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Subjective tinnitus is the conscious perception of sound in the absence of any acoustic source. The literature suggests various tinnitus mechanisms, most of which invoke changes in spontaneous firing rates of central auditory neurons resulting from modification of neural gain. Here, we present an alternative model based on evidence that tinnitus is: (1) rare in people who are congenitally deaf, (2) common in people with acquired deafness, and (3) potentially suppressed by active cochlear implants used for hearing restoration. We propose that tinnitus can only develop after fast auditory fiber activity has stimulated the synapse formation between fast-spiking parvalbumin positive (PV+) interneurons and projecting neurons in the ascending auditory path and coactivated frontostriatal networks after hearing onset. Thereafter, fast auditory fiber activity promotes feedforward and feedback inhibition mediated by PV+ interneuron activity in auditory-specific circuits. This inhibitory network enables enhanced stimulus resolution, attention-driven contrast improvement, and augmentation of auditory responses in central auditory pathways (neural gain) after damage of slow auditory fibers. When fast auditory fiber activity is lost, tonic PV+ interneuron activity is diminished, resulting in the prolonged response latencies, sudden hyperexcitability, enhanced cortical synchrony, elevated spontaneous y oscillations, and impaired attention/stress-control that have been described in previous tinnitus models. Moreover, because fast processing is gained through sensory experience, tinnitus would not exist in congenital deafness. Electrical cochlear stimulation may have the potential to reestablish tonic inhibitory networks and thus suppress tinnitus. The proposed framework unites many ideas of tinnitus pathophysiology and may catalyze cooperative efforts to develop tinnitus therapies. ; German Research Foundation (DFG) DFG-Kni-316-4-1 SPP16-08 DFG Comisión Nacional de Investigación Científica y Tecnológica (CONICYT) CONICYT FONDECYT 1161155 Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT) BASAL FB008 ICM P09-015F European Union's Horizon 2020 research and innovation program under the Marie Sklodowska-Curie Grant 764604 722046 National Institute for Health Research (NIHR)

This is an open-access article distributed under the terms of the Creative Commons Attribution License.-- et al. ; Ca(2+) mediates the functional coupling between L-type Ca(2+) channel (LTCC) and sarcoplasmic reticulum (SR) Ca(2+) release channel (ryanodine receptor, RyR), participating in key pathophysiological processes. This crosstalk manifests as the orthograde Ca(2+)-induced Ca(2+)-release (CICR) mechanism triggered by Ca(2+) influx, but also as the retrograde Ca(2+)-dependent inactivation (CDI) of LTCC, which depends on both Ca(2+) permeating through the LTCC itself and on SR Ca(2+) release through the RyR. This latter effect has been suggested to rely on local rather than global Ca(2+) signaling, which might parallel the nanodomain control of CDI carried out through calmodulin (CaM). Analyzing the CICR in catecholaminergic polymorphic ventricular tachycardia (CPVT) mice as a model of RyR-generated Ca(2+) leak, we evidence here that increased occurrence of the discrete local SR Ca(2+) releases through the RyRs (Ca(2+) sparks) causea depolarizing shift in activation and a hyperpolarizing shift inisochronic inactivation of cardiac LTCC current resulting in the reduction of window current. Both increasing fast [Ca(2+)](i) buffer capacity or depleting SR Ca(2+) store blunted these changes, which could be reproduced in WT cells by RyRCa(2+) leak induced with Ryanodol and CaM inhibition. Our results unveiled a new paradigm for CaM-dependent effect on LTCC gating and further the nanodomain Ca(2+) control of LTCC, emphasizing the importance of spatio-temporal relationships between Ca(2+) signals and CaM function. ; This research program was funded by Inserm, a grant from the Agence National de la Recherche (ANR-09-GENO-034) and a grant from the European Union (FPG, Life Science Genomics and Biotechnology for Health, contract CT 2005 Nu018802, CONTICA). MF-V was funded by Ministerio de Educación y Ciencia of Spain, AR by Conacyt (Project Nu80960), PN by Fondation de la Recherche Medicale, and Telethon grants NuGGP04066 and GGP06007 and FIRB RBNE01XMP4_006, RBLA035A4X_002 from the Ministero dell' Universita e della Ricerca Scientifica e Tecnologica (to SGP and CN). ; Peer reviewed

