Dorsal motor vagal neurons can elicit bradycardia and reduce anxiety-like behavior.

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVNNA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole-cell patch-clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs and is capable of cardioinhibition and robust anxiolysis.

Molecular Connectomics Reveals a Glucagon-Like Peptide 1 Sensitive Neural Circuit for Satiety.

Liraglutide and other agonists of the glucagon-like peptide 1 receptor (GLP-1RAs) are effective weight loss drugs, but how they suppress appetite remains unclear. GLP-1RAs inhibit hunger-promoting Agouti-related peptide (AgRP) neurons of the arcuate hypothalamus (Arc) but only indirectly, implicating synaptic afferents to AgRP neurons. To investigate, we developed a method combining rabies-based connectomics with single-nuclei transcriptomics. Applying this method to AgRP neurons in mice predicts 21 afferent subtypes in the mediobasal and paraventricular hypothalamus. Among these are Trh+ Arc neurons (TrhArc), which express the Glp1r gene and are activated by the GLP-1RA liraglutide. Activating TrhArc neurons inhibits AgRP neurons and decreases feeding in an AgRP neuron-dependent manner. Silencing TrhArc neurons increases feeding and body weight and reduces liraglutide's satiating effects. Our results thus demonstrate a widely applicable method for molecular connectomics, reveal the molecular organization of AgRP neuron afferents, and shed light on a neurocircuit through which GLP-1RAs suppress appetite.

Dorsal Motor Vagal Neurons Can Elicit Bradycardia and Reduce Anxiety-Like Behavior.

Cardiovagal neurons (CVNs) innervate cardiac ganglia through the vagus nerve to control cardiac function. Although the cardioinhibitory role of CVNs in nucleus ambiguus (CVNNA) is well established, the nature and functionality of CVNs in dorsal motor nucleus of the vagus (CVNDMV) is less clear. We therefore aimed to characterize CVNDMV anatomically, physiologically, and functionally. Optogenetically activating cholinergic DMV neurons resulted in robust bradycardia through peripheral muscarinic (parasympathetic) and nicotinic (ganglionic) acetylcholine receptors, but not beta-1-adrenergic (sympathetic) receptors. Retrograde tracing from the cardiac fat pad labeled CVNNA and CVNDMV through the vagus nerve. Using whole cell patch clamp, CVNDMV demonstrated greater hyperexcitability and spontaneous action potential firing ex vivo despite similar resting membrane potentials, compared to CVNNA. Chemogenetically activating DMV also caused significant bradycardia with a correlated reduction in anxiety-like behavior. Thus, DMV contains uniquely hyperexcitable CVNs capable of cardioinhibition and robust anxiolysis.

Leptin receptor neurons in the dorsomedial hypothalamus input to the circadian feeding network.

Salient cues, such as the rising sun or availability of food, entrain biological clocks for behavioral adaptation. The mechanisms underlying entrainment to food availability remain elusive. Using single-nucleus RNA sequencing during scheduled feeding, we identified a dorsomedial hypothalamus leptin receptor-expressing (DMHLepR) neuron population that up-regulates circadian entrainment genes and exhibits calcium activity before an anticipated meal. Exogenous leptin, silencing, or chemogenetic stimulation of DMHLepR neurons disrupts the development of molecular and behavioral food entrainment. Repetitive DMHLepR neuron activation leads to the partitioning of a secondary bout of circadian locomotor activity that is in phase with the stimulation and dependent on an intact suprachiasmatic nucleus (SCN). Last, we found a DMHLepR neuron subpopulation that projects to the SCN with the capacity to influence the phase of the circadian clock. This direct DMHLepR-SCN connection is well situated to integrate the metabolic and circadian systems, facilitating mealtime anticipation.

Altered circadian behavior and light sensing in mouse models of Alzheimer's disease.

