Search

Background: Habitat transitions have considerable consequences in organism homeostasis, as they require the adjustment of several concurrent physiological compartments to maintain stability and adapt to a changing environment. Within the range of molecules with a crucial role in the regulation of different physiological processes, neuropeptides are key agents. Here, we examined the coding status of several neuropeptides and their receptors with pleiotropic activity in Cetacea., Results: Analysis of 202 mammalian genomes, including 41 species of Cetacea, exposed an intricate mutational landscape compatible with gene sequence modification and loss. Specifically for Cetacea, in the 12 genes analysed we have determined patterns of loss ranging from species-specific disruptive mutations (e.g. neuropeptide FF-amide peptide precursor; NPFF) to complete erosion of the gene across the cetacean stem lineage (e.g. somatostatin receptor 4; SSTR4)., Conclusions: Impairment of some of these neuromodulators may have contributed to the unique energetic metabolism, circadian rhythmicity and diving response displayed by this group of iconic mammals., (© 2024. The Author(s).)

Activation of the maternal immune system leads to a downstream cascade of proinflammatory events that culminate in the activation of spontaneous uterine contractions, which is associated with preterm birth. Ras-related C3 botulinum toxin substrate 1 (Rac1) is a crucial protein related to cell contraction and inflammation. The main purpose of this study was to explore the role and function of Rac1's regulation of inflammation through in- vivo and in-vitro experiments. Rac1 inhibitor was used in animal model of preterm birth and cells isolated from the uterine tissues of pregnant mice on gestational day 16 were transfected with adenovirus to knockdown or overexpress Rac1 and treated with the Calcium-calmodulin-dependent protein kinase II (CaMKII) inhibitor KN93. The expression of Rac1, uterine contraction-associated proteins (CAPs) (COX-2 and Connexin43), and inflammatory cytokines, were assessed by Western blotting and RTPCR. LPS upregulated Rac1, COX-2 and Connexin43 expression in uterine smooth muscle cells (USMCs). The expression of inflammatory cytokines, COX-2, and Connexin43 was significantly decreased in shRac1-transfected cells compared with cells stimulated with LPS only. Rac1 overexpression led to an increase in the expression of inflammatory cytokines, COX-2, and Connexin43. Furthermore, after Rac1 overexpression, KN93 reduced the expression of uterine contraction-associated proteins and inflammatory cytokines. It is thought that the effect of Rac1 on inflammatory cytokine and contraction-associated protein expression in USMCs is mediated by CaMKII. Rac1 can modulate the expression of contraction-associated proteins and inflammatory cytokines through the CaMKII pathway. Rac1 could be an effective therapeutic target for improving the outcome of preterm birth., Competing Interests: Conflicts of Interest The authors declare that there are no conflicts of interest., (Copyright © 2024. Published by Elsevier B.V.)

Transient global cerebral ischemia (GCI) results in delayed neuronal death, primarily apoptosis, in the hippocampal CA1 subregion, which leads to severe cognitive deficits. While therapeutic hypothermia is an approved treatment for patients following cardiac arrest, it is associated with various adverse effects. Secretoneurin (SN) is an evolutionarily conserved neuropeptide generated in the brain, adrenal medulla and other endocrine tissues. In this study, SN was infused into the rat brain by intracerebroventricular injection 1 day after GCI, and we demonstrated that SN could significantly preserve spatial learning and memory in the Barnes maze tasks examined on days 14-17 after GCI. To further investigate underlying pathways involved, we demonstrated that, on day 5 after GCI, SN could significantly inhibit GCI-induced expression levels of Apoptosis Inducing Factor (AIF) and cleaved-PARP1, as well as neuronal apoptosis and synaptic loss in the hippocampal CA1 region. Additionally, SN could attenuate GCI-induced activation of both caspase-1 and caspase-3, and the levels of pro-inflammatory cytokines IL-1β and IL-18 in the CA1 region. Mechanically, we observed that treatment with SN effectively inhibited NLRP3 protein elevation and the bindings of NLRP3-ASC and ASC-caspase-1 in hippocampal neurons after GCI. In summary, our data indicate that SN could effectively attenuate NLRP3 inflammasome formation, as well as the activation of caspase-1 and -3, the production of pro-inflammatory cytokines, and ultimately the neuronal apoptotic loss induced by GCI. Potential neuronal pyroptosis, or caspase-1-dependent cell death, could also be involved in ischemic neuronal death, which needs further investigation., Competing Interests: Declaration of competing interest The authors have no competing interests in the manuscript., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aim: The hypothesis of this study is to determine the effects of intracerebroventricular (icv) prokineticin 2 infusion on food consumption and body weight and to elucidate whether it has effects on energy expenditure via the hypothalamus-pituitary-thyroid (HPT) axis in adipose tissue., Material and Methods: A total of 40 rats were used in the study and 4 groups were established: Control, Sham, Prokineticin 1.5 and Prokineticin 4.5 (n=10). Except for the Control group, rats were treated intracerebroventricularly via osmotic minipumps, the Sham group was infused with aCSF (vehicle), and the Prokineticin 1.5 and Prokineticin 4.5 groups were infused with 1.5 nMol and 4.5 nMol prokineticin 2, respectively. Food and water consumption and body weight were monitored during 7-day infusion in all groups. At the end of the infusion, the rats were decapitated and serum TSH, fT4 and fT3 levels were determined by ELISA. In addition, PGC-1α and UCP1 gene expression levels in white adipose tissue (WAT) and brown adipose tissue (BAT), TRH from rat hypothalamic tissue were determined by real-time PCR., Results: Icv prokineticin 2 (4.5 nMol) infusion had no effect on water consumption but reduced daily food consumption and body weight (p<0.05). Icv prokineticin 2 (4.5 nMol) infusion significantly increased serum TSH, fT4 and fT3 levels when compared to Control and Sham groups (p<0.05). Also, icv prokineticin 2 (4.5 nMol) infusion increased the expression of TRH in the hypothalamus tissue and expression of PGC-1α UCP1 in the WAT and BAT (p<0.05)., Conclusion: Icv prokineticin 2 (4.5 nMol) infusion may suppress food consumption via its receptors in the hypothalamus and reduce body weight by stimulating energy expenditure and thermogenesis in adipose tissue through the HPT axis., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

