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The insular cortex is an important hub for sensory and emotional integration. It is one of the areas consistently found activated during pain. While the insular's connections to the limbic system might play a role in the aversive and emotional component of pain, its connections to the descending pain system might be involved in pain intensity coding. Here, we used anterograde tracing with viral expression of mCherry fluorescent protein, to examine the connectivity of insular axons to different brainstem nuclei involved in the descending modulation of pain in detail. We found extensive connections to the main areas of descending pain control, namely, the periaqueductal gray (PAG) and the raphe magnus (RMg). In addition, we also identified an extensive insular connection to the parabrachial nucleus (PBN). Although not as extensive, we found a consistent axonal input from the insula to different noradrenergic nuclei, the locus coeruleus (LC), the subcoereuleus (SubCD) and the A5 nucleus. These connections emphasize a prominent relation of the insula with the descending pain modulatory system, which reveals an important role of the insula in pain processing through descending pathways.

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BACKGROUND: Raphe-type bicuspid aortic valve (BAV) is a potential hostile scenario in trans-catheter aortic valve replacement (TAVR) due to pronounced calcium burden, possibly associated with tapered valve configuration. Trans-Catheter heart valve (THV) sizing strategy (annular vs. supra-annular) is controversial in this valve subtype. OBJECTIVES: To describe the phenotypical characteristics of severe, tapered, raphe-type, BAV stenosis undergoing TAVR and to explore safety and efficacy of modern-generation THVs, analysing the impact of annular and supra-annular sizing strategies on short- and mid-terms outcomes. METHODS: This is a retrospective, multicenter registry enrolling consecutive stenotic Sievers type 1 BAV treated with TAVR. Study population was divided into tapered and non-tapered configuration according to MSCT analysis. Matched comparison between annular and supra-annular sizing groups was performed in tapered population. RESULTS: From January 2016 to June 2023, 897 patients were enrolled. Of them, 696 patients displayed a tapered configuration. Of those, 510 received a THV according to annular sizing. After propensity score matching 186 matched pairs were selected. Technical success (96.2 % vs 94.1 %, OR 1.61 [0.61-4.24], p = 0.34), 30-day device success (83.6 % in both groups, OR 1.42 [0.78-2.57], p = 0.25) and 30-day early safety (71.8 % vs 70.5 %, OR 1.07 [0.68-1.68], p = 0.78) were similar between the annular and supra-annular sizing groups; a higher post-TAVR gradient was observed in supra-annular group, although it was only 2 mmHg mean. At mid-term follow-up, the rate of clinical efficacy was 84.7 %. CONCLUSIONS: TAVR with modern-generation devices is safe and effective for tapered raphe-type BAV, showing comparable results for annular and supra-annular sizing strategies.

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PURPOSE: In the present study, we investigated how tumor distance from midline (TDFM) and depth of invasion (DOI) may affect survival outcomes after compartmental tongue surgery (CTS) for oral tongue squamous cell carcinoma (OTSCC). METHODS: A retrospective series of cT2-T3 OTSCC treated with upfront CTS at our Department from 2010 to 2021 was evaluated. Radiological and pathological DOI and TDFM were correlated. The main outcomes were overall (OS) and loco-regional recurrence free survival (LRRFS). The linear relationship between DOI and TDFM with 2-year OS and LRRFS was tested. Survival estimates were obtained by the Kaplan-Meier method. Univariate analysis was performed for variables of interest, and results expressed in terms of hazard ratios and 95% confidence intervals. RESULTS: A total of 64 patients underwent CTS and neck dissection. No significant difference was found between pathological (pDOI) and radiological DOI (rDOI) (p = 0.321) or between pathological (pTDFM) and radiological TDFM (p = 0.435). Two- and 5-year OS and LRRFS were 85.7% and 70.4%, 84.3% and 76.1%, respectively. A linear and significant relationship with OS (p = 0.020) and LRRFS (p = 0.013) was found for pDOI; although linear, the relationship between pTDFM was not statistically significant for either survival outcomes. Once categorized, the ideal cut-off for pDOI according to OS was set at 10 mm (p = 0.023). CONCLUSION: In patients undergoing CTS for primary OTSCC, magnetic resonance-derived rDOI represents an accurate estimate of pDOI, In contrast, TDFM was not associated with OS suggesting that the median raphe is a safe deep margin for CTS. PROTOCOL N: BS/231,009 retrospectively registered.

