Pyrazolone compounds could inhibit CES1 and ameliorates fat accumulation during adipocyte differentiation.

Carboxylesterase 1 (CES1), a member of the serine hydrolase superfamily, is involved in a wide range of xenobiotic and endogenous substances metabolic reactions in mammals. The inhibition of CES1 could not only alter the metabolism and disposition of related drugs, but also be benefit for treatment of metabolic disorders, such as obesity and fatty liver disease. In the present study, we aim to develop potential inhibitors of CES1 and reveal the preferred inhibitor structure from a series of synthetic pyrazolones (compounds 1-27). By in vitro high-throughput screening method, we found compounds 25 and 27 had non-competitive inhibition on CES1-mediated N-alkylated d-luciferin methyl ester (NLMe) hydrolysis, while compound 26 competitively inhibited CES1-mediated NLMe hydrolysis. Additionally, Compounds 25, 26 and 27 can inhibit CES1-mediated fluorescent probe hydrolysis in live HepG2 cells with effect. Besides, compounds 25, 26 and 27 could effectively inhibit the accumulation of lipid droplets in mouse adipocytes cells. These data not only provided study basis for the design of newly CES1 inhibitors. The present study not only provided the basis for the development of lead compounds for novel CES1 inhibitors with better performance, but also offered a new direction for the explore of candidate compounds for the treatment of hyperlipidemia and related diseases.

Imaging lifespan brain structural growth: From region, to connectome, to gradient.

Throughout human life, the brain undergoes intricate structural changes that support cognition. A study in PLOS Biology introduces new avenues for depicting the trajectory of the brain morphometric connectome and its underlying genetic and molecular mechanisms.

General anesthetic agents induce neurotoxicity through oligodendrocytes in the developing brain.

General anesthetic agents can impact brain function through interactions with neurons and their effects on glial cells. Oligodendrocytes perform essential roles in the central nervous system, including myelin sheath formation, axonal metabolism, and neuroplasticity regulation. They are particularly vulnerable to the effects of general anesthetic agents resulting in impaired proliferation, differentiation, and apoptosis. Neurologists are increasingly interested in the effects of general anesthetic agents on oligodendrocytes. These agents not only act on the surface receptors of oligodendrocytes to elicit neuroinflammation through modulation of signaling pathways, but also disrupt metabolic processes and alter the expression of genes involved in oligodendrocyte development and function. In this review, we summarize the effects of general anesthetic agents on oligodendrocytes. We anticipate that future research will continue to explore these effects and develop strategies to decrease the incidence of adverse reactions associated with the use of general anesthetic agents.

Ultrawide Spectra Camouflage Coatings from Metallic Flake Powder.

Ultrawide-spectra-compatible camouflage materials are imperative for military science and national security due to the continuous advancement of various sophisticated multispectral detectors. However, ultrawide spectra camouflage still has challenges, as the spectral requirements for different bands are disparate and even conflicting. This work demonstrates an ultrawide spectra camouflage material compatible with visible (VIS, 400-800 nm), infrared (IR, 3-5 and 8-14 µm), and microwave (S-Ku bands, 2-12 GHz). The carbon nanotubes adsorbed on porous anodic alumina/aluminum flake powder (CNTs@PAA/AFP) material for ultrawide spectra camouflage is composed of bioinspired porous alumina surface layers for low visible reflection and aluminum flake powder substrate for low infrared emissivity, while the surface of the porous alumina layers is loaded with carbon nanotubes for microwave absorption. Compared with previous low-emissivity materials, CNTs@PAA/AFP has omnidirectional low reflectance (Ravg = 0.29) and high gray scale (72%) in the visible band. Further, it exhibits low emissivity (ε3-5µm = 0.15 and ε8-14µm = 0.18) in the dual infrared atmospheric window, which reduces the infrared lock-on range by 59.6%/49.8% in the mid/far-infrared band at high temperatures (573 K). The infrared camouflage performance calculated from the radiation temperature of CNTs@PAA/AFP coatings is enhanced to over 65%, which is at least 4 times greater than that of its substrate. In addition, the CNTs@PAA/AFP coating achieves high microwave absorption (RLmin = -42.46 dB) and an effective absorption bandwidth (EAB = 7.43 GHz) in the microwave band (S-Ku bands) due to the enhancement of interfacial polarization and conductive losses. This study may introduce new insight and feasible methods for multispectral manipulation, electromagnetic signal processing, and thermal management via bioinspired structural design and fabrication.

