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Objective: This study aims to investigate how reproductive experience (RE) alters thermal preference and thermoregulation in female mice, with a focus on estrogen receptor alpha (ERα)-expressing neurons in the preoptic area (POA). Methods: Thermal preference and body temperature were measured in female mice with and without RE, and virgin female mice with selective deletion of ERα from the POA (ERαPOA-KO). The number and activity of ERα-expressing POA neurons (ERαPOA) were assessed using immunohistochemistry and in vitro electrophysiology in response to temperature changes and ERα agonist. Results: We showed that female mice prefer a cooler environment starting from late pregnancy and persisting long term postpartum. Female mice with RE (>4 weeks post-weaning) displayed lower body temperature and a lower thermal preferred temperature, and lost preference for warm environments (30 °C) but preserved avoidance of cold environments (15 °C). This was associated with a significant decrease in the number of ERαPOA neurons. Importantly, virgin female ERαPOA-KO mice displayed lower thermal preferred temperature and impaired warm preference, mimicking RE mice. We further found that distinct ERαPOA subpopulations can be regulated by temperature changes with or without presynaptic blockers, and by ERα agonist. More importantly, RE decreased the number of warm-activated ERαPOA neurons and reduced the excitatory effects of warmth and estrogen-ERα signaling, while cold-activated ERαPOA neurons were slightly enhanced in female mice with RE. Conclusion: Our results support that the thermosensing ability and estrogenic effects in ERαPOA neurons are regulated by reproductive experience, altering thermal preference.

Contactors are extensively utilized in the control field. Enhancing the response speed and reducing mechanical tremors during switching-in hold great significance in improving contactor’s reliability. A novel A.C. contactor suitable for low-voltage environments has been developed based on the unique properties of the magnetic shape memory alloy (MSMA). It exhibited remarkable characteristics such as large dependent variables, fast response speed, and strong controllability. First, the magnetron characteristics of the MSMA were introduced. Then, the overall structure of the new contactor was designed based on the MSMA output characteristics and the contactor’s design requirements. Next, switching-in characteristics of the contactor under the drive signal were analyzed through simulation. Finally, an experimental measurement was carried out to test the performance of the prototype contactor during separating brake and switching in. The A.C. contactor driven by the MSMA could achieve a response speed of 9.8 ms. The contact movement in the switching process is smooth, which effectively avoids the occurrence of contact bounce in the closing process, which provides theoretical support for the development of the MSMA in the field of low-voltage electrical control application research.

Abstract Background Pro-opiomelanocortin (POMC) neurons play a sexually dimorphic role in body weight and glucose balance. However, the mechanisms for the sex differences in POMC neuron functions are not fully understood. Results We detected small conductance calcium-activated potassium (SK) current in POMC neurons. Secondary analysis of published single-cell RNA-Seq data showed that POMC neurons abundantly express SK3, one SK channel subunit. To test whether SK3 in POMC neurons regulates POMC neuron functions on energy and glucose homeostasis, we used a Cre-loxP strategy to delete SK3 specifically from mature POMC neurons. POMC-specific deletion of SK3 did not affect body weight in either male or female mice. Interestingly, male mutant mice showed not only decreased food intake but also decreased physical activity, resulting in unchanged body weight. Further, POMC-specific SK3 deficiency impaired glucose balance specifically in female mice but not in male mice. Finally, no sex differences were detected in the expression of SK3 and SK current in total POMC neurons. However, we found higher SK current but lower SK3 positive neuron population in male POMC neurons co-expressing estrogen receptor α (ERα) compared to that in females. Conclusion These results revealed a sexually dimorphic role of SK3 in POMC neurons in both energy and glucose homeostasis independent of body weight control, which was associated with the sex difference of SK current in a subpopulation of POMC + ERα + neurons.

