Hyperpolarization Of Neurons Research Articles

Group III metabotropic glutamate receptors: guardians against excitotoxicity in ischemic brain injury, with implications for neonatal contexts

AbstractThe group III metabotropic glutamate receptors (mGluRs), comprising mGluR4, mGluR6, mGluR7, and mGluR8, offer neuroprotective potential in mitigating excitotoxicity during ischemic brain injury, particularly in neonatal contexts. They are G-protein coupled receptors that inhibit adenylyl cyclase and reduce neurotransmitter release, mainly located presynaptically and acting as autoreceptors. This review aims to examine the differential expression and function of group III mGluRs across various brain regions such as the cortex, hippocampus, and cerebellum, with a special focus on the neonatal stage of development. Glutamate excitotoxicity plays a crucial role in the pathophysiology of brain ischemia in neonates. While ionotropic glutamate receptors are traditional targets for neuroprotection, their direct inhibition often leads to severe side effects due to their critical roles in normal neurotransmission and synaptic plasticity. Group III mGluRs provide a more nuanced and potentially safer approach by modulating rather than blocking glutamatergic transmission. Their downstream signaling cascade results in the regulation of intracellular calcium levels, neuronal hyperpolarization, and reduced neurotransmitter release, effectively decreasing excitotoxic signaling without completely suppressing essential glutamatergic functions. Importantly, the neuroprotective effects of group III mGluRs extend beyond direct modulation of glutamate release influencing glial cell function, neuroinflammation, and oxidative stress, all of which contribute to secondary injury cascades in brain ischemia. This comprehensive analysis of group III mGluRs multifaceted neuroprotective potential provides valuable insights for developing novel therapeutic strategies to combat excitotoxicity in neonatal ischemic brain injury.

Ca2+-permeable AMPA receptor-dependent silencing of neurons by KCa3.1 channels during epileptiform activity

Ca2+-activated KCa3.1 channels are known to contribute to slow afterhyperpolarization in pyramidal neurons of several brain areas, while Ca2+-permeable AMPA receptors (CP-AMPARs) may provide a subthreshold source of Ca2+ elevation in the cytoplasm. The functionality of these two types of channels has also been shown to be altered by epileptic disorders. However, the link between KCa3.1 channels and CP-AMPARs is poorly understood, and their potential interaction in epilepsy remains unclear. Here, we address this issue by overexpressing the KCNN4 gene, which encodes the KCa3.1 channel, using patch clamp, imaging, and channel blockers in an in vitro model of epilepsy in neuronal culture. We show that KCNN4 overexpression causes strong hyperpolarization and substantial silencing of neurons during epileptiform activity events, which also prevents KCNN4-positive neurons from firing action potentials (APs) during experimentally induced status epilepticus. Intracellular blocker application experiments showed that the amplitude of hyperpolarization was strongly dependent on CP-AMPARs, but not on NMDA receptors. Taken together, our data strongly suggest that subthreshold Ca2+ elevation produced by CP-AMPARs can trigger KCa3.1 channels to hyperpolarize neurons and protect them from seizures.

A silicon diode–based optoelectronic interface for bidirectional neural modulation

The development of advanced neural modulation techniques is crucial to neuroscience research and neuroengineering applications. Recently, optical-based, nongenetic modulation approaches have been actively investigated to remotely interrogate the nervous system with high precision. Here, we show that a thin-film, silicon (Si)-based diode device is capable to bidirectionally regulate in vitro and in vivo neural activities upon adjusted illumination. When exposed to high-power and short-pulsed light, the Si diode generates photothermal effects, evoking neuron depolarization and enhancing intracellular calcium dynamics. Conversely, low-power and long-pulsed light on the Si diode hyperpolarizes neurons and reduces calcium activities. Furthermore, the Si diode film mounted on the brain of living mice can activate or suppress cortical activities under varied irradiation conditions. The presented material and device strategies reveal an innovated optoelectronic interface for precise neural modulations.

