Excitatory Pathways Research Articles

Fast singlet excited-state deactivation pathway of flavin with a trimethoxyphenyl derivative

Incorporation of the trimethoxyphenyl group at position 7 of flavin can drastically change the photophysical properties of flavin. We show unique fast singlet 1(π,π*) excited state deactivation pathway through nonadiabatic transition to the 1(n,π*) excited- state, and subsequent deactivation to the ground electronic state (S0), closing the photocycle. This mechanism explains the exceptionally weak fluorescence and the short excited–state lifetime for the flavin trimethoxyphenyl derivative and the lack of excited triplet T1 state formation. Full recovery of flavin in its ground state takes place within a 15 ps time window after photoexcitation in a polar solvent such as acetonitrile. According to quantum chemical calculations, the C(2)-O distance elongates by 0.16 Å in the 1(n,π*) state, with respect to the ground state. Intermediate–state structures are predicted by theoretical ab initio calculations and their dynamics are investigated using broadband vis-NIR time-resolved transient absorption and fluorescence up-conversion techniques.

Mediation of mammalian olfactory response by presence of odor-evoked potassium current.

It is well understood that odorants interact with specialized G-protein coupled receptors embedded in the ciliary membrane of olfactory sensory neurons (OSN) which initiates a voltage-generating intracellular cascade of signal transduction events that can be recorded at the epithelial level as an electroolfactogram (EOG). While the depolarizing excitatory pathway in vertebrates involving cyclic adenosine monophosphate (cAMP)-induced Na+/Ca2+ influx and calcium-induced Cl- efflux is well established, there is evidence of potassium-associated inhibitory currents that correspond with cellular activation. While several Ca2+-dependent feedback mechanisms contribute to cellular deactivation which have been commonly attributed to these inhibitory currents, the frequently observed positive ionic conductance prior to excitatory depolarization have led many to suggest an additional earlier inhibitory mechanism at the receptor level that may be independent of downstream calcium influx. Due to conflicting conclusions, the role and mechanism behind Ca2+-independent inhibitory currents in olfactory cells is not fully understood. We investigated the functional and temporal involvement of potassium channels in odor transduction by comparing electroolfactogram (EOG) recordings in rat olfactory epithelia following ion channel inhibition and targeted activation of downstream components with or without potassium-blocking. Several K+-channel blocking agents (4-Aminopyridine, charybdotoxin, & iberiotoxin) demonstrated a diminished pre-action potential positive current that corresponded with reduced excitatory response to odor stimulation that was recovered when blockers were removed. We further assessed EOG responses in the absence of odor or with odor response enhancing zinc nanoparticles. Chemically eliciting membrane excitation in the absence of odor stimulation with a phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (IBMX), in combination with K+-channel inhibition, further indicated potassium channel activation precedes excitatory events and is independent of cAMP-induced calcium influx. These results support previous findings of odor-activated inhibitory potassium currents that may play a functional role in subsequent G-protein activity.

Intrinsic process for upconversion photoluminescence via K -momentum–phonon coupling in carbon nanotubes

We investigate the intrinsic microscopic mechanism of photon upconversion in air-suspended single-walled carbon nanotubes through photoluminescence and upconversion photoluminescence spectroscopy. Nearly linear excitation power dependence of upconversion photoluminescence intensity is observed, indicating a one-photon process as the underlying mechanism. In addition, we find a strongly anisotropic response to the excitation polarization, which reflects the intrinsic nature of the upconversion process. In upconversion photoluminescence excitation spectra, three peaks are observed, which are similar to photoluminescence sidebands of the K-momentum dark singlet exciton. The features in the upconversion photoluminescence excitation spectra are well reproduced by our second-order exciton-phonon interaction model, enabling the determination of phonon energies and relative amplitudes. The analysis reveals that the upconversion photoluminescence can be described as a reverse process of the sideband emission linked to the K-momentum phonon modes. The validity of our model is further reinforced by temperature-dependent upconversion photoluminescence excitation measurements reflecting variations in the phonon population. Our findings underscore the pivotal role of the resonant exciton-phonon coupling in pristine carbon nanotubes and present potential for advanced optothermal technologies by engineering the excitation pathways. Published by the American Physical Society 2024

Unconventional phonon blockade effect in array of three coupled weakly nonlinear nanomechanical resonators