Status and influencing factors of nurses' burnout: A cross-sectional study during COVID-19 regular prevention and control in Jiangsu Province, China.

Background: Chinese nurses working with immense stress may have issues with burnout during COVID-19 regular prevention and control. There were a few studies investigating status of burnout and associated factors among Chinese nurses. However, the relationships remained unclear. Objectives: To investigate status and associated factors of nurses' burnout during COVID-19 regular prevention and control. Methods: 784 nurses completed questionnaires including demographics, Generalized Anxiety Disorder-7, Patient Health Questionnaire-9, Insomnia Severity Index, Impact of Event Scale-revised, Perceived Social Support Scale, Connor-Davidson Resilience Scale, General Self-efficacy Scale and Maslach Burnout Inventory. Results: 310 (39.5%), 393 (50.1%) and 576 (73.5%) of respondents were at high risk of emotional exhaustion (EE), depersonalization (DP) and reduced personal accomplishment (PA). The risk of EE, DP and reduced PA were moderate, high and high. Nurses with intermediate and senior professional rank and title and worked >40 h every week had lower scores in EE. Those worked in low-risk department reported lower scores in PA. Anxiety, post-traumatic stress disorder (PTSD), self-efficacy and social support were influencing factors of EE and DP, while social support and resilience were associated factors of PA. Conclusion: Chinese nurses' burnout during COVID-19 regular prevention and control was serious. Professional rank and title, working unit, weekly working hours, anxiety, PTSD, self-efficacy, social support and resilience were associated factors of burnout.

Comparison of the dural puncture epidural and the standard epidural techniques in patients having labor analgesia maintained using programmed epidural boluses: a prospective double-blinded randomized clinical trial.

BACKGROUND: The dural puncture epidural technique has been shown in some studies to improve the onset and quality of the initiation of labor analgesia compared with the standard epidural technique. However, few studies have investigated whether this technique confers advantages during the maintenance of analgesia. This randomized double-blinded controlled study compared dural puncture epidural analgesia with standard epidural analgesia when analgesia was maintained using programmed intermittent epidural boluses. METHODS: 400 parturients requesting epidural labor analgesia were randomized to have analgesia initiated with a test dose of 3 mL lidocaine 1.5% with epinephrine 15 µg, followed by 12 mL ropivacaine 0.15% mixed with sufentanil 0.5 µg/mL using the dural puncture epidural or the standard epidural technique. After confirming satisfactory analgesia, analgesia was maintained with ropivacaine 0.1% and sufentanil 0.5 µg/mL via programmed intermittent epidural boluses (fixed volume 8 mL, intervals 40 min). We compared local anesthetic consumption, pain scores, obstetric and neonatal outcomes and patient satisfaction. RESULTS: A total of 339 patients completed the study and had data analyzed. There were no differences between the dural puncture epidural and standard epidural groups in ropivacaine consumption (mean difference -0.724 mg, 95% CI of difference -1.450 to 0.001 mg, p=0.051), pain scores, time to first programmed intermittent epidural bolus, the number of programmed intermittent epidural boluses, the number of manual epidural boluses, obstetric outcome or neonatal outcome. Patient satisfaction scores were statistically higher in the dural puncture epidural group but the absolute difference in scores was small. CONCLUSION: Our findings suggest that when labor analgesia is maintained using the programmed intermittent epidural bolus method, there is no significant advantage to initiating analgesia using the dural puncture epidural compared with the standard epidural technique. TRIAL REGISTRATION NUMBER: ChiCTR2200062349.

Role of HCN channels in the functions of basal ganglia and Parkinson's disease.