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons — namely, glucose-inhibited (GI) neurons — paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood glucose and impaired counterregulatory responses during hypoglycemia in mice. Activation of VMHAno4 neurons increased food intake and blood glucose, while chronic inhibition of VMHAno4 neurons ameliorated hyperglycemia in a type 1 diabetic mouse model. Finally, we showed that VMHAno4 neurons represent a unique orexigenic VMH population and transmit a positive valence, while stimulation of neurons that do not express Ano4 in the VMH (VMHnon-Ano4) suppress feeding and transmit a negative valence. Together, our results indicate that the Ano4 channel and VMHAno4 neurons are potential therapeutic targets for human diseases with abnormal feeding behavior or glucose imbalance.

Abstract The brain, particularly the ventromedial hypothalamic nucleus (VMH), has been long known for its involvement in glucose sensing and whole-body glucose homeostasis. However, it is still not fully understood how the brain detects and responds to the changes in the circulating glucose levels, as well as brain-body coordinated control of glucose homeostasis. In this review, we address the growing evidence implicating the brain in glucose homeostasis, especially in the contexts of hypoglycemia and diabetes. In addition to neurons, we emphasize the potential roles played by non-neuronal cells, as well as extracellular matrix in the hypothalamus in whole-body glucose homeostasis. Further, we review the ionic mechanisms by which glucose-sensing neurons sense fluctuations of ambient glucose levels. We also introduce the significant implications of heterogeneous neurons in the VMH upon glucose sensing and whole-body glucose homeostasis, in which sex difference is also addressed. Meanwhile, research gaps have also been identified, which necessities further mechanistic studies in future.

Pro-opiomelanocortin (POMC) neurons are important for the regulation of body weight and glucose balance. The inhibitory tone to POMC neurons is mediated primarily by the GABA receptors. However, the detailed mechanisms and functions of GABA receptors are not well understood. The α5 subunit of GABAA receptor, Gabra5, is reported to regulate feeding, and we found that Gabra5 is highly expressed in POMC neurons. To explore the function of Gabra5 in POMC neurons, we knocked down Gabra5 specifically from mature hypothalamic POMC neurons using the clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 strategy. This POMC-specific knock-down of Gabra5 did not affect body weight or food intake in either male or female mice. Interestingly, the loss of Gabra5 caused significant increases in the firing frequency and resting membrane potential, and a decrease in the amplitude of the miniature inhibitory postsynaptic current (mIPSC) in male POMC neurons. However, the loss of Gabra5 only modestly decreased the frequency of mIPSC in female POMC neurons. Consistently, POMC-specific knock-down of Gabra5 significantly improved glucose tolerance in male mice but not in female mice. These results revealed a sexually dimorphic role of Gabra5 in POMC neuron activity and glucose balance, independent of body weight control.

Since the first clinical trials conducted after World War II, chemotherapeutic drugs have been extensively used in the clinic as the main cancer treatment either alone or as an adjuvant therapy before and after surgery. Although the use of chemotherapeutic drugs improved the survival of cancer patients, these drugs are notorious for causing many severe side effects that significantly reduce the efficacy of anti-cancer treatment and patients’ quality of life. Many widely used chemotherapy drugs including platinum-based agents, taxanes, vinca alkaloids, proteasome inhibitors, and thalidomide analogs may cause direct and indirect neurotoxicity. In this review we discuss the main effects of chemotherapy on the peripheral and central nervous systems, including neuropathic pain, chemobrain, enteric neuropathy, as well as nausea and emesis. Understanding mechanisms involved in chemotherapy-induced neurotoxicity is crucial for the development of drugs that can protect the nervous system, reduce symptoms experienced by millions of patients, and improve the outcome of the treatment and patients’ quality of life.