The neuroendocrine system of crustaceans is complex and regulates many processes, such as development, growth, reproduction, osmoregulation, behavior, and metabolism. Once stimulated, crustaceans' neuroendocrine tissues modulate the release of monoamines, ecdysteroids, and neuropeptides that can act as hormones or neurotransmitters. Over a few decades, research has unraveled some mechanisms governing these processes, substantially contributing to understanding crustacean physiology. More aspects of crustacean neuroendocrinology are being comprehended with molecular biology, transcriptome, and genomics analyses. Hence, these studies will also significantly enhance the ability to cultivate decapods, such as crabs and shrimps, used as human food sources. In this review, current knowledge on crustacean endocrinology is updated with new findings about crustacean hormones, focusing mainly on the main neuroendocrine organs and their hormones and the effects of these molecules regulating metabolism, growth, reproduction, and color adaptation. New evidence about vertebrate-type hormones found in crustaceans is included and discussed. Finally, this review may assist in understanding how the emerging chemicals of environmental concern can potentially impair and disrupt crustacean's endocrine functions and their physiology., Competing Interests: Declaration of competing interest As the corresponding author, I am sending the manuscript “A brief and updated introduction to the neuroendocrine system of crustaceans” in order to submit for publication on the Special Issue “Hormonal Regulation and Disruption in Invertebrates” in the Journal of Molecular and Cellular Endocrinology. In the name of all authors, I certify that this manuscript is not under consideration by any other journal and that all the authors have read the manuscript and agreed to have their names listed as authors. I also certify that all the authors collaborated in the development of this research work. Finally, there is no potential conflict of interest including any financial, personal or other relationships with other people or organizations related to this manuscript., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Animal behavior emerges from collective dynamics of neurons, making it vulnerable to damage. Paradoxically, many organisms exhibit a remarkable ability to maintain significant behavior even after large-scale neural injury. Molecular underpinnings of this extreme robustness remain largely unknown. Here, we develop a quantitative pipeline to measure long-lasting latent states in planarian flatworm behaviors during whole-brain regeneration. By combining >20,000 animal trials with neural network modeling, we show that long-range volumetric peptidergic signals allow the planarian to rapidly restore coarse behavior output after large perturbations to the nervous system, while slow restoration of small-molecule neuromodulator functions refines precision. This relies on the different time and length scales of neuropeptide and small-molecule transmission to generate incoherent patterns of neural activity that competitively regulate behavior. Controlling behavior through opposing communication mechanisms creates a more robust system than either alone and may serve as a generalizable approach for constructing robust neural networks., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Macrophage-to-osteoclast differentiation (osteoclastogenesis) plays an essential role in tumor osteolytic bone metastasis (BM), while its specific mechanisms remain largely uncertain in lung adenocarcinoma BM. In this study, we demonstrate that integrin-binding sialoprotein (IBSP), which is highly expressed in the cancer cells from bone metastatic and primary lesions of patients with lung adenocarcinoma, can facilitate BM and directly promote macrophage-to-osteoclast differentiation independent of RANKL/M-CSF. In vivo results further suggest that osteolytic BM in lung cancer specifically relies on IBSP-induced macrophage-to-osteoclast differentiation. Mechanistically, IBSP regulates the Rac family small GTPase 1 (Rac1)-NFAT signaling pathway and mediates the forward shift of macrophage-to-osteoclast differentiation, thereby leading to early osteolysis. Moreover, inhibition of Rac1 by EHT-1864 or azathioprine in mice models can remarkably alleviate IBSP-induced BM of lung cancer. Overall, our study suggests that tumor-secreted IBSP promotes BM by inducing macrophage-to-osteoclast differentiation, with potential as an early diagnostic maker for BM, and Rac1 can be the therapeutic target for IBSP-promoted BM in lung cancer., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Lissencephaly is a rare brain malformation for which our understanding remains limited due to the absence of suitable animal models that accurately represent human phenotypes. Here, we establish doublecortin (DCX) knockout ferrets as a model that faithfully replicates key features of the disorder. We reveal the critical roles of DCX in neural progenitor cell proliferation and radial glial fiber extension, processes essential for normal cortical development. Utilizing single-nucleus RNA sequencing (snRNA-seq) and spatial transcriptomics, we provide a detailed atlas of the lissencephalic cortex, illustrating disrupted neuronal lamination and the specific interactions between inhibitory and excitatory neurons. These findings enhance our understanding of the cellular and molecular mechanisms underlying lissencephaly and highlight the potential of DCX knockout ferrets as a valuable tool for neurodevelopmental research, offering insights into both the pathology of lissencephaly and the general principles of brain development., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The research of the influences of man-made electromagnetic fields on tick physiology has been very sparse and long neglected since the pioneer studies published in 1996 and 2000. Once multiple behavioral tests confirmed an attraction and possible perception of electromagnetic fields in ticks, a new interest in this topic erupted in recent years. In this study, qRT-PCR is utilized to determine the changes in the mRNA transcript levels of neuropeptides SIFamide and myoinhibitory peptide (mip and sifa) and their representative receptors (mip-r1 and sifa-r1) in the synganglia of the tick Ixodes ricinus irradiated by 900 MHz radiofrequency electromagnetic field. It was determined that 40 V/m intensity has a significant suppressory effect on the transcript levels of all genes after at least 60 minutes of constant exposure in both sexes. Commonly occurring intensity of radiation in urban areas (2 V/m) produced an elevation in mRNA levels after various timespans in every gene. A significant decrease of transcript abundances was detected in females after one hour of exposure to 2 V/m. Results of this study widen the knowledge of EMF-induced alterations in the neurophysiology of I. ricinus, the most commonly distributed hard tick in Europe., (© 2024. The Author(s).)

Survival in animals relies on navigating environments aligned with physiological needs. In Drosophila melanogaster , antennal ionotropic receptors (IRs) sensing humidity changes govern hygrotaxis behavior. This study sheds light on the crucial role of IR8a neurons in the transition from high humidity avoidance to water-seeking behavior when the flies become thirsty. These neurons demonstrate a heightened calcium response toward high humidity stimuli in satiated flies and a reduced response in thirsty flies, modulated by fluctuating levels of the neuropeptide leucokinin, which monitors the internal water balance. Optogenetic activation of IR8a neurons in thirsty flies triggers an avoidance response similar to the moisture aversion in adequately hydrated flies. Furthermore, our study identifies IR40a neurons as associated with dry avoidance, while IR68a neurons are linked to moist attraction. The dynamic interplay among these neurons, each with opposing valences, establishes a preference for approximately 30% relative humidity in well-hydrated flies and facilitates water-seeking behavior in thirsty individuals. This research unveils the intricate interplay between sensory perception, neuronal plasticity, and internal states, providing valuable insights into the adaptive mechanisms governing hygrotaxis in Drosophila ., Competing Interests: Competing interests statement:The authors declare no competing interest.

In C. elegans mechanisms by which peripheral organs relay internal state information to the nervous system remain unknown, although strong evidence suggests that such signals do exist. Here we report the discovery of a peptide of the ancestral insulin superfamily called INS-7 that functions as an enteroendocrine peptide and is secreted from specialized cells of the intestine. INS-7 secretion is stimulated by food withdrawal, increases during fasting and acts as a bona fide gut-to-brain peptide that attenuates the release of a neuropeptide that drives fat loss in the periphery. Thus, INS-7 functions as a homeostatic signal from the intestine that gates the neuronal drive to stimulate fat loss during food shortage. Mechanistically, INS-7 functions as an antagonist at the canonical DAF-2 receptor and functions via FOXO and AMPK signaling in ASI neurons. Phylogenetic analysis suggests that INS-7 bears greater resemblance to members of the broad insulin/relaxin superfamily than to conventional mammalian insulin and IGF peptides. The discovery of an endogenous insulin antagonist secreted by specialized intestinal cells with enteroendocrine functions suggests unexpected and important properties of the intestine and its role in directing neuronal functions., (© 2024. The Author(s).)

Allergic rhinitis (AR) is a chronic, non-infectious condition affecting the nasal mucosa, primarily mediated mainly by IgE. Recent studies reveal that AR is intricately associated not only with type 2 immunity but also with neuroimmunity. Nociceptive neurons, a subset of primary sensory neurons, are pivotal in detecting external nociceptive stimuli and modulating immune responses. This review examines nociceptive neuron receptors and elucidates how neuropeptides released by these neurons impact the immune system. Additionally, we summarize the role of immune cells and inflammatory mediators on nociceptive neurons. A comprehensive understanding of the dynamic interplay between nociceptive neurons and the immune system augments our understanding of the neuroimmune mechanisms underlying AR, thereby opening novel avenues for AR treatment modalities., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Cong, Lv and Xu.)

Amyloid-β (Aβ) aggregates are recognized as initiators of Alzheimer's disease, and their interaction with the nervous system contributes to the progression of neurodegeneration. Herein, we investigated the frequency at which neuropeptides interact with Aβ and affect the aggregation kinetics and cytotoxicity of Aβ. To this end, we established a native mass spectrometry (MS)-centric workflow for screening Aβ-interacting neuropeptides, and six out of 12 neuropeptides formed noncovalent complexes with Aβ species in the MS gas phase. Thioflavin-T fluorescence assays and gel separation indicated that leptin and cerebellin decreased Aβ aggregation, whereas kisspeptin increased this process. In addition, leptin and cerebellin attenuated Aβ-induced cytotoxicity, which was independent of the influence of metal ions. Leptin can chelate copper from copper-bound Aβ species, reducing the cytotoxicity caused by the aggregation of Aβ and metal ion complexes. Overall, our study demonstrated that neuropeptides frequently interact with Aβ and revealed that leptin and cerebellin are potential inhibitors of Aβ aggregation, providing great insight into understanding the molecular mechanism of Aβ interacting with the nervous system and facilitating drug development.