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Introduction: Historically, Parkinson's Disease (PD) research has focused on the dysfunction of dopamine-producing cells in the substantia nigra pars compacta, which is linked to motor regulation in the basal ganglia. Therapies have mainly aimed at restoring dopamine (DA) levels, showing effectiveness but variable outcomes and side effects. Recent evidence indicates that PD complexity implicates disruptions in DA, noradrenaline (NA), and serotonin (5-HT) systems, which may underlie the variations in therapy effects. Methods: We present a system-level bio-constrained computational model that comprehensively investigates the dynamic interactions between these neurotransmitter systems. The model was designed to replicate experimental data demonstrating the impact of NA and 5-HT depletion in a PD animal model, providing insights into the causal relationships between basal ganglia regions and neuromodulator release areas. Results: The model successfully replicates experimental data and generates predictions regarding changes in unexplored brain regions, suggesting avenues for further investigation. It highlights the potential efficacy of alternative treatments targeting the locus coeruleus and dorsal raphe nucleus, though these preliminary findings require further validation. Sensitivity analysis identifies critical model parameters, offering insights into key factors influencing brain area activity. A stability analysis underscores the robustness of our mathematical formulation, bolstering the model validity. Discussion: Our holistic approach emphasizes that PD is a multifactorial disorder and opens promising avenues for early diagnostic tools that harness the intricate interactions among monoaminergic systems. Investigating NA and 5-HT systems alongside the DA system may yield more effective, subtype-specific therapies. The exploration of multisystem dysregulation in PD is poised to revolutionize our understanding and management of this complex neurodegenerative disorder.

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PURPOSE: Access the importance of visualizing the pterygomandibular raphae (PMR) while fixing palatopharyngeous (PPM) muscle to the pterygomandibular raphae (PMR). METHODS: Randomized controlled trial. First group, forty-two OSA patients performed either Anterolateral advancement pharyngoplasty (ALA) or Barbed reposition pharyngoplasty (BRP) while visualizing the PMR according to the following criteria: age between 21 and 60 years, body mass index (BMI) < 35, and patients with lateral pharyngeal collapse diagnosed with drug induced sleep endoscopy (DISE). The results were compared to the second control group of 42 patients performed the same procedures without exposing the PMR. RESULTS: PMR was bilaterally present in 27 (64.28%) patients and bilaterally absent in 5 (11.8%) patients while unilateral in 10 (23.9%) patients. PSG findings in group 1: Apnea hypopnea index (AHI) decreased from 40.84 ± 26.93 to 14.81 ± 7.43 (P < 0.001), mean Lowest oxygen saturation (LOS) significantly increased from 79.25 ± 14.93 to 89.92 ± 10.7 (P < 0.001) and Epworth sleepiness scale (ESS) significantly dropped from 13.25 ± 4.65 to 6.1 ± 2.06 (P < 0.001). Group 2 results showed AHI decrease from 27.50 ± 11.56 to 11.22 ± 7.63 (P ≤ 0.001), LOS increased from 81.86 ± 6.41 to 90.21 ± 3.70 and ESS dropped from 14.95 ± 3.72 to 7.91 ± 3.05. The difference between both groups was not statistically significant (P > 0.001). CONCLUSION: Fixation of PPM to the PMR under direct vision doesn't significantly affect the surgical outcomes but can increase the procedure efficiency and reduce complication rate keeping in mind that PMR may be absent in some patients.