Parkinson's disease (PD) is a motor disorder resulting from dopaminergic neuron degeneration in the substantia nigra caused by age, genetics, and environment. The disease severely impacts a patient's quality of life and can even be life-threatening. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channel is a member of the HCN1-4 gene family and is widely expressed in basal ganglia nuclei. The hyperpolarization-activated current mediated by the HCN channel has a distinct impact on neuronal excitability and rhythmic activity associated with PD pathogenesis, as it affects the firing activity, including both firing rate and firing pattern, of neurons in the basal ganglia nuclei. This review aims to comprehensively understand the characteristics of HCN channels by summarizing their regulatory role in neuronal firing activity of the basal ganglia nuclei. Furthermore, the distribution and characteristics of HCN channels in each nucleus of the basal ganglia group and their effect on PD symptoms through modulating neuronal electrical activity are discussed. Since the roles of the substantia nigra pars compacta and reticulata, as well as globus pallidus externus and internus, are distinct in the basal ganglia circuit, they are individually described. Lastly, this investigation briefly highlights that the HCN channel expressed on microglia plays a role in the pathological process of PD by affecting the neuroinflammatory response.

Self-Catalyzed Synthesis of Length-Controlled One-Dimensional Nickel Oxide@N-Doped Porous Carbon Nanostructures from Metal Ion Modified Nitrogen Heterocycles for Efficient Lithium Storage.

Transition metal oxides with the merits of high theoretical capacities, natural abundance, low cost, and environmental benignity have been regarded as a promising anodic material for lithium ion batteries (LIBs). However, the severe volume expansion upon cycling and poor conductivity limit their cycling stability and rate capability. To address this issue, NiO embedded and N-doped porous carbon nanorods (NiO@NCNR) and nanotubes (NiO@NCNT) are synthesized by the metal-catalyzed graphitization and nitridization of monocrystalline Ni(II)-triazole coordinated framework and Ni(II)/melamine mixture, respectively, and the following oxidation in air. When applied as an anodic material for LIBs, the NiO@NCNR and NiO@NCNT hybrids exhibit a decent capacity of 895/832 mA h g-1 at 100 mA g-1, high rate capability of 484/467 mA h g-1 at 5.0 A g-1, and good long-term cycling stability of 663/634 mA h g-1 at 600th cycle at 1 A g-1, which are much better than those of NiO@carbon black (CB) control sample (701, 214, and 223 mA h g-1). The remarkable electrochemical properties benefit from the advanced nanoarchitecture of NiO@NCNR and NiO@NCNT, which offers a length-controlled one-dimensional porous carbon nanoarchitecture for effective e-/Li+ transport, affords a flexible carbon skeleton for spatial confinement, and forms abundant nanocavities for stress buffering and structure reinforcement during discharge/charging processes. The rational structural design and synthesis may pave a way for exploring advanced metal oxide based anodic materials for next-generation LIBs.

Variations in Cortical Functional Gradients Relate to Dimensions of Psychopathology in Preschool Children.

OBJECTIVE: It is unclear how the functional brain hierarchy is organized in preschool-aged children, and whether alterations in the brain organization are linked to mental health in this age group. Here, we assessed whether preschool-aged children exhibit a brain organizational structure similar to that of older children, how this structure might change over time, and whether it might reflect mental health. METHOD: This study derived functional gradients using diffusion embedding from resting state functional magnetic resonance imaging data of 4.5-year-old children (N = 100, 42 male participants) and 6.0-year-old children (N = 133, 62 male participants) from the longitudinal Growing Up in Singapore Towards healthy Outcomes (GUSTO) cohort. We then conducted partial least-squares correlation analyses to identify the association between the impairment ratings of different mental disorders and network gradient values. RESULTS: The main organizing axis of functional connectivity (ie, principal gradient) separated the visual and somatomotor regions (ie, unimodal) in preschool-aged children, whereas the second axis delineated the unimodal-transmodal gradient. This pattern of organization was stable from 4.5 to 6 years of age. The second gradient separating the high- and low-order networks exhibited a diverging pattern across mental health severity, differentiating dimensions related to attention-deficit/hyperactivity disorder and phobic disorders. CONCLUSION: This study characterized, for the first time, the functional brain hierarchy in preschool-aged children. A divergence in functional gradient pattern across different disease dimensions was found, highlighting how perturbations in functional brain organization can relate to the severity of different mental health disorders.

