Search

The circadian timing system is synchronized by the environmental photic and non-photic signals. Light is the major cue that entrains the master circadian oscillator located in suprachiasmatic nucleus (SCN). With aging condition ocular light impairs because of the age-related deficiencies in the eye as a result the clock becomes less sensitive to light. In such case non-photic cues may play a major role in synchronizing the clock. Earlier studies have linked altered meal timings to induce many physiological changes including serotonin in different brain regions such as hypothalamus, brain stem and striatum. Much is not known about the effect of timed food restriction as a non-photic stimulus on serotonergic system in SCN under aging condition. We report here the synchronizing effects of time-restricted feeding (TRF) as a non-photic stimulus on serotonin and its related metabolites in the SCN and pineal gland of male Wistar rats upon aging. Under food restriction daily rhythmicity of serotonin 5-HT and 5-HTOH was abolished whereas NAS, 5-MIAA and NAT showed a significant decrease in their daily pulses upon food restriction in 3 months (m) old rats. Under forced day time feeding schedule the mean 24 h levels of serotonin have significantly decreased in 12 and 24 m old animals in SCN and pineal gland. Most of the serotonin metabolites in the SCN and pineal gland of 12 and 24 m old ad libitum fed group rats have shown rhythmicity. 5-HT, NAS, MEL and NAT have shown daily rhythm in the SCN of 12 and 24 m old rats whereas 5-MIAA and 5-MTOH did not show daily rhythm in both the age groups. The mean 24 h levels of 5-HTP, 5-HIAA, 5-MIAA, 5-MTOH, MEL and NAT were increased in the pineal gland of 12 and 24 months old rats. This work help demonstrate the role of TRF in synchronising age induced desynchronization in serotonin metabolome. [ABSTRACT FROM AUTHOR]

Despite significant advancements to understand of the neural circuitry involved in anxiety, the neurobiology of trait anxiety remains unclear. The rostral anterior cingulate cortex (rACC) and various pathways have been implicated in its regulation, making it a key to trait anxiety. The present study aimed to investigate the role of these neurotransmitter systems in the rACC in trait anxiety. Since trait anxiety is known to modulate state anxiety, we further investigated this relationship. Specifically, in Experiment I, we used animals with high trait anxiety; in Experiment II, we used animals with low trait anxiety; and in Experiment III, we used animals with medium trait anxiety. Before each behavioral assessment, drugs that either increased or decreased serotonergic (Fluoxetine or WAY-100635), GABAergic (Muscimol or Bicuculline), and glutamatergic (NMDA or Ketamine) neurotransmission in the rACC were administered, along with their respective controls. Additionally, in Experiment IV, all animals from the previous experiments were subjected to the Elevated Plus Maze (EPM) and Hole board (HB) test and evaluated without taking into account their trait anxiety levels. The results of the present study showed that, in Exp I, the modulation of the serotonergic, GABAergic and glutamatergic systems in the rACC decreased trait anxiety in highly anxious rats, while by submitting the animals to HB, the administration of fluoxetine increased state anxiety. In Exp II, the modulation of all systems increased trait anxiety in rats with low trait anxiety, whereas, in HB, state anxiety levels were increased with the administration of NMDA. In Exp III, only the modulation of the glutamatergic system, with NMDA, increased both trait and state anxiety levels. However, none of the evaluated neurotransmitter systems altered the state anxiety modeled in the EPM. Overall, the results of the present study provide new insights into the role of the neurotransmitter systems in the rACC in the regulation of trait anxiety and state anxiety., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Major depressive disorder (MDD) is among the most common mental disorders worldwide and is characterized by dysregulated reward processing associated with anhedonia. Selective serotonin reuptake inhibitors (SSRIs) are the first-line treatment for MDD; however, their onset of action is delayed. Recent reports have shown that serotonin neurons in the dorsal raphe nucleus (DRN) are activated by rewards and play a vital role in reward processing. However, whether antidepressant treatment affects the DRN serotonin neuronal response to rewards in awake animals remains unknown. In this study, we measured the activity of DRN serotonin neurons in awake mice and determined the effects of antidepressants and chronic stress on DRN serotonin neuronal activity. We found that acute treatment with citalopram, an SSRI, significantly decreased sucrose-induced activation of DRN serotonin neurons. The decrease in response to acute citalopram treatment was attenuated by chronic citalopram treatment. Acute treatment with (S)-WAY100135, a 5-HT 1A receptor antagonist, dose-dependently inhibited the response to acute citalopram treatment. These results indicate that autoinhibition by activating 5-HT 1A receptors via acute SSRI treatment may blunt the reward response, which can be recovered after chronic SSRI treatment., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest., (Copyright © 2025 The Authors. Published by Elsevier B.V. All rights reserved.)

Since the 1950s, considerable circumstantial evidence had been presented that endogenous 5-HT (serotonin) synthesized from within the wall of the gastrointestinal (GI) tract played an important role in GI motility and transit. However, identifying the precise functional role of gut-derived 5-HT has been difficult to ascertain, for a number of reasons. Over the past decade, as recording techniques have advanced significantly and access to new genetically modified animals improved, there have been major new insights and major changes in our understanding of the functional role of endogenous 5-HT in the GI tract. Data from many different laboratories have shown that major patterns of GI motility and transit still occur with minor or no, change when all endogenous 5-HT is pharmacologically or genetically ablated from the gut. Furthermore, antagonists of 5-HT 3 receptors are equally, or more potent at inhibiting GI motility in segments of intestine that are completely depleted of endogenous 5-HT. Here, the most recent findings are discussed with regard to the functional role of endogenous 5-HT in enterochromaffin cells and enteric neurons in gut motility and more broadly in some major homeostatic pathways., (© 2022 British Pharmacological Society.)

Background and Purpose: In male rats, the serotonergic system modulates sympathetic outflow at vascular levels, causing sympatho-inhibition and sympatho-excitation, mainly via 5-HT 1D/1A and 5-HT 3 receptors, respectively. However, sex influence on vascular serotonergic regulation has not yet been elucidated. This study aimed to analyse the 5-HT sympatho-modulatory role in female rats, characterising the 5-HT receptors involved., Experimental Approach: Female Wistar (14- to 16-week-old) rats were prepared for sympathetic stimulation. Mean blood pressure (MBP) and heart rate (HR) were continuously measured. Vasopressor responses were obtained by electrical stimulation of the sympathetic outflow (0.1-5 Hz) or i.v. noradrenaline (0.01-0.5 μg·kg -1 ). 5-HT-related drug effects on adrenergic system were determined. Age-matched male rats were used as control., Key Results: Basal MBP in females was lower than in male rats, whereas electrical-induced increases in MBP were similar. In females, 5-HT exerted a dose-dependent inhibition on the sympathetic-evoked vasoconstrictions, that was reproduced by some agonists; 5-CT (5-HT 1/5/7 ) and L-694,247 (5-HT 1D ), whereas the selective 5-HT 2A/2B/2C (α-methyl-5-HT) and 5-HT 3 agonist (1-PBG) increased the electrically-produced vasopressor responses. None of the other drugs tested (targeting 5-HT 1A/1B/1F , 5-HT 2B/2C , 5-HT 4 , 5-HT 5A or 5-HT 7 ) modified these vasoconstrictions. Only 1-PBG (5-HT 3 ) modified the vasoconstrictions induced by exogenous noradrenaline., Conclusions and Implications: In female rats, vascular serotonergic sympatholytic effects are due to prejunctional 5-HT 1D receptor activation, whereas pre and/or postjunctional 5-HT 3 and prejunctional 5-HT 2A receptor activation is involved in the potentiating effect of vascular sympathetic neurotransmission. These findings may open novel sex-differential therapeutic strategies for treating cardiovascular conditions., (© 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer's disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, which are all disrupted in AD. We report here that tau pathology is present in the DRN of individuals 25-80 years old without a known history of dementia, and its prevalence was comparable to the locus coeruleus (LC). By comparison, fewer cases were positive for other pathological proteins including α-synuclein, β-amyloid, and TDP-43. To evaluate how early tau pathology impacts behavior, we overexpressed human P301L-tau in the DRN of mice and observed depressive-like behaviors and hyperactivity without deficits in spatial memory. Tau pathology was predominantly found in neurons relative to glia and colocalized with a significant proportion of Tph2-expressing neurons in the DRN. 5-HT neurons were also hyperexcitable in P301L-tau DRN mice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs). Moreover, astrocytic density was elevated in the DRN and accompanied by an increase in IL-1α and Frk expression, which suggests increased inflammatory signaling. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen. A significant proportion of this tau pathology colocalized with the serotonin reuptake transporter (SERT), suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together these results indicate that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to behavioral dysregulation, 5-HT neuronal dysfunction, and activation of local astrocytes which may be prodromal indicators of AD., Competing Interests: Competing interests: The authors declare that they have no known competing financial interests or personal relationships that could have impacted or appeared to impact this work Ethics approval: All procedures on mice in this study were approved by the Institutional Care and Use Committee at the University of Iowa., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

