Endogenous Modulator Research Articles

Exploratory rearing is governed by hypothalamic MCH neurons according to locus coeruleus.

Information seeking, such as standing on tiptoes to look around in humans, is observed across animals and helps survival. Its rodent analog - unsupported rearing on hind legs - was a classic model in deciphering neural signals of cognition, and is of intense renewed interest in preclinical modeling of neuropsychiatric states. Neural signals and circuits controlling this dedicated decision to seek information remain largely unknown. While studying sub-second timing of spontaneous behavioral acts and activity of MCH neurons (MNs) in behaving male and female mice, we observed large MN activity spikes that aligned to unsupported rears. Complementary causal, loss and gain of function, analyses revealed specific control of rear frequency and duration by MNs and MCHR1 receptors. Activity in a key stress center of the brain - the locus coeruleus noradrenaline cells - rapidly inhibited MNs, and required functional MCH receptors for its endogenous modulation of rearing. By defining a neural module that both tracks and controls rearing, these findings may facilitate further insights into biology of information seeking.Significance Statement Animals, including humans, use movement to interact with their environment - to reach specific targets or gain information, as when standing tall and looking around. Information-seeking is a fundamental behavior related to cognition and neuropsychiatric states. However, the neural circuits underlying it are still unclear. We show that hypothalamic neurons make melanin-concentrating hormone ("MN") are active during a well-known rodent analog of information-seeking - rearing on hind limbs - and contribute to driving these acts of rearing. We also find that locus coeruleus noradrenergic neurons, known for mediating stress responses, inhibit MNs, thus providing a neural link between stress and information-seeking. These results identify a neural substrate of information-seeking, and provide insights into how the brain toggles between conflicting, survival-critical priorities.

The mediating role of pain cognitions and pain sensitivity in the treatment effect of perioperative pain neuroscience education in people undergoing surgery for lumbar radiculopathy

Though perioperative pain neuroscience education (PPNE) positively influences patients’ surgical outcomes, little is known about the mechanisms behind this treatment’s success. Therefore, this study aims to evaluate the potential mediating role of pain cognitions and pain sensitivity in the treatment effect of PPNE on postoperative quality of life in people undergoing surgery for lumbar radiculopathy. This secondary analysis uses data from 120 participants of a randomized controlled trial who were randomized to receive either PPNE or perioperative biomedical education before undergoing surgery for lumbar radiculopathy. Quality of life was assessed 1 year post-surgery using the Short Form 36-item Health Survey physical (SF36-PC) and mental (SF36-MC) component scores. Potential mediators included pain cognitions (i.e., kinesiophobia, pain catastrophizing, and hypervigilance) and pain sensitivity (i.e., endogenous nociceptive modulation), assessed 6 weeks post-surgery. Mediation models were constructed using structural equation modeling, and 95% confidence intervals (CIs) were calculated using 10,000 bootstrap samples. Analyses show a significant total effect for PPNE (estimate=0.464, 95% CI [0.105, 0.825]) and a significant indirect effect via pain catastrophizing on the SF36-PC (estimate=0.124, 95%CI [0.001, 0.293]). No mediating effect was found through the remaining pain cognitions or pain sensitivity measures. Also, no potential mediators were identified for the treatment effect of PPNE on the SF36-MC. Our findings suggest that pain catastrophizing mediates the treatment effect of PPNE on physical health-related quality of life in people undergoing surgery for lumbar radiculopathy. PERSPECTIVEThis secondary analysis identified pain catastrophizing as a mediator for perioperative pain neuroscience education in people undergoing surgery for lumbar radiculopathy. More so, its findings indicate that this educational intervention can enhance the postoperative physical health-related quality of life of these patients by addressing their catastrophizing thoughts.

Characterization of individual bile acids in vivo utilizing a novel low bile acid mouse model.