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A unique nucleus, the cerebrospinal fluid-contacting nucleus (CsfR), has been identified in the brain parenchyma. This nucleus features neurons with somas located within the parenchyma and processes extending into the cerebrospinal fluid (CSF). This anatomical configuration suggests that the CsfR may serve as a crucial interface between the nervous and body fluid regulatory systems, potentially playing a significant role in overall physiological modulation. Despite its importance, the precise biological significance of the CsfR remains to be fully elucidated. Previous research has characterized the CsfR, providing detailed information on its position, neighboring structures, neuron distribution, and 3D reconstruction in both rats and non-human primates, with stereotaxic coordinates specifically provided for the rat model. Given the relevance of mice as a model organism, especially the C57BL/6J strain, this study aims to explore the existence and morphology of the CsfR in mice. Our findings confirm the presence of the CsfR, consistently located in the ventral gray area of the lower part of the aqueduct and the upper part of the fourth ventricle floor. It is bilaterally symmetrical and heart-shaped in the coronal plane, which differs slightly from the Y-shape observed in coronal sections of rats. This study provides significant references for researchers investigating this specialized nucleus.

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The dorsal raphe nucleus (DRN) receives dopaminergic inputs from the ventral tegmental area (VTA). Also, the DRN contains a small population of cells that express dopamine (DRNDA neurons). However, the physiological role of dopamine (DA) in the DRN and its interaction with serotonergic (5-HT) neurons is poorly understood. Several works have reported moderate levels of D1, D2, and D3 DA receptors in the DRN. Furthermore, it was found that the activation of D2 receptors increased the firing of putative 5-HT neurons. Other studies have reported that D1 and D2 dopamine receptors can interact with glutamate NMDA receptors, modulating the excitability of different cell types. In the present work, we used immunocytochemical techniques to determine the kind of DA receptors in the DRN. Additionally, we performed electrophysiological experiments in brainstem slices to study the effect of DA agonists on NMDA-elicited currents recorded from identified 5-HT DRN neurons. We found that D2 and D3 but not D1 receptors are present in this nucleus. Also, we demonstrated that the activation of D2-like receptors increases NMDA-elicited currents in 5-HT neurons through a mechanism involving phospholipase C (PLC) and protein kinase C (PKC) enzymes. Possible physiological implications related to the sleep-wake cycle are discussed.

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Selective serotonin (5-HT) reuptake inhibitors (SSRIs) are commonly prescribed to women during pregnancy and breastfeeding despite posing a risk of adverse cognitive outcomes and affective disorders for the child. The consequences of SSRI-induced excess of 5-HT during development for the brain neuromodulatory 5-HT system remain largely unexplored. In this study, an SSRI - fluoxetine (FLX) - was administered to C57BL/6 J mouse dams during pregnancy and lactation to assess its effects on the offspring. We found that maternal FLX decreased field potentials, impaired long-term potentiation, facilitated long-term depression and tended to increase the density of 5-HTergic fibers in the medial prefrontal cortex (mPFC) of female but not male adolescent offspring. These effects were accompanied by deteriorated performance in the temporal order memory task and reduced sucrose preference with no change in marble burying behavior in FLX-exposed female offspring. We also found that maternal FLX reduced the axodendritic tree complexity of 5-HT dorsal raphe nucleus (DRN) neurons in female but not male offspring, with no changes in the excitability of DRN neurons of either sex. While no effects of maternal FLX on inhibitory postsynaptic currents (sIPSCs) in DRN neurons were found, we observed a significant influence of FLX exposure on kinetics of spontaneous excitatory postsynaptic currents (sEPSCs) in DRN neurons. Finally, we report that no changes in field potentials and synaptic plasticity were evident in the mPFC of the offspring after maternal exposure during pregnancy and lactation to a new antidepressant, vortioxetine. These findings show that in contrast to the mPFC, long-term consequences of maternal FLX exposure on the structure and function of DRN 5-HT neurons are mild and suggest a sex-dependent, distinct sensitivity of cortical and brainstem neurons to FLX exposure in early life. Vortioxetine appears to exert fewer side effects with regards to the mPFC when compared with FLX.