One hallmark of substance use disorder is continued drug use despite negative consequences. When drug-taking behavior is punished with aversive stimuli, i.e. footshock, rats can also be categorized into punishment-resistant or compulsive vs. punishment-sensitive or non-compulsive phenotypes. The serotonin (5-hydroxytryptamine, 5-HT) system modulates responses to both reward and punishment. The goal of the current study was to examine punishment phenotypes in heroin self-administration and to determine the role of dorsal raphe nucleus (DRN) 5-HT neurons in both basal and punished heroin self-administration. First, rats were exposed to punished heroin self-administration and neuronal excitability of DRN 5-HT neurons was compared between punishment-resistant and punishment-sensitive phenotypes using ex vivo electrophysiology. Second, DRN 5-HT neuronal activity was manipulated in vivo during basal and punished heroin self-administration using chemogenetic tools in a Tph2-iCre rat line. While rats separated into punishment-resistant and punishment-sensitive phenotypes for punished heroin self-administration, DRN 5-HT neuronal excitability did not differ between the phenotypes. While chemogenetic inhibition of DRN 5-HT neurons was without effect, chemogenetic activation of DRN 5-HT neurons increased both basal and punished heroin self-administration selectively in punishment-resistant animals. Additionally, the responsiveness to chemogenetic activation of DRN 5-HT neurons in basal self-administration and motivation for heroin in progressive ratio each predicted resistance to punishment. Therefore, our data support the role for the DRN 5-HT system in compulsive heroin self-administration., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Objectives: Depression is a widely prevalent mental disorder, and nutritional interventions play an increasingly important role in its treatment. In this paper, effects of linoleic acid (LA) on depressive behavior in mice induced by gut microbiome disorders were investigated., Methods: Fifty C57BL/6J male mice were randomly separated into five groups, control group (CK), ceftriaxone sodium group (CRO), low-dose linoleic acid group (LLA, 1 g/kg), medium-dose linoleic acid group (MLA, 2 g/kg), and high-dose linoleic acid group (HLA, 5 g/kg). In the LLA, MLA, and HLA groups, mice were treated with ceftriaxone sodium (CRO) to induce depressive behaviors, followed by LA administration. Behavioral tests were used to evaluate depressive behavior. High-throughput sequencing and Hematoxylin-eosin (H&E) staining in gut microenvironment were carried out. ELISA kits were used to measure brain inflammatory factors, and 5-hydroxy-tryptamine (5-HT). Gas chromatography and western blot were used to determine fatty acids compositions and the enzymes expression involved in lipid metabolism in brain respectively., Results: The results showed that 10 weeks CRO treatment contribute to depressive behavior, gut microbiome disturbance, and serotonin system disturbance. LLA and MLA improved the depressive-like behavior, and significantly increased the levels of 5-HT1A, 5-HTT and 5-HT in the hippocampus. LLA was found to improve the diversity of gut microbiome and alleviate colon tissue damage. Meantime, LLA increased the content of linoleic acid, improved the expression of FADS2 and COX-2, increased IL-10 levels, and decreased IL-6 levels in the brain., Discussion: LA alleviated depressive behavior in mice by improving the gut microenvironment, regulate fatty acid metabolism, and modulate inflammation.

Serotonin (5-HT) plays an essential role in reward processing, however, the possibilities to investigate 5-HT action in humans during emotional stimulation are particularly limited. Here we demonstrate the feasibility of assessing reward-specific dynamics in 5-HT synthesis using functional PET (fPET), combining its molecular specificity with the high temporal resolution of blood oxygen level dependent (BOLD) fMRI. Sixteen healthy volunteers underwent simultaneous fPET/fMRI with the radioligand [ 11 C]AMT, a substrate for tryptophan hydroxylase. During the scan, participants completed the monetary incentive delay task and arterial blood samples were acquired for quantifying 5-HT synthesis rates. BOLD fMRI was recorded as a proxy of neuronal activation, allowing differentiation of reward anticipation and feedback. Monetary gain and loss resulted in substantial increases in 5-HT synthesis in the ventral striatum (VStr, +21% from baseline) and the anterior insula (+41%). In the VStr, task-specific 5-HT synthesis was further correlated with BOLD signal changes during reward feedback (ρ = -0.65), but not anticipation. Conversely, 5-HT synthesis in the anterior insula correlated with BOLD reward anticipation (ρ = -0.61), but not feedback. In sum, we provide a robust tool to identify task-induced changes in 5-HT action in humans, linking the dynamics of 5-HT synthesis to distinct phases of reward processing in a regionally specific manner. Given the relevance of altered reward processing in psychiatric disorders such as addiction, depression and schizophrenia, our approach offers a tailored assessment of impaired 5-HT signaling during cognitive and emotional processing., Competing Interests: Competing interests: RL received investigator-initiated research funding from Siemens Healthcare regarding clinical research using PET/MR. He is a shareholder of the start-up company BM Health GmbH since 2019. M. Hacker received consulting fees and/or honoraria from Bayer Healthcare BMS, Eli Lilly, EZAG, GE Healthcare, Ipsen, ITM, Janssen, Roche, and Siemens Healthineers. All other authors report no conflict of interest in relation to this study., (© 2024. The Author(s).)

Background: The present study aims to assess the therapeutic potential of vitamin C (Vit C) on anxiety- and depressive-like behavior induced by abstinence from chronic nicotine-ethanol co-exposure in adolescent male rats., Materials and Methods: Adolescent male rats were divided into seven experimental groups with ten rats as follows: 1) vehicle, 2) Nicotine (Nic)-Ethanol (Eth): received Nic (2 mg/kg) and Eth (20%) in drinking water from 21 to 42 days of age, 3-5) Nic-Eth-Vit C 100/200/400: received Nic and Eth from 21 to 42 days of age and received Vit C 100/200/400 mg/kg from 43 to 63 days of age, 6) Nic-Eth-Bupropion (Bup)- Naloxone (Nal): received Nic and Eth from 21 to 42 days of age and received Bup and Nal from 43 to 63 days of age, and 7) Vit C 400 mg/kg: received Vit C 400 mg/kg from 43 to 63 days of age. Behavioral assessments were done by elevated plus maze (EPM), forced swimming test (FST), marble burring test (MBT), and open field tests (OFT). Furthermore, specific biochemical variables associated with oxidative, inflammatory, and serotonergic profiles were quantified., Results: According to the obtained results, Nic and Eth induced anxiety and depression in treated rats. We showed that two higher doses of Vit C increases the active struggling time in FST and decreases both the time spent in the peripheral zone of OFT and the time spent in the closed arms of EPM. In addition, animals treated by Vit C buried less number of marbles in MBT compared to their control counterparts. Nic and Eth induced oxidative stress and inflammation in cortical tissues of treated rats. Biochemical parameters were improved in the Nic-Eth group receiving Vit C 200/400 mg/kg and Bup-Nal through establishing a balance between oxidant/anti-oxidant and inflammatory/anti-inflammatory mediators. In addition, serotonin level was increased, while Monoamine oxidase (MAO) activity was notably decreased., Conclusion: The present findings support the beneficial effect of Vit C on anxiety- and depressive-like behavior induced by Nic-Eth withdrawal through various mechanisms such as the promotion of antioxidant defense, suppression of inflammatory mediators, and enhancement of serotoninergic function., (© 2024 International Society for Developmental Neuroscience.)

Obesity is a growing global health epidemic with limited orally administered therapeutics. Serotonin (5-HT) is one neurotransmitter which remains an excellent target for new weight-loss therapies, but a gap remains in understanding the mechanisms involved in 5-HT produced in the dorsal Raphe nucleus (DRN) and its involvement in meal initiation. Using an optogenetic feeding paradigm, we showed that the 5-HT DRN ➔arcuate nucleus (ARH) circuit plays a role in meal initiation. Incorporating electrophysiology and ChannelRhodopsin-2-Assisted Circuit Mapping, we demonstrated that 5-HT DRN neurons receive inhibitory input partially from GABAergic neurons in the DRN, and the 5-HT response can be enhanced by hunger. Additionally, deletion of the GABA A receptor subunit in 5-HT neurons inhibits meal initiation with no effect on the satiation process. Finally, we identified the role of dopaminergic inputs via dopamine receptor D2 in enhancing the response to GABA-induced feeding. Thus, our results indicate that 5-HT DRN neurons are inhibited by synergistic inhibitory actions of GABA and dopamine, for the initiation of a meal., 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 Authors. Published by Elsevier Inc. All rights reserved.)