During goal-directed decision-making, animals must integrate information from the external environment and their internal state to maximize resource localization while minimizing energy expenditure. How this complex problem is solved by the nervous system remains poorly understood. Here, using a combined behavioural and neurophysiological approach, we demonstrate that the mollusc Lymnaea performs a sophisticated form of decision-making during food-searching behaviour, using a core system consisting of just two neuron types. The first reports the presence of food and the second encodes motivational state acting as a gain controller for adaptive behaviour in the absence of food. Using an in vitro analogue of the decision-making process, we show that the system employs an energy management strategy, switching between a low- and high-use mode depending on the outcome of the decision. Our study reveals a parsimonious mechanism that drives a complex decision-making process via regulation of levels of tonic inhibition and phasic excitation.

Alcohol is among the most widely used psychoactive substances worldwide. Ethanol metabolites such as acetate, thought to be primarily the result of ethanol breakdown by hepatic aldehyde dehydrogenase 2 (ALDH2), contribute to alcohol's behavioural effects and alcoholism. Here, we show that ALDH2 is expressed in astrocytes in the mouse cerebellum and that ethanol metabolism by astrocytic ALDH2 mediates behavioural effects associated with ethanol intoxication. We show that ALDH2 is expressed in astrocytes in specific brain regions and that astrocytic, but not hepatocytic, ALDH2 is required to produce ethanol-derived acetate in the mouse cerebellum. Cerebellar astrocytic ALDH2 mediates low-dose ethanol-induced elevation of GABA levels, enhancement of tonic inhibition and impairment of balance and coordination skills. Thus, astrocytic ALDH2 controls the production, cellular and behavioural effects of alcohol metabolites in a brain-region-specific manner. Our data indicate that astrocytic ALDH2 is an important, but previously under-recognized, target in the brain to alter alcohol pharmacokinetics and potentially treat alcohol use disorder. Copyright 2021, This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply. ; https://doi.org/10.1038/s42255-021-00357-z

Tinnitus is defined as a phantom sound (ringing in the ears), and can significantly reduce the quality of life for those who suffer its effects. Ten to fifteen percent of the general adult population report symptoms of tinnitus with 1-2% reporting that tinnitus negatively impacts their quality of life. Noise exposure is the most common cause of tinnitus and the military environment presents many challenging high-noise situations. Military noise levels can be so intense that standard hearing protection is not adequate. Recent studies suggest a role for inhibitory neurotransmitter dysfunction in response to noise-induced peripheral deafferentation as a key element in the pathology of tinnitus. The auditory thalamus, or medial geniculate body (MGB), is an obligate auditory brain center in a unique position to gate the percept of sound as it projects to auditory cortex and to limbic structures. Both areas are thought to be involved in those individuals most impacted by tinnitus. For MGB, opposing hypotheses have posited either a tinnitus-related pathologic decrease or pathologic increase in GABAergic inhibition. In sensory thalamus, GABA mediates fast synaptic inhibition via synaptic GABAA receptors (GABAARs) as well as a persistent tonic inhibition via high-affinity extrasynaptic GABAARs and slow synaptic inhibition via GABABRs. Down-regulation of inhibitory neurotransmission, related to partial peripheral deafferentation, is consistently presented as partially underpinning neuronal hyperactivity seen in animal models of tinnitus. This maladaptive plasticity/Gain Control Theory of tinnitus pathology (see Auerbach et al., 2014; Richardson et al., 2012) is characterized by reduced inhibition associated with increased spontaneous and abnormal neuronal activity, including bursting and increased synchrony throughout much of the central auditory pathway. A competing hypothesis suggests that maladaptive oscillations between the MGB and auditory cortex, thalamocortical dysrhythmia, predicts tinnitus pathology (De Ridder et ...