Astrocytes facilitate gabazine-evoked electrophysiological hyperactivity and distinct biochemical responses in mature neuronal cultures.

Gamma-aminobutyric acid (GABA) is the principal inhibitory neurotransmitter in the adult brain that binds to GABA receptors and hyperpolarizes the postsynaptic neuron. Gabazine acts as a competitive antagonist to type A GABA receptors (GABAAR), thereby causing diminished neuronal hyperpolarization and GABAAR-mediated inhibition. However, the biochemical effects and the potential regulatory role of astrocytes in this process remain poorly understood. To address this, we investigated the neuronal responses of gabazine in rat cortical cultures containing varying ratios of neurons and astrocytes. Electrophysiological characterization was performed utilizing microelectrode arrays (MEAs) with topologically controlled microcircuit cultures that enabled control of neuronal network growth. Biochemical analysis of the cultures was performed using traditional dissociated cultures on coverslips. Our study indicates that, upon gabazine stimulation, astrocyte-rich neuronal cultures exhibit elevated electrophysiological activity and tyrosine phosphorylation of tropomyosin receptor kinase B (TrkB; receptor for brain-derived neurotrophic factor), along with distinct cytokine secretion profiles. Notably, neurons lacking proper astrocytic support were found to experience synapse loss and decreased mitogen-activated protein kinase (MAPK) phosphorylation. Furthermore, astrocytes contributed to neuronal viability, morphology, vascular endothelial growth factor (VEGF) secretion, and overall neuronal network functionality, highlighting the multifunctional role of astrocytes.

Calcium plays an essential role in early-stage dendrite injury detection and regeneration

Dendrites are injured in a variety of clinical conditions such as traumatic brain and spinal cord injuries and stroke. How neurons detect injury directly to their dendrites to initiate a pro-regenerative response has not yet been thoroughly investigated. Calcium plays a critical role in the early stages of axonal injury detection and is also indispensable for regeneration of the severed axon. Here, we report cell and neurite type-specific differences in laser injury-induced elevations of intracellular calcium levels. Using a human KCNJ2 transgene, we demonstrate that hyperpolarizing neurons only at the time of injury dampens dendrite regeneration, suggesting that inhibition of injury-induced membrane depolarization (and thus early calcium influx) plays a role in detecting and responding to dendrite injury. In exploring potential downstream calcium-regulated effectors, we identify L-type voltage-gated calcium channels, inositol triphosphate signaling, and protein kinase D activity as drivers of dendrite regeneration. In conclusion, we demonstrate that dendrite injury-induced calcium elevations play a key role in the regenerative response of dendrites and begin to delineate the molecular mechanisms governing dendrite repair.

A hyperpolarizing neuron recruits undocked innexin hemichannels to transmit neural information in Caenorhabditis elegans

While depolarization of the neuronal membrane is known to evoke the neurotransmitter release from synaptic vesicles, hyperpolarization is regarded as a resting state of chemical neurotransmission. Here, we report that hyperpolarizing neurons can actively signal neural information by employing undocked hemichannels. We show that UNC-7, a member of the innexin family in Caenorhabditis elegans, functions as a hemichannel in thermosensory neurons and transmits temperature information from the thermosensory neurons to their postsynaptic interneurons. By monitoring neural activities in freely behaving animals, we find that hyperpolarizing thermosensory neurons inhibit the activity of the interneurons and that UNC-7 hemichannels regulate this process. UNC-7 is required to control thermotaxis behavior and functions independently of synaptic vesicle exocytosis. Our findings suggest that innexin hemichannels mediate neurotransmission from hyperpolarizing neurons in a manner that is distinct from the synaptic transmission, expanding the way of neural circuitry operations.

Fake Xanax: Designer Emerging Benzodiazepine Epidemic Linked to Morbidity and Mortality a Narrative Review.