Bile acids (BAs) are signaling molecules synthesized in the liver initially by CYP7A1 and CYP27A1 in the classical and alternative pathways, respectively. BAs are essential for cholesterol clearance, intestinal absorption of lipids, and endogenous modulators of farnesoid x receptor (FXR). FXR is critical in maintaining BA homeostasis and gut-liver crosstalk. Complex reactions in vivo and the lack of suitable animal models impede our understanding of the functions of individual BAs. In this study, we characterized the in vivo effects of three-day feeding of cholic acid (CA), deoxycholic acid (DCA), or ursodeoxycholic acid (UDCA) at physiological/non-hepatotoxic concentrations in a novel low-BA mouse model (Cyp7a1 -/-/Cyp27a1 -/-, DKO). Liver injury, BA levels and composition and BA signaling by the FXR-fibroblast growth factor 15 (FGF15) axis were determined. Overall, higher basal inflammation and altered lipid metabolism in DKO mice might be associated with low BAs. CA, DCA and UDCA feeding activated FXR signals with tissue specificity. Dietary CA and DCA similarly altered tissue BA profiles to be less hydrophobic, while UDCA promoted a more hydrophobic tissue BA pool with the profiles shifted towards non-12α-OH BAs and secondary BAs. However, UDCA did not offer any overt protective effects as expected. These findings allow us to determine the precise effects of individual BAs in vivo on BA-FXR signaling and overall BA homeostasis in liver physiology and pathologies.

Impact of endogenous analgesia triggered by acupuncture, stress, or noxious stimulation on REM sleep-deprived rats.

Poor sleep increases pain, at least in part, by disrupting endogenous pain modulation. However, the efficacy of endogenous analgesia in sleep-deprived subjects has never been tested. To assess this issue, we chose three different ways of triggering endogenous analgesia: (1) acupuncture, (2) acute stress, and (3) noxious stimulation, and compared their ability to decrease the pronociceptive effect induced by REM-SD (Rapid Eye Movement Sleep Deprivation) with that to decrease inflammatory hyperalgesia in the classical carrageenan model. First, we tested the ability of REM-SD to worsen carrageenan-induced hyperalgesia: Alow dose of carrageenan (30 µg) in sleep-deprived Wistar rats resulted in a potentiated hyperalgesic effectthat was more intense and longer-lasting than that induced by a higher standard dose of carrageenan (100 µg) or by REM-SD alone. Then, we found that (1) acupuncture, performed at ST36, completely reversed the pronociceptive effect induced by REM-SD or by carrageenan; (2) immobilization stress completely reversed the pronociceptive effect of REM-SD, while transiently inhibited carrageenan-induced hyperalgesia; (3) noxious stimulation of the forepaw by capsaicin also reversed the pronociceptive effect of REM-SD and persistently increased the nociceptive threshold above the baseline in carrageenan-treated animals. Therefore, acupuncture, stress, or noxious stimulation reversed the pronociceptive effect of REM-SD, while each intervention affected carrageenan-induced hyperalgesia differently. This study has shown that while sleep loss may disrupt endogenous pain modulation mechanisms, it does not prevent theactivation of these mechanisms to induce analgesia in sleep-deprived individuals.

Postweaning Development Influences Endogenous VPAC1 Modulation of LTP Induced by Theta-Burst Stimulation: A Link to Maturation of the Hippocampal GABAergic System.