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Methylphenidate (MPD) remains a cornerstone pharmacological intervention for managing ADHD, yet its increasing usage among ordinary youth and adults outside clinical contexts necessitates a thorough investigation into its developmental effects. This study seeks to simultaneously investigate the behavioral and neuronal changes within the dorsal raphe (DR) nucleus, a center of serotonergic neurons in the mammalian brain, before and after the administration of varying doses of acute and chronic MPD in freely behaving young and adult rats implanted with DR recording electrodes. Wireless neuronal and behavioral recording systems were used over 10 consecutive experimental days. Eight groups were examined: saline, 0.6, 2.5, and 10.0 mg/kg MPD for both young and adult rats. Six daily MPD injections were administered on experimental days 1 to 6, followed by a three-day washout period and MPD re-administration on experimental day 10 (ED10). The analysis of neuronal activity recorded from 504 DR neurons (DRNs) in young rats and 356 DRNs in adult rats reveals significant age-dependent differences in acute and chronic MPD responses. This study emphasizes the importance of aligning electrophysiological evaluations with behavioral outcomes following extended MPD exposure, elucidating the critical role of DRNs and serotonin signaling in modulating MPD responses and delineating age-specific variations in young versus adult rat models.

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This study aims to further elucidate the efficacy targets of celastrol(CEL) intervention in central inflammation in mice with obesity-depression comorbiditiy, based on the differential mRNA expression in the amygdala(AMY) and dorsal raphe nucleus(DRN) after CEL intervention. C57BL/6J mice were randomly divided into a normal diet group(Chow), a obesity-depression comorbidity(COM) group, and low-, medium-, and high-dose CEL groups(CEL-L, CEL-M, CEL-H, 0.5, 1.0, 2.0 mg·kg~(-1)). The Chow group received a normal diet, while the COM group and CEL-L, CEL-M, CEL-H groups received a high-fat diet combined with chronic stress from wet bedding. After 10 weeks of feeding, the mice were orally administered CEL for three weeks. Subsequently, the AMY and DRN of mice in the Chow, COM, and CEL-H groups were subjected to transcriptome analysis, and the intersection of target differentially expressed genes in both nuclei was visualized using a Venn diagram. The intersected genes were then imported into STRING for protein-protein interaction(PPI) analysis, and Gene Ontology(GO) analysis was performed using DAVID to identify the core targets regulated by CEL in the AMY and DRN. Independent samples were subjected to quantitative real-time PCR(qPCR) to validate the intersection genes. The results revealed that the common genes regulated by CEL in the AMY and DRN included chemokine family genes Ccl2, Ccl5, Ccl7, Cxcl10, Cxcr6, and Hsp70 family genes Hspa1a, Hspa1b, as well as Myd88, Il2ra, Irf7, Slc17a8, Drd2, Parp9, and Nampt. GO analysis showed that the top 5 nodes Ccl2, Cxcl10, Myd88, Ccl5, and Irf7 were all involved in immune-inflammation regulation(P<0.01). The qPCR results from independent samples showed that in the AMY, compared with the results in the Chow group, chemokine family genes, Hsp70, Myd88, Il2ra, Irf7, Slc17a8, Parp9, and Nampt were significantly up-regulated in the COM group, with Drd2 showing a decreasing trend; these pathological changes were significantly improved in the CEL-H group compared to the COM group. In the DRN, compared with the results in the Chow group, chemokine family genes, Hsp70, Myd88, Il2ra, Irf7, Parp9, and Nampt were significantly down-regulated, while Slc17a8 was significantly up-regulated in the COM group; compared with those in the COM group, Cxcr6, Irf7, and Drd2 were significantly up-regulated, while Slc17a8 was significantly down-regulated in the CEL-H group. In both the AMY and DRN, the expression of Irf7 by CEL showed both inhibition and activation in a dose-dependent manner(R~2 were 0.709 8 and 0.917 2, respectively). These findings suggest that CEL can effectively improve neuroinflammation by regulating bidirectional expression of the same target proteins, thereby intervening in the immune activation of the AMY and immune suppression of the DRN in COM mice.

