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Chronic neuropathic pain can result from nervous system injury and can persist in the absence of external stimuli. Although ongoing pain characterizes the disorder, in many individuals, the intensity of this ongoing pain fluctuates dramatically. Previously, it was identified that functional magnetic resonance imaging signal covariations between the midbrain periaqueductal gray (PAG) matter, rostral ventromedial medulla (RVM), and spinal trigeminal nucleus are associated with moment-to-moment fluctuations in pain intensity in individuals with painful trigeminal neuropathy (PTN). Since this brainstem circuit is modulated by higher brain input, we sought to determine which cortical sites might be influencing this brainstem network during spontaneous fluctuations in pain intensity. Over 12 min, we recorded the ongoing pain intensity in 24 PTN participants and classified them as fluctuating (n = 13) or stable (n = 11). Using a PAG seed, we identified connections between the PAG and emotional-affective sites such as the hippocampal and posterior cingulate cortices, the sensory-discriminative posterior insula, and cognitive-affective sites such as the dorsolateral prefrontal (dlPFC) and subgenual anterior cingulate cortices that were altered dependent on spontaneous high and low pain intensity. Additionally, sliding-window functional connectivity analysis revealed that the dlPFC-PAG connection anticorrelated with perceived pain intensity over the entire 12 min period. These findings reveal cortical systems underlying moment-to-moment changes in perceived pain in PTN, which likely cause dysregulation in the brainstem circuits previously identified, and consequently alter the appraisal of pain across time.

Background: Headache is a pain disorder present in populations world-wide with a higher incidence in females. Specifically, the incidences of medication overuse headache (MOH) have increased worldwide. Comorbidities of MOH include photosensitivity, anxiety, "brain fog", and decreased physical activity. The FDA-approved long-lasting selective β2-adrenergic receptor agonist, formoterol, is currently approved for use in severe asthma and chronic obstructive pulmonary disease. Recently, interest in repurposing formoterol for use in other disorders including Alzheimer's disease, and neuropathic pain after spinal cord injury and traumatic brain injury has gained traction. Thus, revisiting known side-effects of formoterol, like headache and anxiety, could inform treatment paradigms. The endocannabinoid (eCB) system is implicated in the etiology of preclinical headache, with observed decreases in the circulating levels of endogenous cannabinoids, referred to as Clinical Endocannabinoid Deficiency. As cross-talk between the eCB system and adrenergic receptors has been reported, this study investigated the role of the eCB system and ability of formoterol to induce headache-like periorbital allodynic behavior. Methods: Female 8-week-old C57Bl/6J mice were treated daily with formoterol (0.3 mg/kg, i.p.) for up to 42-days, during which they were assessed for periorbital allodynia, open field/novel object recognition, and photosensitivity. At the end of the study, the periaqueductal grey (PAG), a brain region known to contribute to both headache induction and maintenance, was collected and subjected to LC-MS to quantify endocannabinoid levels. Results: Mice exhibited periorbital allodynia at nearly all time points tested and photosensitivity from 28-days onward. Levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with cannabinoid receptor 1 (CB1R) expression were altered by both age and upon treatment with formoterol. Administration of FAAH/MAGL inhibitors, to target the eCB system, and a non-selective cannabinoid receptor agonist, WIN 55,212 reversed the formoterol-induced periorbital allodynia. Conclusions: These results suggest that formoterol is dysregulates eCB tone to drive headache-like periorbital allodynic behaviors. These results could help inform preventative treatment options for individuals receiving formoterol, as well as provide information on the interaction between the eCB and adrenergic system. [ABSTRACT FROM AUTHOR]

• The solubility of R1234ze(E) and R1336mzz(E) in two lubricants was tested and compared. • Experimental solubility data were correlated by the NTRL activity coefficient model. • The Henry's constants of R1234ze(E) and R1336mzz(E) in PAG and POE were obtained. Trans-1,3,3,3-tetrafluoropropene (R1234ze(E)) and trans-1,1,1,4,4,4-hexafluorobut-2-ene (R1336mzz(E)) are environmentally friendly working fluids with low global warming potential (GWP) that can be used in compression refrigeration and heat pump systems. In this study, a solubility measurement system was established to assess the solubility of R1234ze(E) and R1336mzz(E) in polyalkylene glycol ether (PAG) and polyol ester (POE) at temperatures (283.15–323.15 K). The Henry's constants for four binary systems R1234ze(E)/PAG, R1336mzz(E)/PAG, R1234ze(E)/POE, and R1336mzz(E)/POE were analyzed and compared. Additionally, The non-random two liquid (NRTL) activity coefficient model was applied to correlate the solubility data in this study. The results indicate that R1234ze(E) exhibits higher solubility in PAG lubricant, while R1336mzz(E) is more easily dissolved in POE lubricant. Moreover, the solubility of R1336mzz(E) in both PAG and POE lubricants shows greater sensitivity to pressure and temperature changes compared to R1234ze(E). The results reported in this study can serve as a valuable guide for the choice of suitable lubricants for R1234ze(E) and R1336mzz(E) in different applications. [ABSTRACT FROM AUTHOR]

Dopaminergic (DA) neurons are known to play a key role in controlling behaviors. While DA neurons in other brain regions are extensively characterized, those in zona incerta (ZITH or A13) receive much less attention and their function remains to be defined. Here it is shown that optogenetic stimulation of these neurons elicited intensive self‐grooming behaviors and promoted place preference, which can be enhanced by training but cannot be converted into contextual memory. Interestingly, the same stimulation increased DA release to periaqueductal grey (PAG) neurons and local PAG antagonism of DA action reduced the elicited self‐grooming. In addition, A13 neurons increased their activity in response to various external stimuli and during natural self‐grooming episodes. Finally, monosynaptic retrograde tracing showed that the paraventricular hypothalamus represents one of the major upstream brain regions to A13 neurons. Taken together, these results reveal that A13 neurons are one of the brain sites that promote appetitive self‐grooming involving DA release to the PAG. [ABSTRACT FROM AUTHOR]

The objective of the present study was to evaluate the diagnostic potential of pregnancy detection methods at an early stage in cattle using transrectal ultrasonography, per-rectal palpation and commercially available PAG based ELISA kit. The study was conducted on 116 crossbred cyclic cows, aged 3-8 years. The cows at estrus were artificially inseminated using 2 doses of quality semen at 10-12 h interval. They were subjected to trans-rectal ultrasonography and PAG test in randomized animals at around 28-35 days' post-insemination. The animals were further examined by second trans-rectal ultrasonography and per-rectal palpation on day 45-50 post-AI. Ultrasonography was found to be more effective in diagnosing early pregnancy followed by PAG test around day 28 and per-rectal examination by day 45-50 post-insemination. However, PAG test was more accurate in diagnosing open cows at the earliest. [ABSTRACT FROM AUTHOR]