Etizolam is a thienodiazepine derivative which produces an anxiolytic effect similar to benzodiazepines such as alprazolam (Xanax). Like classic benzodiazepines, etizolam has a high affinity towards the GABAA receptor, and allosterically potentiates the effects of GABA resulting in neuronal hyperpolarization related to chloride influx. When taken in therapeutic doses, etizolam produces a similar effect to Xanax. Counterfeit Xanax tablets contain variable amounts of etizolam. Tablets with high amounts of etizolam can cause toxicity if ingested, especially when combined with other substances. When toxic symptoms occur in patients, they may include severe sedation, unconsciousness, and depression of the medullary respiratory center. In this regard, there is the potential for death. Additionally, the rise in fake Xanax tablets containing etizolam and other counterfeit medications has been exacerbated by the difference in regulations regarding these substances in different countries as well as the illegal drug trade. Healthcare providers may also play a role through the over- or underprescribing of certain medications. Thus, in order to combat the rise in counterfeit medications such as fake Xanax, international cooperation, regulation, and enforcement of laws pertaining to the manufacture, prescription, and distribution of these substances are needed.

Treponema pallidum-induced prostaglandin E2 secretion in skin fibroblasts leads to neuronal hyperpolarization: A cause of painless ulcers.

Primary syphilis is characterized by painless ulcerative lesions in the genitalia, the aetiology of painless remains elusive. To investigate the role of Treponema pallidum in painless ulcer of primary syphilis, and the mechanisms underlying painless ulcers caused by T. pallidum. An experimental rabbit model of primary syphilis was established to investigate its effects on peripheral nerve tissues. Human skin fibroblasts were used to examine the role of T. pallidum in modulating neurotransmitters associated with pain and to explore the signalling pathways related to neurotransmitter secretion by T. pallidum invitro. Treponema pallidum infection did not directly lead to neuronal damage or interfere with the neuronal resting potential. Instead, it facilitated the secretion of prostaglandin E2 (PGE2) through endoplasmic reticulum stress in both rabbit and human skin fibroblasts, and upregulation of PGE2 induced the hyperpolarization of neurones. Moreover, the IRE1α/COX-2 signalling pathway was identified as the underlying mechanism by which T. pallidum induced the production of PGE2 in human skin fibroblasts. Treponema pallidum promotes PGE2 secretion in skin fibroblasts, leading to the excitation of neuronal hyperpolarization and potentially contributing to the pathogenesis of painless ulcers in syphilis.

Light-Driven Sodium Pump as a Potential Tool for the Control of Seizures in Epilepsy.

The marine flavobacterium Krokinobactereikastus light-driven sodium pump (KR2) generates an outward sodium ion current under 530nm light stimulation, representing a promising optogenetic tool for seizure control. However, the specifics of KR2 application to suppress epileptic activity have not yet been addressed. In the present study, we investigated the possibility of KR2 photostimulation to suppress epileptiform activity in mouse brain slices using the 4-aminopyrindine (4-AP) model. We injected the adeno-associated viral vector (AAV-PHP.eB-hSyn-KR2-YFP) containing the KR2 sodium pump gene enhanced with appropriate trafficking tags. KR2 expression was observed in the lateral entorhinal cortex and CA1 hippocampus. Using whole-cell patch clamp in mouse brain slices, we show that KR2, when stimulated with LED light, induces a substantial hyperpolarization of entorhinal neurons. However, continuous photostimulation of KR2 does not interrupt ictal discharges in mouse entorhinal cortex slices induced by a solution containing 4-AP. KR2-induced hyperpolarization strongly activates neuronal HCN channels. Consequently, turning off photostimulation resulted in HCN channel-mediated rebound depolarization accompanied by a transient increase in spontaneous network activity. Using low-frequency pulsed photostimulation, we induced the generation of short HCN channel-mediated discharges that occurred in response to the light stimulus being turned off; these discharges reliably interrupt ictal activity. Thus, low-frequency pulsed photostimulation of KR2 can be considered as a potential tool for controlling epileptic seizures.