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Maladaptive reactive aggression is a core symptom of neuropsychiatric disorders such as schizophrenia. While uncontrolled aggression dampens societal safety, there is a limited understanding of the neural regulation involved in reactive aggression and its treatment. High levels of aggression have been linked to low serotonin (5-HT) levels. Additionally, post-weaning socially isolated (SI) mice exhibit outbursts of aggression following encountering acute stress, and hyperactivated ventral hippocampus (vHip) involves this stress-provoked escalated aggression. Here, we investigated the potential role of the raphe nucleus projecting to the vHip in modulating aggressive behavior. Chemogenetically activating the dorsal raphe nucleus (DRN) soma projecting the vHip or DRN nerve terminals in the vHip reduced reactive aggression. The reduction of attack behavior was abolished by the pretreatment of 5-HT1B receptor antagonist SB-224289. However, activating the median raphe nucleus (MRN)-to-vHip pathway ameliorated depression-like behavior but did not affect reactive aggression. DRN→vHip activation suppressed the vHip downstream area, the ventromedial hypothalamus (VMH), which is a core aggression area. Intra-vHip infusion of 5-HT1B receptor agonists (anpirtoline, CP-93129) suppressed reactive aggression and decreased c-Fos levels in the vHip neurons projecting to the VMH, suggesting an inhibition mechanism. Our findings indicate that activating the DRN projecting to the vHip is sufficient to inhibit reactive aggression in a 5-HT1B receptor-dependent manner. Thus, targeting 5-HT1B receptor could serve as a promising therapeutic approach to ameliorate symptoms of reactive aggression.

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BACKGROUND: Depressive symptoms often occur in patients with Alzheimer's disease (AD) and exacerbate the pathogenesis of AD. However, the neural circuit mechanisms underlying the AD-associated depression remain unclear. The serotonergic system plays crucial roles in both AD and depression. METHODS: We used a combination of in vivo trans-synaptic circuit-dissecting anatomical approaches, chemogenetic manipulations, optogenetic manipulations, pharmacological methods, behavioral testing, and electrophysiological recording to investigate dorsal raphe nucleus serotonergic circuit in AD-associated depression in AD mouse model. RESULTS: We found that the activity of dorsal raphe nucleus serotonin neurons (DRN5-HT) and their projections to the dorsal hippocampal CA1 (dCA1) terminals (DRN5-HT-dCA1CaMKII) both decreased in brains of early 5×FAD mice. Chemogenetic or optogenetic activation of the DRN5-HT-dCA1CaMKII neural circuit attenuated the depressive symptoms and cognitive impairments in 5×FAD mice through serotonin receptor 1B (5-HT1BR) and 4 (5-HT4R). Pharmacological activation of 5-HT1BR or 5-HT4R attenuated the depressive symptoms and cognitive impairments in 5×FAD mice by regulating the DRN5-HT-dCA1CaMKII neural circuit to improve synaptic plasticity. CONCLUSIONS: These findings provide a new mechanistic connection between depression and AD and provide potential pharmaceutical prevention targets for AD.