Purpose: Cancer patients receiving cisplatin therapy often experience side-effects such as nausea and emesis, but current anti-emetic regimens are suboptimal. Thus, to enable the development of efficacious anti-emetic treatments, the mechanisms of cisplatin-induced emesis must be determined. We therefore investigated these mechanisms in Suncus murinus, an insectivore that is capable of vomiting.Methods: We used a microelectrode array system to examine the effect of cisplatin on the spatiotemporal properties of slow waves in stomach antrum, duodenum, ileum and colon tissues isolated from S. murinus. In addition, we used a multi-wire radiotelemetry system to record conscious animals’ gastric myoelectric activity, core body temperature, blood pressure (BP) and heart rate viability over 96-h periods. Furthermore, we used whole-body plethysmography to simultaneously monitor animals’ respiratory activity. At the end of in vivo experiments, the stomach antrum was collected and immunohistochemistry was performed to identify c-Kit and cluster of differentiation 45 (CD45)-positive cells.Results: Our acute in vitro studies revealed that cisplatin (1–10 μM) treatment had acute region-dependent effects on pacemaking activity along the gastrointestinal tract, such that the stomach and colon responded oppositely to the duodenum and ileum. S. murinus treated with cisplatin for 90 min had a significantly lower dominant frequency (DF) in the ileum and a longer waveform period in the ileum and colon. Our 96-h recordings showed that cisplatin inhibited food and water intake and caused weight loss during the early and delayed phases. Moreover, cisplatin decreased the DF, increased the percentage power of bradygastria, and evoked a hypothermic response during the acute and delayed phases. Reductions in BP and respiratory rate were also observed. Finally, we demonstrated that treatment with cisplatin caused inflammation in the antrum of the stomach and reduced the density of the interstitial cells of Cajal (ICC).Conclusion: These studies indicate that cisplatin treatment of S. murinus disrupted ICC networking and viability and also affected general homeostatic mechanisms of the cardiovascular system and gastrointestinal tract. The effect on the gastrointestinal tract appeared to be region-specific. Further investigations are required to comprehensively understand these mechanistic effects of cisplatin and their relationship to emesis.

Perineuronal nets (PNNs) are widely present in the hypothalamus, and are thought to provide physical protection and ion buffering for neurons and regulate their synaptic plasticity and intracellular signaling. Recent evidence indicates that PNNs in the mediobasal hypothalamus play an important role in the regulation of glucose homeostasis. However, whether and how hypothalamic PNNs are regulated are not fully understood. In the present study, we examined whether PNNs in various hypothalamic regions in mice can be regulated by sex, gonadal hormones, dietary interventions, or their interactions. We demonstrated that gonadal hormones are required to maintain normal PNNs in the arcuate nucleus of hypothalamus in both male and female mice. In addition, PNNs in the terete hypothalamic nucleus display a sexual dimorphism with females higher than males, and high-fat diet feeding increases terete PNNs only in female mice but not in male mice. On the other hand, PNNs in other hypothalamic regions are not influenced by sex, gonadal hormones or dietary interventions. In summary, we demonstrated that hypothalamic PNNs are regulated in a region-specific manner and these results provide a framework to further investigate the potential functions of PNNs in regulating energy/glucose homeostasis at the interplay of sex, gonadal hormones and diets.

Nausea and emesis resulting from disease or drug treatment may be associated with disrupted gastric myoelectric activity (GMA). Conventional analytical techniques can determine the relative degrees of brady-, normo-, and tachygastric power, but lose information relative to the basic slow wave shape. The aim of the present study was to investigate the application of advanced analytical techniques in the analysis of disrupted GMA recorded after administration of sulprostone, a prostaglandin E3/1 agonist, in ferrets. Ferrets were implanted with radiotelemetry devices to record GMA, blood pressure, heart rate (HR) and core body temperature 1 week before the administration of sulprostone (30 μg/kg) or vehicle (saline, 0.5 mL/kg). GMA was initially analyzed using fast Fourier transformations (FFTs) and a conventional power partitioning. Detrended fluctuation analysis (DFA) was also applied to the GMA recordings to reveal information relative to the fluctuation of signals around local trends. Sample entropy (SampEn) analysis was used for examining the regularity of signals. Conventional signal processing techniques revealed that sulprostone increased the dominant frequency (DF) of slow waves, with an increase in the percentage power of the tachygastric range and a decrease in the percentage power of the normogastric range. DFA revealed that sulprostone decreased the fluctuation function, indicative of a loss of the variability of GMA fluctuations around local trends. Sulprostone increased SampEn values, indicating a loss of regularity in the GMA data. Behaviorally, sulprostone induced emesis and caused defecation. It also increased blood pressure and elevated HR, with an associated decrease in HR variability (HRV). Further analysis of HRV revealed a decrease in both low-frequency (LF) and high-frequency (HF) components, with an overall increase in the LF/HF ratio. Sulprostone did not affect core body temperature. In conclusion, DFA and SampEn permit a detailed analysis of GMA, which is necessary to understand the action of sulprostone to modulate gastric function. The action to decrease HRV and increase the LF/HF ratio may be consistent with a shift toward sympathetic nervous system dominance, commonly seen during nausea.