Long-term potentiation (LTP) induced by theta-burst stimulation (TBS) undergoes postweaning developmental changes partially linked to GABAergic circuit maturation. Endogenous vasoactive intestinal peptide (VIP) acting on its VPAC1 receptor strongly influences LTP induced by theta-burst stimulation (TBS), an effect dependent on GABAergic transmission. Although VPAC1 receptor levels are developmentally regulated during embryogenesis, their variation along postweaning development is unknown, as is the VPAC1 modulation of LTP or its relation to hippocampal GABAergic circuit maturation. As such, we investigated how VPAC1 modulation of LTP adjusts from weaning to adulthood along with GABAergic circuit maturation. As described, LTP induced by mild TBS (5 bursts, 4 pulses delivered at 100 Hz) was increasingly greater from weaning to adulthood. The influence of the VPAC1 receptor antagonist PG 97-269 (100 nM) on TBS-induced LTP was much larger in juvenile (3-week-old) than in young adult (6-7-week-old) or adult (12-week-old) rats. This effect was not associated with a developmental decrease in synaptic VPAC1 receptor levels. However, an increase in pre and post-synaptic GABAergic synaptic markers suggests an increase in the number of GABAergic synaptic contacts that is more prominent than the one observed in glutamatergic connections during this period. Conversely, endogenous VPAC2 receptor activation did not significantly influence TBS-induced LTP. VPAC2 receptor levels enhance pronouncedly during postweaning development, but not at synaptic sites. Given the involvement of VIP interneurons in several aspects of hippocampal-dependent learning, neurodevelopmental disorders, and epilepsy, this could provide important insights into the role of VIP modulation of hippocampal synaptic plasticity during normal and altered brain development potentially contributing to epileptogenesis.

Mild Traumatic Brain Injury-Induced Augmented Postsurgical Pain Is Driven by Central Serotonergic Pain-Facilitatory Signaling.

Individuals recovering from mild traumatic brain injury (mTBI) have increased rates of acute and chronic pain. However, the mechanism through which mTBI triggers heightened pain responses and the link between mTBI and postsurgical pain remain elusive. Recent data suggest that dysregulated serotonergic pain-modulating circuits could be involved. We hypothesized that mTBI triggers dysfunction in descending serotonergic pain modulation, which exacerbates acute pain and delays pain-related recovery after surgery. Using mouse models of mTBI and hindpaw incision for postsurgical pain in C57BL/6J mice, mechanical withdrawal thresholds were assessed throughout the postsurgical period. To determine whether mTBI leads to persistent alteration of endogenous opioid tone, mu-opioid receptors (MORs) were blocked with naloxone. Finally, the role of descending serotonergic signaling on postsurgical allodynia in animals with mTBI was examined using ondansetron (5-HT 3 receptor antagonist) or a serotonin-specific neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), to ablate descending serotonergic fibers. The treatment effects on withdrawal thresholds were normalized to baseline (percentage of maximum possible effect, MPE%), and analyzed using paired t -test or 2-way repeated-measures ANOVA with post hoc multiple comparisons. Post-mTBI mice demonstrated transient allodynia in hindpaws contralateral to mTBI, while no nociceptive changes were observed in sham-mTBI animals (mean difference, MD, MPE%, post-mTBI day 3: -60.9; 95% CI, -88.7 to -35.0; P < .001). After hindpaw incision, animals without mTBI exhibited transient allodynia, while mice with prior mTBI demonstrated prolonged postsurgical allodynia (MD-MPE% postsurgical day 14: -65.0; 95% CI, -125.4 to -4.5; P = .04). Blockade of MORs using naloxone transiently reinstated allodynia in mTBI animals but not in sham-mTBI mice (MD-MPE% post-naloxone: -69.9; 95% CI, -94.8 to -45.1; P < .001). Intrathecal administration of ondansetron reversed the allodynia observed post-mTBI and postincision in mTBI mice (compared to vehicle-treated mTBI mice, MD-MPE% post-mTBI day 3: 82.7; 95% CI, 58.5-106.9; P < .001; postsurgical day 17: 62.5; 95% CI, 38.3-86.7; P < .001). Both the acute allodynia after TBI and the period of prolonged allodynia after incision in mTBI mice were blocked by pretreatment with 5,7-DHT (compared to sham-mTBI mice, MD-MPE% post-mTBI day 3: 0.5; 95% CI, -18.5 to 19.5; P = .99; postsurgical day 14: -14.6; 95% CI, -16.7 to 45.9; P = .48). Similar behavioral patterns were observed in hindpaw ipsilateral to mTBI. Collectively, our results show that descending serotoninergic pain-facilitating signaling is responsible for nociceptive sensitization after mTBI and that central endogenous opioid tone opposes serotonin's effects. Understanding brain injury-related changes in endogenous pain modulation may lead to improved pain control for those with TBI undergoing surgery.