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Targeted delivery of α-synuclein using AAV vectors has over the two decades since its introduction developed into a versatile tool for modeling different aspects of synucleinopathy, mimicking those seen in Parkinson's disease and related Lewy body disorders. The viral vector approach to disease modeling is attractive in that the expression of α-synuclein, wild-type or mutated, can be confined to defined anatomical structures and targeted to selected cell populations using either cell-type specific promoter constructs or different natural or engineered AAV serotypes. AAV-α-synuclein was initially used to model progressive α-synuclein pathology in nigral dopamine neurons, and, like the standard 6-OHDA model, it has most commonly been applied unilaterally, using the non-injected side as a reference and control. In recent years, however, the AAV-α-synuclein model has become more widely used to induce Parkinson-like synuclein pathology in other relevant neuronal systems, such as the brainstem noradrenergic and serotonergic neurons, the vagal motor neurons, as well as in oligodendrocytes, the prime target relevant to the pathology seen in multiple system atrophy. The purpose of this review is to give an overview of the progress made in the use of the AAV-α-synuclein model over the last two decades and summarize the state-of-the art in the use of the AAV-α-synuclein model for disease modeling in rats and mice.

Misfolding of the neuronal protein α-synuclein is central to the cellular processes that underlie the development of Parkinson's disease and related disorders, such as dementia with Lewy bodies and multiple system atrophy. Targeted delivery of α-synuclein using adeno-associated virus, AAV, has become a standard tool to model the disease process in animals. This AAV-α-synuclein model of Parkinson's disease was introduced two decades ago and over the ensuing decades it has become a widely used standard tool for experimental studies in animals. The usefulness of the AAV-α-synuclein model is largely due to its flexibility and versatility as an experimental tool. In this review the authors summarize the state-of-the art in this field and review the range of applications that has been developed using AAV-α-synuclein alone, in single hit models, or in combinations with other interacting risk factors, in double hit models.

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Early life adversity has been linked with a higher probability of developing behavioral impairments and environmental manipulation is a strategy that may reduce the negative effects of exposure to adversity in early life. Here, we focused on exploring the influence of environmental enrichment (EE) as a protective factor in the context of early life adversity. We hypothesized that 24 hours of maternal deprivation (MD), in the second week of life, could induce anxiety-like behavior alterations and that exposure to EE could induce resilience to these behaviors due to alterations in the serotonergic system. Male Wistar rats were exposed to MD, on postnatal days 11 and 13, and to EE, after weaning. In adulthood, we performed a series of behavioral tests for fear, anxiety, and locomotor activity. We also measured the levels of serotonin in the amygdala and dorsal raphe nucleus. Our results revealed that MD does not impact fear behavior or the levels of serotonin, while EE decreases locomotor activity in a novel environment and enhances exploration in the predator odor test. EE also decreases serotonin in the amygdala and increases its turnover rate levels. Our findings provide insights into the critical timeframe during which stress exposure impacts the development and confirm that exposure to EE has an independent and protective effect for anxiety-like behaviors later in life.

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Birth stress is a risk factor for psychiatric disorders and associated with exaggerated release of the stress hormone arginine vasopressin (AVP) into circulation and in the brain. In perinatal hippocampus, AVP activates GABAergic interneurons which leads to suppression of spontaneous network events and suggests a protective function of AVP on cortical networks during birth. However, the role of AVP in developing subcortical networks is not known. Here we tested the effect of AVP on the dorsal raphe nucleus (DRN) 5-hydroxytryptamine (5-HT, serotonin) system in male and female neonatal rats, since early 5-HT homeostasis is critical for the development of cortical brain regions and emotional behaviors. We show that AVP is strongly excitatory in neonatal DRN: it increases excitatory synaptic inputs of 5-HT neurons via V1A receptors in vitro and promotes their action potential firing through a combination of its effect on glutamatergic synaptic transmission and a direct effect on the excitability of these neurons. Furthermore, we identified two major firing patterns of neonatal 5-HT neurons in vivo, tonic regular firing and low frequency oscillations of regular spike trains and confirmed that these neurons are also activated by AVP in vivo. Finally, we show that the sparse vasopressinergic innervation in neonatal DRN originates exclusively from cell groups in medial amygdala and bed nucleus of stria terminalis. Hyperactivation of the neonatal 5-HT system by AVP during birth stress may impact its own functional development and affect the maturation of cortical target regions, which may increase the risk for psychiatric conditions later on.