Ghrelin has well-known activity to stimulate appetite and weight gain. Evidence suggests that ghrelin may also have effects in reducing chemotherapy-induced emesis via growth hormone secretagogue receptors (GHS-R1A) in the brain. However, it is not known whether the stimulation of GHS-R1A has broad inhibitory anti-emetic effects. In the present studies, we used Suncus murinus to investigate the potential of the new and novel orally bioavailable brain-penetrating GHS-R1A mimetic, HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]urea), to reduce emesis induced by a variety of emetic challenges. HM01 (1 to 30 mg/kg, p.o.) antagonized emesis induced by cisplatin (30 mg/kg, i.p.) and by motion (4 cm horizontal displacement, 1 Hz) but was ineffective against emesis induced by nicotine (5 mg/kg, s.c.) and copper sulfate (120 mg/kg by intragastric gavage). In other experiments, HM01 (3 mg/kg, p.o.) enhanced the anti-emetic control of a regimen of palonosetron (0.01 mg/kg, p.o.) alone and palonosetron (0.01 mg/kg p.o.) plus netupitant (1 mg/kg, p.o.). HM01 (10 mg/kg, p.o.) also had positive effects in increasing feeding and drinking in nicotine-treated animals, and it shortened the latency to drink in animals treated with cisplatin. These data indicate that brain-penetrating GHS-R1A agonists may have use alone and/or in combination with standard anti-emetic regimens for the treatment of chemotherapy-induced nausea and vomiting and motion sickness.Highlights- The novel orally bioavailable brain-penetrating GHS-R1A agonist, HM01 (1-[(1S)-1-(2,3-dichloro-4-methoxyphenyl)ethyl]-3-methyl-3-[(4R)-1-Methyl-3,3-dimethyl-4-piperidyl]urea), antagonizes motion- and cisplatin-induced emesis.- HM01 did not reduce emesis induced by nicotine or by intragastric copper sulfate.- HM01 has positive effects on food consumption after treatment with nicotine.- HM01 has synergistic effects against cisplatin when combined with palonosetron and palonosetron/netupitant regimens.- It is suggested that GHS-R1A agonists may be protective against chemotherapy-induced nausea and vomiting in combination with traditional anti-emetics and against motion-induced emesis.

Motion sickness occurs under a variety of circumstances and is common in the general population. It is usually associated with changes in gastric motility, and hypothermia, which are argued to be surrogate markers for nausea; there are also reports that respiratory function is affected. As laboratory rodents are incapable of vomiting, Suncus murinus was used to model motion sickness and to investigate changes in gastric myoelectric activity (GMA) and temperature homeostasis using radiotelemetry, whilst also simultaneously investigating changes in respiratory function using whole body plethysmography. The anti-emetic potential of the highly selective histamine H1 receptor antagonists, mepyramine (brain penetrant), and cetirizine (non-brain penetrant), along with the muscarinic receptor antagonist, scopolamine, were investigated in the present study. On isolated ileal segments from Suncus murinus, both mepyramine and cetirizine non-competitively antagonized the contractile action of histamine with pKb values of 7.5 and 8.4, respectively; scopolamine competitively antagonized the contractile action of acetylcholine with pA2 of 9.5. In responding animals, motion (1 Hz, 4 cm horizontal displacement, 10 min) increased the percentage of the power of bradygastria, and decreased the percentage power of normogastria whilst also causing hypothermia. Animals also exhibited an increase in respiratory rate and a reduction in tidal volume. Mepyramine (50 mg/kg, i.p.) and scopolamine (10 mg/kg, i.p.), but not cetirizine (10 mg/kg, i.p.), significantly antagonized motion-induced emesis but did not reverse the motion-induced disruptions of GMA, or hypothermia, or effects on respiration. Burst analysis of plethysmographic-derived waveforms showed mepyramine also had increased the inter-retch+vomit frequency, and emetic episode duration. Immunohistochemistry demonstrated that motion alone did not induce c-fos expression in the brain. Paradoxically, mepyramine increased c-fos in brain areas regulating emesis control, and caused hypothermia; it also appeared to cause sedation and reduced the dominant frequency of slow waves. In conclusion, motion-induced emesis was associated with a disruption of GMA, respiration, and hypothermia. Mepyramine was a more efficacious anti-emetic than cetirizine, suggesting an important role of centrally-located H1 receptors. The ability of mepyramine to elevate c-fos provides a new perspective on how H1 receptors are involved in mechanisms of emesis control.