1. Introduction. Plans, Strategies and Actions -- Categories of Muscles -- Problems of Moving -- A Legacy -- 2. Mechanical Properties of Muscles -- Review of Muscle Anatomy -- Mechanical Properties of Muscle -- Behaviour of Isolated Muscle Stimulated at Subtetanic Rates -- Muscle Mechanics in Intact Man -- Effects of Muscle Properties on Control of Movement -- A Theory of Movement Control which Makes Use of the Mechanical Properties of Muscle -- 3. The Motor Unit -- The Concept of the Motor Unit -- Twitch and Tonic Muscle Fibres -- Physiological Investigation of the Motor Unit -- Histochemical and Biochemical Classification of Muscle Fibres -- Some Electrophysiological Properties of Motoneurones -- Control of Motor Units and their Recruitment Order -- The Study of Motor Units in Human Physiology -- Pathophysiology of the Motor Unit -- 4. Proprioceptors in Muscle, Joint and Skin -- Muscle Receptors: I. The Muscle Spindle -- Muscle Receptors: II. Golgi Tendon Organs -- Muscle Receptors: III. Other Types of Ending -- Joint Receptors -- Cutaneous Mechanoreceptors -- Recordings from Human Afferent Nerve Fibres -- 5. Reflex Pathways in the Spinal Cord -- Classification of Nerve Fibres -- Reflex Pathways from la Muscle Spindle Afferents -- Reflex Pathways from lb Tendon Organ Afferents -- Reflex Pathways from Group II Muscle Afferents and the 'Flexor Reflex Afferents' -- The Renshaw Cell -- Integration in Spinal Reflex Pathways -- Presynaptic Inhibition -- 6. Functional Consequences of Activity in Spinal Reflex Pathways -- The Stretch Reflex in Animals -- Stretch Reflexes in Human Muscles -- The Servo Hypothesis and Alpha-Gamma Coactivation -- The Regulation of Stiffness Hypothesis and lb Effects -- Other Spinal Reflex Pathways -- Cutaneous Reflexes -- Pathophysiology of the Stretch Reflex: Disorders of Muscle Tone -- Pathophysiology of Other Reflex Pathways -- 7. Ascending and Descending Pathways of the Spinal Cord -- Ascending Pathways -- 8. Cerebral Cortex -- Structure of Cerebral Cortex -- Detailed Electrophysiology of Primary Motor (MI) Cortex -- The Pyramidal Tract -- Motor Cortex Cell Activity During Voluntary Movements -- Sensory Input to Motor Cortex -- Other Motor Areas of Cortex -- Supplementary Motor Area -- Motor Functions of Parietal Cortex -- Pathophysiology of Motor Areas of Cerebral Cortex -- 9. The Cerebellum -- Cerebellar Anatomy -- Electrophysiological Studies of the Cerebellum -- Effects of Cerebellar Lesions -- Studies of Cerebellar Dysfunction in Man -- Theories of Cerebellar Function -- 10. The Basal Ganglia -- Anatomy -- Electrophysiological Recordings from Behaving Animals -- Pathophysiology of Diseases of the Basal Ganglia in Man.

HIGHLIGHTS- Calmodulin-dependent Kv7.2 current density without the need of binding calcium.- Kv7.2 current density increase is accompanied with resistance to PI(4,5)P2 depletion.- Kv7.3 current density is insensitive to calmodulin elevation.- Kv7.3 is more sensitive to PI(4,5)P2 depletion in the presence of calmodulin.- Apo-calmodulin influences PI(4,5)P2 dependence in a subunit specific manner.The identification and understanding of critical factors regulating M-current functional density, whose main components are Kv7.2 and Kv7.3 subunits, has profound pathophysiological impact given the important role of the M-current in neuronal excitability control. We report the increase in current density of Kv7.2 channels by calmodulin (CaM) and by a mutant CaM unable to bind Ca2+ (CaM1234) revealing that this potentiation is calcium independent. Furthermore, after co-expressing a CaM binding protein (CaM sponge) to reduce CaM cellular availability, Kv7.2 current density was reduced. Current inhibition after transient depletion of the essential Kv7 co-factor phosphatidylinositol-4,5-bisphosphate (PI(4,5)P2) by activating Danio rerio voltage sensitive phosphatase (DrVSP) was blunted by co-expressing CaM1234 or the CaM sponge. In addition, CaM-dependent potentiation was occluded by tonic elevation of PI(4,5)P2 levels by PI(4)P5-kinase (PIP5K) expression. In contrast to the effect on homomeric Kv7.2 channels, CaM1234 failed to potentiate heteromeric Kv7.2/3 or homomeric Kv7.3 channels. Sensitivity to PI(4,5)P2 depletion of Kv7.2/3 channels was increased after expression of CaM1234 or the CaM sponge, while that of homomeric Kv7.3 was unaltered. Altogether, the data reveal that apo-CaM influences PI(4,5)P2 dependence of Kv7.2, Kv7.2/3, and of Kv7.3 channels in a subunit specific manner. ; This work was supported by grants from the Spanish Ministry of Economy and Competitiveness (BFU2015-66910-R). CM. was funded by the Spanish Ministry of Economy and Competitiveness (PTA2012) and co-financed by the BERC program of the Basque Government. MT was an Ikerbasque Visiting Professor funded by the Basque Government, and work in MT laboratories was supported by Telethon (GGP15113). ; Peer reviewed ; Peer Reviewed