Copyright of Kocatepe Veterinary Journal / Kocatepe Veteriner Dergisi is the property of Afyon Kocatepe University, Faculty of Veterinary Medicine and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background Headache is a pain disorder present in populations world-wide with a higher incidence in females. Specifically, the incidences of medication overuse headache (MOH) have increased worldwide. Comorbidities of MOH include photosensitivity, anxiety, “brain fog”, and decreased physical activity. The FDA-approved long-lasting selective β2-adrenergic receptor agonist, formoterol, is currently approved for use in severe asthma and chronic obstructive pulmonary disease. Recently, interest in repurposing formoterol for use in other disorders including Alzheimer’s disease, and neuropathic pain after spinal cord injury and traumatic brain injury has gained traction. Thus, revisiting known side-effects of formoterol, like headache and anxiety, could inform treatment paradigms. The endocannabinoid (eCB) system is implicated in the etiology of preclinical headache, with observed decreases in the circulating levels of endogenous cannabinoids, referred to as Clinical Endocannabinoid Deficiency. As cross-talk between the eCB system and adrenergic receptors has been reported, this study investigated the role of the eCB system and ability of formoterol to induce headache-like periorbital allodynic behavior. Methods Female 8-week-old C57Bl/6J mice were treated daily with formoterol (0.3 mg/kg, i.p.) for up to 42-days, during which they were assessed for periorbital allodynia, open field/novel object recognition, and photosensitivity. At the end of the study, the periaqueductal grey (PAG), a brain region known to contribute to both headache induction and maintenance, was collected and subjected to LC-MS to quantify endocannabinoid levels. Results Mice exhibited periorbital allodynia at nearly all time points tested and photosensitivity from 28-days onward. Levels of endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), along with cannabinoid receptor 1 (CB1R) expression were altered by both age and upon treatment with formoterol. Administration of FAAH/MAGL inhibitors, to target the eCB system, and a non-selective cannabinoid receptor agonist, WIN 55,212 reversed the formoterol-induced periorbital allodynia. Conclusions These results suggest that formoterol is dysregulates eCB tone to drive headache-like periorbital allodynic behaviors. These results could help inform preventative treatment options for individuals receiving formoterol, as well as provide information on the interaction between the eCB and adrenergic system. Graphical Abstract

Abstract Dopaminergic (DA) neurons are known to play a key role in controlling behaviors. While DA neurons in other brain regions are extensively characterized, those in zona incerta (ZITH or A13) receive much less attention and their function remains to be defined. Here it is shown that optogenetic stimulation of these neurons elicited intensive self‐grooming behaviors and promoted place preference, which can be enhanced by training but cannot be converted into contextual memory. Interestingly, the same stimulation increased DA release to periaqueductal grey (PAG) neurons and local PAG antagonism of DA action reduced the elicited self‐grooming. In addition, A13 neurons increased their activity in response to various external stimuli and during natural self‐grooming episodes. Finally, monosynaptic retrograde tracing showed that the paraventricular hypothalamus represents one of the major upstream brain regions to A13 neurons. Taken together, these results reveal that A13 neurons are one of the brain sites that promote appetitive self‐grooming involving DA release to the PAG.

Chemotherapy-induced peripheral neuropathy (CIPN) is one of the most prevalent and dose-limiting complications in chemotherapy patients. One identified mechanism underlying CIPN is neuroinflammation. Most of this research has been conducted in only male or female rodent models, making direct comparisons regarding the role of sex differences in the neuroimmune underpinnings of CIPN limited. Moreover, most measurements have focused on the dorsal root ganglia (DRG) and/or spinal cord, while relatively few studies have been aimed at characterizing neuroinflammation in the brain, for example the periaqueductal grey (PAG). The overall goals of the present study were to determine (1) paclitaxel-associated changes in markers of inflammation in the PAG and DRG in male and female C57Bl6 mice and (2) determine the effect of prophylactic administration of an anti-inflammatory cannabinoid, cannabigerol (CBG). In Experiment 1, male and female mice were treated with paclitaxel (8–32 mg/kg/injection, Days 1, 3, 5, and 7) and mechanical sensitivity was measured using Von Frey filaments on Day 7 (Cohort 1) and Day 14 (Cohort 2). Cohorts were euthanized on Day 8 or 15, respectively, and DRG and PAG were harvested for qPCR analysis of the gene expression of markers of pain and inflammation Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. In Experiment 2, male and female mice were treated with vehicle or 10 mg/kg CBG i.p. 30 min prior to each paclitaxel injection. Mechanical sensitivity was measured on Day 14. Mice were euthanized on Day 15, and PAG were harvested for qPCR analysis of the gene expression of Aig1, Gfap, Ccl2, Cxcl9, Tlr4, Il6, and Calca. Paclitaxel produced a transient increase in potency to produce mechanical sensitivity in male versus female mice. Regarding neuroinflammation, more gene expression changes were apparent earlier in the DRG and at a later time point in the PAG. Also, more changes were observed in females in the PAG than males. Overall, sex differences were observed for most markers at both time points and regions. Importantly, in both the DRG and PAG, most increases in markers of neuroinflammation and pain occurred at paclitaxel doses higher than those associated with significant changes in the mechanical threshold. Two analytes that demonstrated the most compelling sexual dimorphism and that changed more in males were Cxcl9 and Ccl2, and Tlr4 in females. Lastly, prophylactic administration of CBG protected the male and female mice from increased mechanical sensitivity and female mice from neuroinflammation in the PAG. Future studies are warranted to explore how these sex differences may shed light on the mechanisms of CIPN and how non-psychoactive cannabinoids such as CBG may engage these targets to prevent or attenuate the effects of paclitaxel and other chemotherapeutic agents on the nervous system. [ABSTRACT FROM AUTHOR]

Primiparous and multiparous dairy cattle were evaluated for pregnancy using both transrectal ultrasonography and a point-of-care pregnancy test (Alertys OnFarm Test), which measures pregnancy-associated glycoproteins through lateral diffusion, between Days 28–34 of pregnancy results were compared. A total of 637 animals were included in this study. Pregnancy was confirmed via manual palpation between Days 57–64. Data on parity, calving, and time of artificial insemination (AI) were also collected and evaluated. Overall the accuracy of the lateral diffusion test was 93.1% with 98.9% sensitivity, 88.7 % specificity, 86.8 % positive predictive value, and 99.1% negative predictive value. In heifers, the Alertys OnFarm Test had 100% sensitivity and 81.6% specificity. In contrast, the test had a sensitivity and specificity of 98.5 and 89.5%, respectively for multiparous cows. The pregnancy loss between early diagnosis and confirmation increased with parity. Heifers suffered losses as low as 2.6%, whereas animals in the third parity had significantly more losses (17.9%). Season also affected losses with spring pregnancy losses being considerably higher than autumn losses. The veterinary workload was also evaluated. Using the combined method of pregnancy testing, animals were first tested with the lateral diffusion test; then, the test-negative animals were scanned again, and the number of scanned animals was reduced. The results ranged between 3274% on farms. We concluded that veterinary workload could be reduced by using the point-of-care test. However, farm-level differences may have affected the results of the present study. • Early pregnancy of cattle was evaluated by a point-of-care pregnancy test and transrectal ultrasonography. • The results were greatly influenced by parity and season. • While in heifers the test shows good accuracy, in cows pregnancy loss effects the test results. • When combining the methods veterinary workload reduction can be achieved. [ABSTRACT FROM AUTHOR]

The objectives of the study were to compare the demographic characteristics, presenting complaints, timeliness of diagnosis, and treatments given to all patients diagnosed with obstructive hemivagina ipsilateral renal agenesis (OHVIRA) between the adolescent group (age 10-19) and the adult group (age 20 and above) and to propose a feasible screening test consisting of routine bedside ultrasound to detect renal anomalies in addition to pelvic ultrasound during the assessment of females with gynecologic complications in resource-limited settings. We conducted a retrospective cohort analysis of all patients with OHVIRA at our institution, Sabah Women and Children's Hospital, Malaysia, between the 2013 and 2022. Data were collected by reviewing patients' medical notes. There were a total of 18 patients diagnosed with OHVIRA from 2013 to 2022, aged 10-41 years old. Nine patients (50%) presented during adolescence. Most (88.9%) came with symptoms such as abdominal pain, urinary symptoms, abnormal uterine bleeding, foul-smelling vaginal discharge, and primary infertility, whereas only 2 patients (11.1%) were asymptomatic and diagnosed incidentally. Acute abdomen was more common in the adolescent group (P =.015). No significant difference was found on the side of the renal anomaly. Presenting symptoms vary and are often mimicked other gynecologic or surgical conditions, making the diagnosis difficult and delayed. Some patients were incidentally diagnosed while being managed for other problems, and it was not uncommon to have unnecessary surgery before the correct diagnosis was made. We suggest that all female patients with abdominal and pelvic complaints should be screened for renal anomaly during pelvic scan to improve diagnostic rates. [ABSTRACT FROM AUTHOR]