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OBJECTIVE: Alzheimer's disease (AD) has become a significant global concern, but effective drugs able to slow down AD progression is still lacked. Electroacupuncture (EA) has been demonstrated to ameliorate cognitive impairment in individuals with AD. However, the underlying mechanisms remains poorly understood. This study aimed at examining the neuroprotective properties of EA and its potential mechanism of action against AD. METHODS: APP/PS1 transgenic mice were employed to evaluate the protective effects of EA on Shenshu (BL 23) and Baihui (GV 20). Chemogenetic manipulation was used to activate or inhibit serotonergic neurons within the dorsal raphe nucleus (DRN). Learning and memory abilities were assessed by the novel object recognition and Morris water maze tests. Golgi staining, western blot, and immunostaining were utilized to determine EA-induced neuroprotection. RESULTS: EA at Shenshu (BL 23) and Baihui (GV 20) effectively ameliorated learning and memory impairments in APP/PS1 mice. EA attenuated dendritic spine loss, increased the expression levels of PSD95, synaptophysin, and brain-derived neurotrophic factor in hippocampus. Activation of serotonergic neurons within the DRN can ameliorate cognitive deficits in AD by activating glutamatergic neurons mediated by 5-HT1B. Chemogenetic inhibition of serotonergic neurons in the DRN reversed the effects of EA on synaptic plasticity and memory. CONCLUSION: EA can alleviate cognitive dysfunction in APP/PS1 mice by activating serotonergic neurons in the DRN. Further study is necessary to better understand how the serotonergic neurons-related neural circuits involves in EA-induced memory improvement in AD.

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ETHNOPHARMACOLOGICAL RELEVANCE: Sinisan formula (SNSF), documented in the classic books Shanghan Lun, is known for its ability to regulate liver-qi and treat depression. However, its underlying mechanism, particularly its effects on dynamic real-time neuron activity and circuits remains to be fully elucidated. AIM OF THE STUDY: This study aimed to investigate the antidepressant effect of SNSF and its central nervous system mechanism on depression-like behaviors, focusing on the prefrontal cortex (PFC) to dorsal raphe nucleus (DRN) neural circuit in a stress-induced adolescent animal model. MATERIALS AND METHODS: SNSF comprised four herbs, the root of Bupleurum chinense DC., the root of Paeonia lactiflora Pall., the fruit of Citrus aurantium L., the rhizome of Glycyrrhiza uralensis Fisch., in equal propotions. The adolescent depression animal model was induced by maternal separation (MS) and chronic restraint stress (CRS). In-vivo multichannel physiological electrodes were implanted into the PFC on PND 28 and animals were recorded 5 times during PND 35-46. From PND 47, the behavioral tests were performed to evaluate the antidepressant efficacy of SNSF. Subsequently, brain tissue was collected for Western blot and immunofluorescence staining analysis. Retro virus was injected into the DRN to explore sources of projections received by serotonergic (5-HTergic) neurons. And the PFC-to-DRN circuit was activated or inhibited through chemogenetic techniques to investigate the effects of SNSF on depression-like behaviors. RESULTS: Administration of SNSF for 18 days effectively alleviated depression-like behaviors in MS&CRS adolescent mice. The PFC emerged as the primary glutamatergic projection source of the DRN5-HT neurons. Following SNSF administration for 13/15/18 days, there was an increase in the firing rate of excitatory neurons and excitatory/inhibitory (E/I) ratio in the PFC. MS&CRS stress let to a reduction in the density of 5-HT+ and CaMKII + neurons in the DRN, accompanied by an increase in the density of GAD + neurons in the DRN, while SNSF administration reversed the alterations. Chemogenetic activation of the PFC-to-DRN circuit rescued the depression-like behaviors induced by MS&CRS, whereas suppression of this circuit attenuated the antidepressant effect of SNSF. CONCLUSIONS: SNSF significantly mitigated depression-like behaviors in MS&CRS mice. SNSF exerts its antidepressant effects by increasing the E/I ratio in the PFC and enhancing glutamatergic projections from the PFC to the DRN.