Objective To investigate the effects of Schisandrae Chinensis Fructus lignans on the alertness of the rats with sleep deprived by treadmill exercise and the underlying neurobiological mechanism. Methods According to the random number table method,SD male rats were assigned into control,sleep deprivation,low-,medium-,and high-dose Schisandrae Chinensis Fructus lignans,and atomoxetine hydrochloride groups,with 8 rats in each group.The rats in other groups except the control group were subjected to sleep deprivation by treadmill exercise for 3 d.During the deprivation period,each administration group was administrated with the corresponding drug by gavage,and a 5-9 hole tester was used to test the alertness performance of rats in each group. Furthermore,other SD male rats were selected and randomized into control,sleep deprivation,Schisandrae Chinensis Fructus lignans (67.2 mg/kg) and atomoxetine hydrochloride groups,with 10 rats in each group.The rats were modeled with the sleep deprivation method the same as that above and administrated with corresponding agents.ELISA was employed to measure the serum level of orexin A in each group of rats.The protein levels of c-Fos,orexin receptor 1,and orexin receptor 2 in the prefrontal cortex of rats in each group were observed by immunofluorescence and Western blotting. Results Compared with the control group,sleep deprivation reduced the choice accuracy ( P <0.001) and increased the omission responses,omission percent,and mean correct response latency ( P =0.002, P =0.003, P =0.020).Compared with the sleep deprivation group,medium- and high-dose Schisandrae Chinensis Fructus lignans and atomoxetine hydrochloride improved the alertness of rats,as demonstrated by the increased choice accuracy ( P =0.001, P =0.006, P <0.001) and reduced omission responses ( P =0.001, P =0.001, P <0.001),omission percent ( P =0.001, P =0.002, P <0.001),and mean correct response latency ( P =0.018, P =0.003, P =0.014).Compared with the control group,the sleep deprivation group showed elevated level of orexin A in the serum ( P <0.001),up-regulated expression of c-Fos ( P <0.001),and down-regulated expression of orexin receptor 1 ( P =0.037) in the prefrontal cortex.Compared with the sleep deprivation group,Schisandrae Chinensis Fructus lignans (67.2 mg/kg) and atomoxetine hydrochloride lowered the orexin A level in the serum ( P =0.005, P =0.029),down-regulated the expression of c-Fos ( P =0.028, P =0.036),and up-regulated the expression of orexin receptor 1 ( P =0.043, P =0.013) in the prefrontal cortex. Conclusion Schisandrae Chinensis Fructus lignans may antagonize the alertness decrease caused by sleep deprivation by regulating the secretion of orexin and the expression of orexin receptor 1 in the prefrontal cortex.

Neuritin, also known as candidate plasticity gene 15 (CPG15), was first identified as one of the activity-dependent gene products in the brain. Previous studies have been reported that Neuritin induces neuritogenesis, neurite arborization, neurite outgrowth and synapse formation, which are involved in the development and functions of the central nervous system. However, the role of Neuritin in peripheral nerve injury is still unknown. Given the importance and necessity of Schwann cell dedifferentiation response to peripheral nerve injury, we aim to investigate the molecular mechanism of Neuritin steering Schwann cell dedifferentiation during Wallerian degeneration (WD) in injured peripheral nerve. Herein, using the explants of sciatic nerve, an ex vivo model of nerve degeneration, we provided evidences indicating that Neuritin vividly accelerates Schwann cell dedifferentiation. Moreover, we found that Neuritin promotes Schwann cell demyelination as well as axonal degeneration, phagocytosis, secretion capacity. In summary, we first described Neuritin acts as a positive regulator for Schwann cell dedifferentiation and WD after peripheral nerve injury., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Spotted-wing drosophila, Drosophila suzukii (Matsumura), is an invasive vinegar fly that is a major threat to the small fruits industries globally. Insect capa genes encode multiple neuropeptides, including CAPA-periviscerokinin (CAPA-PVK) peptides, that are specifically known to cause diuresis or anti-diuresis in various organisms. Here we identified and characterized a corresponding G protein-coupled receptor (GPCR) of the D. suzukii CAPA-PVK peptides: CAPA receptor (CAPA-R). To better characterize the behavior of D. suzukii CAPA-R, we used insect cell-based functional expression assays to evaluate responses of CAPA-R against D. suzukii CAPA-PVKs, CAPA-PVKs from five species in Insecta, one species from Mollusca, modified CAPA-PVK peptides, and some PRXamide family peptides: pyrokinin (PK), diapause hormone (DH), and ecdysis-triggering hormone (ETH). Functional studies revealed that the D. suzukii CAPA-R is strongly activated by both of its own natural D. suzukii CAPA-PVKs, and interestingly, it was strongly activated by other CAPA-PVK peptides from Frankliniella occidentallis (Thysanoptera), Solenopsis invicta (Hymenoptera), Helicoverpa zea (Lepidoptera) and Plutella xylostella (Lepidoptera). However, D. suzukii CAPA-R was not activated by Mollusca CAPA-PVK or the other PRXamide peptides. Gene expression analyses showed that the CAPA-R was highly expressed in the Malpighian tubules and moderately in hindgut compared to other digestive organs or the rest of body, supporting diuretic/antidiuretic functionality. When compared across life stages of D. suzukii, expression of CAPA-R was approximately 1.5x greater in the third instar than the other stages and minimally detected in the eggs, 4-day old pupae and 3-day old adults. Our results functionally characterized the D. suzukii CAPA-R and a few short peptides were identified as potential biological targets to exploit the CAPA-R for D. suzukii management., (© 2024 Wiley Periodicals LLC. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Neuropeptides, including tachykinins, CGRP, and somatostatin, are localized in a peptidergic subgroup of nociceptive primary afferent neurons. Tachykinins and CGRP are pronociceptive, somatostatin is an antinociceptive mediator. Intensive drug research has been performed to develop tachykinin and CGRP antagonists, and somatostatin agonists as analgesics. CGRP receptor antagonists are efficacious and well-tolerated drugs in migraine. Monoclonal antibodies against CGRP or its receptor are used for the prophylactic treatment of migraine. Tachykinin NK 1 receptor antagonists failed as analgesics but are used for chemotherapy-induced nausea and vomiting. New, orally active somatostatin 4 receptor agonists are promising drug candidates for treating various pain conditions., Competing Interests: Declaration of competing interest We declare no conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: The skin is an intricate network of both neurons and immunocytes, where emerging evidence has indicated that the regulation of neural-inflammatory processes may play a crucial role in mediating wound healing. Disease associated abnormal immunological dysfunction and peripheral neuropathy are implicated in the pathogenesis of wound healing impairment. However, the mechanisms through which neural-inflammatory interactions modulate wound healing remain ambiguous. Understanding the underlying mechanisms may provide novel insights to develop therapeutic devices, which could manipulate neural-inflammatory crosstalk to aid wound healing. This review aims to comprehensively illustrate the neural-inflammatory interactions during different stages of the repair process. Numerous mediators including neuropeptides secreted by the sensory and autonomic nerve fibers and cytokines produced by immunocytes play an essential part during the distinct phases of wound healing., Competing Interests: Conflicts of interest and sources of funding: none declared., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Type II crustacean hyperglycemic hormone (CHH) neuropeptides play diverse roles in crustaceans. In the hermaphrodite shrimp Lysmata vittata, two transcripts of type II CHHs (molt-inhibiting hormone/gonad-inhibiting hormone, MIH/GIH1 and MIH/GIH2) were identified by transcriptome sequencing, and MIH/GIH1 was later named Lvit-GIH1 for its inhibitory effect on ovarian development. Based on the high similarity of MIH/GIH2 to Lvit-GIH1, we named tentatively MIH/GIH2 as Lvit-GIH2 and explored the role of Lvit-GIH2 in ovarian development. The open reading frame (ORF) of Lvit-GIH2 was 333 bp in length, encoding a precursor consisted of a 32-aa signal peptide and a 78-aa mature peptide, which shared high sequence similarity with the type II subfamily peptides in crustaceans. Notably, Lvit-GIH2 was widely expressed in multiple tissues. The qRT-PCR findings indicated a rising trend in the expression of Lvit-GIH2 from the male phase to the euhermaphrodite phase. Both RNA interference and addition of GIH2 recombinant proteins (rGIH2) experiments showed that Lvit-GIH2 suppressed Lvit-Vg expression in hepatopancreas and Lvit-VgR expression in ovary. To further investigate the role of Lvit-GIH2 in ovarian development, the RNA-sequence analysis was performed to examine the changes in ovary after addition of rGIH2. The results showed that the pathways (Cysteine and methionine metabolism, Apoptosis-multiple species, etc.) and the genes (17bHSD8, IGFR, CHH, etc.) related to ovarian development were negatively regulated by rGIH2. In brief, Lvit-GIH2 might inhibit the ovarian development in L. vittata., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Lan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Antimicrobial peptide (AMP) is an important component of crustaceans' innate immune system. In this study, a short neuropeptide F (sNPF) gene (Pc-sNPF) and a Forkhead box O (FOXO) gene (PcFOXO) from Procambarus clarkii were identified. Analysis findings showed that the expression level of AMP genes differed between male and female P. clarkii. Furthermore, Pc-sNPF and PcFOXO were related to the sex dimorphism of AMP. Knockdown of Pc-sNPF in the eyestalk significantly upregulated the expression of PcFOXO and two anti-lipopolysaccharide factors (PcALF4 and PcALFL) in the intestine of P. clarkii. The expression of PcFOXO in the intestine of female P. clarkii was higher than in that of males. Results from RNA interference revealed that PcFOXO positively regulated the expression of PcALF4 and PcALFL in the intestine of male and female P. clarkii. In summary, our study showed that differences in Pc-sNPF expression in eyestalk of male and female P. clarkii leading to sex dimorphism of AMP expression in the intestine are mediated by the sNPF-FOXO-AMP signal pathway called the eyestalk-intestine axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Neuropeptides play essential roles in coordinating reproduction. Egg-laying hormone (ELH) is conserved in genetic sequence and behavioral function across molluscs, where neuronal clusters secrete ELH to modulate and induce egg-laying. Here we investigated ELH in the nudibranch mollusc, Berghia stephanieae. ELH preprohormone gene orthologs, which showed clade-specific differences at the C-terminus of the predicted bioactive peptide, were identified in brain transcriptomes across several nudipleuran species, including B. stephanieae. ELH shares deep homology with the corticotropin-releasing hormone gene family, which has roles broadly in stress response. Injection of synthesized B. stephanieae ELH peptide into mature individuals induced egg-laying. ELH gene expression in the brain and body was mapped using in-situ hybridization chain reaction. Across the adult brain, 300-400 neurons expressed ELH. Twenty-one different cell types were identified in adults, three of which were located unilaterally on the right side, which corresponds to the location of the reproductive organs. Ten cell types were present in pre-reproductive juvenile stages. An asymmetric cluster of approximately 100 small neurons appeared in the right pedal ganglion of late-stage juveniles. Additional neurons in the pleural and pedal ganglia expressed ELH only in adults that were actively laying eggs and sub-adults that were on the verge of doing so, implicating their direct role in reproduction. Outside the brain, ELH was expressed on sensory appendages, including in presumptive sensory neurons. Its widespread expression in the nudibranch B. stephanieae suggests that ELH plays a role beyond reproduction in gastropod molluscs., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Parkinson's disease (PD) is a complex neurodegenerative disorder characterized by motor and non-motor symptoms. Motor symptoms include bradykinesia, resting tremors, muscular rigidity, and postural instability, while non-motor symptoms include cognitive impairments, mood disturbances, sleep disturbances, autonomic dysfunction, and sensory abnormalities. Some of these symptoms may be influenced by the proper hippocampus functioning, including adult neurogenesis. Doublecortin (DCX) is a microtubule-associated protein that plays a pivotal role in the development and differentiation of migrating neurons. This study utilized postmortem human brain tissue of PD and age-matched control individuals to investigate DCX expression in the context of adult hippocampal neurogenesis. Our findings demonstrate a significant reduction in the number of DCX-expressing cells within the subgranular zone (SGZ), as well as a decrease in the nuclear area of these DCX-positive cells in postmortem brain tissue obtained from PD cases, suggesting an impairment in the adult hippocampal neurogenesis. Additionally, we found that the nuclear area of DCX-positive cells correlates with pH levels. In summary, we provide evidence supporting that the process of hippocampal adult neurogenesis is likely to be compromised in PD patients before cognitive dysfunction, shedding light on potential mechanisms contributing to the neuropsychiatric symptoms observed in affected individuals. Understanding these mechanisms may offer novel insights into the pathophysiology of PD and possible therapeutic avenues., (© 2024 International Society for Neurochemistry.)