Pain exacerbation following physical activity in adults with diabetic neuropathy: Ecological momentary assessment of foot symptoms.

People with diabetic peripheral neuropathy (DPN) report fluctuating foot symptoms. This study used ecological momentary assessment to: (1) compare foot symptoms between days, time points and periods with/without preceding physical activity or pain medication; and (2) determine relationships between symptoms and endogenous pain modulation. Ten low-active Australian adults with probable DPN underwent temporal summation of pain (TSP) and conditioned pain modulation (CPM) then completed mobile phone surveys five times daily for seven days, where they recorded the intensity of six foot symptoms and whether they performed physical activity or consumed pain medication in the preceding three hours. RESULTS: All foot symptoms except numbness were greater in periods following physical activity, whereas periods following pain medication showed greater shooting pain. TSP showed very large correlations with sensitivity to touch, burning pain, shooting pain and prickling/tingling. DISCUSSION: General practitioners should be aware that physical activity might exacerbate symptoms of DPN when encouraging their patients to be active.

Preliminary characterization of age and chronic low back pain effects on multimodal pain sensitivity: a comparison study in older adults with and without chronic low back pain

Though pain sensitivity impairments contribute to chronic pain in younger adults, it is unclear if pain hypersensitivity manifests with aging and is heightened in the geriatric chronic low back pain (CLBP) population. The cross-sectional study preliminarily addressed this gap by measuring pain sensitivity in older adults with CLBP (n=25) as well as pain-free sex-matched older (n=25) and younger adults (n=25). Pain sensitivity was quantified by 8 distinct measures that were subdivided as static (i.e., pressure pain thresholds, heat pain thresholds, fixed mechanical pain, and fixed cold pain) and dynamic pain sensitivity (i.e., mechanical temporal summation, thermal ramp and hold, heat pain aftersensations, and conditioned pain modulation). Test-retest reliability values for pain sensitivity ranged from moderate to excellent (ICCs≥0.500; p’s<0.05). The main effect for group was significant (partial η2 =.413, p<0.001), revealing between-group differences in pain sensitivity on 5 out of 8 tests (p’s≤0.043). Predominantly, both older adult groups demonstrated increased pain facilitation and decreased pain inhibition during dynamic pain sensitivity testing compared to pain-free younger adults (p’s≤0.044). Despite qualitative differences, static and dynamic pain sensitivity responses were statistically similar between older adults with and without chronic LBP (p’s>0.05). Findings suggest pain sensitivity can be reliably measured in older adults and that pain hypersensitivity develops with chronological aging, providing partial support for the theory that pain hypersensitivity may impact geriatric chronic pain populations. Further study is needed to more definitively parse out whether pain hypersensitivity is comparatively heightened in older adults with chronic LBP beyond the influence of chronological aging. PerspectiveThis article establishes that surrogate measures of centrally mediated pain sensitization are heightened with aging. Impaired endogenous pain modulation may influence chronic pain development, maintenance, treatment efficacy, and/or ensuing disability, necessitating research to comprehensively characterize how pain hypersensitivity contributes to geriatric chronic pain conditions.

Milestone review: GABA, from chemistry, conformations, ionotropic receptors, modulators, epilepsy, flavonoids, and stress to neuro-nutraceuticals.