The onset of lactation is characterized by marked increases in calcium (Ca) metabolism. Recently emphasis was placed on understanding the profile and dynamics of blood Ca and serotonin in the peripartal cow in response to this change using a randomized 2 × 2 factorial design. The aims of our study were to determine (1) how a prepartum DCAD diet and the magnitude of Ca decline at the onset of lactation alter circulating blood serotonin and ionized Ca concentration dynamics in the periparturient cow, and (2) the relationship of Ca versus serotonin during the peripartal period. Thirty-two multiparous Holstein cows were blocked by parity (2 vs. >2) to ensure equal parity number across the experiment, previous 305 d milk yield, and expected parturition date and randomly allocated to positive (+120 mEq/kg; +DCAD) or negative (-120 mEq/kg; -DCAD) DCAD diets from 251 d of gestation until parturition (n = 16/diet). Immediately after calving cows were continuously infused for 24 h with (1) an intravenous solution of 10% dextrose or (2) Ca gluconate (CaGlc) to maintain blood ionized Ca concentrations at 1.2 mM (normocalcemia), forming the following 4 treatment groups: negative DCAD and CaGlc (NCa), negative DCAD and dextrose (NDex), positive DCAD and CaGlc (PCa), and positive DCAD and dextrose (PDex; n = 8/treatment). Blood was sampled every 6 h from 102 h before parturition until 96 h postparturition. During the continuous infusion period (the 24 h immediately following parturition) cows were sampled every 30 min. Cows fed a -DCAD diet prepartum had greater circulating serotonin concentrations pre- and postpartum. Time series analyses demonstrated that the pooled mean effect size (ES) of the relationship between ionized Ca and serotonin 36 h before parturition was significantly positive (ES = 0.164) prepartum. We also observed that the overall pooled mean ES of the relationship between prepartum blood pH 24 h prior and serotonin was significantly positive (ES = 0.111); however, for individual treatment groups, relationships were identified between blood pH and serotonin 18 and 6 h before only for the NDex group. Our data suggest that serotonin is an important factor in the regulation of Ca homeostasis during the prepartal period and that the mechanism may be integrated with blood pH., (The Authors. Published by Elsevier Inc. on behalf of the American Dairy Science Association®. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).)

In the present study authors studied the effect of caffeic acid (CA) in chronic unpredictable mild stress (CUMS) and dexamethasone (DEXA) model of depression. CUMS (21 days) and DEXA (1.5 mg/kg × 21 days) was used for the induction of depression and anxiety related behavior. Locomotor activity was determined using actophotometer. Depression related behavior was determined using tail suspension test (TST) and forced swim test (FST) whereas for the determination of anxiety related behavior elevated plus maze (EPM) test was used. Following behavioral studies, mice were sacrificed by decapitation method. Hippocampus was dissected and was used for the neurochemical assays including 5-HT (serotonin), glutamate, nitrite and gamma-aminobutyric acid (GABA). The results obtained suggested that the CA (25-100 mg/kg, i.p.) did not affect the activity count in CUMS exposed and DEXA treated mice. CA (50 mg/kg) evoked anxiogenic reactions in CUMS model by increasing the hippocampal nitrite and glutamate level while CA (50 mg/kg) exerted anxiolysis in DEXA model by reducing the level of 5-HT. In CUMS model, CA exerted antidepressant like effect by increasing the hippocampal nitric oxide (NO) level, in DEXA model CA exerted antidepressant like effect by reducing the hippocampal glutamate level. CA failed to reverse DEXA mediated nNOS inhibition and therefore decreases hippocampal glutamate level to exert antidepressant like effect. Thus, CA modulate anxiety and depression related neurobehavioral alterations in both CUMS and DEXA models., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Elsevier Inc. All rights reserved.)

CD44 is a transmembrane protein that plays an essential role in transducing extracellular stimuli into intracellular signaling cascades, especially in cancer cells. Recent studies have shown that CD44 contributes to metabolic regulation. However, the effect of CD44 on adipogenesis in white adipose tissue (WAT) remains unclear. Herein, the expression of CD44 was largely increased in the inguinal and epididymal WAT of obese mice. Ablation or neutralization of CD44 inhibited adipogenesis in cultured adipocytes. CD44-deficient mice were resistant to high-fat diet-induced obesity and metabolic dysfunction. RNA-sequencing, together with functional studies, revealed that reduced expression of tryptophan 5-hydroxylase 2 (Tph2) in WAT was responsible for the repressed adipogenesis in the absence of CD44. The application of 5-hydroxytryptamine, a product of TPH2, rescued the repressed adipogenesis induced by CD44 neutralization. Moreover, the inhibition of TPH2 by p-chlorophenylalanine recapitulated the beneficial phenotypes observed in CD44-deficient mice. Taken together, these data indicate that CD44 plays a pivotal role in adipogenesis in WAT. In this regard, CD44 and its downstream target TPH2 may hold great therapeutic potential for treating excessive adiposity-related metabolic disorders, such as obesity, insulin resistance, and type 2 diabetes., Competing Interests: Disclosure Statement None declared., (Copyright © 2025 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Exposure to stress in early life can have a significant impact on individuals. However, the effects of early-life stress (ELS) on prosocial behavior remain unclear, as do the underlying mechanisms. In this study, ICR juvenile mice were subjected to juvenile chronic social defeat stress (jCSDS) between postnatal days 32 and 41, during which body weight changes were continuously monitored. The behaviors of adult mice were evaluated using the open field test (OFT), the social interaction test (SIT), and the prosocial choice task (PCT). ELISA was used to quantify serum levels of oxytocin, serotonin, and dopamine. The density of dendritic spines in the basolateral amygdala was evaluated by Golgi staining. Behavioral test results showed that jCSDS induced anxiety-like behavior and decreased prosocial selection tendency in mice. Additionally, exposure to jCSDS increased the serum levels of oxytocin, decreased those of serotonin, and increased the density of dendritic spines in the basolateral amygdala. Correlation analysis indicated that prosocial behavior was negatively correlated with serum oxytocin levels and dendritic spine density in the basolateral amygdala. These results suggested that jCSDS reduced prosocial behavior, possibly due to changes in serum oxytocin contents and adaptive changes in amygdaloid neurons., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Neuronal structural plasticity gives the adult brain the capacity to adapt to internal or external factors by structural and molecular changes. These plastic processes seem to be mediated, among others, by the action of the neurotransmitter serotonin through specific receptors (5-HTRs). Previous studies have shown that the maturation of granule cells in the hippocampus is mediated by 5-HT3. In the present study, we wanted to check if the neural maturation in layer II piriform cortex is also mediated by 5-HT3. In the piriform cortex, in contrast to the hippocampus, there is no postnatal neurogenesis. All immature neurons (PSA-NCAM immunoreactive) were originated prenatally. Immature cells in this area begin as small cells (type I cells) that then mature to larger cells (type II cells), and finally, mature to principal cells (PSA-NCAM immunonegative). To study the role of 5HT3 in this population, we first demonstrated the presence of 5HT3 receptors on both type I and II cells. Then we increased serotonin concentration using chronic fluoxetine administration, producing a reduction in the number of type I cells and an increment of type II cells but not an induction in the final stage of maturation to principal cells, as shown by the higher number of immature cells than in controls. This effect was blocked by ondansetron (a 5 HT3 antagonist). In conclusion, serotonin induces the progression from type I cells to type II cells but not from the later to mature PSA-NCAM immunonegative neurons. This effect is mediated by 5-HT3 receptors present in the immature cells., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Chai Shao Jie Yu Granules (CSJY) is a renowned and time-honored formula employed in clinical practice for the management of various conditions, notably depression. Depression, a prevalent psychiatric disorder, poses challenges with limited effective treatment options. Traditional herbal medicines have garnered increasing attention in the realm of combating depression, being perceived as safer alternatives to pharmacotherapy., Aim of the Study: To explore the effects and mechanisms of CSJY in chronic unpredictable mild stress (CUMS)-induced depression., Materials and Methods: Rat models of CUMS-induced depression were established, and the rats were randomly allocated into six groups: Control, CUMS, CUMS + Paroxetine (PX), CUMS + CSJY-L, CUMS + CSJY-M, and CUMS + CSJY-H. Throughout the study, the rats' body weight was monitored. Depression-related behaviors were assessed using the sucrose preference test (SPT) and open field test (OFT). High-performance liquid chromatography-mass spectrometry (HPLC-MS) measured monoamine neurotransmitters in the rat cortex and hippocampus. We measured adrenocorticotropic hormone (ACTH), corticosterone (CORT), and corticotropin-release hormone (CRH) levels in rat serum. Additionally, network pharmacology was employed to predict relevant molecular targets and potential mechanisms, followed by in vivo validation. Western blot analysis was conducted to evaluate the protein levels of 5-hydroxytryptamine/serotonin receptor 1A (5-HT1A) and Glutamate (Glu)-related proteins, such as p-GluA1, GluA1, p-GluN1, GluN1, p-GluN2A and GluN2A in the hippocampus., Results: In behavioral assessments, CUMS rats exhibited depressive behaviors, which were ameliorated by CSJY or PX treatment. Moreover, CSJY or PX treatment increased serotonin (5-HT) levels. It reduced the kynurenine/tryptophan (KYN/TRP) and gamma-aminobutyric acid/glutamate (GABA/Glu) in the hippocampus and cortex, as well as reduced serum levels of ACTH, CORT and CRH. Furthermore, CSJY or PX administration enhanced the decreased expression of p-GluN1/GluN1 while upregulating 5-HT1A and p-GluA1/GluA1 levels in the CUMS group., Conclusion: CSJY demonstrated the ability to alleviate depressive behaviors in CUMS-induced depression rats, potentially through the inhibition of the hypothalamic-pituitary-adrenal (HPA) axis, modulation of monoamine neurotransmitters, and glutamatergic neurons. These findings suggest that CSJY could serve as a promising treatment option for depression., 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 Authors. Published by Elsevier B.V. All rights reserved.)