Periventricular nodular heterotopia (PNH), the most common brain malformation diagnosed in adulthood, is characterized by the presence of neuronal nodules along the ventricular walls. PNH is mainly associated with mutations in the FLNA gene - encoding an actin-binding protein - and patients often develop epilepsy. However, the molecular mechanisms underlying the neuronal failure still remain elusive. It has been hypothesized that dysfunctional cortical circuitry, rather than ectopic neurons, may explain the clinical manifestations. To address this issue, we depleted FLNA from cortical pyramidal neurons of a conditional Flna flox/flox mice by timed in utero electroporation of Cre recombinase. We found that FLNA regulates dendritogenesis and spinogenesis thus promoting an appropriate excitatory/inhibitory inputs balance. We demonstrated that FLNA modulates RAC1 and cofilin activity through its interaction with the Rho-GTPase Activating Protein 24 (ARHGAP24). Collectively, we disclose an uncharacterized role of FLNA and provide strong support for neural circuit dysfunction being a consequence of FLNA mutations., Competing Interests: Declaration of competing interest None., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: What textbooks usually call the sublingual gland in humans is in reality a tissue mass of two types of salivary glands, the anteriorly located consisting of a cluster of minor sublingual glands and the posteriorly located major sublingual gland with its outlet via Bartholin's duct. Only recently, the adrenergic and cholinergic innervations of the major sublingual gland was reported, while information regarding the neuropeptidergic and nitrergic innervations is still lacking., Methods: Bioptic and autoptic specimens of the human major sublingual gland were examined by means of immunohistochemistry for the presence of vasoactive intestinal peptide (VIP)-, neuropeptide Y (NPY)-, substance P (SP)-, calcitonin gene related-peptide (CGRP)-, and neuronal nitric oxide synthase (nNOS)-labeled neuronal structures., Results: As to the neuropeptidergic innervation of secretory cells (here in the form of mucous tubular and seromucous cells), the findings showed many VIP-containing nerves, few NPY- and SP-containing nerves and a lack of CGRP-labeled nerves. As to the neuropeptidergic innervation of vessels, the number of VIP-containing nerves was modest, while, of the other neuropeptide-containing nerves under study, only few (SP and CGRP) to very few (NPY) nerves were observed. As to the nitrergic innervation, nNOS-containing nerves were very few close to secretory cells and even absent around vessels., Conclusion: The various innervation patterns may suggest potential transmission mechanisms involved in secretory and vascular responses of the major sublingual gland., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 The Authors. Published by Elsevier GmbH.. All rights reserved.)