Arising out of a PhD project more than 50 years ago to synthesise analogues of the neurotransmitter GABA, a series of new chemical entities were found to have selective actions on ionotropic GABA receptors. Several of these neurochemicals are now commercially available. A new subtype of these receptors was discovered that could be a target for the treatment of myopia, the facilitation of learning and memory, and the improvement of post-stroke motor recovery. The development of these new chemical entities over many years demonstrates the importance of neurochemicals with which to investigate selective aspects of GABA receptors and illustrates the significance of collaboration between chemists and biologists in neurochemistry. Vital were the improvements in synthetic organic chemistry and the use of functional human receptors expressed in oocytes. Current interest in ionotropic GABA receptors includes the clinical development of subtype-specific agents and the role of gain-of-function receptor variants in epilepsy. Dietary flavonoids were found to cross the blood-brain barrier to influence brain function. Natural and synthetic flavonoids had a range of effects on GABA receptors, ranging from positive, silent, and negative allosteric modulators, to even second-order modulation of first-order modulators. Flavonoids have been called "a new family of benzodiazepines." Like benzodiazepines, flavonoids reduce stress. Stress produces changes in GABA receptors in the brain that may be because of changes in endogenous modulators, such as neurosteroids and corticosteroids. GABA also occurs naturally in the diet leading to studies of the effects of oral GABA on brain function. This finding has resulted in studies of GABA and related neurochemicals as neuro-nutraceuticals. GABA systems in the gut microbiome are essential to such studies. The actions of oral GABA and of GABA-enriched beverages and foodstuffs are now an area of considerable scientific and commercial interest. GABA is a deceptively simple chemical that can take up many shapes, which may underlie its complex functions. The need for new chemical entities with selective actions for further studies highlights the need for continuing collaboration between chemists and biologists.

TR(i)P Goes On: Auxiliary TRP Channel Subunits?

Transient receptor potential (TRP) cation channels are a diverse family of channels whose members play prominent roles as cellular sensors and effectors. The important role of TRP channels (and mechanosensitive piezo channels) in the complex interaction of our senses with the environment was underlined by the award of the Nobel Prize in Physiology or Medicine to 2 pioneers in this field, David Julius and Ardem Patapoutian. There are many competent and comprehensive reviews on many aspects of the TRP channels, and there is no intention to expand on them. Rather, after an introduction to the nomenclature, the molecular architecture of native TRP channel/protein complexes in vivo will be summarized using TRP channels of the canonical transient receptor potential subfamily as an example. This molecular architecture provides the basis for the signatures of native canonical transient receptor potential currents and their control by endogenous modulators and potential drugs.

A novel composition of endogenous metabolic modulators improves red blood cell properties in sickle cell disease.

The most common forms of sickle cell disease (SCD) are sickle cell anemia (SCA; HbSS) and HbSC disease. In both, especially the more dense, dehydrated and adherent red blood cells (RBCs) with reduced deformability are prone to hemolysis and sickling, and thereby vaso-occlusion. Based on plasma amino acid profiling in SCD, a composition of 10 amino acids and derivatives (RCitNacQCarLKHVS; Axcella Therapeutics, USA), referred to as endogenous metabolic modulators (EMMs), was designed to target RBC metabolism. The effects of ex vivo treatment with the EMM composition on different RBC properties were studied in SCD (n=9 SCA, n=5 HbSC disease). Dose-dependent improvements were observed in RBC hydration assessed by hemocytometry (MCV, MCHC, dense RBCs) and osmotic gradient ektacytometry (Ohyper). Median (interquartile range [IQR]) increase in Ohyper compared to vehicle was 4.9% (4.0%-5.5%), 7.5% (6.9%-9.4%), and 12.8% (11.5%-14.0%) with increasing 20×, 40×, and 80X concentrations, respectively (all p<0.0001). RBC deformability (EImax using oxygen gradient ektacytometry) increased by 8.1% (2.2%-12.1%; p=0.0012), 9.6% (2.9%-15.1%; p=0.0013), and 13.3% (5.7%-25.5%; p=0.0007), respectively. Besides, RBC adhesion to subendothelial laminin decreased by 43% (6%-68%; p=0.4324), 58% (48%-72%; p=0.0185), and 71% (49%-82%; p=0.0016), respectively. Together, these results provide a rationale for further studies with the EMM composition targeting multiple RBC properties in SCD.