Phonon antibunching, a phenomenon arising from the quantum statistics of mechanical vibrations, has attracted significant attention due to its potential applications in quantum information processing, sensing, and energy harvesting. Here, we present a comprehensive investigation of phonon antibunching in a system consisting of three weakly nonlinear coupled nanomechanical resonators. We analytically derive and study the antibunching behavior of phonons in the proposed system and bring insight into the underlying mechanisms. The optimal phonon blockade results from destructive quantum interference due to distinct two-phonon excitation pathways. Due to this quantum interference, these unconventional phonon blockade systems can achieve antibunched statistics even in weakly nonlinear regimes, in contrast to conventional phonon blockade systems that require strong nonlinearity. We show that with the inclusion of an additional resonator, there are multiple additional two-phonon excitation pathways compared to two resonator cases, which results in stronger phonon antibunching and supports single phonon for longer duration. These findings are interesting for practical phononics using coupled-resonator systems.

3D-printed copolymer semi-cavity sensor with inner optical filter-effecting quantum dots photoluminescence for multiple drugs and amino acids detection

Here, we demonstrate a prototype for a novel optical sensor based on 3D-printed copolymer semi-cavity embedded with colloidal ZnCuInS (ZCIS) quantum dots (QDs) and utilizing the optical filter-effect in the QDs photoluminescence excitation pathway by analytes in the solution. First, in situ copolymerization of styrene and n-butyl methacrylate (P(S-BMA)) with colloidal ZCIS QDs allowed formation of solid P(S-BMA) matrix homogeneously impregnated with QDs. Then QDs@P(S-BMA) mixed with polylactic acid (PLA) has been processed into QDs@P(S-BMA)@PLA hybrid filaments using extruder. Then, a semi-cavity optical cell was 3D-printed out of QDs@P(S-BMA)@PLA filaments. Such 3D-printed semi-cavity cell can be used as the optical sensor on various molecules utilizing the optical absorption by analyte molecules through inner filter effect (IFE) of a properly selected QDs excitation beam. The multiple drug and amino acid molecules have been utilized having selective UV absorption to examine our proof of concept.

Detection of Nickel Atoms Released from Electrodes in Spark Discharges Using Laser-Induced Fluorescence.

The reduction of greenhouse gas emissions and the effort of carbon neutrality require the improvement of spark-ignition engines in terms of efficiency and capability to operate on renewable fuels. The electrode wear of spark plugs, used for ignition of novel fuels and lean mixtures, emerges as a significant challenge in this transition. Understanding the physical mechanism and influence of spark operation parameters of the wear process is thus important. Compared to the conventional methodology of performing long-term wear tests, laser-based optical diagnostics methods are capable of assessing electrode wear during one single or a few spark discharges. In this work, the necessary initial steps required for performing optical investigations using laser-induced fluorescence (LIF) are presented. Several excitation pathways of nickel atoms were investigated, and 336.96 nm was identified as the optimal one. This excitation approach yielded emissions between 338.75 and 353.58 nm, effectively avoiding the major interference from N2 plasma emission in spark discharges. Additionally, a linear relationship in fluorescence signal intensity with excitation energy up to 400 µJ was observed. These findings indicate the potential of LIF for in situ diagnostics of electrode wear, contributing to engine development in both efficiency and compatibility with sustainable fuels.

Model based optimization for refractive index mismatched light sheet imaging

Selective plane illumination microscopy (SPIM) is an optical sectioning imaging approach based on orthogonal light pathways for excitation and detection. The excitation pathway has an inverse relation between the optical sectioning strength and the effective field of view (FOV). Multiple approaches exist to extend the effective FOV, and here we focus on remote focusing to axially scan the light sheet, synchronized with a CMOS camera’s rolling shutter. A typical axially scanned SPIM configuration for imaging large samples utilizes a tunable optic for remote focusing, paired with air objectives focused into higher refractive index media. To quantitatively explore the effect of remote focus choices and sample space refractive index mismatch on light sheet intensity distributions, we developed an open-source computational approach for integrating ray tracing and field propagation. We validate our model’s performance against experimental light sheet profiles for various SPIM configurations. Our findings indicate that optimizing the position of the sample chamber relative to the excitation optics can enhance image quality by balancing aberrations induced by refractive index mismatch. We validate this prediction using a home-built, large sample axially scanned SPIM configuration and calibration samples. Our open-source, extensible modeling software can easily extend to explore optimal imaging configurations in diverse light sheet imaging settings.