Background Poncirin is flavanone derivative (isolated from Poncirus trifoliata) with known pharmacological activities such as anti-tumor, anti-osteoporotic, anti-inflammatory and anti-colitic. The present study aimed to explore the anti-allodynic and anti-hyperalgesic potentials of poncirin in murine models of inflammatory pain. Methods The analgesic potential of poncirin was evaluated in formalin-, acetic acid-, carrageenan- and Complete Freund's Adjuvant (CFA)-induced inflammatory pain models in mice. Anti-allodynic and anti-hyperalgesic activities were measured using Von Frey filaments, Randall Selitto, hotplate and cold acetone tests. The serum nitrite levels were determined using Griess reagent. The Quantitative Real-time PCR (qRT-PCR) was performed to assess the effect of poncirin on mRNA expression levels of inflammatory cytokines and anti-oxidant enzymes. Results Intraperitoneal administration of poncirin (30 mg/kg) markedly reduced the pain behavior in both acetic acid-induced visceral pain and formalin-induced tonic pain models used as preliminary screening tools. The poncirin (30 mg/kg) treatment considerably inhibited the mechanical hyperalgesia and allodynia as well as thermal hyperalgesia and cold allodynia. The qRT-PCR analysis showed noticeable inhibition of pro-inflammatory cytokines (mRNA expression levels of TNF-α, IL-1β and IL-6) (p < 0.05) in poncirin treated group. Similarly, poncirin treatment also enhanced the mRNA expressions levels of anti-oxidant enzymes such as transcription factor such as nuclear factor (erythroid-derived 2)-like 2 (Nrf2) (p < 0.05), heme oxygenase (HO-1) (p < 0.05) and superoxide dismutase (SOD2) (p < 0.05). Chronic treatment of poncirin for 6 days did not confer any significant hepatic and renal toxicity. Furthermore, poncirin treatment did not altered the motor coordination and muscle strength in CFA-induced chronic inflammatory pain model. Conclusion The present study demonstrated that poncirin treatment significantly reduced pain behaviors in all experimental models of inflammatory pain, suggesting the promising analgesic potential of poncirin in inflammatory pain conditions. ; The Higher Education Commission (HEC) of Pakistan (under the SRGP funding No. 357SRGP/HEC/2014) supported the study only financially and was not involved in the designing of the project. The authors are grateful to the National Research Foundation of Korea (NRF), Seoul National University, grant funded by the Korean Government (MSIP) (No. 2009–0083533). The Proff: Yeong Shik Kim (National Research Foundation of Korea (NRF), Seoul National University) was actively involved in the designing of the experiment and analysis of the results.

O cumaru (Dipteryx odorata (Aubl.) é uma leguminosa da família Fabaceae, suas sementes são muito utilizadas na extração do óleo, o qual é bastante utilizado pela medicina popular como antiespasmódico, tônico, anti-inflamatório, reumatismos e antimicrobiano. A cumarina está presente na semente e também em toda a extensão da planta. O objetivo deste trabalho foi obter o óleo da semente e o extrato de folhas, realizar ensaios biológicos com o extrato e elaboração de um produto biotecnológico. O estudo foi realizado no laboratório de Química Orgânica da Universidade Federal do Amazonas, no qual as sementes foram coletadas, maceradas, para extração do óleo, em seguida, se realizou análise por cromatografia de camada delgada (CCD) do óleo da semente. As folhas foram maceradas, e preparadas as exsicatas, utilizou-se o óleo na produção do produto e para os ensaios biológicos frente às bactérias: Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae. Os resultados obtidos da extração das sementes foram o óleo e os cristais brancos em forma de agulha. Após análises cromatográficas (CCD) do extrato das folhas foi possível observar a presença de cumarina. O ensaio biológico com os cristais frente às bactérias S. aureus, E. coli, K. Pneumoniae apresentou halo de inibição. Assim, o óleo e a cumarina presentes na semente podem atuar como antibacteriano natural para o tratamento de várias doenças infecciosas causadas pela bactéria S. aureus. Foi possível formular um creme hidratante incorporando o óleo obtido da semente.