Ethnopharmacological Relevance: Mulberry leaf (Folium Mori) is a dried leaf of the dicotyledonous mulberry tree and is a homologous food and medicine. Treating insomnia with it is a common practice in traditional Chinese medicine. But still, its potential sleep-improving mechanism remains to be elucidated., Aim of Review: Potential bioactive components and mechanisms of the sleep-improving effect of purified flavone from mulberry leaves (MLF) were explored through in vivo experiments, network pharmacology analysis, and molecular experimental validation., Materials and Methods: The mice model was established by pentobarbital sodium induction to evaluate the sleep-improving effect of MLF. The MLF's chemical composition was identified through a liquid chromatograph quadrupole time-of-flight mass spectrometer (Q-TOF LC/MS) to elucidate its sleep-improving active ingredient. At last, the underlying mechanism of MLF's sleep-improving effect was elucidated through neurotransmitter detection (ELISA), network pharmacology analysis, and molecular experimental validation (quantitative real-time PCR and western blotting)., Results: MLF could dramatically reduce sleep latency by 35%, prolong sleep duration by 123%, and increase the sleep rate of mice through increasing γ-aminobutyric acid (GABA) and serotonin (5-HT) release in serum, hypothalamus, and hippocampus. Q-TOF LC/MS identified 17 flavonoid components in MLF. Network pharmacological analysis suggested that the key sleep-improving active ingredients in MLF might be quercetin, kaempferol, morin, and delphinidin. The key path for MLF to improve sleep might be the tryptophan metabolism and neuroactive ligand-receptor interaction, and the key targets might be gamma-aminobutyric acid type A receptor subunit alpha2 Gene (GABRA2) and serotonin 1A (5-HT1A) receptors., Conclusions: MLF has shown significant sleep-improving effects in mice and may take effect through regulating the GABA and 5-HT receptors., 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 B.V. All rights reserved.)

It is common knowledge that the cerebellum is a structure of the central nervous system that influences the processes of balance and motor coordination. Recently its influence on social interactions has also been emphasized. The sigma receptor agonist: 3-di-o-tolylguanidine (DTG) is characterized by high affinity for sigma 1 and sigma 2 receptors, widely distributed in the cerebellum. In the experiment we assessed the effect of long term administration of DTG to adult male Sprague Dawley rats on social behavior and the concentration of neurotransmitters in the cerebellum. DTG was administered orally at a dose of 3 mg/kg body weight (bw) (DTG3), 10 mg/kg bw (DTG10) and 30 mg/kg bw (DTG30) for 9 weeks before the behavioral test. After the experiment, the concentration of catecholamines and amino acids in the cerebellum was assessed using high performance liquid chromatography (HPLC). Treatment groups showed reductions in social interactions such as grooming, sniffing and total time spent interacting. At the same time, it was shown that in the group receiving the lowest dose of the drug, a decrease in the concentration of dopamine and serotonin in the cerebellum was observed. Furthermore, changes in the concentration of taurine, alanine, glutamic acid and gamma-aminobutyric acid were observed in the treated groups. We found that long term administration of DTG disturbs animals' social interactions and the concentration of neurotransmitters in the cerebellum., 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 International Brain Research Organization (IBRO). Published by Elsevier Inc. All rights reserved.)

Backgrounds: Memory and emotion are especially vulnerable to psychiatric disorders such as post-traumatic stress disorder (PTSD), which is linked to disruptions in serotonin (5-HT) metabolism. Over 90% of the 5-HT precursor tryptophan (Trp) is metabolized via the Trp-kynurenine (KYN) metabolic pathway, which generates a variety of bioactive molecules. Dysregulation of KYN metabolism, particularly low levels of kynurenic acid (KYNA), appears to be linked to neuropsychiatric disorders. The majority of KYNA is produced by the aadat (kat2) gene-encoded mitochondrial kynurenine aminotransferase (KAT) isotype 2. Little is known about the consequences of deleting the KYN enzyme gene., Methods: In CRISPR/Cas9-induced aadat knockout ( kat2 -/- ) mice, we examined the effects on emotion, memory, motor function, Trp and its metabolite levels, enzyme activities in the plasma and urine of 8-week-old males compared to wild-type mice., Results: Transgenic mice showed more depressive-like behaviors in the forced swim test, but not in the tail suspension, anxiety, or memory tests. They also had fewer center field and corner entries, shorter walking distances, and fewer jumping counts in the open field test. Plasma metabolite levels are generally consistent with those of urine: antioxidant KYNs, 5-hydroxyindoleacetic acid, and indole-3-acetic acid levels were lower; enzyme activities in KATs, kynureninase, and monoamine oxidase/aldehyde dehydrogenase were lower, but kynurenine 3-monooxygenase was higher; and oxidative stress and excitotoxicity indices were higher. Transgenic mice displayed depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits, coupled with a decrease in KYNA, a shift of Trp metabolism toward the KYN-3-hydroxykynurenine pathway, and a partial decrease in the gut microbial Trp-indole pathway metabolite., Conclusions: This is the first evidence that deleting the aadat gene induces depression-like behaviors uniquely linked to experiences of despair, which appear to be associated with excitatory neurotoxic and oxidative stresses. This may lead to the development of a double-hit preclinical model in despair-based depression, a better understanding of these complex conditions, and more effective therapeutic strategies by elucidating the relationship between Trp metabolism and PTSD pathogenesis., (© 2025 The Author(s). Published by IMR Press.)

Gastrin is secreted following a rise in gastric pH, leading to gastric acid secretion. Sleeve gastrectomy (SG), a bariatric surgery where 80% of the gastric corpus is excised, presents a challenge for gastric pH homeostasis. Using histology, and single-cell RNA sequencing of the gastric epithelium in 12 women, we observed that SG is associated with an increase in a sub-population of acid-secreting parietal cells that overexpress respiratory enzymes and an increase in histamine-secreting enterochromaffin-like cells (ECLs). ECLs of SG-operated patients overexpressed genes coding for biosynthesis of neuropeptides and serotonin. Mathematical modeling showed that pH homeostasis by gastrin is analogous to non-linear proportional and integral control, that drives adaptation of the epithelium to acid-secretion demand. Quantitative model predictions were validated in patients. The results demonstrate human gastric epithelium remodeling following SG at the molecular and cellular levels, and more generally how trophic hormones enable robust adaptation of tissue function to meet physiological demand., Competing Interests: Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

The gut microbiome has emerged as a growing focus of research and public health interest, leading to the frequent exploration of probiotic dietary supplements as potential treatments for various disorders, such as anxiety and depression. In the present report, changes in inflammation and microbiome composition were assessed in model mice exhibiting depressive-like behaviors that were exposed to the probiotic Lactobacillus zhachilii HBUAS52074 T . It was found that L. zhachilii HBUAS52074 T alleviated the severity of depressive-like behaviors while increasing serum 5-HT concentrations. Moreover, L. zhachilii HBUAS52074 T modulated the composition of the gut microbiota, resulting in a decrease in the abundance of Prevotella and an increase in the abundance of Lactobacillus . Additionally, supplementation with L. zhachilii HBUAS52074 T enhanced intestinal barrier function and reduced inflammation in peripheral blood, as well as in the hippocampal and prefrontal cortical tissues. Correlational analyses indicated that the abundance of Lactobacillus was positively correlated with the social interaction ratio, time spent in the center, entries into the center, as well as serum 5-HT and serum IL-10 levels but negatively correlated with immobility time. Overall, chronic social defeat stress was found to be associated with inflammation and the exacerbation of depressive-like behaviors. The above findings suggested that L. zhachilii HBUAS52074 T supplementation was sufficient to alter the parameters. Collectively, these data suggest that L. zhachilii HBUAS52074 T , derived from naturally fermented foods, may possess therapeutic potential for the treatment of depression.