Circadian symptoms have long been observed in Alzheimer's disease (AD) and often appear before cognitive symptoms, but the mechanisms underlying circadian alterations in AD are poorly understood. We studied circadian re-entrainment in AD model mice using a "jet lag" paradigm, observing their behavior on a running wheel after a 6 h advance in the light:dark cycle. Female 3xTg mice, which carry mutations producing progressive amyloid beta and tau pathology, re-entrained following jet lag more rapidly than age-matched wild type controls at both 8 and 13 months of age. This re-entrainment phenotype has not been previously reported in a murine AD model. Because microglia are activated in AD and in AD models, and inflammation can affect circadian rhythms, we hypothesized that microglia contribute to this re-entrainment phenotype. To test this, we used the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, which rapidly depletes microglia from the brain. Microglia depletion did not alter re-entrainment in either wild type or 3xTg mice, demonstrating that microglia activation is not acutely responsible for the re-entrainment phenotype. To test whether mutant tau pathology is necessary for this behavioral phenotype, we repeated the jet lag behavioral test with the 5xFAD mouse model, which develops amyloid plaques, but not neurofibrillary tangles. As with 3xTg mice, 7-month-old female 5xFAD mice re-entrained more rapidly than controls, demonstrating that mutant tau is not necessary for the re-entrainment phenotype. Because AD pathology affects the retina, we tested whether differences in light sensing may contribute to altered entrainment behavior. 3xTg mice demonstrated heightened negative masking, a circadian behavior measuring responses to different levels of light, and re-entrained dramatically faster than WT mice in a jet lag experiment performed in dim light. 3xTg mice show a heightened sensitivity to light as a circadian cue that may contribute to accelerated photic re-entrainment. Together, these experiments demonstrate novel circadian behavioral phenotypes with heightened responses to photic cues in AD model mice which are not dependent on tauopathy or microglia.

Comparison of the Particulate Steroids, Betamethasone and Methylprednisolone, in Caudal Steroid Injection Under Ultrasound Guidance.

BACKGROUND: Pain relief in lumbar disc hernias is a challenging condition. This study retrospectively compared particulate steroids, methylprednisolone acetate (mid-term effective), against betamethasone acetate (long-term effective) on ultrasound-guided caudal epidural injection for lumbar disc herniation. METHODS: A total of 40 patients with L4-5 and/or L5-S1 disc herniation were treated with ultrasound-guided caudal epidural injection between September 2021 and June 2022. Nineteen patients who were given methylprednisolone acetate (group A) as a steroid and a total of 21 patients who were used betamethasone acetate (Group B) were retrospectively collected, and their pain levels and functional improvement were compared retrospectively before, immediately after, and 3 weeks after the injection in terms of the visual analog scale (VAS) and Oswestry Disability Index (ODI) as the efficacy value. RESULTS: There was no statistically significant difference between the groups regarding age, gender, and body mass index (P > 0.05). In group A, preop VAS was 8.84 ± 0.76, immediate postop period 3.10 ± 1.37, and postop third week was 4.73 ± 2.32. In group B, the preop VAS was 8.76 ± 0.76, the postop early period was 3.14 ± 1.27, and the postop third week was 3.12 ± 1.30. In group A preop ODI was 49.84 ± 9.11 and postop third week was 22.84 ± 6.44. In group B, the preop ODI was 46.71 ± 16.15 and postop third week was 30.80 ± 17.65. Significant changes were observed in the reduction of VAS values after the procedure in both groups during the early postoperative period and the third week (P value < 0.05). However, a significant difference was not found between the changes in VAS values between the groups (P value > 0.005). Similarly, significant changes were observed in the decrease of ODI values after the procedure in both groups during the early postoperative period and the third week (P value < 0.05). However, no significant difference was observed in the ODI scores between the two groups. CONCLUSIONS: No significant difference was observed between betamethasone and methylprednisolone. Both steroid groups showed a substantial improvement in the preoperative pain scores of the patients.

Comprehensive evaluation of photoelectrochemical performance dependence on geometric features of ZnO nanorod electrodes.