Palavras-chave: Extração do Óleo. Cumarina. Produto Biotecnológico.

Abstract
Coumaru (Dipteryx odorata (Aubl.) is a legume of the Fabaceae family, its seeds are widely used in oil extraction, which is widely used by folk medicine as an antispasmodic, tonic, anti-inflammatory, rheumatism and antimicrobial. Coumarin is present in the seed and also in the entire length of the plant. The objective of this work was to obtain the seed oil or the leaf extract, to perform biological tests with the extract and to elaborate a biotechnological product. The study was carried out in the Organic Chemistry laboratory, where the seeds were collected, macerated, for oil extraction, then a CCD analysis of the seed oil was carried out, the leaves were macerated, and the exsiccates were prepared, the oil was used in the product production and for biological tests against bacteria: Staphylococcus aureus, Escherichia coli, Klebsiella pneumoniae. The results obtained from the seeds extraction were oil and white crystals. After a chromatographic analysis (CCD) of the leaf extract, it was possible to observe the presence of coumarin. The biological assay with the crystals against the bacteria S. aureus, E. coli, K. Pneumoniae showed an inhibition halo. Thus, the oil and coumarin present in the seed can act as a natural antibacterial for the treatment of various infectious diseases caused by the bacteria S. aureus. It was possible to formulate a moisturizing cream incorporating the oil obtained from the seed.

Keywords: Cumaru Oil Extraction. Coumarin. Biotechnological Product.

 It has been a very long time since I have been away from home this long--October 2016--when I spent a month of my last sabbatical in Tokyo [I just received word that I will be spending 3 months abroad x 2 over the next 1.5 years, but more on that later].  This time, two weeks in South Korea and nearly a week in Denmark.  The packing was not that challenging since it is fall in both places although Seoul and Busan were decidedy warmer than Copenhagen and mostly much drier.I was in South Korea to do the next project's first case study (well, mine, as Phil has already been traveling for some of his).  And then I went to Copenhagen to present the findings to a group I have never met before--the International Society of Military Scientists.  There are some civ-mil folks, but also strategy people, military culture analysts, and all kinds of stuff.  The trick is that the South Korean case was/is not easy to code or figure out.  I did have good access and had much help from a great team of fixer/interpreters, but I need to spend more time thinking about the case, talking to experts, and reading more.  So, the presentation was a bit tricky.  But it went ok. Folks keep finding the project to be interesting.So, let me instead compare the two trips: Costs (food, taxi): Cost:  South Korea.  Copenhagen is simply a very expensive place, and Seoul/Busan are not.  I kept doing the exchange rate math here in Copenhagen and kept freaking out just a bit.Bike Danger: Denmark.  So quiet, so many.Availability of Bomb Shelters, Emergency Gear: South Korea Easy for the linguistically lame: Denmark.  I have no inhibitions there about speaking English, as everyone responds in kind thus far.  Also, the alphabet is the same with some strange looking o's, so I can figure much out.  Not so much in Korea.Weather: South Korea.  Much drier and warmer.Walking tourism: Busan > Copenhagen > Seoul.  All three places are great, but I have been to Copenhagen a few times before and to Seoul once before so novelty here wins out.Food: I kept finding Indonesian food in Korea, so that's a win right there.Sleep: oy.  Not great in either place.  Jet lag plus hard to control room temps and those duvets that mean either hot or cold and nothing in between.  Oy, and flying my preferred airline is indeed better than not.  The Lufthansa flight from Seoul to Munich was about as long as the flight from Newark to Japan, but it was econ, no plus, which mean no room before the inconsiderate person in front of me decided to repeatedly slam her seat as far as it could go, hitting my knees and bouncing my ipad off my little table.  Shitty seats are shitty seats, no matter the airline, but when I have a bit of status, I can get at least those precious two or three inches that make all the difference.  When I fly, I always am thankful that I am not tall.  I am bummed I missed the Vimy Gala as Jacqui O'Neill rocks mightily, and while her talk was not aimed at undoing the damage done by last year's craptastic speaker, it was still an excellent tonic.  Funny what happens when you take the decision-making out of the old boys network's hands.