The pathophysiology of migraine remains to be elucidated. We have recently shown that interictal migraineurs exhibit reduced fractional anisotropy (FA) in the root entry zone of the trigeminal nerve when compared to controls, but it is not known if this altered nerve anatomy is associated with changes within the brainstem or higher cortical brain regions. Diffusion tensor imaging of the brain was used to calculate regional measures of structure, including mean diffusivity (MD), axial diffusivity (AX) and radial diffusivity (RD) in addition to voxel-based morphometry of T1-weighted anatomical images. Linear relationships between trigeminal nerve anatomy (FA) and MD throughout the brainstem and/or higher cortical regions were determined in both controls (n = 31, brainstem; n = 38, wholebrain) and interictal migraineurs (n = 32, brainstem; n = 38, wholebrain). Additionally, within the same brain areas, relationships of AX and RD with nerve FA were determined. We found that in both interictal migraine and control participants, decreasing trigeminal nerve FA was associated with significantly increased MD in brainstem regions including the spinal trigeminal nucleus and midbrain periaqueductal gray matter (PAG), and in higher brain regions such as the hypothalamus, insula, posterior cingulate, primary somatosensory and primary visual (V1) cortices. Whereas, both control and migraineur groups individually displayed significant inverse correlations between nerve FA and MD, in migraineurs this pattern was disrupted in the areas of the PAG and V1, with only the control group displaying a significant linear relationship (PAG controls r = -0.58, p = 0.003; migraineurs r = -0.25, p = 0.17 and V1 controls r = -0.52, p = 0.002; migraineurs r = -0.10, p = 0.55). Contrastingly, we found no gray matter volume changes in brainstem or wholebrain areas. These data show that overall, trigeminal nerve anatomy is significantly related to regional brain structure in both controls and migraineurs. Importantly, the PAG showed a disruption of this relationship in migraineurs suggesting that the anatomy and possibly the function of the PAG is uniquely altered in episodic migraine, which may contribute to altered orofacial pain processing in migraine.

Expectations can profoundly modulate pain experience, during which the periaqueductal gray (PAG) plays a pivotal role. In this article, we focus on motivationally evoked neural activations in cortical and brainstem regions both before and during stimulus administration, as has been demonstrated by experimental studies on pain-modulatory effects of expectations, in the hope of unraveling how the PAG is involved in descending and ascending nociceptive processes. This motivational perspective on expectancy effects on the perception of noxious stimuli sheds new light on psychological and neuronal substrates of pain and its modulation, thus having important research and clinical implications. [ABSTRACT FROM AUTHOR]

• There is no concentration gradient when the bottom viscosity reaches the minimum. • Viscosity of low oil charge is lower and duration of low viscosity is longer. • Lack of lubricant in the oil sump leads to low viscosity during startup. • Bearing cover modification efficiently enhances the viscosity of low oil charge. • Bearing cover modification allows R290 compressor to use low viscosity grade oil. As an A3 refrigerant, the charge of the natural refrigerant R290 in the refrigeration system is limited. The use of partially miscible lubricants and a reduction of the lubricant charge can effectively decrease the refrigerant charge. These two measures affect the startup dynamic characteristics of the compressor and the air conditioner. In this paper, variations in system temperature, pressure, and oil sump parameters during the cold startup process of a 1.5P R290 split inverter room air conditioner with different charges of PAG VG40 were experimentally measured under the rated cooling and low-temperature heating condition. The experimental results showed that the viscosity of the refrigerant/lubricant mixture of low lubricant charge (LLC) was lower than that of the normal lubricant charge (NLC), and the duration of low viscosity with LLC was longer. The low viscosity during startup is mainly due to the insufficient amount of lubricant in the oil sump. Three measures were proposed to alleviate the problem of low startup viscosity. Among them, the modification of the bearing cover effectively improved the viscosity of the LLC mixture, and the minimum viscosity of the bearing cover with LLC was even higher than that of the prototype with NLC. Furthermore, the bearing cover modification allows using a lower viscosity grade of lubricant for R290 rotary compressors. [ABSTRACT FROM AUTHOR]

Glutamine (Gln), glutamate (Glu), and γ-amino butyric acid (GABA) are essential amino acids for brain metabolism and function. Astrocyte-derived Gln is the precursor for the two most important neurotransmitters in the central nervous system (CNS), which are the excitatory neurotransmitter Glu and the inhibitory neurotransmitter GABA. In addition to their roles in neurotransmission, these amino acids can be used as alternative substrates in brain metabolism that enable metabolic coupling between astrocytes and neurons in the glutamate–glutamine cycle (GGC). The disturbed homeostasis of these amino acids within the tripartite synapse may be involved in the pathogenesis of various neurological diseases. Interactions between astrocytes and neurons in terms of Gln, Glu, and GABA homeostasis were studied in different phases of experimental allergic encephalomyelitis (EAE) in Lewis rats. The results of the study showed a decrease in the transport (uptake and release) of Gln and GABA in both neuronal and astrocyte-derived fractions. These effects were fully or partially reversed when the EAE rats were treated with memantine, a NMDA receptor antagonist. Changes in the expression and activity of selected glutamine/glutamate metabolizing enzymes, such as glutamine synthase (GS) and phosphate-activated glutaminase (PAG), which were affected by memantine, were observed in different phases of EAE. The results suggested perturbed homeostasis of Gln, Glu, and GABA during EAE, which may indicate alterations in neuron–astrocyte coupling and dysfunction of the tripartite synapse. Memantine appears to partially regulate the disturbed relationships between Gln, Glu, and GABA. [ABSTRACT FROM AUTHOR]

IntroductionThe periaqueductal gray (PAG) mediates the antinociceptive properties of analgesics, including opioids and cannabinoids. Administration of either opioids or cannabinoids into the PAG induces antinociception. However, most studies characterizing the antinociceptive properties of cannabinoids in the PAG have been conducted in naive animals. Few studies have reported on the role of CB1 receptors in the PAG during conditions which would prompt the administration of analgesics, namely, during pain states.ObjectivesTo examine inflammatory pain-induced changes in CB1 receptor expression and function in the midbrain periaqueductal gray.MethodsIn this study, we used the Complete Freund Adjuvant model to characterize CB1 receptor expression and G-protein coupling during persistent inflammatory pain.ResultsInflammatory pain induced an upregulation in the expression of synaptic CB1 receptors in the PAG. Despite this pain-induced change in CB1 expression, there was no corresponding upregulation of CB1 mRNA after the induction of inflammatory pain, suggesting a pain-induced recruitment of CB1 receptors to the synaptic sites within PAG neurons or increased coupling efficiency between the receptor and effector systems. Inflammatory pain also enhanced ventrolateral PAG CB1 receptor activity, as there was an increase in CP55,940-stimulated G-protein activation compared with pain-naïve control animals.ConclusionThese findings complement a growing body of evidence which demonstrate pain-induced changes in brain regions that are responsible for both the analgesic and rewarding properties of analgesic pharmacotherapies. Because much of our understanding of the pharmacology of cannabinoids is based on studies which use largely pain-naïve male animals, this work fills in important gaps in the knowledge base by incorporating pain-induced adaptations and cannabinoid pharmacology in females.