A circuit motif for color in the human foveal retina

The neural pathways that start human color vision begin in the complex synaptic network of the foveal retina where signals originating in long (L), middle (M), and short (S) wavelength-sensitive cone photoreceptor types are compared through antagonistic interactions, referred to as opponency. In nonhuman primates, two cone opponent pathways are well established: an L vs. M cone circuit linked to the midget ganglion cell type, often called the red-green pathway, and an S vs. L + M cone circuit linked to the small bistratified ganglion cell type, often called the blue-yellow pathway. These pathways have been taken to correspond in human vision to cardinal directions in a trichromatic color space, providing the parallel inputs to higher-level color processing. Yet linking cone opponency in the nonhuman primate retina to color mechanisms in human vision has proven particularly difficult. Here, we apply connectomic reconstruction to the human foveal retina to trace parallel excitatory synaptic outputs from the S-ON (or "blue-cone") bipolar cell to the small bistratified cell and two additional ganglion cell types: a large bistratified ganglion cell and a subpopulation of ON-midget ganglion cells, whose synaptic connections suggest a significant and unique role in color vision. These two ganglion cell types are postsynaptic to both S-ON and L vs. M opponent midget bipolar cells and thus define excitatory pathways in the foveal retina that merge the cardinal red-green and blue-yellow circuits, with the potential for trichromatic cone opponency at the first stage of human vision.

(Invited) Resonant Exciton Transfer in Mixed-Dimensional Heterostructures for Overcoming Dimensional Restrictions in Optical Processes

Nanomaterials exhibit unique optical phenomena, in particular excitonic quantum processes occurring at room temperature. The low dimensionality, however, imposes strict requirements for conventional optical excitation, and an approach for bypassing such restrictions is desirable. Here we report on exciton transfer in carbon-nanotube/tungsten-diselenide heterostructures, where band alignment can be systematically varied. The mixed-dimensional heterostructures display a pronounced exciton reservoir effect where the longer-lifetime excitons within the two-dimensional semiconductor are funneled into carbon nanotubes through diffusion. This new excitation pathway presents several advantages, including larger absorption areas, broadband spectral response, and polarization-independent efficiency. When band alignment is resonant, we observe substantially more efficient excitation via tungsten diselenide compared to direct excitation of the nanotube. We further demonstrate simultaneous bright emission from an array of carbon nanotubes with varied chiralities and orientations. Our findings show the potential of mixed-dimensional heterostructures and band alignment engineering for energy harvesting and quantum applications through exciton manipulation.Parts of this study are supported by JSPS (KAKENHI JP22K14624, JP22K14625, JP21K14484, JP22F22350, JP22K14623, JP21H05233, JP23H00262, JP20H02558) and MEXT (ARIM JPMXP1222UT1135). Y.R.C. is supported by JSPS (International Research Fellow). N.F. and C.F.F. are supported by RIKEN Special Postdoctoral Researcher Program. We thank the Advanced Manufacturing Support Team at RIKEN for technical assistance.[1] N. Fang, D. Yamashita, S. Fujii, M. Maruyama, Y. Gao, Y. R. Chang, C. F. Fong, K. Otsuka, K. Nagashio, S. Okada, Y. K. Kato, "Resonant exciton transfer in mixed-dimensional heterostructures for overcoming dimensional restrictions in optical processes," Nature Commun., accepted (2023). Preprint at arXiv:2307.07124.

Chronic morphine treatment induces sex- and synapse-specific cellular tolerance on thalamo-cortical mu opioid receptor signaling.