The impact of geometric features, light absorption spectra, and electrochemical active surface area on photoelectrochemical properties was investigated in this work. Nanoforests of ZnO nanorods with rationally controlled morphologies were grown on ITO substrates by the hydrothermal method and utilized as a model for this purpose. The size of the nanorods was systematically adjusted by varying the concentration of polyethyleneimine as a cation surfactant in the growth solution. It was found that the emergent geometric characteristics (i.e. the aspect ratio) increased almost at the same pace as the electrochemically active surface area, but the light scattering effect slightly increased as a result of the random spatial orientation of the nanorods. The large surface area and the void space between nanorods increased the photon-to-current conversion efficiency by promoting the hole transfer process at the electrode/electrolyte interface. A maximum photocurrent density of 0.06 mA cm-2 (0.5 V vs. NHE) for smaller diameter and length ZnO nanorods (ZnO-P1) was obtained under 365 nm UV light illumination. Additionally, we provide visual evidence that a shorter photogenerated hole diffusion distance results in improved charge separation efficiency using Mn2+ as the photogenerated hole imaging agent. Therefore, the present work demonstrates a facile strategy for nanoforest morphology improvement for generating strong contact at the ZnO NR electrode/electrolyte interface, which is favourable in energy conversion and storage technologies.

Altered circadian behavior and light sensing in mouse models of Alzheimer's disease.

Circadian symptoms have long been observed in Alzheimer's disease (AD) and often appear before cognitive symptoms, but the mechanisms underlying circadian alterations in AD are poorly understood. We studied circadian re-entrainment in AD model mice using a "jet lag" paradigm, observing their behavior on a running wheel after a six hour advance in the light:dark cycle. Female 3xTg mice, which carry mutations producing progressive amyloid beta and tau pathology, re-entrained following jet lag more rapidly than age-matched wild type controls at both 8 and 13 months of age. This re-entrainment phenotype has not been previously reported in a murine AD model. Because microglia are activated in AD and in AD models, and inflammation can affect circadian rhythms, we hypothesized that microglia contribute to this re-entrainment phenotype. To test this, we used the colony stimulating factor 1 receptor (CSF1R) inhibitor PLX3397, which rapidly depletes microglia from the brain. Microglia depletion did not alter re-entrainment in either wild type or 3xTg mice, demonstrating that microglia activation is not acutely responsible for the re-entrainment phenotype. To test whether mutant tau pathology is necessary for this behavioral phenotype, we repeated the jet lag behavioral test with the 5xFAD mouse model, which develops amyloid plaques, but not neurofibrillary tangles. As with 3xTg mice, 7-month-old female 5xFAD mice re-entrained more rapidly than controls, demonstrating that mutant tau is not necessary for the re-entrainment phenotype. Because AD pathology affects the retina, we tested whether differences in light sensing may contribute to altered entrainment behavior. 3xTg mice demonstrated heightened negative masking, an SCN-independent circadian behavior measuring responses to different levels of light, and re-entrained dramatically faster than WT mice in a jet lag experiment performed in dim light. 3xTg mice show a heightened sensitivity to light as a circadian cue that may contribute to accelerated photic re-entrainment. Together, these experiments demonstrate novel circadian behavioral phenotypes with heightened responses to photic cues in AD model mice which are not dependent on tauopathy or microglia.

A leptin-responsive hypothalamic circuit inputs to the circadian feeding network.

Salient cues, such as the rising sun or the availability of food, play a crucial role in entraining biological clocks, allowing for effective behavioral adaptation and ultimately, survival. While the light-dependent entrainment of the central circadian pacemaker (suprachiasmatic nucleus, SCN) is relatively well defined, the molecular and neural mechanisms underlying entrainment associated with food availability remains elusive. Using single nucleus RNA sequencing during scheduled feeding (SF), we identified a leptin receptor (LepR) expressing neuron population in the dorsomedial hypothalamus (DMH) that upregulates circadian entrainment genes and exhibits rhythmic calcium activity prior to an anticipated meal. We found that disrupting DMHLepR neuron activity had a profound impact on both molecular and behavioral food entrainment. Specifically, silencing DMHLepR neurons, mis-timed exogenous leptin administration, or mis-timed chemogenetic stimulation of these neurons all interfered with the development of food entrainment. In a state of energy abundance, repetitive activation of DMHLepR neurons led to the partitioning of a secondary bout of circadian locomotor activity that was in phase with the stimulation and dependent on an intact SCN. Lastly, we discovered that a subpopulation of DMHLepR neurons project to the SCN with the capacity to influence the phase of the circadian clock. This leptin regulated circuit serves as a point of integration between the metabolic and circadian systems, facilitating the anticipation of meal times.

