD. Also, other perceptual disorders that show similarity to HPPD cannot be ruled out in presentations to clinical treatment. Taken together, evidence is still sparse, though low-level visual processing may play an important role. A novel finding of this review study, evidenced by our new cases, is that ecstasy (MDMA) use may also induce symptoms of HPPD.

GPBA: a GPCR for bile acids and an emerging therapeutic target for disorders of digestion and sensation.

Bile acids (BAs) are digestive secretions that are necessary for the emulsification and absorption of dietary fats. Given the episodic nature of BA secretion and intestinal re-absorption, the circulating and tissue levels of BAs, like those of the gut hormones, fluctuate in fasting and fed states, and BA levels and forms are markedly affected by disease. BAs exert widespread hormonal-like effects by activating receptors in the nucleus and at the plasma membrane. The nuclear steroid receptors mediate the genomic actions of BAs on BA, glucose and lipid homeostasis. GPBA (TGR5) is a G-protein coupled plasma membrane receptor for BAs that mediates many of the rapid, non-genomic actions of BAs. GPBA has been implicated in the control of glucose homeostasis, inflammation and liver functions. Recent observations have revealed an unexpected role for GPBA in the nervous system. GPBA is expressed by enteric neurons and enterochromaffin cells that control peristalsis, and GPBA mediates the prokinetic actions of BAs in the colon that have been known for millennia. GPBA is also present on primary spinal afferent and spinal neurons that are necessary for sensory transduction. BA-induced activation of GPBA in the sensory nervous system promotes scratching behaviours and analgesia, which may contribute to the pruritus and painless jaundice that are observed in some patients with chronic cholestatic disease, where circulating BA concentrations are markedly increased. Thus, GPBA has emerged as an intriguing target for diverse metabolic, inflammatory, digestive and sensory disorders, where agonists and antagonists may be of value.

Beclin 1 mitigates motor and neuropathological deficits in genetic mouse models of Machado-Joseph disease.

Machado-Joseph disease or spinocerebellar ataxia type 3, the most common dominantly-inherited spinocerebellar ataxia, results from translation of the polyglutamine-expanded and aggregation prone ataxin 3 protein. Clinical manifestations include cerebellar ataxia and pyramidal signs and there is no therapy to delay disease progression. Beclin 1, an autophagy-related protein and essential gene for cell survival, is decreased in several neurodegenerative disorders. This study aimed at evaluating if lentiviral-mediated beclin 1 overexpression would rescue motor and neuropathological impairments when administered to pre- and post-symptomatic lentiviral-based and transgenic mouse models of Machado-Joseph disease. Beclin 1-mediated significant improvements in motor coordination, balance and gait with beclin 1-treated mice equilibrating longer periods in the Rotarod and presenting longer and narrower footprints. Furthermore, in agreement with the improvements observed in motor function beclin 1 overexpression prevented neuronal dysfunction and neurodegeneration, decreasing formation of polyglutamine-expanded aggregates, preserving Purkinje cell arborization and immunoreactivity for neuronal markers. These data show that overexpression of beclin 1 in the mouse cerebellum is able to rescue and hinder the progression of motor deficits when administered to pre- and post-symptomatic stages of the disease.

Biological determinants of postural disorders in elderly women.

Postural control impairments and dizziness, which are major health problems with high secondary morbidity and mortality, increase with aging. Elevated homocysteine (Hcy) level is an age-related metabolic disorder, known to be involved in cardiovascular, neurological, and multisensory dysfunctions. Elevated Hcy level might be involved in sensory balance control systems impairment and dizziness occurrence. Dizziness, fitness Instrumental Activity of Daily Living scale (fitness IADL), systolic arterial pressure with ankle-brachial blood pressure index and homocysteinemia were studied in 61 noninstitutionized elderly women. Clinical balance tests (timed "Up and Go", 10-m walking and one-leg balance) and posturography (including sensory conflicting situations [SCS] and cognitive conflicting situations [CCS]) were performed. Clinical balance control was lower in dizzy women who presented particularly poor stability in SCS. Dizziness was related to low fitness IADL scores (odds ratio [OR] 0.452, 95% CI 0.216-0.946) and to elevated Hcy (OR 8.084, 95% CI 1.992-32.810). Elevated Hcy was correlated with balance disorders both in SCS and CCS. Dizziness is associated with a reduced ability in balance control management. Hcy is related both to dizziness and low postural performance. This relation between elevated Hcy levels and balance impairments, resulting in dizziness, may be explained by its angiotoxicity and neurotoxicity.