Physical activity and endogenous pain modulation in older people: a scoping review protocol.

This scoping review aims to provide an overview of the existing literature on physical activity and endogenous pain modulation (EPM), assessed using conditioned pain modulation (CPM), with a specific focus on older people with chronic pain. Approximately 20% of the European population reports chronic pain, highlighting the problem of chronic pain in the general population. This prevalence increases to 50% in older people. Physical activity is one of the most frequently used treatments for pain management and relief. A possible mechanism underlying the positive effects of physical activity on pain may be related to its influence on EPM. The review will map i) types of physical activity used to study its effect on EPM in older people; ii) intervention protocols investigating physical activity and EPM, measured using CPM, in older people experiencing pain; and iii) knowledge gaps requiring further research or interventions adapted to older people with pain. This review will consider studies of people aged 60 years or older, using CPM to examine the effect of physical activity on EPM. All types of care settings will be eligible. This review will be conducted in accordance with the JBI methodology for scoping reviews. The following databases will be searched: MEDLINE (Ovid), CINAHL (EBSCOhost), Embase, Cochrane Library, Web of Science, JBI Evidence Synthesis , PsycINFO, and PEDro. Open Science Framework https://osf.io/e7ndy/.

Lack of Annexin A1 Exacerbates Inflammatory Response in Acute Endometritis Model.

Annexin A1 (AnxA1) is a glucocorticoid-inducible protein and an important endogenous modulator of inflammation. However, its effect in the endometrial microenvironment is poorly explained. This study aimed to evaluate the role of endogenous AnxA1 in an endometritis mouse model induced by lipopolysaccharide (LPS). Female C57BL/6 wild-type (WT) and AnxA1-/- mice were divided into two groups: SHAM and LPS. To induce endometritis, mice received a vaginal infusion of 50 μL of LPS (1 mg/mL) dissolved in phosphate-buffered saline. After 24 h, the mice were euthanized, and blood and uteri samples were collected. The endometrium inflammatory scores were significantly increased in the LPS-treated group. AnxA1-/- mice from the LPS group demonstrated a significant increase in the number of degranulated mast cell levels compared to AnxA1-/- SHAM mice. The Western blotting analysis revealed that a lack of AnxA1 promoted the upregulation of NLRP3 and pro-IL-1β in the acute endometritis animal model compared to WT LPS animals. LPS-induced endometritis increased the number of blood peripheral leukocytes in both WT and AnxA1-/- mice compared with SHAM group mice (p < 0.001). AnxA1-/- mice also showed increased plasma levels of IL-1β (p < 0.01), IL-6, IL-10, IL-17, and TNF-α (p < 0.05) following LPS-induced endometritis. In conclusion, a lack of endogenous AnxA1 exacerbated the inflammatory response in an endometritis model via NLRP3 dysregulation, increased uterine mast cell activation, and plasma pro-inflammatory cytokine release.

Leveraging Endogenous Pain Modulation for Analgesia.

Leveraging Endogenous Pain Modulation for Analgesia.

Role of Natural Compounds Modulating Heme Catabolic Pathway in Gut, Liver, Cardiovascular, and Brain Diseases.

The crucial physiological process of heme breakdown yields biliverdin (BV) and bilirubin (BR) as byproducts. BV, BR, and the enzymes involved in their production (the "yellow players-YP") are increasingly documented as endogenous modulators of human health. Mildly elevated serum bilirubin concentration has been correlated with a reduced risk of multiple chronic pro-oxidant and pro-inflammatory diseases, especially in the elderly. BR and BV per se have been demonstrated to protect against neurodegenerative diseases, in which heme oxygenase (HMOX), the main enzyme in the production of pigments, is almost always altered. HMOX upregulation has been interpreted as a tentative defense against the ongoing pathologic mechanisms. With the demonstration that multiple cells possess YP, their propensity to be modulated, and their broad spectrum of activity on multiple signaling pathways, the YP have assumed the role of an adjustable system that can promote health in adults. Based on that, there is an ongoing effort to induce their activity as a therapeutic option, and natural compounds are an attractive alternative to the goal, possibly requiring only minimal changes in the life style. We review the most recent evidence of the potential of natural compounds in targeting the YP in the context of the most common pathologic condition of adult and elderly life.