Primary, Dural-based, Ewing sarcoma in a pediatric patient: presentation of a rare tumor entity with literature review.

Primary Ewing's sarcoma originating from the calvaria bone and/or underlying Dural involvement has been reported relatively rarely in the literature. Those originating from the dura and invading the bone above it in both directions, both towards the brain parenchyma and via the dura, are even rarer. CASE DESCRIPTION: We present a case of a 14-year-old girl with no known focal neurological deficit who presented with the complaint of vertigo for only 2 months. In neuroradiological examination, the left frontoparietal region of the brain showed the presence of a tumor originating from the dura, invading both bone and brain parenchyma. No other tumor location was discovered after radiological examination. Since the patient had a shift in the brain and progressive loss of strength on the right side, the patient was taken to surgery for tumor excision. The frozen result sent per-operatively was consistent with a round blue cell tumor. Adjuvant chemotherapy treatment was given to the patient after the definitive pathology report was compatible with Ewing's sarcoma. CONCLUSION: The patient had an uneventful neurological recovery without permanent neurological deficit. When the patient was kept under close clinical and radiological surveillance 1 year after the operation, no recurrence of the disease was observed. Bone marrow biopsy results and pet computerized tomography results confirmed the case of primary intracerebral Ewing sarcoma. This case illustrates an extremely rare location of primary Ewing's sarcoma with a set of clinical signs and symptoms extremely rare for this location of this rare disease entity.

Effects of different maceration techniques on the colour, polyphenols and antioxidant capacity of grape juice.

This study investigated the effects of different maceration techniques on the colour parameters, phenolic content and antioxidant activity of grape juice. Maceration techniques influenced colour parameters, and a* and Hue ranged from -0.77 to 0.55 and 60.90 to 104.40, respectively. The microwave and microwave and sonication combination increased the total monomeric anthocyanin, phenolic and flavonoid contents. Malvidin 3-O-glucoside increased more than twofold, and delphinidin 3-O-glucoside and cyanidin 3-O-glucoside increased one fold according to the enzymatic method in the microwave treatments. The microwave technique was the most effective technique for antioxidant capacity, but sonication, cold and thermosonication results were lower than enzymatic treatment. The microwave and microwave and sonication enhanced the polyphenols with strong antioxidant power, such as catechin from 0.87 to 37.40 and trans-resveratrol from 0.09 to 0.23 mg/100 g, by comparison with the enzymatic technique. The findings suggested these two techniques were the most effective techniques for maceration.

Food-induced dopamine signaling in AgRP neurons promotes feeding.

Obesity comorbidities such as diabetes and cardiovascular disease are pressing public health concerns. Overconsumption of calories leads to weight gain; however, neural mechanisms underlying excessive food consumption are poorly understood. Here, we demonstrate that dopamine receptor D1 (Drd1) expressed in the agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons of the arcuate hypothalamus is required for appropriate responses to a high-fat diet (HFD). Stimulation of Drd1 and AgRP/NPY co-expressing arcuate neurons is sufficient to induce voracious feeding. Delivery of a HFD after food deprivation acutely induces dopamine (DA) release in the ARC, whereas animals that lack Drd1 expression in ARCAgRP/NPY neurons (Drd1AgRP-KO) exhibit attenuated foraging and refeeding of HFD. These results define a role for the DA input to the ARC that encodes acute responses to food and position Drd1 signaling in the ARCAgRP/NPY neurons as an integrator of the hedonic and homeostatic neuronal feeding circuits.

Dopamine systems and biological rhythms: Let's get a move on.