The central nervous system (CNS) plays a critical role in signal integration in animals and allows the orchestration of life processes to maintain homeostasis. Current research clearly shows that inflammatory processes can also be modulated by the CNS via the neuroendocrine system. One of the neuropeptide families that participate in vertebrates in this process is orexins (OXs). Interestingly, our previous results suggested that a similar dependency may also exist between neuropeptides and immune system activity in insects. Due to the structural homology of orexin and allatotropin receptors and the functional similarity between these two neuropeptide families, the main aim of this research was to perform a complex analysis of the relationships between allatotropin (AT) and the insect immune response. Our results revealed functional similarities between vertebrate OXs and insect ATs. Similar effects were observed in the profile of the expression level of the gene encoding the AT precursor in the Tenebrio molitor nervous system and in the general action of Tenmo-AT on selected immune parameters of the tested beetles. Moreover, for the first time in insects, we confirmed the role of cytokines in the modulation of neuroendocrine system by determining the effect of Spätzle-like protein injection on the expression of genes encoding AT precursor and receptor. All these results are important for understanding the evolutionary basis of hormonal regulation of the immune response., Competing Interests: Declaration of competing interest The authors declare no competing interests. G.N. is employed by the company genXone S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Heat stress (HS) is a global serious issue in the poultry industry with numerous adverse effects, including increased stress, depressed feed intake (FI), poor growth performance and higher mortality. Herbal adaptogens, plant extracts considered as stress response modifiers, are metabolic regulators that improve an organism's ability to adapt to and minimize damage from environmental stresses. Previously, we showed that herbal adaptogen supplementation increased FI and body weight (BW) of broiler (meat-type) chickens reared under HS conditions. Therefore, we hypothesized that these effects may be mediated through modulation of hypothalamic feeding-related neuropeptides. Male Cobb 500 chicks were reared in 12 environmental chambers with three diets: a corn-soybean-based diet (C) and two herbal adaptogen-supplemented diets at 500 g/1000 kg (NR-PHY-500) and 1 kg/1000 kg (NR-PHY-1000). Broilers in 9 chambers were exposed to chronic cyclic HS (35 °C for 8 h/day) from d29 to d42, while 3 chambers were maintained at 24 °C (thermoneutral, TN) for all 42 days. Hypothalamic samples were collected on d42 from each group, both before the onset of HS (Pre-HS) that day and after 3 h of HS (post-HS). Hypothalamic expressions of neuropeptide Y (NPY) receptors Y4 and Y7, Corticotropin-releasing hormone (CRH), orexin receptor 1 (ORXR1), melanocortin receptors (MC1R, MC4R, and MC5R), visfatin and neurosecretory protein GL (NPGL) genes were significantly upregulated by adaptogen supplementation. The hypothalamic expression of MC2R was affect by period, with a significant upregulation during post-HS phase. There was a significant period by treatment interaction for hypothalamic orexin and adiponectin expression. The hypothalamic expression of NPY, Y1, Y2, Y5, Y6, proopiomelanocortin (POMC), cocaine and amphetamine regulated transcript (CART), agouti-related peptide (AgRP), ORXR2, AdipR1/2, MC3R, and ghrelin was not affected by diet supplementation nor by HS exposure. In conclusion, these findings suggest that in-feed supplementation of adaptogen might improve FI and growth via modulation of hypothalamic feeding-related neuropeptides in heat-stressed broilers., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Early brain injury (EBI) is closely associated with poor prognosis in patients with subarachnoid haemorrhage (SAH), with autophagy playing a pivotal role in EBI. However, research has shown that the stimulator of interferon genes (STING) pathway impacts autophagic flux. While the regulatory impact of neuritin on EBI and autophagic flux has been established previously, the underlying mechanism remains unclear. This study aimed to determine the role of the cGAS-STING pathway in neuritin-mediated regulation of autophagic flux following SAH., Methods: A SAH model was established in male Sprague-Dawley rats via intravascular perforation. Neuritin overexpressions using adeno-associated virus, the STING antagonist "C-176," and the activator, "CMA," were determined to investigate the cGAS-STING pathway's influence on autophagic flux and brain injury post-SAH, along with the neuritin's regulatory effect on STING. In this study, SAH grade, neurological score, haematoxylin and eosin (H&E) staining, brain water content (BWC), sandwich enzyme-linked immunosorbent assay, Evans blue staining, immunofluorescence staining, western blot analysis, and transmission electron microscopy (TEM) were examined., Results: Neuritin overexpression significantly ameliorated neurobehavioural scores, blood-brain barrier injury, brain oedema, and impaired autophagic flux in SAH-induced rats. STING expression remarkably increased post-SAH. C-176 and CMA mitigated and aggravated autophagic flux injury and brain injury, respectively, while inhibiting and enhancing STING, respectively. Particularly, CMA treatment nullified the protective effects of neuritin against autophagic flux and mitigated brain injury., Conclusion: Neuritin alleviated EBI by restoring impaired autophagic flux after SAH through the regulation of the cGAS-STING pathway., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Objective: We aimed to assess the effects of neuroserpin and its combination with hypothermia on hypoxic-ischemic (HI) brain injury in neonatal rats. Neuroserpin is an axon-secreted serine protease inhibitor and is important for brain development, neuronal survival, and synaptic plasticity., Study Design: Male Wistar-Albino rats on postnatal day 7 (P7) were randomly divided into five groups: sham group ( n  = 10), (HI; n  = 10), hypoxic-ischemic hypothermia (HIH; n  = 10), hypoxic-ischemic neuroserpin (HIN; n  = 10), and hypoxic-ischemic neuroserpin-hypothermia (HINH; n  = 10). The P7 rat brain's maturation is similar to a late preterm human brain at 34 to 36 weeks of gestation. HI was induced in rats on P7 as previously described. A single dose of 0.2 µM neuroserpin (HINH and HIN) or an equivalent volume of phosphate-buffered saline (sham, HIH, and HI) was administered intraventricularly by a Hamilton syringe immediately after hypoxia. In the follow-up, pups were subjected to systemic hypothermia or normothermia for 2 hours. Euthanasia was performed for histopathological evaluation on P10. Apoptosis was detected by caspase-3 activity and terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and was counted in the hippocampus., Results: In comparison to the HI group, the TUNEL-positive and caspase-3-positive neurons in the sham, HIN, HIH, and HINH groups were considerably lower (13.4 ± 1.0 vs. 1.9 ± 0.9, 6.0 ± 0.9, 5.3 ± 1.6, and 4.0 ± 1.1; p  < 0.001) and (13.5 ± 1.7 vs. 1.2 ± 0.7, 9.1 ± 2.7, 4.8 ± 1.0, and 3.9 ± 1.6; p  < 0.001). HIN, HIH, and HINH, compared to the sham group, showed more TUNEL-positive and caspase-3-positive neurons (6.0 ± 0.9, 5.3 ± 1.6, 4.0 ± 1.1 vs. 1.9 ± 0.9 and 9.1 ± 2.7, 4.8 ± 1.0, 3.9 ± 1.6 vs. 1.2 ± 0.7; p  < 0.001). The HINH group (synergistic effect) had significantly fewer TUNEL-positive neurons and caspase-3-positive neurons than the HIN group (4.0 ± 1.1 vs. 6.0 ± 0.9 and 3.9 ± 1.6 vs. 9.1 ± 2.7; p  < 0.001)., Conclusion: Our study showed that both neuroserpin alone and as an adjuvant treatment for hypothermia may have a neuroprotective effect on brain injury., Key Points: · Neuroserpin decreased brain injury.. · Neuroserpin showed a synergistic effect when used as an adjuvant treatment for hypothermia.. · The neuroprotective effect of neuroserpine was related to its antiapoptotic properties.., Competing Interests: None declared., (Thieme. All rights reserved.)

One of the most extensively studied members of the Ras superfamily of small GTPases, Rac1 is an intracellular signal transducer that remodels actin and phosphorylation signaling networks. Previous studies have shown that Rac1-mediated signaling is associated with hippocampal-dependent working memory and longer-term forms of learning and memory and that Rac1 can modulate forms of both pre- and postsynaptic plasticity. How these different cognitive functions and forms of plasticity mediated by Rac1 are linked, however, is unclear. Here, we show that spatial working memory in mice is selectively impaired following the expression of a genetically encoded Rac1 inhibitor at presynaptic terminals, while longer-term cognitive processes are affected by Rac1 inhibition at postsynaptic sites. To investigate the regulatory mechanisms of this presynaptic process, we leveraged new advances in mass spectrometry to identify the proteomic and post-translational landscape of presynaptic Rac1 signaling. We identified serine/threonine kinases and phosphorylated cytoskeletal signaling and synaptic vesicle proteins enriched with active Rac1. The phosphorylated sites in these proteins are at positions likely to have regulatory effects on synaptic vesicles. Consistent with this, we also report changes in the distribution and morphology of synaptic vesicles and in postsynaptic ultrastructure following presynaptic Rac1 inhibition. Overall, this study reveals a previously unrecognized presynaptic role of Rac1 signaling in cognitive processes and provides insights into its potential regulatory mechanisms., Competing Interests: JK, EB, PS, NM, PP, JK, WW, ES, BR, SS No competing interests declared, (© 2024, Kim et al.)

Neuropeptides (NPs) and their cognate receptors are critical effectors of diverse physiological processes and behaviors. We recently reported of a noncanonical function of the Drosophila Glucose-6-Phosphatase ( G6P ) gene in a subset of neurosecretory cells in the central nervous system that governs systemic glucose homeostasis in food-deprived flies. Here, we show that G6P- expressing neurons define six groups of NP-secreting cells, four in the brain and two in the thoracic ganglion. Using the glucose homeostasis phenotype as a screening tool, we find that neurons located in the thoracic ganglion expressing FMRFamide NPs ( FMRFa G6P neurons) are necessary and sufficient to maintain systemic glucose homeostasis in starved flies. We further show that G6P is essential in FMRFa G6P neurons for attaining a prominent Golgi apparatus and secreting NPs efficiently. Finally, we establish that G6P- dependent FMRFa signaling is essential for the build-up of glycogen stores in the jump muscle which expresses the receptor for FMRFamides. We propose a general model in which the main role of G6P is to counteract glycolysis in peptidergic neurons for the purpose of optimizing the intracellular environment best suited for the expansion of the Golgi apparatus, boosting release of NPs and enhancing signaling to respective target tissues expressing cognate receptors., Competing Interests: Competing interests statement:The authors declare no competing interest.

Sensory neurons specialize in detecting and signaling the presence of diverse environmental stimuli. Neuronal injury or disease may undermine such signaling, diminishing the availability of crucial information. Can animals distinguish between a stimulus not being present and the inability to sense that stimulus in the first place? To address this question, we studied Caenorhabditis elegans nematode worms that lack gentle body touch sensation due to genetic mechanoreceptor dysfunction. We previously showed that worms can compensate for the loss of touch by enhancing their sense of smell, via an FLP-20 neuropeptide pathway. Here, we find that touch-deficient worms exhibit, in addition to sensory compensation, also cautious-like behavior, as if preemptively avoiding potential undetectable hazards. Intriguingly, these behavioral adjustments are abolished when the touch neurons are removed, suggesting that touch neurons are required for signaling the unavailability of touch information, in addition to their conventional role of signaling touch stimulation. Furthermore, we found that the ASE taste neurons, which similarly to the touch neurons, express the FLP-20 neuropeptide, exhibit altered FLP-20 expression levels in a touch-dependent manner, thus cooperating with the touch circuit. These results imply a novel form of neuronal signaling that enables C. elegans to distinguish between lack of touch stimulation and loss of touch sensation, producing adaptive behavioral adjustments that could overcome the inability to detect potential threats., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Staum et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