Background and Objective: Endoplasmic reticulum stress (ERS), as a primary defense mechanism against stress, is closely related to mental disorders, but its pathogenesis is still unclear. This research seeks to explore the influence of ERS-nucleotide-bound oligomerized domain-like receptor protein 3 (NLRP3) signaling on mice's depressive-like behaviors and cognitive impairment., Design and Method: We carried out a study on 32 male C57BL/6J mice to investigate how chronic unpredictable mild stress (CUMS) can give rise to depressive-like behaviors and cognitive dysfunction, randomly dividing them into control, model, inhibitor, and agonist groups. We utilized ELISA to quantify dopamine (DA) and 5-hydroxytryptamine (5-HT) levels. Using Nissl and hematoxylin and eosin (H&E) staining, we assessed the number and morphology of hippocampal neurons and cells. Western blot and immunofluorescence staining detected the changes in ERS and inflammation-related pathways in the hippocampus., Results: CUMS could induce ERS and activate NLRP3 inflammasome, causing neuronal damage and histopathological changes, eventually leading to depressive-like behaviors and cognitive impairment in mice. The abnormal activation of NLRP3 inflammasome could be restored by ERS blocker 4-phenyl butyric acid (PBA), thus reducing neuronal damage, and ameliorating depressive-like behaviors and cognitive disorder in mice., Conclusion: Our study demonstrates a previously unknown link between ERS and NLRP3 inflammasome in CUMS mice. The ERS-NLRP3 signaling pathway may be activated by CUMS, potentially resulting in mice exhibiting depressive-like behaviors and cognitive dysfunction. Theoretical foundations for elucidating the pathogenesis of depression, as well as its prevention and treatment, will be established through the results., Competing Interests: Declaration of competing interest The authors hereby state that they do not have any conflicts of interest., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Backgrounds: The influence of serotonin function on social phobia has been well-documented, yet the polygenic risk score of serotonergic polymorphisms for social phobia remains unclear., Methods: We assessed two aspects of social phobia (i.e., social interaction anxiety and social phobia scrutiny fear) and created a polygenic risk score of seven serotonergic polymorphisms in two independent samples., Results: The results from both samples indicated that a greater polygenic risk score, denoting a higher risk of anxiety, was associated with higher levels of social interaction anxiety and social phobia scrutinizing fear. Interestingly, the association between polygenic risk score and social interaction anxiety was mediated by interpersonal adaptability., Conclusion: These findings demonstrate the importance of serotonergic polymorphisms in social phobia and unveil a psychological pathway whereby interpersonal adaptability mediates the effect of serotonergic polymorphisms on social phobia., Competing Interests: Declaration of competing interest The authors declared that they had no conflicts of interest concerning their authorship or the publication of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Cocaine use disorder (CUD) is a chronic and relapsing neuropsychiatric disorder characterized by structural and functional brain lesions, posing a significant public health challenge. While the disruptive effects of cocaine on neurotransmitter systems (receptors/transporters) have been well established, the patterns of brain structural abnormalities in CUD and its interaction with other factors remain an ongoing topic of investigation. We employed source-based morphometry (SBM), a multivariate approach on 50 CUD participants and 50 matched healthy controls from the public SUDMEX CONN dataset. This method allowed us to identify co-varying patterns of brain tissue volume differences, and further explore the effect of average cocaine dosage through moderation analysis. Spatial correlation analysis was also performed to examine micro-macro structural consistency between tissue volume variations and chemoarchitectural distribution of dopamine and serotonin. Our SBM analysis findings were consistent with reward-related neuroadaptations in the striato-thalamo-cortical and limbic pathways and also exhibited co-localization with the distribution of dopamine and serotonin systems. The moderation analysis suggested that the average dosage positively strengthens cocaine consumption years' effect on brain structures. By integrating our findings of gray and white matter volume differences and corresponding neurotransmitter profiles, this comprehensive view not only strengthens our understanding of the brain's structural abnormalities in CUD, but also reveals potential mechanisms underlying its development and progression., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

The antidepressant-like activity of two psychoplastogens, ibogainalog (IBG) and ibogaminalog (DM506), was studied in naïve mice using the forced swim test (FST) and tail suspension test (TST). The behavioral results showed that a single administration of 25 mg/kg DM506 or 10 mg/kg IBG induced antidepressant-like activity in naïve mice in a volinanserin-sensitive manner that persisted for 72 h. Similar results were observed using the chronic immobilization stress (CIS) test, in which depression symptoms were reduced for 48 h. To assess the contribution of serotonergic and/or norepinephrinergic neurotransmission, serotonin (5-HT) and norepinephrine (NE) levels were depleted. The reduction in 5-HT levels, but not NE levels, inhibited the antidepressant-like activity of ibogalogs, suggesting that serotonergic transmission may play a more significant role than norepinephrinergic transmission. Concurrently, DM506, IBG, and TBG (derived from tabernanthine) inhibited monoamine transporters with the following order of selectivity: SERT > NE transporter > dopamine transporter. The IBG exhibited the highest selectivity for SERT. Only TBG inhibited monoamine oxidase A activity, indicating its relatively minor role. Radioligand and functional assays showed that all ibogalogs bind to the 5-HT 2 receptor subfamily (DM506 > IBG > TBG) and fully activate 5-HT 2A/2C receptors with similar potency in the nM range. However, they act as competitive antagonists of the 5-HT 2B receptor, with DM506 as an exception, exhibiting partial but potent agonist activity. In conclusion, ibogalogs induce acute and sustained antidepressant-like activity in naïve and depressed mice through mechanisms involving 5-HT 2A receptor activation and serotonergic transmission., Competing Interests: Declaration of competing interest We confirm that there are no known conflicts of interest associated with this publication. Furthermore, there has been no significant financial support for this work that could have influenced its outcome., (Copyright © 2024. Published by Elsevier Inc.)

To investigate the effects of chronic exposure to the cardiotonic steroid digoxin on locomotor activity, anxiety, and brain tissue monoamine content in Zebrafish. In total 24 adult (3-5 months) wild-type experimentally naïve zebrafish (50 : 50 ratio of females to males) were housed in 4-L tanks, in groups of six animals per tank. Two μM Digoxin was maintained in half of the tanks for 7 days. The 'Novel tank test' was performed on day 7 and the animals were euthanized. Concentrations of dopamine, serotonin, and their metabolites were then quantified in brain tissue using HPLC-ED. Seven-day exposure to 2 μM water solution of digoxin caused robust hyperlocomotion and reduced anxiety-like behavior in adult zebrafish in the 'Novel tank test'. The treatment also evoked pronounced neurochemical responses in zebrafish, including increased whole-brain 3-methoxytyramine, reduced norepinephrine and serotonin, and unaltered dopamine, homovanillic acid or 5-hydroxyindoleacetic acid levels. Deficits in monoaminergic (dopaminergic, serotonergic, and noradrenergic) neurotransmission are a key pathogenetic factor for multiple neuropsychiatric and neurodegenerative diseases. Commonly used clinically to treat cardiac conditions, cardiotonic steroids can affect dopaminergic neurotransmission. Chronic exposure to digoxin evokes hyperactivity-like behavior accompanied by altered monoamine neurotransmission in zebrafish, which may be relevant to understanding the central nervous system side effects of cardiotonic steroids., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objective: This study aims to explore the therapeutic mechanism of Massa Medicata Fermentata (MMF) with different formulations on spleen deficiency constipation in mice by analyzing gastrointestinal hormones, D-xylose, intestinal microbiota, and intestinal enzyme activities., Methods: A spleen deficiency constipation model was established using an oral administration of Sennae Folium decoction combined with controlled diet and water intake. After successful model establishment, the mice with spleen deficiency constipation were treated with MMF S1, S2, S3. Following the intervention, serum samples from each group of mice were collected to measure VIP, 5-HT, and D-xylose. Additionally, small intestine contents were analyzed for intestinal enzyme activity and subjected to 16S rRNA high-throughput sequencing., Results: Mice with spleen deficiency constipation showed significant decreases in body weight and fecal water content. In contrast, the body weight of the CS2 and CS3 groups returned to normal levels, and fecal water content in the CS2 and CS3 groups also returned to normal. The MMF S2 and S3 significantly increased protease and sucrase enzymes levels compared with CM group. Serum D-xylose levels were significantly reduced in the CM and CS2 group. VIP levels increased significantly in the CM group but decreased in the CS2 and CS3 groups. Additionally, 5-HT levels in the CM and CS1 groups decreased significantly, with the CS2 group returning to normal and the CS3 group showing significant increases. 16S rRNA sequencing analysis revealed that all three MMF formulations effectively restored the intestinal microbiota composition in mice. LEfSe analysis identified characteristic microbiota linked to different intervention groups. The CS3 group significantly upregulated the chloroalkane and chloroalkene degradation and vibrio cholerae pathogenic cycle pathways compared to the CM group. Candidatus_Arthromitus in the CS3 group and Psychrobacter in the CS2 group were positive and negative correlations with 5-HT and VIP, respectively., Conclusion: The three formulations of MMF significantly alleviated spleen deficiency constipation symptoms by modulating intestinal enzyme activities, D-xylose, VIP, and 5-HT levels, and restoring intestinal microbiota balance. Psychrobacter and Candidatus_Arthromitus were identified as potential biomarkers for the treatment of spleen deficiency constipation. Different formulations of MMF have different mechanisms of regulating constipation through intestinal microbiota., 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 © 2025 Liang, Wan, Li, Peng and Chen.)

Vesicular monoamine transporter 2 (VMAT2) is crucial for packaging monoamine neurotransmitters into synaptic vesicles, with their dysregulation linked to schizophrenia, mood disorders, and Parkinson's disease. Tetrabenazine (TBZ) and valbenazine (VBZ), both FDA-approved VMAT2 inhibitors, are employed to treat chorea and tardive dyskinesia (TD). Our study presents the structures of VMAT2 bound to substrates serotonin (5-HT) and dopamine (DA), as well as the inhibitors TBZ and VBZ. Utilizing cryo-electron microscopy (cryo-EM), mutagenesis functional assays, and molecular dynamics (MD) simulations, we elucidate the mechanisms of substrate transport and drug inhibition. Our MD simulations indicate potential binding poses of substrate (5-HT) in both cytosol-facing and lumen-facing states, emphasizing the significance of protonation of key acidic residues for substrate release. We demonstrate that TBZ locks VMAT2 in a lumen-facing occluded state, while VBZ stabilizes it in a lumen-facing conformation. These insights enhance our understanding of VMAT2 function and provide valuable insights for the development of novel therapeutic strategies for psychiatric disorders., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background and Purpose: We investigated the relationship between serotonergic and dopaminergic specific binding transporter ratios (SBRs) over 4 years in Parkinson's disease (PD) patients. We assessed serotonergic innervation's potential compensatory role for dopaminergic denervation, association with PD symptoms, and involvement in the development of levodopa-induced dyskinesia (LID)., Methods: SBRs of the midbrain and striatum were evaluated from [I-123] N-ω-fluoropropyl-2β-carbomethoxy-3β-(4-iodophenyl)nortropane SPECT images at baseline and after 4 years. Correlations between SBRs and PD symptoms were analyzed, alongside interval changes., Results: Study included 177 PD patients (110 males, 67 females; mean age 61.0 ± 9.0 years). Significant worsening was observed in Hoehn and Yahr staging and Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) Part II and III scores over 4 years (p < 0.05, p < 0.001, and p < 0.001, respectively). SBRs of the caudate, putamen, and midbrain declined significantly (p < 0.001). Midbrain and striatal SBRs correlated significantly at both baseline and 4-year follow-up (p < 0.0001). Striatal SBRs correlated significantly with MDS-UPDRS II and III scores at both time points, while midbrain SBRs correlated with changes in MDS-UPDRS III scores over the 4 years (p < 0.01). Putamen and midbrain SBRs at 4 years were significantly lower in patients who developed LID compared to those who did not (p < 0.05)., Conclusion: The study demonstrates correlations between midbrain and putamen SBRs and MDS-UPDRS scores over 4 years in PD patients. Midbrain serotonin dysfunction may contribute to the development of LID., (© 2025 American Society of Neuroimaging.)