A new synthesis strategy for nitrogen-doped carbon nanofibers with cobalt oxide nanoparticles as anodic electrode materials for lithium ion batteries.

Nitrogen-doped carbon nanoribbons and nanotubes decorated with Co3O4 nanoparticles were prepared by a metal-catalyzed graphitization-nitridization and oxidization process, using triazole and melamine as a solid nitrogen/carbon co-source, and assessed as anodes of lithium ion batteries (LIBs). These composite anodes display perfect electrochemical performance, indicating their potential for application in LIBs.

Post-Hospital Falls Among the Older Population: The Temporal Pattern in Risk and Healthcare Burden.

OBJECTIVES: Older adults are prone to falls following hospital discharge, resulting in healthcare utilization and costs. The fall risk might change over time after discharge. To fill research gaps in this area, this study examined the temporal pattern in incidence and healthcare burden of post-hospital falls in older adults. DESIGN: A territory-wide retrospective cohort study was conducted. SETTING AND PARTICIPANTS: Participants were Hong Kong adults aged ≥65 years and discharged from hospitals between January 2007 and December 2017. METHODS: The participants were followed for 12 months to identify fall-related inpatient episodes, accident and emergency department (AED) visits, and mortality after discharge. The post-hospital falls were further analyzed in 2 subcategories (1) only requiring AED visits and (2) requiring hospitalization. The incidence rate and faller incidence proportion for total falls and subcategories during the different periods were examined. The corresponding healthcare utilization and costs were calculated. RESULTS: Among the 606,392 older adults discharged from hospitals during the study period, 28,593 individuals (4.7%) experienced at least 1 post-hospital fall within 12 months, resulting in a total of 33,158 falls (57 per 1000 person-years). Out of post-hospital falls presenting to hospitals, one-third only required AED visits, and two-thirds required hospitalization. The fall incidence rate peaked in the first 3 weeks after discharge and gradually decreased to a stable level from the fourth to ninth week. The annual healthcare costs related to post-hospital falls exceeded USD 28.9 million in older adults, with the mean cost per faller and fall being USD 11,129 and USD 9596. CONCLUSIONS AND IMPLICATIONS: The fall-related healthcare utilizations after discharge impose a substantial economic burden on older adults. During the first 9 weeks, particularly the first 3 weeks, older adults were at high risk of falling. The efforts on resource allocation for fall prevention are suggested to prioritize this period.

Utilization of deep neuromuscular blockade combined with reduced abdominal pressure in laparoscopic radical gastrectomy for gastric cancer: An academic perspective.