How cellular adaptations give rise to opioid analgesic tolerance to opioids like morphine is not well understood. For one, pain is a complex phenomenon comprising both sensory and affective components, largely mediated through separate circuits. Glutamatergic projections from the medial thalamus (MThal) to the anterior cingulate cortex (ACC) are implicated in processing of affective pain, a relatively understudied component of the pain experience. The goal of this study was to determine the effects of chronic morphine exposure on mu-opioid receptor (MOR) signaling on MThal-ACC synaptic transmission within the excitatory and feedforward inhibitory pathways. Using whole cell patch-clamp electrophysiology and optogenetics to selectively target these projections, we measured morphine-mediated inhibition of optically evoked postsynaptic currents in ACC layer V pyramidal neurons in drug-naïve and chronically morphine-treated mice. We found that morphine perfusion inhibited the excitatory and feedforward inhibitory pathways similarly in females but caused greater inhibition of the inhibitory pathway in males. Chronic morphine treatment robustly attenuated morphine presynaptic inhibition within the inhibitory pathway in males, but not females, and mildly attenuated presynaptic inhibition within the excitatory pathway in both sexes. These effects were not observed in MOR phosphorylation-deficient mice. This study indicates that chronic morphine treatment induces cellular tolerance to morphine within a thalamo-cortical circuit relevant to pain and opioid analgesia. Furthermore, it suggests this tolerance may be driven by MOR phosphorylation. Overall, these findings improve our understanding of how chronic opioid exposure alters cellular signaling in ways that may contribute to opioid analgesic tolerance.NEW & NOTEWORTHY Opioid signaling within the anterior cingulate cortex (ACC) is important for opioid modulation of affective pain. Glutamatergic medial thalamus (MThal) neurons synapse in the ACC and opioids, acting through mu opioid receptors (MORs), acutely inhibit synaptic transmission from MThal synapses. However, the effect of chronic opioid exposure on MThal-ACC synaptic transmission is not known. Here, we demonstrate that chronic morphine treatment induces cellular tolerance at these synapses in a sex-specific and phosphorylation-dependent manner.

Metal-Organic Framework with Dual Excitation Pathways as Efficient Bifunctional Catalyst for Photo-assisted Li-O2 Batteries.

Li-O2 batteries (LOBs) have sparked significant interest due to their fascinating high theoretical energy density. However, the large overpotential for the formation and oxidation of Li2O2 during charge and discharge process seriously hinders the further development and application of LOBs. In this work, metal-organic frameworks (MOFs) with different metal clusters (Fe, Ti, Zr) are successfully synthesized, and they are employed as the photoelectrodes for the photo-assisted LOBs. The special dual excitation pathways of Fe-MOF under illumination and the superior separation efficiency of photocarriers, which significantly enhance the activation of O2/Li2O2, improving the catalytic activity of oxygen reduction reaction and oxygen evolution reaction. Moreover, compared to traditional inorganic semiconductor crystals, Fe-MOF exhibits large specific surface area and excellent O2 adsorption ability. Therefore, the LOB with Fe-MOF as the cathode exhibits large specific capacity, ultralow charge/discharge overpotential of 0.22V at 0.05mA cm-2 and excellent stability of 195 cycles under illumination. This study provides an environmentally friendly and highly efficient photocatalyst for LOBs, and a new strategy for designing photoelectrodes.

Resolving plasmon-mediated high-order multiphoton excitation pathways in dolmen nanostructures using ultrafast nonlinear optical interferometry.

The multiphoton excitation pathways of plasmonic nanorod assemblies are described. By using dolmen structures formed from the directed assembly of three gold nanorods, plasmon-mediated three-photon excitation is resolved. These high-order multiphoton excitation channels were accessed by resonantly exciting a hybrid mode of the dolmen structure that was resonant with the 800-nm carrier wavelength of an ultrafast laser system. Rotation of the exciting field polarization to a non-resonant configuration did not generate third-order responses. Hence, the multiphoton excitation and resultant non-equilibrium electron distributions were generated by structure- and mode-selective excitation. Correlation between high-order and resonant plasmon excitation was achieved through sub-cycle time-resolved interferometric detection of incoherent nonlinear emission signals. The results illustrate the advantages of nonlinear optical interferometry and Fourier analysis for distinguishing plasmon-mediated processes from those that do not require plasmon excitation.

The dual role of a novel Sinorhizobium meliloti chemotaxis protein CheT in signal termination and adaptation.