The shape estimation technique can help solve the end positioning or grasping control of soft robots. However, there is a lack of sensing and modeling techniques for accurate deformation estimation and soft robots with axial elongation, e.g., pneumatic soft actuators (PSAs). This paper presents a shape-self-sensing pneumatic soft actuator (SPSA) with integrated liquid-metal piecewise curvature sensors (LMCSs). Two types of LM composite (Ga-In-Sn/Ga2O3 composites for the sensor and Ga-In-Sn/NdFeB/Ni for the electronic wire) were used to build the strain sensor network. Furthermore, a piecewise variable curvature (PVC) model was developed to predict the bending deformation of the soft actuator. A two-SPSAs-based gripper was built to test the identification performance of LMCSs. The results indicate that SPSA could perform contact and size identification using the PVC model. In addition, the K-nearest neighbors (KNN) algorithm was used to classify the shape of the targets. Finally, the circular, triangular, and square targets were identified with an accuracy rate of 93.3%. The work was expected to be applied to the size and shape perception and deformation planning of soft robots. [ABSTRACT FROM AUTHOR]

Light plays an essential role in a variety of physiological processes, including vision, mood, and glucose homeostasis. However, the intricate relationship between light and an animal's feeding behavior has remained elusive. Here, we found that light exposure suppresses food intake, whereas darkness amplifies it in male mice. Interestingly, this phenomenon extends its reach to diurnal male Nile grass rats and healthy humans. We further show that lateral habenula (LHb) neurons in mice respond to light exposure, which in turn activates 5-HT neurons in the dorsal Raphe nucleus (DRN). Activation of the LHb5-HTDRN circuit in mice blunts darkness-induced hyperphagia, while inhibition of the circuit prevents light-induced anorexia. Together, we discovered a lightresponsive neural circuit that relays the environmental light signals to regulate feeding behavior in mice. [ABSTRACT FROM AUTHOR]

Obesity is a serious global health problem because of its increasing prevalence and comorbidities, but its treatments are limited. The serotonin 2C receptor (5-HT2CR), a G-protein-coupled receptor, activates proopiomelanocortin (POMC) neurons in the arcuate nucleus of hypothalamus (ARH) to reduce appetite and weight gain. However, several 5-HT analogs targeting this receptor, e.g., lorcaserin (Lor), suffer from diminished efficacy to reduce weight after prolonged administration. Here, we show that barbadin (Bar), a novel b-arrestin/b2-adaptin inhibitor, can prevent 5-HT2CR internalization in cells and potentiate long-term effects of Lor to reduce appetite and body weight in male mice. Mechanistically, we demonstrate that Bar co-treatment can effectively maintain the sensitivity of the 5-HT2CR in POMCARH neurons, despite prolonged Lor exposure, thereby allowing these neurons to be activated through opening the transient receptor potential cation (TRPC) channels. Thus, our results prove the concept that inhibition of 5-HT2CR desensitization can be a valid strategy to improve the long-term weight loss effects of Lor or other 5-HT2CR agonists, and also provide an intellectual framework to develop effective long-term management of weight by targeting 5-HT2CR desensitization. [ABSTRACT FROM AUTHOR]