BACKGROUND: Few studies have examined the specific efficacy of deep neuromuscular blockade (NMB) combined with pneumoperitoneal pressure reduction in laparoscopic radical gastrectomy (LRG) in the elderly. AIM: To investigate the application effect of deep neuromuscular blockade (NMB) combined with reduced pneumoperitoneum pressure in LRG for gastric cancer (GC) in elderly patients and its influence on inflammation. METHODS: Totally 103 elderly patients with GC treated in our hospital between January 2020 and January 2022 were retrospectively analyzed. Among them, 45 patients treated with surgery based on deep NMB and conventional pneumoperitoneum pressure were assigned to the control group, while the rest of the 58 patients who underwent surgery based on deep NMB and reduced pneumoperitoneum pressure were assigned to the observation group. The two groups were compared in the changes of the Leiden-surgical rating scale score, serum tumor necrosis fact-α (TNF-α) and interleukin 6 (IL-6) before and after therapy. The visual analogue scale (VAS) was adopted for evaluating the shoulder pain of patients at 8 h, 24 h and 48 h after the operation. The driving pressure of the two groups at different time points was also compared. Additionally, the operation time, pneumoperitoneum time, infusion volume, blood loss, extubation time after surgery, residence time in the resuscitation room, TOF% = 90% time and post-anesthetic recovery room (PACU) stay time were all recorded, and adverse PACU-associated respiratory events were also recorded. The postoperative hospitalization time and postoperative expenses of the two groups were counted and compared. RESULTS: No significant difference was found between the two groups at the time of skin incision, 60 minutes since the operation and abdominal closure after surgery (P > 0.05). The observation group exhibited significantly lower VAS scores than the control group at 24 and 48h after surgery (P < 0.05). Additionally, the observation group had significantly lower driving pressure than the control group at 5 min and 60 min after the establishment of pneumoperitoneum (P < 0.05). Additionally, the two groups were similar in terms of the operation time, pneumoperitoneum time, infusion volume, blood loss, extubation time after surgery, residence time in the resuscitation room and TOF% = 90% time (P > 0.05), and the observation group showed significantly lower TNF-α and IL-6 Levels than the control group at 24 h after therapy (P < 0.05). Moreover, the incidence of adverse events was not significantly different between the two groups (P > 0.05), and the observation group experienced significantly less hospitalization time and postoperative expenses than the control group (P < 0.05). CONCLUSION: Deep NMB combined with reduced pneumoperitoneum pressure can decrease the VAS score of shoulder pain and inflammatory reaction, without hindering the surgical vision and increasing adverse PACU-associated respiratory events, and can thus shorten the hospitalization time and treatment cost for patient.

Mapping and candidate gene analysis of clustered bud on the main inflorescence in Brassica napus L.

Breeding rapeseed varieties with more main inflorescence siliques is an idea for developing rapeseed varieties that are suitable for light and simplified cultivation. The Brassica napus exhibited cluster bud of the main inflorescence (Bnclib) gene. At the fruiting stage, the main inflorescence had more siliques, higher density, and more main inflorescences. Moreover, the top of the main inflorescence bifurcated. Genetic analysis showed that the separation ratio between Bnclib and the wild type in the F2 generation was 3:1, which indicated that the trait was a single-gene-dominant inheritance. Among the 24 candidate genes, only one gene, BnaA03g53930D, showed differential expression between the groups (False discovery rate, FDR ≤ 0.05, |log2FC|≤ 1). qPCR verification of the BnaA03g53930D gene between Huyou 17 and its Bnclib near-isogenic line showed that BnaA03g53930D was significantly differentially expressed in the stem tissue of Huyou 17 and its Bnclib near-isogenic line (Bnclib NIL). The determination of gibberellin (GA), brassinolide (BR), cytokinin (CTK), jasmonic acid (JA), growth hormone (IAA), and strigolactone (SL) content in the shoot apex of Huyou 17 by Bnclib NIL and wild type showed that all six hormones significantly differed between the Bnclib NIL and Huyou 17. It is necessary to conduct further research on the interactions between JA and the other five hormones and the main inflorescence bud clustering in B. napus.

Histamine signaling in the bed nucleus of the stria terminalis modulates stress-induced anxiety.

BACKGROUND: Anxiety disorder is one of the most prevalent psychiatric disorders. Intriguingly, dysfunction of the central histaminergic system, which is recognized as a general regulator for whole-brain activity, may result in anxiety, suggesting an involvement of the central histaminergic signaling in the modulation of anxiety. However, the neural mechanisms involved have not been fully identified. METHODS: Here, we examined the effect of histaminergic signaling in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors both in normal and acute restraint stressed male rats by using anterograde tracing, immunofluorescence, qPCR, neuropharmacology, molecular manipulation and behavioral tests. RESULTS: We found that histaminergic neurons in the hypothalamus send direct projections to the BNST, which forms a part of the circuitry involved in stress and anxiety. Infusion of histamine into the BNST produced anxiogenic effect. Moreover, histamine H1 and H2 receptors are expressed and distributed in the BNST neurons. Blockade of histamine H1 or H2 receptors in the BNST did not affect anxiety-like behaviors in normal rats, but ameliorated anxiogenic effect induced by acute restraint stress. Furthermore, knockdown of H1 or H2 receptors in the BNST induced anxiolytic effect in acute restraint stressed rats, which confirmed the pharmacological results. LIMITATIONS: A single dose of histamine receptor antagonist was used. CONCLUSIONS: Together, these findings demonstrate a novel mechanism for the central histaminergic system in the regulation of anxiety, and suggest that inhibition of histamine receptors may be a useful strategy for treating anxiety disorder.