Huntington's disease (HD) is a fatal neurodegenerative disease associated with autophagy disorder and mitochondrial dysfunction. Here, we identified therapeutic potential of perillaldehyde (PAE), a monoterpene compound obtained from Perilla frutescens (L.) Britt., in the Caenorhabditis elegans (C. elegans) model of HD, which included lifespan extension, healthspan improvement, decrease in polyglutamine (polyQ) aggregation, and preservation of mitochondrial network. Further analyses indicated that PAE was able to induce autophagy and mitochondrial unfolded protein reaction (UPR mt ) activation and positively regulated expression of associated genes. In lgg-1 RNAi C. elegans or C. elegans with UPR mt -related genes knockdown, the effects of PAE treatment on polyQ aggregation or rescue polyQ-induced toxicity were attenuated, suggesting that its neuroprotective activity depended on autophagy and UPR mt . Moreover, we found that pharmacological and genetic activation of UPR mt generally protected C. elegans from polyQ-induced cytotoxicity. Finally, PAE promoted serotonin synthesis by upregulating expression of TPH-1, and serotonin synthesis and neurosecretion were required for PAE-mediated UPR mt activation and its neuroprotective activity. In conclusion, PAE is a potential therapy for polyQ-related diseases including HD, which is dependent on autophagy and cell-non-autonomous UPR mt activation., (© 2024 International Union of Biochemistry and Molecular Biology.)

Previous studies from our lab suggest that transportation of early adulthood ducks can have long lasting physiological effects. To better understand how transportation affects the ducks' physiology, we evaluated several central and peripheral parameters. Thirty-six, 23-week-old ducks were collected at a commercial breeder facility and randomly assigned to one of three treatment groups (n = 6/sex/treatment): 1) caught and euthanized (control), 2) caught and put in a crated in the pen for 90 min (crate), or 3) caught, crated, and transported in a truck for 90 min (transport) to simulate actual transportation. Blood was collected for serum corticosterone and blood smear analyses. Brains were hemisected and each half was dissected into three brain areas: caudal mesencephalon (CM), rostral mesencephalon (RM), and diencephalon (DI). Mass spectrometry was run on the right half of the brain, and gene expression of TPH1, TPH2, TH, CRH, and NPY were measured on the left half of brain using qRT-PCR. Serum corticosterone levels were increased (p = 0.01) in crated hens and in transported hens and drakes (p = 0.0084) when compared to control. HLR was increased (p = 0.035) in crated hens and transported hens and drakes compared to control. No differences in serotonin turnover were observed in drakes but increased in hens within the CM and RM from control to crate (p = 0.01) and crate to transport (p = 0.016). There were no differences in DA turnover or in gene expression for all brain areas for drakes and CM and RM for hens. Within the DI, hens showed a decrease (p = 0.03) in TPH1 for transport compared to crate. Overall, transportation elicits an acutely stressful event that increases corticosterone and HLR in a sex dependent manner where hens appear to be more reactive to the stressor than drakes. Our data supports that when assessing a stress response, care must be given to the sex of the bird and to the relative timepoint of sampling compared to the perceived onset of the stressor., Competing Interests: Conflict of interest The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

As an adjunct therapy, metformin enhances the efficacy of conventional antidepressant medications. However, its mode of action remains unclear. Here, metformin was found to ameliorate depression-like behaviors in mice exposed to chronic restraint stress (CRS) by normalizing the dysbiotic gut microbiome. Fecal transplants from metformin-treated mice ameliorated depressive behaviors in stressed mice. Microbiome profiling revealed that Akkermansia muciniphila (A. muciniphila), in particular, was markedly increased in the gut by metformin and that oral administration of this species alone was sufficient to reverse CRS-induced depressive behaviors and normalize aberrant stress-induced 5-hydroxytryptamine (5-HT) metabolism in the brain and gut. Untargeted metabolomic profiling further identified the bile acid metabolites taurocholate and deoxycholic acid as direct A. muciniphila-derived molecules that are, individually, sufficient to rescue the CRS-induced impaired 5-HT metabolism and depression-like behaviors. Thus, we report metformin reprograms 5-HT metabolism via microbiome-brain interactions to mitigate depressive syndromes, providing novel insights into gut microbiota-derived bile acids as potential therapeutic candidates for depressive mood disorders from bench to bedside., 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 Inc.)

The medial prefrontal cortex (mPFC) is closely associated with various psychopathologies in humans, and its dysfunction is invariably accompanied by abnormalities in the serotonin (5-hydroxytryptamine, 5-HT) system of the brain. In this study, in-vivo extracellular recording techniques were used to investigate changes in the excitability of pyramidal neurons and interneurons in the rat mPFC following injection of 5,7-dihydroxytryptamine (5,7-DHT) into the bilateral lateral ventricles to damage the serotoninergic neurons. The levels of 5-HT in the mPFC and dorsal raphe nucleus of rats were determined by high-performance liquid chromatography. The results showed that the levels of 5-HT were significantly reduced in the mPFC and dorsal raphe nucleus two weeks after injection of 5,7-DHT into the bilateral lateral ventricles, relative to the normal group. The discharge frequency of pyramidal neurons in the mPFC was markedly increased compared to the normal group, with a significant rise in burst discharge, while the average discharge frequency of interneurons was significantly reduced and tended towards irregular activity. The results of the study indicated that the brain's 5-HT neurotransmitter system not only directly affects the activity of mPFC pyramidal neurons but also modulates the electrical activity of interneurons, thereby regulating the local microcircuitry within the mPFC and participating in its function., 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 B.V. All rights reserved.)

Serotonergic psychedelics have potential therapeutic effects in treating anxiety and mood disorders, often after a single dose, and are suggested to have plasticity-inducing action. However, a comprehensive mechanism of action is still lacking. Here, we investigated how a single dose of the short-acting 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) acts on gene expression from microdissected brain regions (anterior cingulate cortex - ACC; basolateral amygdala - BLA; ventral hippocampus CA1 region - vCA1 and dentate gyrus-DG) of naive and stressed mice. Specifically, we compared gene expression of Arc, Zif268, BDNF, CREB, mTORC1, NR2A, TRIP8b, and NFkB in mice injected with 5-MeO-DMT or saline at different time points (1 h, 5 h, or 5 days prior). 5-MeO-DMT altered mRNA expression of immediate early genes Arc and ZiF268 in the ACC, BLA, and vCA1, while NR2A expression was decreased after 5 h in the vCA1. We also found a long-term increase in TRIP8b, a gene related to the modulation of neuronal activity, in the vCA1 after 5 days. Behaviorally, 5-MeO-DMT treated mice showed mixed anxiolytic and anxiogenic effects in the elevated plus maze and open field test 24 h or 5 days after treatment. However, pre-treated mice subjected to acute stress showed both lower corticosterone levels and robust anxiolytic effects of 5-MeO-DMT administration. Together, our findings provide insights into the molecular actions of 5-MeO-DMT in the brain related to anxiolytic effects of behavior., Competing Interests: Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Sertraline, one of the most commonly used antidepressants, has exhibited a progressively escalating trend in usage over the course of the last decades years, which have been exacerbated by the COVID-19 pandemic. Here, this study assessed the transgenerational effects of sertraline on the aquatic microcrustacean Daphnia magna, a parthenogenetic model species. The parental D. magna (G0) were exposed to environmentally relevant concentrations of sertraline (0.1 and 10 μg/L) for 21 days at individual and population level, and observed exposure triggered specific increased fecundity and desynchronized molting. These alterations were partially inherited through three subsequent non-exposed generations (G1, G2, and G3), as evidenced by increased fecundity and disordered molting in G1, reduced fecundity in G2, and reduced body size of G3-offspring. The molt-related genes neverland 1 and hormone receptor 3 were significantly different to the control group simultaneously only in the exposed generation, which may well be responsible for the molting asynchrony. Vitellogenin plays an important role in reproduction, and our results indicate that its abnormal expression persists up to G3, which was highly correlated with the expression of serotonin transporter, the drug target of sertraline. This finding suggested that sertraline possesses a sustained reproductive toxicity and disrupting potential and may be associated with serotonin dysregulation caused by compensatory feedback of serotonin transporter. In combination with male birth and upregulation of doublesex and vitellogenin, sertraline was deemed to trigger a self-defense response of D. magna, known as "abandon-ship" by increasing reproductive inputs. However, no males was found in individual reproduction test in each generation, which may suggest some interaction between sertraline and population density. Our findings emphasize that the toxic effects of sertraline can be transferred to unexposed generations, even with different adverse consequences, implying that future studies need to focus on transgenerational delayed effects and the underlying mechanisms., 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.)