Induced synchronization by endogenous noise modulation in finite-size random neural networks: A stochastic mean-field study.

Event-related synchronization and desynchronization (ERS/ERD) are well-known features found experimentally in brain signals during cognitive tasks. Their understanding promises to have much better insights into neural information processes in cognition. Under the hypothesis that neural information affects the endogenous neural noise level in populations, we propose to employ a stochastic mean-field model to explain ERS/ERD in the γ-frequency range. The work extends previous mean-field studies by deriving novel effects from finite network size. Moreover, numerical simulations of ERS/ERD and their analytical explanation by the mean-field model suggest several endogenous noise modulation schemes, which may modulate the system's synchronization.

Structural mapping of patient-associated KCNMA1 gene variants

KCNMA1-linked channelopathy is a neurological disorder characterized by seizures, motor abnormalities, and neurodevelopmental disabilities. The disease mechanisms are predicted to result from alterations in KCNMA1-encoded BK K+ channel activity; however, only a subset of the patient-associated variants have been functionally studied. The localization of these variants within the tertiary structure or evaluation by pathogenicity algorithms has not been systematically assessed. In this study, 82 nonsynonymous patient-associated KCNMA1 variants were mapped within the BK channel protein. Fifty-three variants localized within cryoelectron microscopy-resolved structures, including 21 classified as either gain of function (GOF) or loss of function (LOF) in BK channel activity. Clusters of LOF variants were identified in the pore, the AC region (RCK1), and near the Ca2+ bowl (RCK2), overlapping with sites of pharmacological or endogenous modulation. However, no clustering was found for GOF variants. To further understand variants of uncertain significance (VUSs), assessments by multiple standard pathogenicity algorithms were compared, and new thresholds for sensitivity and specificity were established from confirmed GOF and LOF variants. An ensemble algorithm was constructed (KCNMA1 meta score (KMS)), consisting of a weighted summation of this trained dataset combined with a structural component derived from the Ca2+-bound and unbound BK channels. KMS assessment differed from the highest-performing individual algorithm (REVEL) at 10 VUS residues, and a subset were studied further by electrophysiology in HEK293 cells. M578T, E656A, and D965V (KMS+;REVEL–) were confirmed to alter BK channel properties in voltage-clamp recordings, and D800Y (KMS–;REVEL+) was assessed as benign under the test conditions. However, KMS failed to accurately assess K457E. These combined results reveal the distribution of potentially disease-causing KCNMA1 variants within BK channel functional domains and pathogenicity evaluation for VUSs, suggesting strategies for improving channel-level predictions in future studies by building on ensemble algorithms such as KMS.

Towards understanding human–environment feedback loops: the Atacama Desert case

The overall trajectory for the human–environment interaction has been punctuated by demographic boom-and-bust cycles, phases of growth/overshooting as well as of expansion/contraction in productivity. Although this pattern has been explained in terms of an interplay between population growth, social upscaling, ecosystem engineering and climate variability, the evoked demographic–resource-complexity mechanisms have not been empirically tested. By integrating proxy data for population sizes, palaeoclimate and internal societal factors into empirical modelling approaches from the population dynamic theory, we evaluated how endogenous (population sizes, warfare and social upscaling) and exogenous (climate) variables module the dynamic in past agrarian societies. We focused on the inland Atacama Desert, where populations developed agriculture activities by engineering arid and semi-arid landscapes during the last 2000 years. Our modelling approach indicates that these populations experienced a boom-and-bust dynamic over the last millennia, which was coupled to structure feedback between population sizes, hydroclimate, social upscaling, warfare and ecosystem engineering. Thus, the human–environment loop appears closely linked with cooperation, competition, limiting resources and the ability of problem-solving. This article is part of the theme issue ‘Evolution and sustainability: gathering the strands for an Anthropocene synthesis’.