Sinorhizobium meliloti senses nutrients and compounds exuded from alfalfa host roots and coordinates an excitation, termination, and adaptation pathway during chemotaxis. We investigated the role of the novel S. meliloti chemotaxis protein CheT. While CheT and the Escherichia coli phosphatase CheZ share little sequence homology, CheT is predicted to possess an α-helix with a DXXXQ phosphatase motif. Phosphorylation assays demonstrated that CheT dephosphorylates the phosphate-sink response regulator, CheY1~P by enhancing its decay two-fold but does not affect the motor response regulator CheY2~P. Isothermal Titration Calorimetry (ITC) experiments revealed that CheT binds to a phosphomimic of CheY1~P with a KD of 2.9 μM, which is 25-fold stronger than its binding to CheY1. Dissimilar chemotaxis phenotypes of the ΔcheT mutant and cheT DXXXQ phosphatase mutants led to the hypothesis that CheT exerts additional function(s). A screen for potential binding partners of CheT revealed that it forms a complex with the methyltransferase CheR. ITC experiments confirmed CheT/CheR binding with a KD of 19 μM, and a SEC-MALS analysis determined a 1:1 and 2:1 CheT/CheR complex formation. Although they did not affect each other's enzymatic activity, CheT binding to CheY1~P and CheR may serve as a link between signal termination and sensory adaptation.

Self-Reporting Conjugated Polymer Nanoparticles for Superoxide Generation and Detection.

Conjugated polymer nanoparticles (CPNs or Pdots) have become increasingly popular fluorophores for multimodal applications that combine imaging with phototherapeutic effects. Reports of CPNs in photodynamic therapy applications typically focus on their ability to generate singlet oxygen. Alternatively, CPN excited states can interact with oxygen to form superoxide radical anion and a CPN-based hole polaron, both of which can have deleterious effects on fluorescence properties. Here, we demonstrate that CPNs prepared from the common conjugated polymer poly[(9,9-dioctylfluorenyl-2,7-diyl)-alt-co-(1,4-benzo-{2,1',3}-thiadiazole)] (PFBT, also known as F8BT) generate superoxide upon irradiation. We use the same CPNs to detect superoxide by doping them with a superoxide-responsive hydrocyanine dye developed by Murthy and co-workers. Superoxide induces off-to-on fluorescence switching by converting quenching hydrocyanine dyes to fluorescent cyanine dyes that act as fluorescence resonance energy transfer (FRET) acceptors for PFBT chromophores. Amplified FRET from the multichromophoric CPNs yields fluorescence signal intensities that are nearly 50 times greater than when the dye is excited directly or over 100 times greater when signal readout is from the CPN channel. The dye loading level governs the maximum amount of superoxide that induces a change in fluorescence properties and also influences the rate of superoxide generation by furnishing competitive excited state deactivation pathways. These results suggest that CPNs can be used to deliver superoxide in applications in which it is desirable and provide a caution for fluorescence-based CPN applications in which superoxide can damage fluorophores.

Boric Acid Matrix‐Activated nπ* Transition of Guest Chromophores: from Pure Fluorescence to Efficient Afterglow

AbstractEl‐Sayed rule highlights the important role of heteroatoms (e.g., N, O, and S) and the corresponding nπ* transition in designing efficient organic phosphors. Nevertheless, for some heteroatom‐rich fluorophores, their phosphorescence is quite weak (e.g., fluorescein), since the nπ* components are absent in the whole transitions. Here, these chromophores (mainly with n electron‐containing twisted structure) are found doping into the boric acid (BA) matrix can activate the nπ* transition for efficient afterglow luminescence. For example, doping purely green‐emitting fluorescein into BA yielded a high afterglow quantum yield (≈24%) and a long‐lasting, blue‐shifted cyan afterglow (>10 s). The covalent/non‐covalent interactions between the BA matrix and the guests resulted in twisting the n electron‐containing structure to promote the spin‐orbit coupling process, leading to the generation of new excited state triplet transition pathways. Since the guest chromophores feature visible light absorption, a series of multi‐color afterglow phosphors with visible or white light excitation are successfully constructed.

Evaluation of the mechanism of action of paracetamol, drotaverine, and peppermint oil and their effects in combination with hyoscine butylbromide on colonic motility: human ex-vivo study.