[Display omitted] • Preoperative pain facilitates postoperative cognitive function. • A new circuit exists between PAG and DR. • Inhibition of PAG-DR circuit decreases the cognitive function in rats. Postoperative cognitive dysfunction (POCD) is a medically induced, rapidly occurring postoperative disease, which is hard to recover and seriously threatens the quality of life, especially for elderly patients, so it is important to identify the risk factors for POCD and apply early intervention to prevent POCD. As we have known, pain can impair cognition, and many surgery patients experience different preoperative pain, but it is still unknown whether these patients are vulnerable for POCD. Here we found that chronic pain (7 days, but not 1 day acute pain) induced by Complete Freund's Adjuvant (CFA) injected in the hind paw of rats could easily induce spatial cognition and memory impairment after being exposed to sevoflurane anesthesia. Next, for the mechanisms, we focused on the Periaqueductal Gray Matter (PAG), a well-known pivotal nucleus in pain process. It was detected the existence of neural projection from ventrolateral PAG (vlPAG) to adjacent nucleus Dorsal Raphe (DR), the origin of serotonergic projection for the whole cerebrum, through virus tracing and patch clamp recordings. The Immunofluorescence staining and western blot results showed that Tryptophan Hydroxylase 2 (TPH2) for serotonin synthesis in the DR was increased significantly in the rats treated with CFA for 7 days and sevoflurane for 3 hours, while chemo-genetic inhibition of the vlPAG-DR projection induced obvious spatial learning and memory impairment. Our study suggests that preoperative chronic pain may facilitate cognitive function impairment after receiving anesthesia through the PAG-DR neural circuit, and preventative analgesia should be a considerable measure to reduce the incidence of POCD. [ABSTRACT FROM AUTHOR]

Morphine is one of the most effective and widely used analgesic drugs. However, chronic morphine use caused opioid-induced hyperalgesia (OIH). The development of OIH limits the use of morphine. The mechanisms of OIH are not fully understood. Toll-like receptor4 (TLR4) and glutamate receptors in the periaqueductal gray (PAG) are critical in OIH, however, the association between TLR4 and N-methyl-D-aspartate Receptors (NMDARs) activation in PAG remains unclear. Microglia activation, increased TLR4/p65 nuclear factor-kappa B (p65 NF-κB) and proinflammatory cytokines in microglia, and phosphorylation of NMDAR1 subunit (NR1) and NMDAR2B subunit (NR2B) in neurons were observed in PAG of OIH mice. Up-regulations of TLR4/p65 NF-κB and proinflammatory cytokines (IL-1β, IL-6, TNF-α) in BV2 cells were prevented by inhibiting and knocking down TLR4. By inhibiting myeloid differentiation factor 2 (MD2) and knocking down the High-mobility group box 1 (HMGB1), we found that morphine activated TLR4 by HMGB1 but not MD2. We co-cultured Neuro- 2a (N2A) with BV2 microglial cell line and found that instead of directly phosphorylating NMDAR subunits, morphine increased the phosphorylation of NR1 and NR2B by inducing TLR4-mediated microglia inflammation. Knocking TLR4 out of PAG by Lentivirus-GFP-TLR4 shRNA reversed these changes and relieved OIH. Our findings suggested that the secretion of HMGB1 induced by morphine-activated TLR4 in microglia, and the proinflammatory factors released by activated microglia phosphorylated NR1 and NR2B of adjacent neurons, induced increased neuronal excitability. In conclusion, TLR4/NMDARs in PAG were involved in the development and maintenance of OIH and supported novel strategies for OIH treatment. [ABSTRACT FROM AUTHOR]

The periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) are critically important hubs in the endogenous analgesia pathway. Technological and conceptual advances have permitted the identification and targeting of neural ensembles in the PAG and RVM during complex behaviors, revealing that they divergently modulate distinct components of somatosensation. In vivo imaging, viral tracing, and molecular genetic manipulations have afforded a new layer of insight by characterizing the function of genetically defined neuronal populations within the PAG and RVM. How these identified pathways coordinate other autonomic, motivational, and defensive responses during ongoing nociception remains to be addressed in greater detail. Further investigations into the PAG and RVM in the descending modulation of nociception, itch, and other complex behaviors are ongoing. Decades of research have suggested that stimulation of supraspinal structures, such as the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM), inhibits nocifensive responses to noxious stimulation through a process known as descending modulation. Electrical stimulation and pharmacologic manipulations of the PAG and RVM identified transmitters and neuronal firing patterns that represented distinct cell types. Advances in mouse genetics, in vivo imaging, and circuit tracing methods, in addition to chemogenetic and optogenetic approaches, allowed the characterization of the cells and circuits involved in descending modulation in further detail. Recent work has revealed the importance of PAG and RVM neuronal cell types in the descending modulation of pruriceptive as well as nociceptive behaviors, underscoring their roles in coordinating complex behavioral responses to sensory input. This review summarizes how new technical advances that enable cell type-specific manipulation and recording of neuronal activity have supported, as well as expanded, long-standing views on descending modulation. [ABSTRACT FROM AUTHOR]

The transmembrane adaptor phosphoprotein associated with glycosphingolipid-enriched microdomains 1 (PAG) is phosphorylated in T cells downstream of PD-1 signaling and contributes to the resulting functional inhibition of multiple cellular processes. Furthermore, PAG expression is negatively correlated with survival in multiple human tumors and is a driver of murine tumor growth and immune evasion. Here we develop an antibody that targets the extracellular domain of human PAG, with cross-reactivity to murine PAG. We demonstrate that this antibody binds to extracellular PAG on intact cells and affects T cell activation. Finally, we show that administration of anti-PAG monoclonal antibody in combination with anti-PD-1 antibody to mice bearing MC38 tumors limited tumor growth and enhanced T cell infiltration to tumors.

Abstract: The periaqueductal gray (PAG) represents a key target of projection neurons residing in the spinal dorsal horn. In comparison to lamina I spinoparabrachial neurons, little is known about the intrinsic and synaptic properties governing the firing of spino-PAG neurons, or whether such activity is modulated by neonatal injury. In this study, this issue was addressed using ex vivo whole-cell patch clamp recordings from lamina I spino-PAG neurons in adult male and female FVB mice after hindpaw incision at postnatal day (P)3. Spino-PAG neurons were classified as high output, medium output, or low output based on their action potential discharge after dorsal root stimulation. The high-output subgroup exhibited prevalent spontaneous burst firing and displayed initial burst or tonic patterns of intrinsic firing, whereas low-output neurons showed little spontaneous activity. Interestingly, the level of dorsal root-evoked firing significantly correlated with the resting potential and membrane resistance but not with the strength of primary afferent-mediated glutamatergic drive. Neonatal incision failed to alter the pattern of monosynaptic sensory input, with most spino-PAG neurons receiving direct connections from low-threshold C-fibers. Furthermore, primary afferent-evoked glutamatergic input and action potential discharge in adult spino-PAG neurons were unaltered by neonatal surgical injury. Finally, Hebbian long-term potentiation at sensory synapses, which significantly increased afferent-evoked firing, was similar between P3-incised and naive littermates. Collectively, these data suggest that the functional response of lamina I spino-PAG neurons to sensory input is largely governed by their intrinsic membrane properties and appears resistant to the persistent influence of neonatal tissue damage. [ABSTRACT FROM AUTHOR]