Optogenetic stimulation suppresses ictal activity in a 4-aminopyridine model of epileptic activity <i>in vitro</i>

The WHO estimates that nearly 1% of the population suffers from epilepsy. Despite advances in the development of new antiepileptic drugs, seizures cannot be completely eliminated in nearly one-third of patients. One promising approach to the treatment of epilepsy may be gene therapy. Because epileptic activity is caused by an imbalance between excitation and inhibition, researchers have focused primarily on regulating neuronal excitability. Initially, the main approaches were based on the hyperexpression of inhibitory peptides such as galanin or NPY, or the suppression of neuronal excitability by the hyperexpression of potassium channels in neurons. However, these effects should be well calculated and strictly dosed, as it is difficult to correct the expression later. If the expression is too low, the anticonvulsant effect will not be achieved, and if the expression is too high, the neuronal networks will be impaired due to strong inhibition. For this reason, methodological approaches to treatment in which the effect on the neuronal excitability in the epileptic focus can be controlled are of great interest. Optogenetic methods offer such an advantage. Optogenetics uses light to alter the excitability of specific neuronal populations and can also be used in a biofeedback paradigm in which the light source is activated only at the risk of generating seizure activity. A number of optogenetic tools have now been developed, including light-activated cationic (e.g., ChR2) and anion channels (ACR), metabotropic receptors, pumps (NpHR, Arch), and enzymes. However, the optogenetic approach has a number of technical difficulties in delivering the light source and the risk of developing an immune response to the expression of rhodopsins. This report reviews the experience of practical application of optogenetic tools in the use of 4-aminopyridine in vitro model of epileptiform activity in experiencing slices of the entorhinal cortex. We tested the efficacy of suppressing ictal activity using several variants of optogenetic stimulation: (1) activation of excitatory and inhibitory neurons (in Thy1-ChR2-YFP mice), (2) activation of inhibitory interneurons only (in PV-Cre mice after virus injection with the channelodopsin-2 gene), hyperpolarization of excitatory neurons after expression of (3) archaeodopsin or (4) a light-dependent sodium pump. We found that ictal activity was successfully suppressed when low-frequency optogenetic stimulation induced regular interictal activity. Usually, interictal activity was induced by rhythmic synchronous activation of the principal neurons of the entorhinal cortex. In other cases, the ictal activity was preserved, although its characteristics may have changed. We determined the parameters of optogenetic stimulation that were most effective in suppressing ictal activity. The availability of a wide range of gene therapy approaches for epilepsy that have demonstrated efficacy in preclinical studies suggests that clinical trials of some of these approaches will begin in the next few years.

Kv2 channels contribute to neuronal activity within the vagal afferent-nTS reflex arc.

Diversity in the functional expression of ion channels contributes to the unique patterns of activity generated in visceral sensory A-type myelinated neurons versus C-type unmyelinated neurons in response to their natural stimuli. In the present study, Kv2 channels were identified as underlying a previously uncharacterized delayed rectifying potassium current expressed in both A- and C-type nodose ganglion neurons. Kv2.1 and 2.2 appear confined to the soma and initial segment of these sensory neurons; however, neither was identified in their central presynaptic terminals projecting onto relay neurons in the nucleus of the solitary tract (nTS). Kv2.1 and Kv2.2 were also not detected in the peripheral axons and sensory terminals in the aortic arch. Functionally, in nodose neuron somas, Kv2 currents exhibited frequency-dependent current inactivation and contributed to action potential repolarization in C-type neurons but not A-type neurons. Within the nTS, the block of Kv2 currents does not influence afferent presynaptic calcium influx or glutamate release in response to afferent activation, supporting our immunohistochemical observations. On the other hand, Kv2 channels contribute to membrane hyperpolarization and limit action potential discharge rate in second-order neurons. Together, these data demonstrate that Kv2 channels influence neuronal discharge within the vagal afferent-nTS circuit and indicate they may play a significant role in viscerosensory reflex function.NEW & NOTEWORTHY We demonstrate the expression and function of the voltage-gated delayed rectifier potassium channel Kv2 in vagal nodose neurons. Within sensory neurons, Kv2 channels limit the width of the broader C-type but not narrow A-type action potential. Within the nucleus of the solitary tract (nTS), the location of the vagal terminal field, Kv2 does not influence glutamate release. However, Kv2 limits the action potential discharge of nTS relay neurons. These data suggest a critical role for Kv2 in the vagal-nTS reflex arc.