Drotaverine, paracetamol, and peppermint oil are often prescribed for the treatment of gastrointestinal spasm and pain. This study aimed to evaluate the effect of these drugs alone and combined with the well-known antispasmodic hyoscine butylbromide on the human colon. Colon samples were obtained from macroscopically normal regions of 68 patients undergoing surgery and studied in muscle bath. Drotaverine, paracetamol, and peppermint oil were tested alone and in combination with hyoscine butylbromide on (1) spontaneous contractility induced by isometric stretch (in the presence of 1µM tetrodotoxin) and (2) contractility induced by 10-5M carbachol and after (3) electrical field stimulation-induced selective stimulation of excitatory (in the presence of 1mMNω-nitro-L-arginine and 10µM MRS2179) and (4) inhibitory (under non-adrenergic, non-cholinergic conditions) pathways. (5) Drotaverine alone was also tested on cAMP-dependent pathway activated by forskolin. Compared with the vehicle, drotaverine and paracetamol (10-9-10-5M) did not modify spontaneous contractions, carbachol-induced contractions, and responses attributed to selective activation of excitatory pathways. The addition of hyoscine butylbromide (10-7-10-5M), concentration-dependently reduced myogenic contractions and carbachol- and electrical field stimulation-induced contractile responses. The association of paracetamol (10-4M) and hyoscine butylbromide (10-7-10-5M) was not different from hyoscine butylbromide alone (10-7-10-5M). At higher concentrations (10-3M-3*10-3M), paracetamol decreased myogenic and carbachol-induced contractions. The adenylate cyclase activator, forskolin, concentration-dependently reduced contractility, leading to smooth muscle relaxation. The effect of forskolin 10-7M was concentration-dependently enhanced by drotaverine (10-6M-10-5M). Peppermint oil reduced myogenic activity and carbachol- and electrical field stimulation-induced contractions. The association of hyoscine butylbromide and peppermint oil was synergistic since the interaction index measured with the isobologram was lower than 1. No effect was seen on the neural-mediated inhibitory responses with any of the drugs studied although peppermint oil reduced the subsequent off-contraction. Drotaverine and hyoscine butylbromide have a complementary effect on human colon motility as one stimulates the cAMP inhibitory pathway and the other inhibits the excitatory pathway. Peppermint oil is synergic with hyoscine butylbromide suggesting that a combination therapy may be more effective in treating patients. In contrast, at therapeutic concentrations, paracetamol does not modify colonic contractility, suggesting that the association of paracetamol and hyoscine butylbromide has independent analgesic and antispasmodic properties.

Acute social defeat during adolescence promotes long-lasting aggression through activation of the medial amygdala.

Traumatic stress, particularly during critical developmental periods such as adolescence, has been strongly linked to an increased propensity and severity of aggression. Existing literature underscores that being a victim of abuse can exacerbate aggressive behaviors, with the amygdala playing a pivotal role in mediating these effects. Historically, animal models have demonstrated that traumatic stressors can increase attack behavior, implicating various amygdala nuclei. Building on this foundation, our previous work has highlighted how traumatic stress invokes long-lasting aggression via an excitatory pathway within the posterior ventral medial amygdala (MeApv). In the current study, we sought to further delineate this mechanism by examining the effects of acute social defeat during adolescence on aggressive behaviors and neural activation in mice. Using a common social defeat paradigm, we first established that acute social defeat during late adolescence indeed promotes long-lasting aggression, measured as attack behavior 7 days after the defeat session. Immunolabeling with c-Fos demonstrated that acute social defeat activates the MeApv and ventrolateral aspect of the ventromedial hypothalamus (VmHvl), consistent with our previous studies that used foot shock as an acute stressor. Finally, chemogenetically inhibiting excitatory MeApv neurons during social defeat significantly mitigated the aggression increase without affecting non-aggressive social behavior. These results strongly suggest that the MeApv plays a critical role in the onset of aggression following traumatic social experience, and offer the MeA as a potential target for therapeutic interventions.

The Endogenous Pain Modulatory System as a Healing Mechanism: A Proposal on How to Measure and Modulate It.