Despite fine tuning voluntary movement as the most prominently studied function of the cerebellum, early human studies suggested cerebellar involvement emotion regulation. Since, the cerebellum has been associated with various mood and anxiety-related conditions. Research in animals provided evidence for cerebellar contributions to fear memory formation and extinction. Fear and anxiety can broadly be referred to as defensive states triggered by threat and characterized by multimodal adaptations such as behavioral and cardiac responses integrated into an intricately orchestrated defense reaction. This is mediated by an evolutionary conserved, highly interconnected network of defense-related structures with functional connections to the cerebellum. Projections from the deep cerebellar nucleus interpositus to the central amygdala interfere with retention of fear memory. Several studies uncovered tight functional connections between cerebellar deep nuclei and pyramis and the midbrain periaqueductal grey. Specifically, the fastigial nucleus sends direct projections to the ventrolateral PAG to mediate fear-evoked innate and learned freezing behavior. The cerebellum also regulates cardiovascular responses such as blood pressure and heart rate-effects dependent on connections with medullary cardiac regulatory structures. Because of the integrated, multimodal nature of defensive states, their adaptive regulation has to be highly dynamic to enable responding to a moving threatening stimulus. In this, predicting threat occurrence are crucial functions of calculating adequate responses. Based on its role in prediction error generation, its connectivity to limbic regions, and previous results on a role in fear learning, this review presents the cerebellum as a regulator of integrated cardio-behavioral defensive states. [ABSTRACT FROM AUTHOR]

Unmyelinated low-threshold mechanoreceptors (C-tactile, CT) in the human skin are important for signaling information about hedonic aspects of touch. We have previously reported that CT-targeted brush stroking by means of a robot reduces experimental mechanical pain. To improve the ecological validity of the stimulation, we developed standardized human–human touch gestures for signaling attention and calming. The attention gesture is characterized by tapping of the skin and is perceived as neither pleasant nor unpleasant, i.e., neutral. The calming gesture is characterized by slow stroking of the skin and is perceived as moderately to very pleasant. Furthermore, the attention (tapping) gesture is ineffective, whereas the calming (stroking) gesture is effective in activating CT-afferents. We conducted an fMRI study (n = 32) and capitalized on the previous development of touch gestures. We also developed an MR compatible stimulator for high-precision mechanical pain stimulation of the thenar region of the hand. Skin-to-skin touching (stroking or tapping) was applied and was followed by low and high pain. When the stroking gesture preceded pain, the pain was rated as less intense. When the tapping gesture preceded the pain, the pain was rated as more intense. Individual pain perception related to insula activation, but the activation was not higher for stroking than for tapping in any brain area during the stimulation period. However, during the evaluation period, stronger activation in the periaqueductal gray matter was observed after calming touch compared to after tapping touch. This finding invites speculation that human–human gentle skin stroking, effective in activating CT-afferents, reduced pain through neural processes involving CT-afferents and the descending pain pathway. [ABSTRACT FROM AUTHOR]

The neural mechanisms responsible for the initiation and expression of migraines remain unknown. Although there is growing evidence of changes in brainstem anatomy and function between attacks, very little is known about brainstem function and structure in the period immediately prior to a migraine. The aim of this investigation is to use brainstem-specific analyses of diffusion weighted images to determine whether the brainstem pain processing regions display altered structure in individuals with migraine across the migraine cycle, and in particular immediately prior to a migraine. Diffusion tensor images (29 controls, 36 migraineurs) were used to assess brainstem anatomy in migraineurs compared with controls. We found that during the interictal phase, migraineurs displayed greater mean diffusivity (MD) in the region of the spinal trigeminal nucleus (SpV), dorsomedial pons (dmPons)/dorsolateral pons (dlPons), and midbrain periaqueductal gray matter (PAG)/cuneiform nucleus (CNF). Remarkably, the MD returned to controls levels during the 24-h period immediately prior to a migraine, only to increase again within the three following days. Additionally, fractional anisotropy (FA) was significantly elevated in the region of the medial lemniscus/ventral trigeminal thalamic tract in migraineurs compared with controls over the entire migraine cycle. These data show that regional brainstem anatomy changes over the migraine cycle, with specific anatomical changes occurring in the 24-h period prior to onset. These changes may contribute to the activation of the ascending trigeminal pathway by either an increase in basal traffic or by sensitizing the trigeminal nuclei to external triggers, with activation ultimately resulting in perception of head pain during a migraine attack.

The main pregnancy test method for dairy cows is rectal palpation performed around 40–45 days from last insemination. This is an invasive examination that disrupts the cow’s routine, potentially affecting its well-being. We examined the effectiveness of a commercial kit for performing pregnancy tests on milk samples compared to rectal palpation at 28- and 42-days post insemination. Accordingly, the purpose of the current study was to check if performing early pregnancy test instead of rectal palpation would result in better welfare and improvement of the reproductive performance, at least in part, of the cows. At 28 days, we examined the effect of early pregnancy testing on reproductive performance, especially number of days open. At 42 days, we determined the pregnancy test methods’ effects on cow welfare measures and milk production. For the day 28 experiment, cows on one farm were divided into two groups: one milk-tested for pregnancy on 28 to 30 days after insemination, and the other tested by routine veterinary examination (42 to 45 days after insemination). The milk test resulted in a 16-day reduction in days open for cows identified as non-pregnant on day 28 compared to day 42 (rectal examination), potentially improving reproductive performance on the dairy farm. For the day 42 experiment, test effects on cow welfare as seen in pedometer data and milk production were examined on two large dairy farms. Test-day milk production did not differ significantly between milk-tested and rectally palpated groups, but well-being indices of milk-tested cows improved, especially in winter months. The reason for this can be because, in the summer, cows are interrupted due to colling activities. In addition to fewer days open and economic improvement, early milk tests for pregnancy can free up the practitioner for other tasks on the dairy farm.

IntroductionThe high prevalence and severe symptoms of migraines in humans emphasizes the need to identify underlying mechanisms that can be targeted for therapeutic benefit. Clinical Endocannabinoid Deficiency (CED) posits that reduced endocannabinoid tone may contribute to migraine development and other neuropathic pain conditions. While strategies that increase levels of the endocannabinoid n-arachidonoylethanolamide have been tested, few studies have investigated targeting the levels of the more abundant endocannabinoid, 2-arachidonoylgycerol, as an effective migraine intervention.MethodsCortical spreading depression was induced in female Sprague Dawley rats via KCl (potassium chloride) administration, followed by measures of endocannabinoid levels, enzyme activity, and neuroinflammatory markers. Efficacy of inhibiting 2-arachidonoylglycerol hydrolysis to mitigate periorbital allodynia was then tested using reversal and prevention paradigms.ResultsWe discovered reduced 2-arachidonoylglycerol levels in the periaqueductal grey associated with increased hydrolysis following headache induction. Pharmacological inhibition of the 2-arachidonoylglycerol hydrolyzing enzymes, α/β-hydrolase domain-containing 6 and monoacylglycerol lipase reversed and prevented induced periorbital allodynia in a cannabinoid receptor-dependent manner.DiscussionOur study unravels a mechanistic link between 2-arachidonoylglycerol hydrolysis activity in the periaqueductal grey in a preclinical, rat model of migraine. Thus, 2-arachidonoylglycerol hydrolysis inhibitors represent a potential new therapeutic avenue for the treatment of headache.