The small G-protein Ras-related C3 botulinum toxin substrate 1 (Rac1) promotes the formation of filamentous actin (F-actin). Actin is a major component of dendritic spines, and we previously found that alcohol alters actin composition and dendritic spine structure in the nucleus accumbens (NAc) and the dorsomedial striatum (DMS). To examine if Rac1 contributes to these alcohol-mediated adaptations, we measured the level of GTP-bound active Rac1 in the striatum of mice following 7 weeks of intermittent access to 20% alcohol. We found that chronic alcohol intake activates Rac1 in the DMS of male mice. In contrast, Rac1 is not activated by alcohol in the NAc and DLS of male mice or in the DMS of female mice. Similarly, closely related small G-proteins are not activated by alcohol in the DMS, and Rac1 activity is not increased in the DMS by moderate alcohol or natural reward. To determine the consequences of alcohol-dependent Rac1 activation in the DMS of male mice, we inhibited endogenous Rac1 by infecting the DMS of mice with an adeno-associated virus (AAV) expressing a dominant negative form of the small G-protein (Rac1-DN). We found that overexpression of AAV-Rac1-DN in the DMS inhibits alcohol-mediated Rac1 signaling and attenuates alcohol-mediated F-actin polymerization, which corresponded with a decrease in dendritic arborization and spine maturation. Finally, we provide evidence to suggest that Rac1 in the DMS plays a role in alcohol-associated goal-directed learning. Together, our data suggest that Rac1 in the DMS plays an important role in alcohol-dependent structural plasticity and aberrant learning., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Astrocytes specifically synthesize and release endozepines, a family of regulatory peptides including octadecaneuropeptide (ODN). We have previously reported that ODN rescues neurons and astrocytes from 6-OHDA-induced oxidative stress and cell death. The purpose of this study was to examine the potential implication of miR-34b, miR-29a, and miR-21 in the protective activity of ODN on 6-OHDA-induced oxidative stress and cell death in cultured rat astrocytes. Flow cytometry analysis showed that 6-OHDA increased the number of early apoptotic and apoptotic dead cells while treatment with the subnanomolar dose of ODN significantly reduced the number of apoptotic cells induced by 6-OHDA. 6-OHDA-treated astrocytes exhibited the over-expression of miR-21 (+118%) associated with a knockdown of miR-34b (-61%) and miR-29a (-49%). Co-treatment of astrocytes with ODN blocked the 6-OHDA-stimulated production of ROS and NO and stimulation of Bax and caspase-3 gene transcription. Concomitantly, ODN down-regulated the expression of miR-34b and miR-29a and rescued the 6-OHDA-associated reduced expression of miR21, indicating that ODN regulates their expression during cell death. Transfection with miR-21-3p inhibitor prevented the effect of 6-OHDA against cell death. In conclusion, our study indicated that (i) the expression of miRNAs miR-34b, miR-29a, and miR-21 is modified in astrocytes under 6-OHDA injury and (ii) that ODN prevents this deregulation to induce its neuroprotective action. The present study identified miR-21 as an emerging candidate and as a promising pharmacological target that opens new neuroprotective therapeutic strategies in neurodegenerative diseases, especially in Parkinson's disease.

Insects have about 50 neuropeptide genes and about 70 genes, coding for neuropeptide G protein-coupled receptors (GPCRs). An important, but small family of evolutionarily related insect neuropeptides consists of adipokinetic hormone (AKH), corazonin, and AKH/corazonin-related peptide (ACP). Normally, insects have one specific GPCR for each of these neuropeptides. The tick Ixodes scapularis is not an insect, but belongs to the subphylum Chelicerata, which comprises ticks, scorpions, mites, spiders, and horseshoe crabs. Many of the neuropeptides and neuropeptide GPCRs occurring in insects, also occur in chelicerates, illustrating that insects and chelicerates are evolutionarily closely related. The tick I. scapularis is an ectoparasite and health risk for humans, because it infects its human host with dangerous pathogens during a blood meal. Understanding the biology of ticks will help researchers to prevent tick-borne diseases. By annotating the I. scapularis genome sequence, we previously found that ticks contain as many as five genes, coding for presumed ACP receptors. In the current paper, we cloned these receptors and expressed each of them in Chinese Hamster Ovary (CHO) cells. Each expressed receptor was activated by nanomolar concentrations of ACP, demonstrating that all five receptors were functional ACP receptors. Phylogenetic tree analyses showed that the cloned tick ACP receptors were mostly related to insect ACP receptors and, next, to insect AKH receptors, suggesting that ACP receptor genes and AKH receptor genes originated by gene duplications from a common ancestor. Similar duplications have probably occurred for the ligand genes, during a process of ligand/receptor co-evolution. Interestingly, chelicerates, in contrast to all other arthropods, do not have AKH or AKH receptor genes. Therefore, the ancestor of chelicerates might have lost AKH and AKH receptor genes and functionally replaced them by ACP and ACP receptor genes. For the small family of AKH, ACP, and corazonin receptors and their ligands, gene losses and gene gains occur frequently between the various ecdysozoan clades. Tardigrades, for example, which are well known for their survival in extreme environments, have as many as ten corazonin receptor genes and six corazonin peptide genes, while insects only have one of each, or none., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Cornelis Grimmelikhuijzen reports financial support was provided by Carlsberg Foundation. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Temperature is a critical environmental cue that controls the development and lifespan of many animal species; however, mechanisms underlying low-temperature adaptation are poorly understood. Here, we describe cold-inducible diapause (CID), another type of diapause induced by low temperatures in Caenorhabditis elegans. A premature stop codon in heat shock factor 1 (hsf-1) triggers entry into CID at 9 °C, whereas wild-type animals enter CID at 4 °C. Furthermore, both wild-type and hsf-1(sy441) mutant animals undergoing CID can survive for weeks, and resume growth at 20 °C. Using epistasis analysis, we demonstrate that neural signalling pathways, namely tyraminergic and neuromedin U signalling, regulate entry into CID of the hsf-1 mutant. Overexpression of anti-ageing genes, such as hsf-1, XBP1/xbp-1, FOXO/daf-16, Nrf2/skn-1, and TFEB/hlh-30, also inhibits CID entry of the hsf-1 mutant. Based on these findings, we hypothesise that regulators of the hsf-1 mutant CID may impact longevity, and successfully isolate 16 long-lived mutants among 49 non-CID mutants via genetic screening. Furthermore, we demonstrate that the nonsense mutation of MED23/sur-2 prevents CID entry of the hsf-1(sy441) mutant and extends lifespan. Thus, CID is a powerful model to investigate neural networks involving cold acclimation and to explore new ageing mechanisms., (© 2024. The Author(s).)

Female mosquitoes produce eggs in gonadotrophic cycles that are divided between a previtellogenic and vitellogenic phase. Previtellogenic females consume water and sugar sources like nectar while also being attracted to hosts for blood feeding. Consumption of a blood meal activates the vitellogenic phase, which produces mature eggs and suppresses host attraction. In this study, we tested the hypothesis that neuropeptide Y-like hormones differentially modulate host attraction behavior in the mosquito Aedes aegypti . A series of experiments collectively indicated that enteroendocrine cells (EECs) in the posterior midgut produce and release neuropeptide F (NPF) into the hemolymph during the previtellogenic phase which stimulates attraction to humans and biting behavior. Consumption of a blood meal, which primarily consists of protein by dry weight, down-regulated NPF in EECs until mature eggs developed, which was associated with a decline in hemolymph titer. NPF depletion depended on protein digestion but was not associated with EEC loss. Other experiments showed that neurons in the terminal ganglion extend axons to the posterior midgut and produce RYamide, which showed evidence of increased secretion into circulation after a blood meal. Injection of RYamide-1 and -2 into previtellogenic females suppressed host attraction, while coinjection of RYamides with or without short NPF-2 also inhibited the host attraction activity of NPF. Overall, our results identify NPF and RYamide as gut-associated hormones in A. aegypti that link host attraction behavior to shifts in diet during sequential gonadotrophic cycles., Competing Interests: Competing interests statement:The authors declare no competing interest.

Natalisin (NTL) is a conserved neuropeptide, only present in insects, that has been reported to regulate their sexual activity. In this study, we investigated the involvement of NTL in the reproductive behaviors of a major invasive pest, Spodoptera frugiperda. We identified NTL precursor-encoded transcripts, and evaluated their transcript levels in different stages and tissues of S. frugiperda. The results showed that the NTL transcript level was expressed in both male and female pupae and both male and female adults in the later stage. It was highly expressed in male pupae, 3-day-old male and female adults, and 5-day-old male adults. In different tissues, the expression level is higher in the male and female adult brain and male testis. Immunohistochemical staining of the brain of S. frugiperda female and male adults revealed that three pairs of brain neurons of S. frugiperda adults of both sexes secreted and expressed NTL. To study the role of NTL in reproductive behaviors, NTL was silenced in S. frugiperda male and female adults by RNA interference (RNAi) technology, the results showed that silencing NTL could significantly affect the sexual activity behavior of the adults, reducing the calling rate of females, the courtship rate of males, and the mating rate. In summary, this study emphasizes the important role of NTL in regulating the mating behavior and sexual activity of S. frugiperda in both male and female adults, potentially laying a foundation to employ NTL as a new insect-specific target to control populations of pest insects., (© 2024. The Author(s).)