Chronic pain is highly burdening and multifactorial in etiology. The endogenous-pain-healing system restores body tissue to a non-painful state after an injury leading to pain, and its disruption could represent a relevant mechanism, especially for nursing interventions. To review the literature and summarize the results that support this hypothesis. We hypothesized that the mechanism behind this system mainly depends on the endogenous pain modulatory system (EPMS), which is responsible for inhibiting pain after tissue healing is complete and facilitating it when tissue damage is still present. Different biomarkers can quantify EPMS functioning. We reviewed the literature and included relevant information regarding this hypothesis. First, conditioned pain modulation (CPM) measures pain inhibition and is a possible predictor for pain chronification. Second, motor cortex excitability measures the cortical control of the EPMS, which can be assessed through transcranial magnetic stimulation (using intracortical inhibition) or electroencephalography. Modifiable factors disrupt its functioning, such as sleep deprivation, medication overuse, and mental health status, but could be protective, such as exercise, certain medications, mind-body techniques, and non-invasive neuromodulation therapies. The acquisition of neurophysiological knowledge of how the chronicity of pain occurs and the EPMS involvement in this process may allow for better management of these patients. We raised the hypothesis that the impairment of the EPMS (altered cortical excitability and descendent pain modulation pathways) seems to be related to the disruption of the pain healing process and its chronicity. Further longitudinal studies evaluating the relationship between these biomarkers and chronic pain development are necessary.

Fast Inhibition Slows and Desynchronizes Mouse Auditory Efferent Neuron Activity.

The encoding of acoustic stimuli requires precise neuron timing. Auditory neurons in the cochlear nucleus (CN) and brainstem arewell suited for accurate analysis of fast acoustic signals, given their physiological specializations of fast membrane time constants, fast axonal conduction, and reliable synaptic transmission. The medial olivocochlear (MOC) neurons that provide efferent inhibition of the cochlea reside in the ventral brainstem and participate in these fast neural circuits. However, their modulation of cochlear function occurs over time scales of a slower nature. This suggests the presence of mechanisms that reduce MOC inhibition of cochlear function. To determine how monaural excitatory and inhibitory synaptic inputs integrate to affect the timing of MOC neuron activity, we developed a novel in vitro slice preparation ("wedge-slice"). The wedge-slice maintains the ascending auditory nerve root, the entire CN and projecting axons, while preserving the ability to perform visually guided patch-clamp electrophysiology recordings from genetically identified MOC neurons. The "in vivo-like" timing of the wedge-slice demonstrates that the inhibitory pathway accelerates relative to the excitatory pathway when the ascending circuit is intact, and the CN portion of the inhibitory circuit is precise enough to compensate for reduced precision in later synapses. When combined with machine learning PSC analysis and computational modeling, we demonstrate a larger suppression of MOC neuron activity when the inhibition occurs with in vivo-like timing. This delay of MOC activity may ensure that the MOC system is only engaged by sustained background sounds, preventing a maladaptive hypersuppression of cochlear activity.

Mechanisms for dysregulation of excitatory-inhibitory balance underlying allodynia in dorsal horn neural subcircuits.

Chronic pain is a wide-spread condition that is debilitating and expensive to manage, costing the United States alone around $600 billion in 2010. In a common type of chronic pain called allodynia, non-painful stimuli produce painful responses with highly variable presentations across individuals. While the specific mechanisms remain unclear, allodynia is hypothesized to be caused by the dysregulation of excitatory-inhibitory (E-I) balance in pain-processing neural circuitry in the dorsal horn of the spinal cord. In this work, we analyze biophysically-motivated subcircuit structures that represent common motifs in neural circuits in layers I-II of the dorsal horn. These circuits are hypothesized to be part of the neural pathways that mediate two different types of allodynia: static and dynamic. We use neural firing rate models to describe the activity of populations of excitatory and inhibitory interneurons within each subcircuit. By accounting for experimentally-observed responses under healthy conditions, we specify model parameters defining populations of subcircuits that yield typical behavior under normal conditions. Then, we implement a sensitivity analysis approach to identify the mechanisms most likely to cause allodynia-producing dysregulation of the subcircuit's E-I signaling. We find that disruption of E-I balance generally occurs either due to downregulation of inhibitory signaling so that excitatory neurons are "released" from inhibitory control, or due to upregulation of excitatory neuron responses so that excitatory neurons "escape" their inhibitory control. Which of these mechanisms is most likely to occur, the subcircuit components involved in the mechanism, and the proportion of subcircuits exhibiting the mechanism can vary depending on the subcircuit structure. These results suggest specific hypotheses about diverse mechanisms that may be most likely responsible for allodynia, thus offering predictions for the high interindividual variability observed in allodynia and identifying targets for further experimental studies on the underlying mechanisms of this chronic pain condition.