How dopamine signaling regulates biological rhythms is an area of emerging interest. Here we review experiments focused on delineating dopamine signaling in the suprachiasmatic nucleus, nucleus accumbens, and dorsal striatum to mediate a range of biological rhythms including photoentrainment, activity cycles, rest phase eating of palatable food, diet-induced obesity, and food anticipatory activity. Enthusiasm for causal roles for dopamine in the regulation of circadian rhythms, particularly those associated with food and other rewarding events, is warranted. However, determining that there is rhythmic gene expression in dopamine neurons and target structures does not mean that they are bona fide circadian pacemakers. Given that dopamine has such a profound role in promoting voluntary movements, interpretation of circadian phenotypes associated with locomotor activity must be differentiated at the molecular and behavioral levels. Here we review our current understanding of dopamine signaling in relation to biological rhythms and suggest future experiments that are aimed at teasing apart the roles of dopamine subpopulations and dopamine receptor expressing neurons in causally mediating biological rhythms, particularly in relation to feeding, reward, and activity.

A building block-based beam-break (B5) locomotor activity monitoring system and its use in circadian biology research.

Locomotor activity is one of the most commonly assayed animal behaviors. It is the gold standard for assessing behavioral circadian rhythmicity. Here, we develop a flexible and affordable locomotor activity monitoring system that does not interfere with the behavior of animals. We validate the reliability of the system in multiple circadian biology research scenarios. This device is customizable and can be used for many animal species.

Local Drd1-neurons input to subgroups of arcuate AgRP/NPY-neurons.

Obesity is a pandemic afflicting more than 300 million people worldwide, driven by consumption of calorically dense and highly rewarding foods. Dopamine (DA) signaling has been implicated in neural responses to highly palatable nutrients, but the exact mechanisms through which DA modulates homeostatic feeding circuits remains unknown. A subpopulation of arcuate (ARC) agouti-related peptide (AgRP)/neuropeptide Y (NPY) (ARCAgRP/NPY+) neurons express the D(1A) dopamine receptor (Drd1) and are stimulated by DA, suggesting one potential avenue for dopaminergic regulation of food intake. Using patch clamp electrophysiology, we evaluated the responses of ARC Drd1-expressing (ARCDrd1+) neurons to overnight fasting and leptin. Collectively, ARCDrd1+ neurons were less responsive to caloric deficit than ARCAgRP/NPY+ neurons; however, ARCDrd1+ neurons were inhibited by the satiety hormone leptin. Using Channelrhodopsin-2-Assisted Circuit Mapping, we identified novel subgroups of ARCDrd1+ neurons that inhibit or excite ARCAgRP/NPY+ neurons. These findings suggest dopamine receptive neurons have multimodal actions in food intake circuits.

Lack of TRPV1 Channel Modulates Mouse Gene Expression and Liver Proteome with Glucose Metabolism Changes.

To investigate the role of the transient receptor potential channel vanilloid type 1 (TRPV1) in hepatic glucose metabolism, we analyzed genes related to the clock system and glucose/lipid metabolism and performed glycogen measurements at ZT8 and ZT20 in the liver of C57Bl/6J (WT) and Trpv1 KO mice. To identify molecular clues associated with metabolic changes, we performed proteomics analysis at ZT8. Liver from Trpv1 KO mice exhibited reduced Per1 expression and increased Pparα, Pparγ, Glut2, G6pc1 (G6pase), Pck1 (Pepck), Akt, and Gsk3b expression at ZT8. Liver from Trpv1 KO mice also showed reduced glycogen storage at ZT8 but not at ZT20 and significant proteomics changes consistent with enhanced glycogenolysis, as well as increased gluconeogenesis and inflammatory features. The network propagation approach evidenced that the TRPV1 channel is an intrinsic component of the glucagon signaling pathway, and its loss seems to be associated with increased gluconeogenesis through PKA signaling. In this sense, the differentially identified kinases and phosphatases in WT and Trpv1 KO liver proteomes show that the PP2A phosphatase complex and PKA may be major players in glycogenolysis in Trpv1 KO mice.

False positive effect of sulfur sources used in growing and processing of vine (Vitis Vinifera L.) leaves on the results of dithiocarbamate analysis based on carbon disulfide measurement.