In mammals, intrinsic 24 h or circadian rhythms are primarily generated by the suprachiasmatic nuclei (SCN). Rhythmic daily changes in the transcriptome and proteome of SCN cells are controlled by interlocking transcription-translation feedback loops (TTFLs) of core clock genes and their proteins. SCN cells function as autonomous circadian oscillators, which synchronize through intercellular neuropeptide signalling. Physiological and behavioural rhythms can be severely disrupted by genetic modification of a diverse range of genes and proteins in the SCN. With the advent of next generation sequencing, there is unprecedented information on the molecular profile of the SCN and how it is affected by genetically targeted alteration. However, whether the expression of some genes is more readily affected by genetic alteration of the SCN is unclear. Here, using publicly available datasets from recent RNA-seq assessments of the SCN from genetically altered and control mice, we evaluated whether there are commonalities in transcriptome dysregulation. This was completed for four different phases across the 24 h cycle and was augmented by Gene Ontology Molecular Function (GO:MF) and promoter analysis. Common differentially expressed genes (DEGs) and/or enriched GO:MF terms included signalling molecules, their receptors, and core clock components. Finally, examination of the JASPAR database indicated that E-box and CRE elements in the promoter regions of several commonly dysregulated genes. From this analysis, we identify differential expression of genes coding for molecules involved in SCN intra- and intercellular signalling as a potential cause of abnormal circadian rhythms., (© 2024 The Author(s). European Journal of Neuroscience published by Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Doublecortin (DCX)-positive neural progenitor-like cells are purported components of the cancer microenvironment. The number of DCX-positive cells in tissues reportedly correlates with cancer progression; however, little is known about the mechanism by which these cells affect cancer progression. Here we demonstrated that DCX-positive cells, which are found in all major histological subtypes of lung cancer, are cancer-associated Schwann cells (CAS) and contribute to the chemoresistance of lung cancer cells by establishing an adrenergic microenvironment. Mechanistically, the activation of the Hippo transducer YAP/TAZ was involved in the acquisition of new traits of CAS and DCX positivity. We further revealed that CAS express catecholamine-synthesizing enzymes and synthesize adrenaline, which potentiates the chemoresistance of lung cancer cells through the activation of YAP/TAZ. Our findings shed light on CAS, which drive the formation of an adrenergic microenvironment by the reciprocal regulation of YAP/TAZ in lung cancer tissues., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Oscillatory networks underlying rhythmic motor behaviors, and sensory and complex neural processing, are flexible, even in their neuronal composition. Neuromodulatory inputs enable neurons to switch participation between networks or participate in multiple networks simultaneously. Neuromodulation of internetwork synapses can both recruit and coordinate a switching neuron in a second network. We previously identified an example in which a neuron is recruited into dual-network activity via peptidergic modulation of intrinsic properties. We now ask whether the same neuropeptide also modulates internetwork synapses for internetwork coordination. The crab ( Cancer borealis ) stomatogastric nervous system contains two well-defined feeding-related networks (pyloric, food filtering, ∼1 Hz; gastric mill, food chewing, ∼0.1 Hz). The projection neuron MCN5 uses the neuropeptide Gly 1 -SIFamide to recruit the pyloric-only lateral posterior gastric (LPG) neuron into dual pyloric- plus gastric mill-timed bursting via modulation of LPG's intrinsic properties. Descending input is not required for a coordinated rhythm, thus intranetwork synapses between LPG and its second network must underlie coordination among these neurons. However, synapses between LPG and gastric mill neurons have not been documented. Using two-electrode voltage-clamp recordings, we found that graded synaptic currents between LPG and gastric mill neurons (lateral gastric, inferior cardiac, and dorsal gastric) were primarily negligible in saline, but were enhanced by Gly 1 -SIFamide. Furthermore, LPG and gastric mill neurons entrain each other during Gly 1 -SIFamide application, indicating bidirectional, functional connectivity. Thus, a neuropeptide mediates neuronal switching through parallel actions, modulating intrinsic properties for recruitment into a second network and as shown here, also modulating bidirectional internetwork synapses for coordination. NEW & NOTEWORTHY Neuromodulation can enable neurons to simultaneously coordinate with separate networks. Both recruitment into, and coordination with, a second network can occur via modulation of internetwork synapses. Alternatively, recruitment can occur via modulation of intrinsic ionic currents. We find that the same neuropeptide previously determined to modulate intrinsic currents also modulates bidirectional internetwork synapses that are typically ineffective. Thus, complementary modulatory peptide actions enable recruitment and coordination of a neuron into a second network.

Oxytocin (OXT), a neuropeptide consisting of only nine amino acids, is synthesized in the paraventricular and supraoptic nuclei of the hypothalamus. Although OXT is best known for its role in lactation and parturition, recent research has shown that it also has a significant impact on social behaviors in mammals. However, a comprehensive review of this topic is still lacking. In this paper, we systematically reviewed the effects of OXT on social behavior in mammals. These effects of OXT from the perspective of five key behavioral dimensions were summarized: parental behavior, anxiety, aggression, attachment, and empathy. To date, researchers have agreed that OXT plays a positive regulatory role in a wide range of social behaviors, but there have been controversially reported results. In this review, we have provided a detailed panorama of the role of OXT in social behavior and, for the first time, delved into the underlying regulatory mechanisms, which may help better understand the multifaceted role of OXT. Levels of OXT in previous human studies were also summarized to provide insights for diagnosis of mental disorders., Competing Interests: Declaration of Competing Interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neuropeptide F is a key hormone that controls feeding in invertebrates, including decapod crustaceans. We investigated the differential expression of Macrobrachium rosenbergii neuropeptide F (MrNPF) in the digestive organs of female prawns, M. rosenbergii, during the ovarian cycle. By using RT-qPCR, the expression of MrNPF mRNA in the esophagus (ESO), cardia (CD), and pylorus (PY) of the foregut (FG) gradually increased from stage II and peaked at stage III. In the midgut (MG), hindgut (HG), and hepatopancreas (HP), MrNPF mRNA increased from stage I, reaching a maximal level at stage II, and declined by about half at stages III and IV (P < 0.05). In the ESO, CD, and PY, strong MrNPF-immunoreactivities were seen in the epithelium, muscle, and lamina propria. Intense MrNPF-ir was found in the MG cells and the muscular layer. In the HG, MrNPF-ir was detected in the epithelium of the villi and gland regions, while MrNPF-ir was also more intense in the F-, R-, and B-cells in the HP. However, we found little colocalization between the MrNPF and PGP9.5/ChAT in digestive tissues, implying that most of the positive cells might not be neurons but could be digestive tract-associated endocrine cells that produce and secrete MrNPF to control digestive organ functions in feeding and utilizing feed. Taken together, our first findings indicated that MrNPF was differentially expressed in digestive organs in correlation with the ovarian cycle, suggesting an important link between MrNPF, the physiology of various digestive organs in feeding, and possibly ovarian maturation in female M. rosenbergii., (© 2024. The Author(s).)