Despite fine tuning voluntary movement as the most prominently studied function of the cerebellum, early human studies suggested cerebellar involvement emotion regulation. Since, the cerebellum has been associated with various mood and anxiety-related conditions. Research in animals provided evidence for cerebellar contributions to fear memory formation and extinction. Fear and anxiety can broadly be referred to as defensive states triggered by threat and characterized by multimodal adaptations such as behavioral and cardiac responses integrated into an intricately orchestrated defense reaction. This is mediated by an evolutionary conserved, highly interconnected network of defense-related structures with functional connections to the cerebellum. Projections from the deep cerebellar nucleus interpositus to the central amygdala interfere with retention of fear memory. Several studies uncovered tight functional connections between cerebellar deep nuclei and pyramis and the midbrain periaqueductal grey. Specifically, the fastigial nucleus sends direct projections to the ventrolateral PAG to mediate fear-evoked innate and learned freezing behavior. The cerebellum also regulates cardiovascular responses such as blood pressure and heart rate-effects dependent on connections with medullary cardiac regulatory structures. Because of the integrated, multimodal nature of defensive states, their adaptive regulation has to be highly dynamic to enable responding to a moving threatening stimulus. In this, predicting threat occurrence are crucial functions of calculating adequate responses. Based on its role in prediction error generation, its connectivity to limbic regions, and previous results on a role in fear learning, this review presents the cerebellum as a regulator of integrated cardio-behavioral defensive states.

The purpose of this study was to evaluate resident trainees' perspectives on the pediatric and adolescent gynecology (PAG) training in obstetrics and gynecology training programs in Europe. This study was a cross-sectional survey using an online questionnaire, on the basis of the PAG training in obstetrics and gynecology section of the European Board & College of Obstetrics and Gynaecology Project of Achieving Consensus in Training curriculum. We aimed to survey the national programs in 35 European Network of Trainees in Obstetrics and Gynaecology (ENTOG) member countries. Taking part in the survey was voluntary. The questionnaire was shared on the ENTOG online platforms. Ninety obstetrics and gynecology trainees in 33 of 35 countries responded to our questionnaire. Of the 35 ENTOG member countries, 33 participated in the survey, and a total of 90 responses were collected, giving a response rate of 9% of all European trainees and representing 94% of the member countries. Only 27% of trainees reported having a PAG rotation during their training program, and a PAG elective was only available to 34% of the trainees. Forty-one percent reported that PAG training was not included in their curriculum (no official rotations or lectures planned). Despite the lack of formal training, 72% of trainees felt able to diagnose and manage prepubertal vaginal bleeding and adnexal masses in children and adolescents by the end of their training. Most (58%) also confirmed that they could determine indications for treatment of vulval, vaginal, perineal, and rectal conditions. However, despite scoring positively for the management and counseling of subjects that often overlap with adult patients, such as "contraception in adolescents with health problems," "acute abdominal pain," "menstrual abnormalities," and "vaginal discharge," the study revealed poorer scores when the trainees were asked about more specific PAG topics such as "premature puberty" and "developmental disorders of the genital tract." Most core training programs across Europe do not include formal PAG training, and trainees reported a need to improve the provision of core PAG training in Europe. [ABSTRACT FROM AUTHOR]

The pathophysiological mechanisms of overactive bladder syndrome (OAB) remain largely unknown, with major involvement of the central nervous system (CNS). The periaqueductal gray (PAG) is a brainstem area which is indicated to play an essential role in bidirectional communication between the bladder and the CNS. We aimed to assess consistency of PAG functional organization across different bladder sensory states in OAB patients. We propose, that PAG functional organization patterns across sensory states will differ between controls and OAB patients. We analyzed fMRI scans at 7 Tesla from six controls and two OAB patients. The Louvain module detection algorithm was applied to parcellate the PAG in empty and full bladder states. We assessed within-subject consistency and investigated differences in this consistency between both groups. High within-subject agreement of PAG parcellations between empty and full bladder states was demonstrated in both groups. Additionally, we showed that the correlations between PAG clusters in both bladder states were significantly different in patients compared to controls (p = 0.039). The methods introduced here offer a promising tool to assess functional organization of the PAG and understand the underlying pathology and the role of this region in OAB syndrome. [ABSTRACT FROM AUTHOR]

To reduce fuel consumption, the automotive air-conditioning (AAC) system's coefficient of performance (COP) needs to be improved. The use of a diverse selection of hybrid nanolubricant composition ratios is expected to improve the properties of single nanolubricants, resulting in improved AAC system performance. The goal of this study was to find the best combination of hybrid nanolubricants for the best performance of the AAC system. Al2O3-SiO2/PAG hybrid nanolubricants at 0.06% volume concentrations with various composition ratios (20:80, 40:60, 50:50, 60:40, and 80:20) were investigated. An initial refrigerant charge of up to 155 g and a compressor speed of up to 2100 rpm were used in the experiment. The cooling capacity, compressor work, and COP of the AAC system were measured to determine its efficiency. The COP enhancement and compressor work reduction were recorded up to 16.31% and 18.65% for the 60:40 composition ratio, respectively. The maximum cooling capacity up to 75.84% was recorded for the 80:20 ratio, followed by 60:40. The maximum COP value of 8.81 for 155 g of hybrid nanolubricants was obtained at 900 rpm with a 60:40 composition ratio. Therefore, for optimal performance in the AAC system, a 60:40 composition ratio of the Al2O3-SiO2/PAG nanolubricant combination is strongly recommended. [ABSTRACT FROM AUTHOR]

The cooling properties of different cooling mediums were studied and heat treatment of high chromium cast iron was carried out by different cooling mediums. The results showed that the maximum cooling rate, cooling rate at 300 °C and the quenching liquid cooling capacity of water at 20 °C was 193.6 °C/s, 88.6 °C/s and 2431.1, respectively. With the increase in PAG concentration, the maximum cooling rate and the cooling rate at 300 °C of the coolant decreased. The microstructure of high chromium cast iron treated by water cooling, 10% PAG coolant and 20% coolant was white carbide + tempered martensite + retained austenite, and its impact toughness and fracture toughness were gradually improved. The water-cooled high chromium cast iron had the highest Rockwell hardness of 66.2 HRC, good wear resistance of 0.6103 g and the greatest friction coefficient of 0.4233, the high chromium cast iron treated with 10% PAG had the best wear resistance of 0.5715 and the lowest friction coefficient 0.4182, the high chromium cast iron treated with 20% PAG had the lowest Rockwell hardness 58.1 HRC and the worst wear resistance 0.8213 g. [ABSTRACT FROM AUTHOR]

Chronic itch severely reduces the quality of life of patients. Electroacupuncture (EA) is widely used to treat chronic itch. However, the underlying mechanism of this therapeutic action of EA is largely unknown. Cannabinoid CB1 receptors in the ventrolateral periaqueductal gray (vlPAG) mediate the analgesic effect of EA. Using a dry skin-induced itch model in mice, we determined whether EA treatment reduces chronic itch via CB1 receptors in the vlPAG. We showed that the optimal inhibitory effect of EA on chronic itch was achieved at the high frequency and high intensity (100 Hz and 3 mA) at "Quchi" (LI11) and "Hegu" (LI14) acupoints, which are located in the same spinal dermatome as the cervical skin lesions. EA reversed the increased expression of CB1 receptors in the vlPAG and decreased the concentration of 5-hydroxytryptamine (5-HT) in the medulla oblongata and the expression of gastrin-releasing peptide receptors (GRPR) in the cervical spinal cord. Furthermore, knockout of CB1 receptors on GABAergic neurons in the vlPAG attenuated scratching behavior and the 5-HT concentration in the medulla oblongata. In contrast, knockout of CB1 receptors on glutamatergic neurons in the vlPAG blocked the antipruritic effects of EA and the inhibitory effect of EA on the 5-HT concentration in the medulla oblongata. Our findings suggest that EA treatment reduces chronic itch by activation of CB1 receptors on glutamatergic neurons and inhibition of CB1 receptors on GABAergic neurons in the vlPAG, thereby inhibiting the 5-HT release from the medulla oblongata to GRPR-expressing neurons in the spinal cord. Our findings suggest that EA attenuates chronic itch via activating CB1 receptors expressed on glutamatergic neurons and downregulating CB1 receptors on GABAergic neurons in the vlPAG, leading to the reduction in 5-HT release in the rostroventral medulla and GRPR signaling in the spinal cord. Our study not only advances our understanding of the mechanisms of the therapeutic effect of EA on chronic itch but also guides the selection of optimal parameters and acupoints of EA for treating chronic itch. [ABSTRACT FROM AUTHOR]