Overexpression of KCNN4 channels in principal neurons produces an anti-seizure effect without reducing their coding ability.

Gene therapy offers a potential alternative to the surgical treatment of epilepsy, which affects millions of people and is pharmacoresistant in ~30% of cases. Aimed at reducing the excitability of principal neurons, the engineered expression of K+ channels has been proposed as a treatment due to the outstanding ability of K+ channels to hyperpolarize neurons. However, the effects of K+ channel overexpression on cell physiology remain to be investigated. Here we report an adeno-associated virus (AAV) vector designed to reduce epileptiform activity specifically in excitatory pyramidal neurons by expressing the human Ca2+-gated K+ channel KCNN4 (KCa3.1). Electrophysiological and pharmacological experiments in acute brain slices showed that KCNN4-transduced cells exhibited a Ca2+-dependent slow afterhyperpolarization that significantly decreased the ability of KCNN4-positive neurons to generate high-frequency spike trains without affecting their lower-frequency coding ability and action potential shapes. Antiepileptic activity tests showed potent suppression of pharmacologically induced seizures in vitro at both single cell and local field potential levels with decreased spiking during ictal discharges. Taken together, our findings strongly suggest that the AAV-based expression of the KCNN4 channel in excitatory neurons is a promising therapeutic intervention as gene therapy for epilepsy.

SAT592 Sexually Dimorphic Modulation Of Arcuate Kisspeptin Neurons Activity In Response To NPY

Abstract Disclosure: N.D. Mansano: None. R. Frazao: None. Kisspeptin neurons are part of an intricate brain circuit that receives neuronal inputs related tonutritional status from at least three neuronal populations, including NPY/AgRP and POMC neurons of the arcuate nucleus of the hypothalamus (ARH) and cells in the ventral premammillary nucleus. Its well-known action on the HPG axis, hypothalamic kisspeptin neurons also modulate the activity of specific neurons of the paraventricular and the dorsomedial nuclei of the hypothalamus, regions involved in the regulation of appetite and energy expenditure. However, it is not completely elucidated if NPY can influence the HPG axis through the modulation of kisspeptin neuron activity. To determine the NPY effect in the hypothalamic kisspeptin neurons we performed whole-cell patch-clamp recordings. The hypothalamic slices were obtained from the adult Kiss1/hrGFP female (diestrus-stage) or male mice. Kisspeptin cells located in the arcuate nucleus of the hypothalamus (ARHkisspeptin) and at the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeNkisspeptin) were recorded. On female mice, ARHkisspeptin neurons exhibited a rest membrane potential (RMP) average of -52.5±2.5 mV (-40 to -62 mV) and 1.3±0.2 GΩ input resistance (IR). NPY induced the hyperpolarization of 45% of the ARHkisspeptin neurons (n= 9 of 20 cells, out of 9 mice). ARHkisspeptin neuron’s RMP hyperpolarization was followed by a significant decrease in IR and frequency of action potentials (fAPS). In the AVPV/PeNkisspeptin neurons showed RMP average of -69.6±1.9 mV (-51 to - 88 mV) and IR of 0.8±0.09 GΩ (n=18 cells out of 9 mice). No significant NPY-induced effect was noted when recordings were performed on AVPV/PeNkisspeptin cells from female mice. To elucidate if the ARHkisspeptin neuron’s hyperpolarization depends on action potentials (APs) mediated by synaptic transmission we further evaluated NPY effects in the presence of TTX and amino acid receptor antagonists (6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, 10μM), DL-2-amino-5-phosphonopentanoic acid (AP5, 50μM), and picrotoxin (50μM). NPY induced no effect on ARHkisspeptin neuron’s RMP, and IR in the presence of TTX and amino acid receptor antagonists. Suggesting that NPY-induced hyperpolarization of ARHkisspeptin neurons is an indirect effect. To further verify whether sex must be considered as a biological variable to study the NPY effect, we recorded ARHkisspeptin cells from male mice. ARHkisspeptin neurons recorded from male mice exhibited RPM average of -55.6±1.5 (-45 to -66 mV) and IR of 1.5±0.15 GΩ (n= 13 cells out of 10 mice). Interestingly, NPY induced no effect on RMP, IR, or fAPs in male animals. In conclusion, our results suggest that NPY-induced hyperpolarization of ARHkisspeptin cells depends on AP’s mediate synaptic transmission, as a sex-specific effect. Presentation: Saturday, June 17, 2023