Vine leaves, which are produced fresh, brined or fermented from the leaves of Vitis Vinifera in Türkiye are an important food. Sulfur is used as a pesticide and sulfur compounds can be used as additives during the growing and processing of the vine leaves. These sulfur sources cause positive results on carbon disulfide (CS2) measurements by GC-MS. Therefore, the main objective of the present study was to investigate the effects of residues of sulfur or sulfur compounds on dithiocarbamate analysis methods based on CS2 measurement. For this, vine leaves were produced by controlled agricultural production and processed as brine under controlled conditions. The sulfur dioxide (SO2) and dithiocarbamate analysis were carried out on the vine leave obtained by applying sulfur spraying in agricultural treatments and brined vine leaves produced by adding sodium metabisulfite (SM), and control samples of each stage. SO2 was not detected in any of the samples in this study. SO2 residues did not occur in the vine leaves as a result of the sulfur spraying application and therefore did not have a false positive effect on dithiocarbamate analysis. However, approximately 0.15 mg kg-1 false positive dithiocarbamate was detected, which is thought to originate from natural sulfur in the vine leaves. The effect of SM, which was used in low concentration in the production of brined vine leaves, on dithiocarbamate results was limited. Even if SM was not used, the total false positive dithiocarbamate result in the brined vine leaves production process was approximately determined as 0.20 mg kg-1. This study showed that the dithiocarbamates analysis method based on CS2 measurement may lead to false positive results in brined vine leaves since sulfur compounds are found naturally in vine leaves.

Boosting the Photoelectrochemical Performance of Au/ZnO Nanorods by Co-Occurring Gradient Doping and Surface Plasmon Modification.

Band bending modification of metal/semiconductor hybrid nanostructures requires low-cost and effective designs in photoelectrochemical (PEC) water splitting. To this end, it is evinced that gradient doping of Au nanoparticles (NPs) inwards the ZnO nanorods (NRs) through thermal treatment facilitated faster transport of the photo-induced charge carriers. Systematic PEC measurements show that the resulting gradient Au-doped ZnO NRs yielded a photocurrent density of 0.009 mA/cm2 at 1.1 V (vs. NHE), which is 2.5-fold and 8-fold improved compared to those of Au-sensitized ZnO and the as-prepared ZnO NRs, respectively. The IPCE and ABPE efficiency tests confirmed the boosted photoresponse of gradient Au-incorporated ZnO NRs, particularly in the visible spectrum due to the synergistic surface plasmonic effect of Au NPs. A gradient Au dopant profile promoted the separation and transfer of the photo-induced charge carriers at the electrolyte interface via more upward band bending according to the elaborated electrochemical impedance spectroscopy and Kelvin probe force microscopy analyses. Therefore, this research presents an economical and facile strategy for preparing gradient plasmonic noble NP-incorporated semiconductor NRs, which have excellent potential in energy conversion and storage technologies.

Long-term high fat diet consumption reversibly alters feeding behavior via a dopamine-associated mechanism in mice.

Obesity is a costly, global epidemic that is perpetuated by an unhealthy diet. A significant factor in the initial consumption and maintenance of an unhealthy diet is the abundance of highly palatable, calorically dense foods. The aim of the present study is to better understand the effects of high fat diet (HFD) consumption on food valuation and preference, and to elucidate the neurobiological mechanisms mediating these effects. By using a novel food preference assay, we found that prolonged consumption of a HFD diminishes preference for and consumption of the more calorically dense food choice when two lab diets are presented. Additionally, we demonstrated that prolonged HFD consumption dampens ventral tegmental c-fos induction during hedonic feeding, implicating the mesolimbic dopamine signaling pathway as a target of HFD. Notably, both the changes in food preference and this reduced c-fos induction were reversed during withdrawal from HFD. Further, HFD-induced alterations in food preference were attenuated by exercise. Our findings suggest that prolonged HFD consumption leads to anhedonia and altered feeding choices, and this is associated with changes in mesolimbic dopamine signaling.