Naturalistic viewing increases individual identifiability based on connectivity within functional brain networks.

Naturalistic viewing (NV) is currently considered a promising paradigm for studying individual differences in functional brain organization. While whole brain functional connectivity (FC) under NV has been relatively well characterized, so far little work has been done on a network level. Here, we extend current knowledge by characterizing the influence of NV on FC in fourteen meta-analytically derived brain networks considering three different movie stimuli in comparison to resting-state (RS). We show that NV increases identifiability of individuals over RS based on functional connectivity in certain, but not all networks. Furthermore, movie stimuli including a narrative appear more distinct from RS. In addition, we assess individual variability in network FC by comparing within- and between-subject similarity during NV and RS. We show that NV can evoke individually distinct NFC patterns by increasing inter-subject variability while retaining within-subject similarity. Crucially, our results highlight that this effect is not observable across all networks, but rather dependent on the network-stimulus combination. Our results confirm that NV can improve the detection of individual differences over RS and underline the importance of selecting the appropriate combination of movie and cognitive network for the research question at hand.

Ameliorating parkinsonian motor dysfunction by targeting histamine receptors in entopeduncular nucleus-thalamus circuitry.

In Parkinson's disease (PD), reduced dopamine levels in the basal ganglia have been associated with altered neuronal firing and motor dysfunction. It remains unclear whether the altered firing rate or pattern of basal ganglia neurons leads to parkinsonism-associated motor dysfunction. In the present study, we show that increased histaminergic innervation of the entopeduncular nucleus (EPN) in the mouse model of PD leads to activation of EPN parvalbumin (PV) neurons projecting to the thalamic motor nucleus via hyperpolarization-activated cyclic nucleotide-gated (HCN) channels coupled to postsynaptic H2R. Simultaneously, this effect is negatively regulated by presynaptic H3R activation in subthalamic nucleus (STN) glutamatergic neurons projecting to the EPN. Notably, the activation of both types of receptors ameliorates parkinsonism-associated motor dysfunction. Pharmacological activation of H2R or genetic upregulation of HCN2 in EPNPV neurons, which reduce neuronal burst firing, ameliorates parkinsonism-associated motor dysfunction independent of changes in the neuronal firing rate. In addition, optogenetic inhibition of EPNPV neurons and pharmacological activation or genetic upregulation of H3R in EPN-projecting STNGlu neurons ameliorate parkinsonism-associated motor dysfunction by reducing the firing rate rather than altering the firing pattern of EPNPV neurons. Thus, although a reduced firing rate and more regular firing pattern of EPNPV neurons correlate with amelioration in parkinsonism-associated motor dysfunction, the firing pattern appears to be more critical in this context. These results also confirm that targeting H2R and its downstream HCN2 channel in EPNPV neurons and H3R in EPN-projecting STNGlu neurons may represent potential therapeutic strategies for the clinical treatment of parkinsonism-associated motor dysfunction.

Homotopic local-global parcellation of the human cerebral cortex from resting-state functional connectivity.

Resting-state fMRI is commonly used to derive brain parcellations, which are widely used for dimensionality reduction and interpreting human neuroscience studies. We previously developed a model that integrates local and global approaches for estimating areal-level cortical parcellations. The resulting local-global parcellations are often referred to as the Schaefer parcellations. However, the lack of homotopic correspondence between left and right Schaefer parcels has limited their use for brain lateralization studies. Here, we extend our previous model to derive homotopic areal-level parcellations. Using resting-fMRI and task-fMRI across diverse scanners, acquisition protocols, preprocessing and demographics, we show that the resulting homotopic parcellations are as homogeneous as the Schaefer parcellations, while being more homogeneous than five publicly available parcellations. Furthermore, weaker correlations between homotopic parcels are associated with greater lateralization in resting network organization, as well as lateralization in language and motor task activation. Finally, the homotopic parcellations agree with the boundaries of a number of cortical areas estimated from histology and visuotopic fMRI, while capturing sub-areal (e.g., somatotopic and visuotopic) features. Overall, these results suggest that the homotopic local-global parcellations represent neurobiologically meaningful subdivisions of the human cerebral cortex and will be a useful resource for future studies. Multi-resolution parcellations estimated from 1479 participants are publicly available (https://github.com/ThomasYeoLab/CBIG/tree/master/stable_projects/brain_parcellation/Yan2023_homotopic).