Salts of short-chain fatty acids increase the activity of the large conductance, Ca<sup>2+</sup>-activated K<sup>+</sup> channels and reduce calcium oscillations in rat GH3 cells

The short-chain fatty acids such as acetic, propionic and butyric acids are microbiota metabolites that can exert a series of physiological effects both in the intestine and other organs, including the central nervous system. The present work aimed to examine the effects of sodium acetate, propionate, and butyrate on the activity of large conductance Ca2+ activated K+ channels and calcium oscillations in rat pituitary GH3 cells. It has been shown that fatty acids under study cause a dose-dependent increase in the amplitude of total outward potassium currents and these effects are prevented by tetraethylammonium, a Ca2+ activated K+ channel blocker, indicating the involvement of Ca2+ activated K+ channels in the effects of fatty acids. It is worthy of note that fatty acids increased open probability of single channels with no changes in the amplitude and the mean channel open time. In addition, fatty acids were associated with a significant reduction in the amplitude and frequency of Ca2+ oscillations in GH3 cells. An increase in potassium conductance and a decrease in the intracellular Ca2+ level can mediate the effects of short-chain fatty acids in various excitable structures, such as a relaxation of intestinal and vascular smooth muscle cells, hyperpolarization of neurons, and the regulation of hormone and neurotransmitter release.

A proton-inhibited DEG/ENaC ion channel maintains neuronal ionstasis and promotes neuronal survival under stress

The nervous system participates in the initiation and modulation of systemic stress. Ionstasis is of utmost importance for neuronal function. Imbalance in neuronal sodium homeostasis is associated with pathologies of the nervous system. However, the effects of stress on neuronal Na+ homeostasis, excitability, and survival remain unclear. We report that the DEG/ENaC family member DEL-4 assembles into a proton-inactivated sodium channel. DEL-4 operates at the neuronal membrane and synapse to modulate Caenorhabditis elegans locomotion. Heat stress and starvation alter DEL-4 expression, which in turn alters the expression and activity of key stress-response transcription factors and triggers appropriate motor adaptations. Similar to heat stress and starvation, DEL-4 deficiency causes hyperpolarization of dopaminergic neurons and affects neurotransmission. Using humanized models of neurodegenerative diseases in C.elegans, we showed that DEL-4 promotes neuronal survival. Our findings provide insights into the molecular mechanisms by which sodium channels promote neuronal function and adaptation under stress.