Motion sickness occurs under a variety of circumstances and is common in the general population. It is usually associated with changes in gastric motility, and hypothermia, which are argued to be surrogate markers for nausea; there are also reports that respiratory function is affected. As laboratory rodents are incapable of vomiting, Suncus murinus was used to model motion sickness and to investigate changes in gastric myoelectric activity (GMA) and temperature homeostasis using radiotelemetry, whilst also simultaneously investigating changes in respiratory function using whole body plethysmography. The anti-emetic potential of the highly selective histamine H1 receptor antagonists, mepyramine (brain penetrant), and cetirizine (non-brain penetrant), along with the muscarinic receptor antagonist, scopolamine, were investigated in the present study. On isolated ileal segments from Suncus murinus, both mepyramine and cetirizine non-competitively antagonized the contractile action of histamine with pKb values of 7.5 and 8.4, respectively; scopolamine competitively antagonized the contractile action of acetylcholine with pA2 of 9.5. In responding animals, motion (1Hz, 4 cm horizontal displacement, 10 min) increased the percentage of the power of bradygastria, and decreased the percentage power of normogastria whilst also causing hypothermia. Animals also exhibited an increase in respiratory rate and a reduction in tidal volume. Mepyramine (50 mg/kg, i.p.) and scopolamine (10 mg/kg, i.p.), but not cetirizine (10 mg/kg, i.p.), significantly antagonized motion-induced emesis but did not reverse the motion-induced disruptions of GMA, or hypothermia, or effects on respiration. Burst analysis of plethysmographic-derived waveforms showed mepyramine also had increased the inter-retch+vomit frequency, and emetic episode duration. Immunohistochemistry demonstrated that motion alone did not induce c-fos expression in the brain. Paradoxically, mepyramine increased c-fos in brain areas regulating emesis control, and caused hypothermia; it also appeared to cause sedation and reduced the dominant frequency of slow waves. In conclusion, motion-induced emesis was associated with a disruption of GMA, respiration, and hypothermia. Mepyramine was a more efficacious anti-emetic than cetirizine, suggesting an important role of centrallylocated H1 receptors. The ability of mepyramine to elevate c-fos provides a new perspective on how H1 receptors are involved in mechanisms of emesis control. [ABSTRACT FROM AUTHOR]

The major female ovarian hormone, 17ß-estradiol (E2), can alter neuronal excitability within milliseconds to regulate a variety of physiological processes. Estrogen receptor-a (ERa), classically known as a nuclear receptor, exists as a membrane-bound receptor to mediate this rapid action of E2, but the ionic mechanisms remain unclear. Here, we show that a membrane channel protein, chloride intracellular channel protein-1 (Clic1), can physically interact with ERa with a preference to the membrane-bound ERa. Clic1-mediated currents can be enhanced by E2 and reduced by its depletion. In addition, Clic1 currents are required to mediate the E2-induced rapid excitations in multiple brain ERa populations. Further, genetic disruption of Clic1 in hypothalamic ERa neurons blunts the regulations of E2 on female body weight balance. In conclusion, we identified the Clic1 chloride channel as a key mediator for E2-induced rapid neuronal excitation, which may have a broad impact on multiple neurobiological processes regulated by E2. [ABSTRACT FROM AUTHOR]

Declined memory is a hallmark of Alzheimer's disease (AD). Experiments in rodents and human postmortem studies suggest that serotonin (5-hydroxytryptamine, 5-HT) plays a role in memory, but the underlying mechanisms are unknown. Here, we investigate the role of 5-HT 2C receptor (5-HT2CR) in regulating memory. Transgenic mice expressing a humanized HTR2C mutation exhibit impaired plasticity of hippocampal ventral CA1 (vCA1) neurons and reduced memory. Further, 5-HT neurons project to and synapse onto vCA1 neurons. Disruption of 5-HT synthesis in vCA1-projecting neurons or deletion of 5-HT2CRs in the vCA1 impairs neural plasticity and memory. We show that a selective 5-HT2CR agonist, lorcaserin, improves synaptic plasticity and memory in an AD mouse model. Cumulatively, we demonstrate that hippocampal 5-HT2CR signaling regulates memory, which may inform the use of 5-HT2CR agonists in the treatment of dementia. [ABSTRACT FROM AUTHOR]