Simple Summary: Dairy cows' fertility is very important for the success of the dairy farm. In addition, welfare issues are very important and can have an effect on cow performance. A pregnancy test is a routine precoder in cows that is usually conducted by rectal palpation performed around 40–45 days from last insemination. Another possibility is a milk test performed 28 days post insemination. The second procedure does not require the use of headlocks. This study compares those two methods and tests the effects on cow welfare and reproductive performance. The milk test resulted in a 16-day reduction in days open for cows identified as non-pregnant on day 28 compared to day 42 (rectal examination). Well-being indices such as rest time and lying ratio of milk-tested cows improved, especially in winter. In addition to fewer days open and economic improvement, early milk tests for pregnancy can free up the practitioner for other tasks on the dairy farm. The main pregnancy test method for dairy cows is rectal palpation performed around 40–45 days from last insemination. This is an invasive examination that disrupts the cow's routine, potentially affecting its well-being. We examined the effectiveness of a commercial kit for performing pregnancy tests on milk samples compared to rectal palpation at 28- and 42-days post insemination. Accordingly, the purpose of the current study was to check if performing early pregnancy test instead of rectal palpation would result in better welfare and improvement of the reproductive performance, at least in part, of the cows. At 28 days, we examined the effect of early pregnancy testing on reproductive performance, especially number of days open. At 42 days, we determined the pregnancy test methods' effects on cow welfare measures and milk production. For the day 28 experiment, cows on one farm were divided into two groups: one milk-tested for pregnancy on 28 to 30 days after insemination, and the other tested by routine veterinary examination (42 to 45 days after insemination). The milk test resulted in a 16-day reduction in days open for cows identified as non-pregnant on day 28 compared to day 42 (rectal examination), potentially improving reproductive performance on the dairy farm. For the day 42 experiment, test effects on cow welfare as seen in pedometer data and milk production were examined on two large dairy farms. Test-day milk production did not differ significantly between milk-tested and rectally palpated groups, but well-being indices of milk-tested cows improved, especially in winter months. The reason for this can be because, in the summer, cows are interrupted due to colling activities. In addition to fewer days open and economic improvement, early milk tests for pregnancy can free up the practitioner for other tasks on the dairy farm. [ABSTRACT FROM AUTHOR]

Objective: If a small for gestational age (SGA) foetus needs to be delivered because of severity (<3rd centile) attempting induction of labor theoretically increases the risk of caesarean section and neonatal acidosis, but these risks are poorly understood. This article aims to assess the risk of caesarean section and neonatal acidosis in attempted vaginal birth of a moderately preterm foetus in the setting of severe SGA., Method: A single-centre hospital-based observational study conducted over a period of 17 consecutive years in mothers with a single foetus in cephalic presentation with severe SGA (<3rd centile) needing foetal extraction. Neonatal acidosis was considered moderate if pH<7.10 and severe if pH<7.0. The degree of severity of SGA was estimated according to the birth weight ratio., Results: Four hundred and thirty-four foetuses with severe SGA were included during the period, 140 of whom were born after induction (32.3%). In this group, 66.4% of women achieved a vaginal birth (66.4%; 95% CI [58.0-74.2]) and the risk of moderate or severe acidosis was doubled compared with the group of foetuses who had undergone a planned caesarean section (7.9% vs. 3.1%, OR=2.7 [1.1-6.7]). Neither gestational age nor the degree of growth restriction was significantly related to the risk of caesarean section or to the risk of moderate or severe neonatal acidosis., Conclusion: In cases of severe SGA before 37weeks' gestation, induction of labour allows vaginal delivery in two-thirds of cases. It is accompanied by a doubling of the risk of moderate or severe neonatal acidosis., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

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The pathophysiology of migraine remains to be elucidated. We have recently shown that interictal migraineurs exhibit reduced fractional anisotropy (FA) in the root entry zone of the trigeminal nerve when compared to controls, but it is not known if this altered nerve anatomy is associated with changes within the brainstem or higher cortical brain regions. Diffusion tensor imaging of the brain was used to calculate regional measures of structure, including mean diffusivity (MD), axial diffusivity (AX) and radial diffusivity (RD) in addition to voxel-based morphometry of T1-weighted anatomical images. Linear relationships between trigeminal nerve anatomy (FA) and MD throughout the brainstem and/or higher cortical regions were determined in both controls (n = 31, brainstem; n = 38, wholebrain) and interictal migraineurs (n = 32, brainstem; n = 38, wholebrain). Additionally, within the same brain areas, relationships of AX and RD with nerve FA were determined. We found that in both interictal migraine and control participants, decreasing trigeminal nerve FA was associated with significantly increased MD in brainstem regions including the spinal trigeminal nucleus and midbrain periaqueductal gray matter (PAG), and in higher brain regions such as the hypothalamus, insula, posterior cingulate, primary somatosensory and primary visual (V1) cortices. Whereas, both control and migraineur groups individually displayed significant inverse correlations between nerve FA and MD, in migraineurs this pattern was disrupted in the areas of the PAG and V1, with only the control group displaying a significant linear relationship (PAG controls r = –0.58, p = 0.003; migraineurs r = –0.25, p = 0.17 and V1 controls r = −0.52, p = 0.002; migraineurs r = –0.10, p = 0.55). Contrastingly, we found no gray matter volume changes in brainstem or wholebrain areas. These data show that overall, trigeminal nerve anatomy is significantly related to regional brain structure in both controls and migraineurs. Importantly, the PAG showed a disruption of this relationship in migraineurs suggesting that the anatomy and possibly the function of the PAG is uniquely altered in episodic migraine, which may contribute to altered orofacial pain processing in migraine.

Introduction Depression is the most common comorbidity of migraine. The brain of migraineurs with depression shows differences compared to migraine only or depression only patients. The comorbidity may affect specific regions such as the periaqueductal gray matter (PAG) which is important in negative emotion regulation and pain modulatory system. Objectives We hypothesized that the alterations in PAG functional connectivity (FC) may play a role in migraineurs vulnerability for depression. Methods A resting-state fMRI was conducted with 34 episodic migraine without aura patients and 41 control subjects. All participants were medication free and they did not have any psychiatric or chronic disorders. Depressive symptoms were measured with Zung Self-Rating Depression Scale. To investigate the relationship between depressive symptoms and PAG functional connectivity, Zung scores were used as covariates in each groups’ PAG-FC analysis using the Statistical Parametric Mapping (SPM12) toolbox in MATLAB environment. Results There were no significant difference between migraine and control group in Zung scores (p=0.394). Negative correlation was found between Zung scores and PAG-FC with thalamus, fusiform gyrus, middle occipital gyrus and calcarine (pFWE

Descending pain modulatory systems (DPMS) that originate within the brain and act to modulate spinal nociceptive transmission are a major determinant of the acute and chronic pain experience. Investigations of these systems in basic scientific research is critical to the development of therapeutic strategies for the relief of pain. Despite our best efforts, something is lost in translation. This article will explore whether this is due in part to a primary focus on sensory modality leading to a failure to differentiate between descending control of A- vs. C-fiber mediated spinal nociception.