Comparison of intrathecal dexmedetomidine and intrathecal fentanyl as an adjuvant to bupivacaine during spinal anaesthesia for lower limb orthopedic surgery

Background: In this study, we have compared the addition of fentanyl 25 mcg and dexmedetomidine 5 mcg to 15 mg of 0.5% hyperbaric bupivacaine for spinal anesthesia separately for patient undergoing lower limb orthopedic surgery. Dexmedetomidine is an α-2 adrenoreceptor agonist and it can prolong the motor and sensory block for long spinal anesthesia. It act by binding to presynaptic C-fiber and postsynaptic dorsal horn neurons. The analgesic action is a result of depression of release of C-fiber transmitters and hyperpolarization of postsynaptic dorsal horn neurons. Aims and Objectives: The present study compares the onset, duration of sensory and motor block, postoperative analgesia, hemodynamic changes, and adverse effects of intrathecal dexmedetomidine and intrathecal fentanyl as an adjuvant to bupivacaine during spinal anesthesia for lower limb orthopedic surgery. Materials and Methods: Patient was randomly grouped by close-envelope technique into the three equal group of 30 in each group. Total 90 patients were including in this study. The blind nature of the study was maintained and the study drug is given according as, Group-1: 15 mg of 0.5% hyperbaric bupivacaine. (Control group), Group-2: 15 mg of 0.5% hyperbaric bupivacaine with 25 mcg of fentanyl, and Group-3: 15 mg of 0.5% hyperbaric bupivacaine with 5 mcg dexmedetomidine for spinal anesthesia. Results: Patients in dexmedetomidine Group-3 had a significantly longer sensory (160±18.5 min) and motor block (242±22 min) time as compared to patients in fentanyl and control group (P<0.001). The time to first request of analgesic in the post-operative period was also longer in dexmedetomidine group (245±3.6 min) when compared to bupivacaine and fentanyl in which it was 125±1.0 min and 220±2.5 min, respectively (P<0.001). Conclusion: We concluded that intrathecal dexmedetomidine with bupivacaine for spinal anesthesia is associated with prolong motor and sensory block then fentanyl 25 μg with bupivacaine and bupivacaine alone.

IL-10/β-Endorphin-Mediated Neuroimmune Modulation on Microglia during Antinociception.

Microglia are glial cells centrally related to pathophysiology and neuroimmunological regulation of pain through microglia-neuron crosstalk mechanisms. In contrast, anti-inflammatory mechanisms guided by immunological effectors such as IL-10 trigger the secretion of analgesic substances, culminating in the differential expression of genes encoding endogenous opioid peptides, especially β-endorphin. Thus, when β-endorphin binds to the µ-opioid receptor, it generates neuronal hyperpolarization, inhibiting nociceptive stimuli. This review aimed to summarize the recent advances in understanding the mechanism by which IL-10/β-endorphin can reduce pain. For this, databases were searched for articles from their inception up until November 2022. Two independent reviewers extracted the data and assessed the methodological quality of the included studies, and seventeen studies were considered eligible for this review. Several studies have demonstrated the impact of IL-10/β-endorphin in reducing pain, where IL-10 can stimulate GLP-1R, GRP40, and α7nAChR receptors, as well as intracellular signaling pathways, such as STAT3, resulting in increased β-endorphin expression and secretion. In addition, molecules such as gabapentinoids, thalidomide, cynandione A, morroniside, lemairamin, and cinobufagin, as well as non-pharmacological treatments such as electroacupuncture, reduce pain through IL-10 mediated mechanisms, reflecting a microglia-dependent β-endorphin differential increase. This process represents a cornerstone in pain neuroimmunology knowledge, and the results obtained by different studies about the theme are presented in this review.