New march towards the regeneration of sensation and cognition: hear more, see more and learn more.

As many human sensory and cognitive diseases are caused by irreversible damage or loss of certain types of neurons, methodologies aimed at replacement of lost neurons are key to restore lost sensation. Recent advances in generation of ear-cell progenitors, optic-cup structures and cortical neurons from human embryonic stem cells and induced pluripotent stem cells provide versatile tools for modeling human diseases and developing cells for replacement therapies.

Lipidomic profiling of phosphocholine-containing brain lipids in mice with sensorimotor deficits and anxiety-like features after exposure to Gulf War agents.

The central nervous system (CNS)-based symptoms of Gulf War Illness (GWI) include motor dysfunction, anxiety, and cognitive impairment. Gulf War (GW) agents, such as pyridostigmine bromide (PB), permethrin (PER), N,N-diethyl-meta-toluamide (DEET), and stress, are among the contributory factors to the pathobiology of GWI. This study characterizes disturbances in phosphocholine-containing lipids that accompany neurobehavioral and neuropathological features associated with GW agent exposure. Exposed mice received PB orally, dermal application of PER and DEET and restraint stress daily for 28 days, while controls received vehicle during this period. Neurobehavioral studies included the rotarod, open field, and Morris water maze tests. Histopathological assessments included glial fibrillary acid protein, CD45, and Nissl staining. Liquid chromatography/mass spectrometry with source collision-induced dissociation in negative and positive ionization scanning modes was performed to characterize brain phosphatidylcholine (PC) and sphingomyelin (SM). A significant increase in ether containing PC (ePC34:0, ePC36:2, and ePC36:1) or long-chain fatty acid-containing PC (38:1, 40:4, 40:2) was observed in exposed mice compared with controls. Among differentially expressed PCs, levels of those with monounsaturated fatty acids were more affected than those with saturated and polyunsaturated fatty acids. Sensorimotor deficits and anxiety, together with an increase in astrocytosis, were observed in exposed mice compared with controls. These lipid changes suggest that alterations in peroxisomal pathways and stearoyl-CoA desaturase activity accompany neurobehavioral and neuropathological changes after GW agent exposure and represent possible treatment targets for the CNS symptoms of GWI.

Mutations of FLVCR1 in posterior column ataxia and retinitis pigmentosa result in the loss of heme export activity.

The feline leukemia virus subgroup C receptor 1 (FLVCR1) is a heme exporter that maintains the intracellular heme concentration. FLVCR1 was previously assumed to be involved in Diamond-Blackfan anemia, and it was recently reported that mutations in the FLVCR1 gene are found in patients with posterior column ataxia and retinitis pigmentosa (PCARP). Four mutations in FLVCR1 (Asn121Asp, Cys192Arg, Ala241Thr, and Gly493Arg) are located within putative transmembrane domains; however, the effects of FLVCR1 mutations on PCARP are unclear. In this study, we analyzed the function of FLVCR1 mutants by using a fluorescent heme analog as a transporter substrate, and found that all 4 FLVCR1 mutants lost their heme export activity. To investigate the mechanism responsible for this loss of activity, we determined the subcellular localization of FLVCR1 mutants. FLVCR1 mutants did not localize to the plasma membrane and were observed in intracellular structures, including lysosomes. We hypothesize that the loss of function of FLVCR1 mutants is caused by their mislocation. We examined the half-life of FLVCR1 in cells, which was >16h for wild-type FLVCR1 compared with 2-4h for the mutants. Based on these results, we propose that FLVCR1 mutants failed to fold properly in the ER, were rapidly degraded in the lysosomes, and therefore, could not export heme out of cells. Thus, accumulation of heme in FLVCR1-mutant cells could cause cellular toxicity.