N-methylserotonin (NMS) is a valuable indole alkaloid with therapeutic potential for psychiatric and neurological disorders, and it is used in health foods, cosmetics, and weight loss supplements. However, environmental challenges and low reaction efficiencies significantly hinder cost-effective, large-scale production of NMS in plants or through chemical synthesis. Herein, we have successfully engineered Escherichia coli strains to enhance NMS production from L-tryptophan using whole-cell catalysis. We developed multiple biosynthesis pathways incorporating modules for serotonin (5-hydroxytryptamine, 5-HT), tetrahydromonapterin (MH₄), and S-adenosylmethionine (SAM) synthesis. To enhance MH₄ availability, we employed a high-activity Bacillus subtilis FolE and minimized carbon flux loss through targeted gene knockouts in competitive metabolic pathways, improving 5-HT production. Additionally, we constructed a comprehensive SAM biosynthesis module to facilitate transmethylation by a selected N-methyltransferase fused with ProS2. These engineered modules were coexpressed in two plasmids within the optimized strain NMS-19, producing 128.6 mg/L of NMS in a 5-L bioreactor using fed-batch cultivation-a 92-fold increase over the original strain. This study introduces a viable strategy for NMS production and provides insights into the biosynthesis of SAM-dependent methylated tryptamine derivatives., Competing Interests: Declaration of competing interests The authors declare no competing financial interest., (Copyright © 2024 International Metabolic Engineering Society. Published by Elsevier Inc. All rights reserved.)

Background: Perturbations of intestinal serotonergic neurotransmission seem to be involved in bowel dysmotility associated with irritable bowel syndrome (IBS) with diarrhea. Oral administration of probiotics is an emerging strategy to improve IBS symptoms, possibly via influencing local serotonin metabolism and neurotransmission. In the present study, we evaluated the effects of the yeast Saccharomyces boulardii CNCM I-745 (S. boulardii) on intestinal motility and serotonergic receptors., Methods: Isolated rat ileum was contracted in a cumulative concentration way by serotonin (5-HT), various 5-HT agonists or by acetylcholine to determine their effective concentration 50% (EC 50 ). Single concentrations of S. boulardii or 5-HT antagonists were added before agonists to identify the receptors targeted by S. boulardii., Results: The serotonin antagonists 5-HT 1A WAY100635, 5-HT 2A ketanserin and 5-HT 4 GR113808 inhibited 5-HT-induced contractions in a concentration-dependent manner. S. boulardii between 0.05 and 1.5 mg/mL increased the EC 50 value of 5-HT suggesting an inhibitory effect against serotonin-induced contraction. Ileum contractions induced by the serotonin agonist 5-HT 1 carboxamidotryptamine or by the serotonin agonist 5-HT 2 alpha-methyl-5-HT were significantly reduced by S. boulardii at 1.5 mg/mL. The yeast did not affect acetylcholine-induced ileum contraction., Conclusion: S. boulardii CNCM I-745 possesses relaxant properties on the rat ileum involving the inhibition of 5-HT and more specifically 5-HT 1A and 5-HT 2A/2B/2C receptor-induced contractions. These data suggest that the attenuation of 5-HT-induced ileal contractions by S. boulardii represents a probable mechanism of action sustaining its efficacy in patients affected by IBS with diarrhea., Competing Interests: Declarations. Competing interest: The authors declare no competing interests., (© 2024. The Author(s).)

It has been shown that chronic restraint stress (CRS) increases adrenal 5-HT levels and turnover through a mechanism that appears unrelated to tryptophan hydroxylase (TPH). In the present study we re-analyzed the effects of CRS (20 min/day) for 14 days relative to control (CTRL) conditions on TPH expression, distribution, and activity in rat adrenal glands. On day 15, adrenal glands were collected for TPH1 and TPH2 immunohistochemistry, Western blot, and RT-PCR; TPH activity was estimated by quantification of 5-hydroxytryptophan (5-HTP) and, indirectly, through measurement of 5-HT and 5-hydroxindolacetic acid (5-HIAA) levels and turnover (5-HIAA/5-HT ratio) by HPLC. TPH expression and activity in the dorsal raphe nucleus (DRN) were also determined for comparison. TPH1 and TPH2 immunostaining was observed in the adrenal medulla, and measurable levels of TPH1 and TPH2 protein and mRNA were detected in rat adrenal glands from CTRL animals. CRS exposure noticeably increased TPH2- but not THP1-immunostaining in the medulla and the outer adrenocortical areas of left (LAG) but not of right adrenal glands (RAG). In addition, CRS exposure increased TPH2 protein and mRNA levels in LAG; however, both measures decreased in DRN. Finally, CRS treatment produced an increase and a decrease of TPH activity and 5-HT turnover in LAG and DRN, respectively. Results indicate that TPH is indeed expressed in rat adrenal glands. Exposure to CRS upregulates TPH2 in LAG, while inducing downregulation of it in the DRN. Then, the increased levels of 5-HT in LAG from CRS-exposed animals likely results from TPH2-mediated synthesis., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare, (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Serotonin signaling plays critical roles in social and emotional behaviors. Likewise, decades of research demonstrate that the amygdala is a prime modulator of social behavior. Permanent excitotoxic lesions and transient amygdala inactivation consistently increase social behaviors in non-human primates. In rodents, acute systemic administration of drugs that increase serotonin signaling is associated with decreased social interactions. However, in primates, the direct involvement of serotonin signaling in the amygdala, particularly in affiliative social interaction, remains unexplored. Here, we examined the effects of serotonin manipulations within the amygdala on social behavior in eight pairs of familiar male macaques. We microinfused drugs targeting the serotonin system into either the basolateral (BLA) or central (CeA) amygdala and measured changes in social behavior. Surprisingly, the results demonstrated no significant differences in social behavior following the infusion of a selective serotonin reuptake inhibitor, 5-HT 1A agonist or antagonist, 5-HT 2A agonist or antagonist, or 5-HT 3 agonist or antagonist into either the BLA or CeA. These findings suggest that serotonin signaling in the amygdala does not directly contribute to the regulation of social behavior between familiar conspecifics. Future research should explore alternative mechanisms and potential interactions with other brain regions to gain a comprehensive understanding of the complex neural circuitry governing social behavior., Competing Interests: Declarations. Conflict of interests: The authors declare no competing financial interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Changan Granule (CAG) is a drug product developed from a traditional Chinese medicine (TCM) empirical prescription for diarrhea-predominant irritable bowel syndrome (IBS-D). The action mechanism and effective compounds of CAG in the treatment of IBS-D are not well understood., Purpose: This study aimed to investigate the effectiveness, action mechanism and effective compounds of CAG for treating IBS-D., Methods: Network pharmacology was used to screen the related pathways and active compounds of CAG in the treatment of IBS-D. Neonatal mother-infant separation, acetic acid enema and colorectal dilation were employed to construct IBS-D model for in vivo study. The effectiveness of CAG was evaluated in accordance with the results of body weight measurement, fecal water content determination, abdominal withdraw reflex test, open field test, sucrose preference test, forced swimming test and hematoxylin-eosin (HE) staining. The protein and mRNA levels of key molecules regulated by CAG were assessed through enzyme-linked immunosorbent assay (ELISA), western blotting, and reverse transcription quantitative polymerase chain reaction (RT-qPCR). The active compounds from CAG screened by network pharmacology were investigated with Caco-2 and RIN-14B cell models in vitro., Results: Network pharmacological analysis showed that CAG regulated 5-hydroxytryptamine (5-HT) signaling pathway and tetrahydropalmatine, formononetin and corydaline might be the potential effective compounds. The validation experiments showed that CAG restored the decreased body weight, and alleviated intestinal sensitivity, low-grade inflammation, diarrhea, frequent defecation, anxiety and depression of IBS-D rats through regulating the expression levels of 5-HT, tryptophan hydroxylase (TPH)1/2, serotonin transporter (SERT), 5-hydroxytryptamine-3 and -4 receptors (5-HT 3 R and 5-HT 4 R) in brain-gut axis (BGA). Tetrahydropalmatine and formononetin were confirmed to be the potential effective compounds of CAG in regulating 5-HT signaling pathway., Conclusion: CAG exhibits therapeutic effect on IBS-D rats through regulating 5-HT signaling pathway in BGA. Tetrahydropalmatine and formononetin are major potential effective compounds. Our findings provide scientific basis for the clinical use and drug development of CAG for IBS-D., 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 GmbH.)