A thalamic-primary auditory cortex circuit mediates resilience to stress

Resilience enables mental elasticity in individuals when rebounding from adversity. In this study, we identified a microcircuit and relevant molecular adaptations that play a role in natural resilience. We found that activation of parvalbumin (PV) interneurons in the primary auditory cortex (A1) by thalamic inputs from the ipsilateral medial geniculate body (MG) is essential for resilience in mice exposed to chronic social defeat stress. Early attacks during chronic social defeat stress induced short-term hyperpolarizations of MG neurons projecting to the A1 (MGA1 neurons) in resilient mice. In addition, this temporal neural plasticity of MGA1 neurons initiated synaptogenesis onto thalamic PV neurons via presynaptic BDNF-TrkB signaling in subsequent stress responses. Moreover, optogenetic mimicking of the short-term hyperpolarization of MGA1 neurons, rather than merely activating MGA1 neurons, elicited innate resilience mechanisms in response to stress and achieved sustained antidepressant-like effects in multiple animal models, representing a new strategy for targeted neuromodulation.

Barbiturates and pyrazolopyridines for the treatment of postpartum depression-repurposing of two drug classes.

Zulresso (brexanolone) is an aqueous formulation of the neurosteroid, allopregnanolone, and the only FDA-approved medication for the treatment of postpartum depression (PPD). While brexanolone is effective for the treatment of PPD, lengthy infusion time and high cost can be prohibitive. Failure of GABAA receptors to adapt to fluctuating neurosteroid levels is considered to predispose women to mood disorders in the postpartum period. Brexanolone is thought to act via stimulation of δ subunit-containing GABAA receptors, which are extrasynaptic and localized to particular brain regions. Neurosteroid stimulation of δ subunit-containing GABAA receptors leads to sustained inhibition (hyperpolarization) of GABAergic neurons, which makes δ subunit-containing GABAA receptors a potentially important pharmacologic target. Barbiturates and pyrazolopyridines are potent stimulators of δ subunit-containing GABAA receptors and therefore potentially cost-effective treatments for PPD. Barbiturates are often not prescribed, owing to risk of dependence and respiratory depression. The pyrazolopyridines were tested several decades ago for anxiety and depression but never developed commercially. Herein we use the FDA-approved dosing schedule of brexanolone and GABAA receptor binding data from various animal models to examine the safety, efficacy, and potential clinical utility of barbiturates and pyrazolopyridines for the treatment of PPD. We suggest consideration of repurposing barbiturates and pyrazolopyridines as safe and readily available treatment alternatives for PPD.

Activation of GABAB receptors in central amygdala attenuates activity of PKCδ + neurons and suppresses punishment-resistant alcohol self-administration in rats

Alcohol use despite negative consequences is a core phenomenon of alcohol addiction. We recently used alcohol self-administration that is resistant to footshock punishment as a model of this behavior, and found that activity of PKCδ + GABAergic neurons in the central amygdala (CeA) is a determinant of individual susceptibility for punishment resistance. In the present study, we examined whether activation of GABAB receptors in CeA can attenuate the activity of PKCδ + neurons in this region, and whether this will result in suppression of punishment- resistant alcohol self-administration in the minority of rats that show this behavior. Systemic administration of the clinically approved GABAB agonist baclofen (1 and 3 mg/kg) dose- dependently reduced punishment-resistant alcohol self-administration. Bilateral microinjections of baclofen into CeA (64 ng in 0.3 µl/side) reduced the activity of PKCδ + neurons, as measured by Fos expression. This manipulation also selectively suppressed punished alcohol self-administration in punishment-resistant rats. Expression analysis indicated that virtually all CeA PKCδ + neurons express the GABAB receptor. Using in vitro electrophysiology, we found that baclofen induced hyperpolarization of CeA neurons, reducing their firing rate in response to depolarizing current injections. Together, our findings provide a potential mechanism that contributes to the clinical efficacy of baclofen in alcohol addiction. Therapeutic use of baclofen itself is limited by problems of tolerance and need for dose escalation. Our findings support a mechanistic rationale for developing novel, improved alcohol addiction medications that target GABAB receptors, and that lack these limitations, such as e.g., GABAB positive allosteric modulators (PAM:s).