As a predominately positive emotion, nostalgia serves various adaptive functions, including a recently revealed analgesic effect. The current fMRI study aimed to explore the neural mechanisms underlying the nostalgia-induced analgesic effect on noxious thermal stimuli of different intensities. Human participants' (males and females) behavior results showed that the nostalgia paradigm significantly reduced participants' perception of pain, particularly at low pain intensities. fMRI analysis revealed that analgesia was related to decreased brain activity in pain-related brain regions, including the lingual and parahippocampal gyrus. Notably, anterior thalamic activation during the nostalgia stage predicted posterior parietal thalamus activation during the pain stage, suggesting that the thalamus might play a key role as a central functional linkage in the analgesic effect. Moreover, while thalamus-PAG functional connectivity was found to be related to nostalgic strength, periaqueductal gray-dorsolateral prefrontal cortex (PAG-dlPFC) functional connectivity was found to be associated with pain perception, suggesting possible analgesic modulatory pathways. These findings demonstrate the analgesic effect of nostalgia and, more importantly, shed light on its neural mechanism. [ABSTRACT FROM AUTHOR]

Abstract Background MicroRNAs indirectly orchestrate myriads of essential biological processes. A wide diversity of miRNAs of the neurodevelopmental importance characterizes the brain tissue, which, however, exhibits region-specific miRNA profile differences. One of the most conservative regions of the brain is periaqueductal grey (PAG) playing vital roles in significant functions of this organ, also those observed to be sex-influenced. The domestic pig is an important livestock species but is also believed to be an excellent human model. This is of particular importance for neurological research because of the similarity of pig and human brains as well as difficult access to human samples. However, the pig PAG profile has not been characterized so far. Moreover, molecular bases of sex differences connected with brain functioning, including miRNA expression profiles, have not been fully deciphered yet. Methods Thus, in this study, we applied next-generation sequencing to characterize pig PAG expressed microRNAs. Furthermore, we performed differential expression analysis between females and males to identify changes of the miRNA profile and reveal candidates underlying sex-related differences. Results As a result, known brain-enriched, and new miRNAs which will expand the available profile, were identified. The downstream analysis revealed 38 miRNAs being differentially expressed (DE) between female and male samples. Subsequent pathway analysis showed that they enrich processes vital for neuron growth and functioning, such as long-term depression and axon guidance. Among the identified sex-influenced miRNAs were also those associated with the PAG physiology and diseases related to this region. Conclusions The obtained results broaden the knowledge on the porcine PAG miRNAome, along with its dynamism reflected in different isomiR signatures. Moreover, they indicate possible mechanisms associated with sex-influenced differences mediated via miRNAs in the PAG functioning. They also provide candidate miRNAs for further research concerning, i.e., sex-related bases of physiological and pathological processes occurring in the nervous system. Graphical abstract

Noxious events that can cause physical damage to the body are perceived as threats. In the brainstem, the periaqueductal gray (PAG) ensures survival by generating an appropriate response to these threats. Hence, the experience of pain is coupled with threat signaling and interfaces in the dl/l and vlPAG columns. In this study, we triangulate the functional circuits of the dl/l and vlPAG by using static and time-varying functional connectivity (FC) in multiple fMRI scans in healthy participants (n = 37, 21 female). The dl/l and vlPAG were activated during cue, heat, and rating periods when the cue signaled a high threat of experiencing heat pain and when the incoming intensity of heat pain was unknown. Responses were significantly lower after low threat cues. The two regions responded similarly to the cued conditions but showed prominent distinctions in the extent of FC with other brain regions. Thus, both static and time-varying FC showed significant differences in the functional circuits of dl/l and vlPAG in rest and task scans. The dl/lPAG consistently synchronized with the salience network and the thalamus, suggesting a role in threat detection, while the vlPAG exhibited more widespread synchronization and frequently connected with memory/language and sensory regions. Hence, these two PAG regions process heat pain when stronger pain is expected or when it is uncertain, and preferentially synchronize with distinct brain circuits in a reproducible manner. The dl/lPAG seems more directly involved in salience detection, while the vlPAG seems engaged in contextualizing threats.

The pivotal role of the periaqueductal grey (PAG) in fear learning is reinforced by the identification of neurons in male rat ventrolateral PAG (vlPAG) that encode fear memory through signalling the onset and offset of an auditory-conditioned stimulus during presentation of the unreinforced conditioned tone (CS+) during retrieval. Some units only display CS+ onset or offset responses, and the two signals differ in extinction sensitivity, suggesting that they are independent of each other. In addition, understanding cerebellar contributions to survival circuits is advanced by the discovery that (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation leads in subsequent retrieval to (a) disruption of the temporal precision of vlPAG offset, but not onset responses to CS+, and (b) an increase in duration of freezing behaviour. And (ii) chemogenetic manipulation of the MCN-vlPAG projection during fear acquisition (a) reduces the occurrence of fear-related ultrasonic vocalisations, and (b) during subsequent retrieval, slows the extinction rate of fear-related freezing. These findings show that the cerebellum is part of the survival network that regulates fear memory processes at multiple timescales and in multiple ways, raising the possibility that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities.

The periaqueductal gray (PAG) is a region of the midbrain implicated in a variety of behaviors including defensive responses to threat. Despite the wealth of knowledge pertaining to the differential functional roles of the PAG columns in nonhuman and human research, the basic functional connectivity of the PAG at rest has not been well characterized. Therefore, the current study utilized 7-Tesla magnetic resonance imaging (MRI) to characterize PAG functional connectivity at rest and task activation under uncertain threat. A sample of 53 neurologically healthy undergraduate participants (Mage = 22.2, s.d.age = 3.62) underwent structural and resting state functional MRI scans. Supporting previous work, voxel-wise analyses showed that the PAG is functionally connected to emotion regulation and fear networks. The comparison of functional connectivity of PAG columns did not reveal any significant differences. Thirty-five participants from the same sample also completed an uncertain threat task with blocks of three conditions—no shock, predictable shock and unpredictable shock. There were no robust activity differences within the PAG columns or the whole PAG across conditions although there was differential activity at the voxel level in the PAG and in other regions theoretically relevant to uncertain threat. Results of this study elucidate PAG connectivity at rest and activation in response to uncertain threat. [ABSTRACT FROM AUTHOR]

Opposite emotions like fear and reward states often utilize the same brain regions. The bed nucleus of the stria terminalis (BNST) comprises one hub for processing fear and reward processes. However, it remains unknown how dorsal BNST (dBNST) circuits process these antagonistic behaviors. Here, we exploited a combined Pavlovian fear and reward conditioning task that exposed mice to conditioned tone stimuli (CS)s, either paired with sucrose delivery or footshock unconditioned stimuli (US). Pharmacological inactivation identified the dorsal BNST as a crucial element for both fear and reward behavior. Deep brain calcium imaging revealed opposite roles of two distinct dBNST neuronal output pathways to the periaqueductal gray (PAG) or paraventricular hypothalamus (PVH). dBNST neural activity profiles differentially process valence and Pavlovian behavior components: dBNST-PAG neurons encode fear CS, whereas dBNST-PVH neurons encode reward responding. Optogenetic activation of BNST-PVH neurons increased reward seeking, whereas dBNST-PAG neurons attenuated freezing. Thus, dBNST-PVH or dBNST-PAG circuitry encodes oppositely valenced fear and reward states, while simultaneously triggering an overall positive affective response bias (increased reward seeking while reducing fear responses). We speculate that this mechanism amplifies reward responding and suppresses fear responses linked to BNST dysfunction in stress and addictive behaviors. [ABSTRACT FROM AUTHOR]