Preening cups are a semi-open water source for Pekin duck enrichment. To evaluate the ducks' affective state, we combined measuring welfare by walking a transect in the barn with mass spectrometry and qRT-PCR to measure brain neurotransmitter levels and gene expression for serotonin (5-HT) and dopamine (DA) synthesis and metabolism. 5-HT and DA have been established as indicators of mental state and emotions. We visited 4 standard commercial barns that housed approximately 6000-9000 ducks (one preening cup per 1500 ducks) and collected samples on d21 prior to preening cup placement, d28 one week after preening cup placement, and d35 one day prior to processing. Litter samples (n = 3/barn/day) were collected and transect walks were conducted to evaluate the welfare of the birds. Brain samples (n = 8/day/barn) were collected from two locations: ducks actively using the preening cups (PC) and ducks across the barn not actively using the preening cups (CON). The brains were hemisected and dissected in three brain areas: caudal mesencephalon (CM), rostral mesencephalon (RM), and diencephalon (DI). Litter samples showed no significant differences between collection dates. The transect showed significant differences in feather quality, feather cleanliness, and eye due to age, but not preening cups. The right hemisphere showed no differences in 5-HT turnover. For DA turnover, there are differences in CM (p < 0.05) and DI (p < 0.001) over time, but no differences between PC and CON. The left hemisphere measured TPH1, TPH2, and TH. CM and DI brain areas are not significantly different. Within the RM, there is a significant increase in TPH1 expression for ducks on d35 when compared to ducks on d28 and d21. These results suggest that 5-HT and DA do not differ due to duck location. However, DA activity increases as these ducks age. DA is an important neurotransmitter and activity increases as an animal grows allowing for behavioral development. Our data shows that commercial preening cups do not negatively impact ducks' welfare or affective state., Competing Interests: Disclosures The authors declare no conflict of interest., (Copyright © 2024. Published by Elsevier Inc.)

Ulcerative colitis (UC) is an inflammatory bowel disease and psychological factors may be one of its pathogeneses. Selective serotonin reuptake inhibitor drug such as paroxetine with an effective anti-depression ability may be a new option for UC treatment. To evaluate the therapeutic effect of paroxetine on the exacerbation of UC symptoms caused by depression, a dual model of C57BL/6 mice was established using dextran sulphate sodium and chronic unpredictable mild stress (CUMS). Behavioural experiments, H&E staining and the level of 5-hydroxytryptamine (5-HT) in the brain were used to demonstrate successful replication of the CUMS model. The levels of 5-HT, TNF-α and IL-1β in the colon and the activity of MPO in the serum were determined by ELISA kits. The levels of some gut microbiota in the faeces were measured by qPCR and faecal differential metabolites were analysed by 1 H NMR. The results indicate that CUMS can exacerbate UC symptoms in mice by exacerbating inflammation, and UC+CUMS can disrupt gut microbiota and fatty acid metabolism. Paroxetine can improve the mental state of mice, reduce serum MPO activity, but increase TNF-α and IL-1β levels in the colon. In addition, paroxetine also can restore the intestinal flora of mice and improve intestinal absorption and metabolic function of amino acids and short-chain fatty acids., (© 2024 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.)

Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) widely used for depression, but its potential effects on gut microbiota regulation and vagus nerve-mediated serotonin receptor expression have not been well studied. We investigated changes in the gut microbiome regulated by fluoxetine and vagus nerve-mediated expression of several serotonin (5-HT) receptor types associated with anxiety and depression. Oral administration of fluoxetine alleviated lipopolysaccharide (LPS)-induced depressive and anxiety behaviors, increased 5-HT1A, 2 C, and melanocortin 4 (MC4) receptor expression, and the composition of Lactobacillus in mice's gut microbiome. In contrast, in the vagotomized group, fluoxetine did not modulate behaviors and receptor expression. Increased Lactobacillus composition was found to correlate significantly with behavioral test results. The importance of Lactobacillus growth to the efficacy of fluoxetine was confirmed by the effectiveness of fluoxetine, which was reduced by co-administering antibiotics. To determine the additional impact of the gut microbiome, we isolated Limosilactobacillus reuteri and Ligilactobacillus murinus, which were increased in the fluoxetine-treated group and administrated. The results showed that administration of each strain improved anxious or depressive behavior, as did fluoxetine, and vagotomy eliminated these effects. These results suggest that fluoxetine administration increases the proportion of Lactobacillus in the gut, which modulates 5-HT1A, 2 C, and MC4 receptor expression through the enteric nervous system and improves depression., 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 Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Sleep deprivation (SLD) is a widespread condition that disrupts physiological functions and may increase mortality risk. Valeriana officinalis, a traditional medicinal herb known for its sedative and hypnotic properties, contains isobicyclogermacrenal (IG), a newly isolated active compound. However, research on the therapeutic potential of IG for treating SLD remains limited., Methods: In this study, IG was extracted and characterized from Valeriana officinalis, and an SLD model was established in rats using p-chlorophenylalanine (PCPA). Behavioral tests and pathological studies were conducted to assess the effects of IG on SLD, and transcriptomic and metabolomic analyses were utilized to investigate its underlying mechanisms., Results: IG administration significantly improved the cognitive performance of SLD rats in behavioral tests and ameliorated histological injuries in the hippocampus and cerebral cortex. IG treatment increased the levels of brain-derived neurotrophic factor (BDNF) and neurotransmitters such as serotonin (5-HT) in SLD rats. Additionally, IG directly targets TFRC, thereby improving iron metabolism in the hippocampus. Comprehensive transcriptomic and metabolomic analyses revealed that the improvements from IG stemmed from the mitigation of abnormalities in iron metabolism, cholesterol metabolism, and glutathione metabolism, leading to reduced oxidative stress, ferroptosis, and neuroinflammation in the hippocampus caused by SLD., Conclusions: Collectively, these findings suggest that IG has the potential to ameliorate neurological damage and cognitive impairment caused by SLD, offering a novel strategy for protection against the adverse effects of SLD., 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 GmbH. All rights reserved.)

Rationale : The periaqueductal gray (PAG) is a central hub for the regulation of aggression, whereas the circuitry and molecular mechanisms underlying this regulation remain uncharacterized. In this study, we investigate the role of a distinct cell type, Tachykinin 2 -expressing (Tac2 + ) neurons, located in the dorsomedial PAG (dmPAG) and their modulation of aggressive behavior in mice. Methods : We combined activity mapping, in vivo Ca 2+ recording, chemogenetic and pharmacological manipulation, and a viral-based translating ribosome affinity purification (TRAP) profiling using a mouse resident-intruder model. Results : We revealed that dmPAG Tac2 neurons are selectively activated by fighting behaviors. Chemogenetic activation of these neurons evoked fighting behaviors, while inhibition or genetic ablation of dmPAG Tac2 neurons attenuated fighting behaviors. TRAP profiling of dmPAG Tac2 neurons revealed an enrichment of serotonin-associated transcripts in response to fighting behaviors. Finally, we validated these effects by selectively administering pharmacological agents to the dmPAG, reversing the behavioral outcomes induced by chemogenetic manipulation. Conclusions : We identify dmPAG Tac2 neurons as critical modulators of aggressive behavior in mouse and thus suggest a distinct molecular target for the treatment of exacerbated aggressive behaviors in populations that exhibit high-level of violence., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

As a result of a long evolutionary history, serotonin plays a variety of physiological roles, including neurological, cardiovascular, gastrointestinal, and endocrine functions. While many of these activities can be accommodated within the serotoninergic activity, recent findings have revealed an unsuspected role of serotonin in orchestrating host and microbial dialogue at the tryptophan dining table, to the benefit of local and systemic homeostasis. Herein we review the dual role of serotonin at the host-microbe interface and discuss how unraveling the interconnections among the host and microbial pathways of tryptophan degradation may help to accommodate the versatility of serotonin in physiology and pathology., Competing Interests: Declaration of 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 The Authors. Published by Elsevier Ltd.. All rights reserved.)

In the decades since their discovery in plants in the mid-to-late 1900s, melatonin ( N -acetyl-5-methoxytryptamine) and serotonin (5-methoxytryptamine) have been established as their own class of phytohormone and have become popular targets for examination and study as stress ameliorating compounds. The indoleamines play roles across the plant life cycle from reproduction to morphogenesis and plant environmental perception. There is growing interest in harnessing the power of these plant neurotransmitters in applied and agricultural settings, particularly as we face increasingly volatile climates for food production; however, there is still a lot to learn about the mechanisms of indoleamine action in plants. A recent explosion of interest in these compounds has led to exponential growth in the field of melatonin research in particular. This concept paper aims to summarize the current status of indoleamine research and highlight some emerging trends.

Social isolation (SI) in humans can lead to various psychological and physical abnormalities. However, the molecular mechanisms and potential drug treatments for this illness are not well understood. Drosophila, a social organism, exhibits distinct behavioral defects under SI conditions, such as reduced sleep and loss of sugar intake preference. By examining the transcriptional profiles of SI flies, we discovered significant impacts on metabolic pathways. Notably, serotonin (5-HT) levels were reduced in the brains of SI flies. Treatment with 5-HT reversed the behavioral defects in SI flies. 5-HT is known to regulate mitochondrial synthesis in mouse brain, and we found it also enhances mitochondrial biogenesis in flies. Further investigation revealed that the 5-HT 7 receptor subtype was involved in SI behavior. To activate mitochondrial metabolism, we overexpressed phosphoglycerate kinase (Pgk), an enzyme in the glycolytic pathway, in neurons. This overexpression rescued the behavioral defects in SI flies. Additionally, terazosin, an alpha-1 adrenergic receptor antagonist known to activate Pgk, produced a similar rescue effect. Our study elucidates a key principle of SI-induced psychological damage and proposes a drug targeting strategy for future validation., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)