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Parkinson's disease (PD) is characterized by motor impairments caused by degeneration of dopamine neurons in the substantia nigra pars compacta. In addition to these symptoms, PD patients often suffer from non-motor comorbidities including sleep and psychiatric disturbances, which are thought to depend on concomitant alterations of serotonergic and noradrenergic transmission. A primary locus of serotonergic neurons is the dorsal raphe nucleus (DRN), providing brain-wide serotonergic input. Here, we identified electrophysiological and morphological parameters to classify serotonergic and dopaminergic neurons in the murine DRN under control conditions and in a PD model, following striatal injection of the catecholamine toxin, 6-hydroxydopamine (6-OHDA). Electrical and morphological properties of both neuronal populations were altered by 6-OHDA. In serotonergic neurons, most changes were reversed when 6-OHDA was injected in combination with desipramine, a noradrenaline (NA) reuptake inhibitor, protecting the noradrenergic terminals. Our results show that the depletion of both NA and dopamine in the 6-OHDA mouse model causes changes in the DRN neural circuitry.

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Calcium calmodulin-dependent protein kinase (CaMK) mediates calcium-induced neural gene activation. CaMK also inhibits the non-syndromic intellectual disability gene, Freud-1/CC2D1A, a transcriptional repressor of human serotonin-1A (5-HT1A) and dopamine-D2 receptor genes. The altered expression of these Freud-1-regulated genes is implicated in mental illnesses such as major depression and schizophrenia. We hypothesized that Freud-1 is blocked by CaMK-induced phosphorylation. The incubation of purified Freud-1 with either CaMKIIα or CaMKIV increased Freud-1 phosphorylation that was partly prevented in Freud-1-Ser644Ala and Freud-1-Thr780Ala CaMK site mutants. In human SK-N-SH neuroblastoma cells, active CaMKIV induced the serine and threonine phosphorylation of Freud-1, and specifically increased Freud-1-Thr780 phosphorylation in transfected HEK-293 cells. The activation of purified CaMKIIα or CaMKIV reduced Freud-1 binding to its DNA element on the 5-HT1A and dopamine-D2 receptor genes. In SK-N-SH cells, active CaMKIV but not CaMKIIα blocked the Freud-1 repressor activity, while Freud-1 Ser644Ala, Thr780Ala or dual mutants were resistant to inhibition by activated CaMKIV or calcium mobilization. These results indicate that the Freud-1 repressor activity is blocked by CaMKIV-induced phosphorylation at Thr780, resulting in the up-regulation of the target genes, such as the 5-HT1A receptor gene. The CaMKIV-mediated inhibition of Freud-1 provides a novel de-repression mechanism to induce 5-HT1A receptor expression for the regulation of cognitive development, behavior and antidepressant response.

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Exposure to stressors has profound effects on sleep that have been linked to serotonin (5-HT) neurons of the dorsal raphe nucleus (DR). However, the DR also comprises glutamatergic neurons expressing vesicular glutamate transporter type 3 (DRVGLUT3), leading us to examine their role. Cell-type-specific tracing revealed that DRVGLUT3 neurons project to brain areas regulating arousal and stress. We found that chemogenetic activation of DRVGLUT3 neurons mimics stress-induced sleep perturbations. Furthermore, deleting VGLUT3 in the DR attenuated stress-induced sleep perturbations, especially after social defeat stress. In the DR, VGLUT3 is found in subsets of 5-HT and non-5-HT neurons. We observed that both populations are activated by acute stress, including those projecting to the ventral tegmental area. However, deleting VGLUT3 in 5-HT neurons minimally affected sleep regulation. These findings suggest that VGLUT3 expression in the DR drives stress-induced sleep perturbations, possibly involving non-5-HT DRVGLUT3 neurons.

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