Repetitive Transcranial Magnetic Stimulation of the Human Motor Cortex Modulates Processing of Heat Pain Sensation as Assessed by the Offset Analgesia Paradigm.

Offset analgesia (OA), which is defined as a disproportionately large reduction in pain perception following a small decrease in a heat stimulus, quantifies temporal aspects of endogenous pain modulation. In this study on healthy subjects, we aimed to (i) determine the Heat Pain Threshold (HPT) and the response to constant and dynamic heat stimuli assessing sensitization, adaptation and OA phenomena at the thenar eminence; (ii) evaluate the effects of high-frequency repetitive Transcranial Magnetic Stimulation (rTMS) of the primary motor cortex (M1) on these measures. Twenty-four healthy subjects underwent quantitative sensory testing before and after active or sham 10 Hz rTMS (1200 stimuli) of the left M1, during separate sessions. We did not observe any rTMS-related changes in the HPT or visual analogue scale (VAS) values recorded during the constant trial. Of note, at baseline, we did not find OA at the thenar eminence. Only after active rTMS did we detect significantly reduced VAS values during dynamic heat stimuli, indicating a delayed and attenuated OA phenomenon. rTMS of the left M1 may activate remote brain areas that belong to the descending pain modulatory and reward systems involved in the OA phenomenon. Our findings provide insights into the mechanisms by which rTMS of M1 could exert its analgesic effects.

Ендогенна та екзогенна нейростероїдна модуляція пам’яті щурів з алкогольною залежністю та агресивним типом поведінки

Alcoholism and chronic stress lead to impaired cognitive functions, which are regulated, in particular, by neurosteroid hormones. Exogenous administration of progesterone is one of the ways to influence the brain system of hormonal and neurotransmitter regulation. The effect of intranasal administration of low doses of progesterone on endogenous neurosteroid modulation of working and spatial memory in male rats with alcohol dependence and aggressive behavior was investigated. Alcohol dependence in male rats was modeled by voluntary intake of bread soaked in ethanol solution at a dose of 1.2 g/kg for 30 days. Aggressiveness was determined using the sensory contact method and the “partition” test. To study memory processes in rats, neuroethological methods of testing working (recognition of new objects) and spatial (orientation in the Barnes maze) memory were used. Progesterone was administered intranasally at a dose of 80 μg per rat for 10 days. Progesterone, testosterone, and cortisol levels were measured in the frontal neocortex (FC), hippocampus, and serum using enzyme-linked immunosorbent assay kits. The stimulatory effect of alcoholization on spatial memory and impairment of working memory in male rats with aggressive behavior was found. Zoosocial conflict on the background of prolonged alcohol consumption leads to impaired object recognition and spatial orientation against the background of neurosteroid imbalance: a decrease in progesterone and testosterone content in the FC, hippocampus, serum, and an increase in cortisol levels in these structures. Intranasal administration of progesterone to rats with alcohol dependence and aggressive behavior offsets the negative effects of confrontational relationships on working memory processes, restores the acquired experience to the baseline (however, the processes of object differentiation remain weakened); leads to improved spatial memory. The favorable effects of progesterone on memory are accompanied by a decrease in the imbalance of hormonal influences in brain structures with the restoration of progesterone and testosterone concentrations in the FC, hippocampus and serum against the background of weakening of stress-induced glucocorticoid activity. Therefore, intranasal administration of low doses of progesterone improves working and spatial memory in male rats with alcohol dependence and aggressive behavior due to the tendency to restore the balance of hormones (progesterone, testosterone, cortisol) in the brain structures responsible for memory.