Histamine bidirectionally regulates the intrinsic excitability of parvalbumin-positive neurons in the lateral globus pallidus and promotes motor behaviour.

BACKGROUND AND PURPOSE: Parvalbumin (PV)-positive neurons are a type of neuron in the lateral globus pallidus (LGP) which plays an important role in motor control. The present study investigated the effect of histamine on LGPPV neurons and motor behaviour. EXPERIMENTAL APPROACH: Histamine levels in LGP as well as its histaminergic innervation were determined through brain stimulation, microdialysis, anterograde tracing and immunostaining. Mechanisms of histamine action were detected by immunostaining, single-cell qPCR, whole-cell patch-clamp recording, optogenetic stimulation and CRISPR/Cas9 gene-editing techniques. The effect of histamine on motor behaviour was detected by animal behavioural tests. KEY RESULTS: A direct histaminergic innervation in LGP from the tuberomammillary nucleus (TMN) and a histamine-induced increase in the intrinsic excitability of LGPPV neurons were determined by pharmacological blockade or by genetic knockout of the histamine H1 receptor (H1 R)-coupled TWIK-related potassium channel-1 (TREK-1) and the small-conductance calcium-activated potassium channel (SK3), as well as by activation or overexpression of the histamine H2 receptor (H2 R)-coupled hyperpolarization-activated cyclic nucleotide-gated channel (HCN2). Histamine negatively regulated the STN → LGPGlu transmission in LGPPV neurons via the histamine H3 receptor (H3 R), whereas blockage or knockout of H3 R increased the intrinsic excitability of LGPPV neurons. CONCLUSIONS AND IMPLICATIONS: Our results indicated that the endogenous histaminergic innervation in the LGP can bidirectionally promote motor control by increasing the intrinsic excitability of LGPPV neurons through postsynaptic H1 R and H2 R, albeit its action was negatively regulated by the presynaptic H3 R, thereby suggesting possible role of histamine in motor deficits manifested in Parkinson's disease (PD).

Receptor and Ionic Mechanism of Histamine on Mouse Dorsolateral Striatal Neurons.

The dorsolateral striatum (DLS) is the critical neural substrate that plays a role in motor control and motor learning. Our past study revealed a direct histaminergic projection from the tuberomammillary nucleus (TMN) of the hypothalamus to the rat striatum. However, the afferent of histaminergic fibers in the mouse DLS, the effect of histamine on DLS neurons, and the underlying receptor and ionic mechanisms remain unclear. Here, we demonstrated a direct histaminergic innervation from the TMN in the mouse DLS, and histamine excited both the direct-pathway spiny projection neurons (d-SPNs) and the indirect-pathway spiny projection neurons (i-SPNs) of DLS via activation of postsynaptic H1R and H2R, albeit activation of presynaptic H3R suppressed neuronal activity by inhibiting glutamatergic synaptic transmission on d-SPNs and i-SPNs in DLS. Moreover, sodium-calcium exchanger 3 (NCX3), potassium-leak channels linked to H1R, and hyperpolarization-activated cyclic nucleotide-gated channel 2 (HCN2) coupled to H2R co-mediated the excitatory effect induced by histamine on d-SPNs and i-SPNs in DLS. These results demonstrated the pre- and postsynaptic receptors and their downstream multiple ionic mechanisms underlying the inhibitory and excitatory effects of histamine on d-SPNs and i-SPNs in DLS, suggesting a potential modulatory effect of the central histaminergic system on the DLS as well as its related motor control and motor learning.