Rac1 is a key regulator of the cytoskeleton and neuronal plasticity, and is known to play a critical role in psychological and cognitive brain disorders. To elucidate the engram specific Rac1 signaling in fear memory, a doxycycline (Dox)-dependent robust activity marking (RAM) system was used to label dorsal dentate gyrus (DG) engram cells in mice during contextual fear conditioning. Rac1 mRNA and protein levels in DG engram cells were peaked at 24 h (day 1) after fear conditioning and were more abundant in the fear engram cells than in the non-engram cells. Optogenetic activation of Rac1 in a temporal manner in DG engram cells before memory retrieval decreased the freezing level in the fear context. Optogenetic activation of Rac1 increased autophagy protein 7 (ATG7) expression in the DG engram cells and activated DG microglia. Microglia-specific transcriptomics and fluorescence in situ hybridization revealed that overexpression of ATG7 in the fear engram cells upregulated the mRNA of Toll-like receptor TLR2/4 in DG microglia. Knockdown of microglial TLR2/4 rescued fear memory destabilization induced by ATG7 overexpression or Rac1 activation in DG engram cells. These results indicate that Rac1-driven communications between engram cells and microglia contributes to contextual fear memory destabilization, and is mediated by ATG7 and TLR2/4, and suggest a novel mechanistic framework for the cytoskeletal regulator in fear memory interference., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Neuritin plays an important role in promoting nerve injury repair and maintaining synaptic plasticity, making it a potential therapeutic target for the treatment of nerve injury and neurodegenerative diseases. The present study aimed to obtain an active, unlabeled neuritin protein. Initially, a neuritin protein expression system with an enterokinase site was constructed in Escherichia coli. After optimizing induction conditions and screening for high expression, a neuritin recombinant protein with purity exceeding 85 % was obtained through Ni-affinity chromatography. Subsequently, unlabeled neuritin with a molecular weight of 11 kDa was obtained through the enzymatic cleavage of the His label using an enterokinase. Furthermore, a neuritin recombinant protein with purity exceeding 95 % was obtained using gel chromatography. Functional investigations revealed that neurite outgrowth of PC12 cells was stimulated by the isolated neuritin. This study establishes a method to obtain active and unlabeled neuritin protein, providing a foundation for subsequent research on its biological functions., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Ischemic stroke represents a significant global health challenge, often resulting in death or long-term disability, particularly among the elderly, where advancing age stands as the most unmodifiable risk factor. Arising from the blockage of a brain-feeding artery, the only therapies available to date aim at removing the blood clot to restore cerebral blood flow and rescue neuronal cells from death. The prevailing treatment approach involves thrombolysis by administration of recombinant tissue plasminogen activator (tPA), albeit with a critical time constraint. Timely intervention is imperative, given that delayed thrombolysis increases tPA leakage into the brain parenchyma, causing harmful effects. Strategies to preserve tPA's vascular benefits while shielding brain cells from its toxicity have been explored. Notably, administering neuroserpin (Ns), a brain-specific tPA inhibitor, represents one such approach. Following ischemic stroke, Ns levels rise and correlate with favorable post-stroke outcomes. Studies in rodent models of focal cerebral ischemia have demonstrated the beneficial effects of Ns administration. Ns treatment maintains blood-brain barrier (BBB) integrity, reducing stroke volume. Conversely, Ns-deficient animals exhibit larger stroke injury, increased BBB permeability and enhanced microglia activation. Furthermore, Ns administration extends the therapeutic window for tPA intervention, underscoring its potential in stroke management. Remarkably, our investigation reveals the presence of Ns within extracellular vesicles (EVs), small membrane-surrounded particles released by all cells and critical for intercellular communication. EVs influence disease outcome following stroke through cargo transfer between cells. Clarifying the role of EVs containing NS could open up urgently needed novel therapeutic approaches to improve post-ischemic stroke outcome.

The neuromodulator orexin has been identified as a key factor for motivated arousal including recent evidence that sleep deprivation-induced enhancement of reward behavior is modulated by orexin. While orexin is not necessary for either reward or arousal behavior, orexin neurons' broad projections, ability to sense the internal state of the animal, and high plasticity of signaling in response to natural rewards and drugs of abuse may underlie heightened drug seeking, particularly in a subset of highly motivated reward seekers. As such, orexin receptor antagonists have gained deserved attention for putative use in addiction treatments. Ongoing and future clinical trials are expected to identify individuals most likely to benefit from orexin receptor antagonist treatment to promote abstinence, such as those with concurrent sleep disorders or high craving, while attention to methodological considerations will aid interpretation of the numerous preclinical studies investigating disparate aspects of the role of orexin in reward and arousal., Competing Interests: Declaration of Competing Interest We have no conflicts of interest to disclose and have disclosed the use of AI (ChatGPT) for its use in creating a title based on key words., (Published by Elsevier Inc.)

The menopause transition is an important period in a woman's life, during which she is at an increased risk of mood disorders. Estrogen and progesterone fluctuations during the menopausal transition and very low levels of estradiol after menopause have a profound effect on the central nervous system (CNS), causing an imbalance between excitatory and inhibitory inputs. Changes in neurotransmission and neuronal interactions that occur with estradiol withdrawal disrupt the normal neurological balance and may be associated with menopausal symptoms. Hot flushes, depressed mood and anxiety are all symptoms of menopause that are a consequence of the complex changes that occur in the CNS, involving many signaling pathways and neurotransmitters (i.e. γ-aminobutyric acid, serotonin, dopamine), neurosteroids (i.e. allopregnanolone), and neuropeptides (i.e. kisspeptin, neurokinin B). All these pathways are closely linked, and the complex interactions that exist are not yet fully understood. This review summarizes the neuroendocrine changes in the CNS during the menopausal transition, with particular emphasis on those that underlie mood changes., Competing Interests: Declaration of competing interest The authors declare that they have no competing interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Neuropeptides are biomolecules with crucial physiological functions. Accurate identification of neuropeptides is essential for understanding nervous system regulatory mechanisms. However, traditional analysis methods are expensive and laborious, and the development of effective machine learning models continues to be a subject of current research. Hence, in this research, we constructed an SVM-based machine learning neuropeptide predictor, iNP&#95;ESM, by integrating protein language models Evolutionary Scale Modeling (ESM) and Unified Representation (UniRep) for the first time. Our model utilized feature fusion and feature selection strategies to improve prediction accuracy during optimization. In addition, we validated the effectiveness of the optimization strategy with UMAP (Uniform Manifold Approximation and Projection) visualization. iNP&#95;ESM outperforms existing models on a variety of machine learning evaluation metrics, with an accuracy of up to 0.937 in cross-validation and 0.928 in independent testing, demonstrating optimal neuropeptide recognition capabilities. We anticipate improved neuropeptide data in the future, and we believe that the iNP&#95;ESM model will have broader applications in the research and clinical treatment of neurological diseases.

Linked rhythmic behaviors, such as respiration/locomotion or swallowing/chewing, often require coordination for proper function. Despite its prevalence, the cellular mechanisms controlling coordination of the underlying neural networks remain undetermined in most systems. We use the stomatogastric nervous system of the crab Cancer borealis to investigate mechanisms of internetwork coordination, due to its small, well-characterized feeding-related networks (gastric mill [chewing, ∼0.1 Hz]; pyloric [filtering food, ∼1 Hz]). Here, we investigate coordination between these networks during the Gly 1 -SIFamide neuropeptide modulatory state. Gly 1 -SIFamide activates a unique triphasic gastric mill rhythm in which the typically pyloric-only LPG neuron generates dual pyloric-plus gastric mill-timed oscillations. Additionally, the pyloric rhythm exhibits shorter cycles during gastric mill rhythm-timed LPG bursts, and longer cycles during IC, or IC plus LG gastric mill neuron bursts. Photoinactivation revealed that LPG is necessary to shorten pyloric cycle period, likely through its rectified electrical coupling to pyloric pacemaker neurons. Hyperpolarizing current injections demonstrated that although LG bursting enables IC bursts, only gastric mill rhythm bursts in IC are necessary to prolong the pyloric cycle period. Surprisingly, LPG photoinactivation also eliminated prolonged pyloric cycles, without changing IC firing frequency or gastric mill burst duration, suggesting that pyloric cycles are prolonged via IC synaptic inhibition of LPG, which indirectly slows the pyloric pacemakers via electrical coupling. Thus, the same dual-network neuron directly conveys excitation from its endogenous bursting and indirectly funnels synaptic inhibition to enable one network to alternately decrease and increase the cycle period of a related network., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 Gnanabharathi et al.)

The RFamide peptide family is a group of proteins that share a common C-terminal arginine-phenylalanine-amide motif. To date, the family comprises five groups in mammals: neuropeptide FF, LPXRFamides/RFamide-related peptides, prolactin releasing peptide, QRFP, and kisspeptins. Different RFamide peptides have their own cognate receptors and are produced by different cell populations, although they all can also bind to neuropeptide FF receptors with different affinities. RFamide peptides function in the brain as neuropeptides regulating key aspects of homeostasis such as energy balance, reproduction, and cardiovascular function. Furthermore, they are involved in the organization of the stress response including modulation of pain. Considering the interaction between stress and various parameters of homeostasis, the role of RFamide peptides may be critical in the development of stress-related neuropathologies. This review will therefore focus on the role of RFamide peptides as possible key hubs in stress and stress-related psychopathologies. The neurotransmitter coexpression profile of RFamide-producing cells is also discussed, highlighting its potential functional significance. The development of novel pharmaceutical agents for the treatment of stress-related disorders is an ongoing need. Thus, the importance of RFamide research is underlined by the emergence of peptidergic and G-protein coupled receptor-based therapeutic targets in the pharmaceutical industry.