Search Results (125)

The serotonergic system, originating in the raphe nuclei, differentially modulates the dorsal and ventral hippocampus, which are implicated in cognition and emotion, respectively. Emerging evidence from rodent models (e.g., neonatal ventral hippocampal lesion, pharmacological NMDA receptor antagonist exposure) and human postmortem studies indicates dorsoventral serotonergic alterations in schizophrenia. These data include elevated 5-HT1A receptor expression in the dorsal hippocampus, linking serotonergic hypofunction to cognitive deficits, and hyperactive 5-HT2A/3 receptor signaling and denser serotonergic innervation in the ventral hippocampus driving local hyperexcitability associated with psychosis and stress responsivity. These dorsoventral serotonergic alterations are shown to disrupt the excitation–inhibition balance, impair synaptic plasticity, and disturb network oscillations, as established by in vivo electrophysiology and functional imaging. Synthesizing these multi-level findings, we propose a novel “dorsoventral serotonin imbalance” model of schizophrenia, in which ventral hyperactivation predominantly contributes to psychotic symptoms and dorsal hypoactivity underlies cognitive deficits. We further highlight promising preclinical evidence that selective targeting of region- and receptor-specific targeting, using both pharmacological agents and emerging delivery technologies, may offer novel therapeutic opportunities enabling symptom-specific strategies in schizophrenia. Full article

Antenatal inflammation/infection is a major cause of neonatal apnoea and hypoventilation. Prostaglandin E2 (PGE₂) is a key inflammatory mediator associated with depression of fetal and neonatal breathing. We aimed to determine whether antenatal ibuprofen, a cyclooxygenase inhibitor that reduces synthesis of PGE₂, restores fetal breathing movements (FBM) in late-gestation fetal sheep exposed to systemic lipopolysaccharide (LPS). Fetal sheep (125 days gestation, d; term ~148 d) were instrumentally monitored for continuous measurement of FBM and physiological parameters. At 130 d fetuses were randomly allocated between groups receiving i.v. saline (CTL_SAL, n = 9), escalating doses of LPS (i.v.) over 3 days (LPS_SAL, n = 8), or ibuprofen one hour after each LPS dose (LPS_IBU, n = 8). Regular plasma samples were collected for PGE₂ assessment. At 135 d, cerebrospinal fluid and brainstem tissue were collected at autopsy for assessments of PGE₂ expression, and immunohistochemical quantification of astrocytes and microglia within key brainstem respiratory centres was performed to assess inflammation. LPS exposure increased PGE₂ levels in plasma, cerebrospinal fluid and the RTN/pFRG (p < 0.05) and decreased the incidence, amplitude and amount of the accentuated (>5 mmHg) FBMs. Ibuprofen reduced plasma and RTN/pFRG PGE₂ expression (p < 0.01 and p = 0.031, respectively) but did not restore FBMs. Astrocyte and microglial density increased in the RTN/pFRG, NTS and raphe nucleus in LPS_IBU fetuses, compared to LPS_SAL (p < 0.05). Antenatal ibuprofen treatment did not restore depressed FBM, despite reducing the circulating and brainstem PGE₂ levels in LPS-exposed fetal sheep. Other inflammatory pathways or more specific targeting of PGE₂ may be more effective in preventing apnoea caused by exposure to intrauterine infection/inflammation. Full article

This study reports two novel species, Gogorevia contracta sp. nov. and G. recticentralis sp. nov., which were isolated from freshwater environments in South Korea. Using an integrative taxonomic approach, we conducted morphological analyses using light microscopy and scanning electron microscopy, along with molecular phylogenetic investigations using SSU rRNA and rbcL gene sequences. Phylogenetic reconstructions highlighted the distinct characteristics of both species, confirming their classification within the genus Gogorevia and elucidating their evolutionary relationships. Morphologically, G. contracta was characterized by a bow-tie-shaped central area and circular depressions in the rapheless valve, whereas G. recticentralis exhibited a rectangular-to-wedge-shaped central area with parallel striae near the center of the raphe valve. Our findings highlighted the ecological significance of Gogorevia species and suggested their potential role as bioindicators of water quality in relatively unpolluted freshwater systems. Over the past decade, our research has focused on the taxonomic and ecological study of diatoms in the Han River system and identified 136 species, including nine newly described taxa. The findings of the present study contribute to a growing understanding of Gogorevia diversity, underscore the importance of region-specific diatom indices, and support the integration of morphological and molecular methods into diatom systematics. Full article

Background: Dorsal raphe serotonin (5-hydroxytryptamine, 5-HT) neurons are spontaneously active and release 5-HT that is critical for normal brain function and regulates mood and emotion. Serotonin reuptake inhibitors (SSRIs) increase the synaptic and extracellular 5-HT level and are effective in treating depression. Treatment of two weeks or longer is often required for SSRIs to produce clinical benefits. The cellular mechanism underlying this delay is not fully understood. Methods and Results: Using whole-cell patch clamp recording in brain slices, here we show that the GABAergic inputs inhibit the spike firing of raphe 5-HT neurons. This GABAergic regulation was reduced by 5-HT; additionally, this 5-HT effect was prevented by the G-protein-activated inwardly rectifying potassium (GirK) channel inhibitor tertiapin-Q, indicating a contribution of 5-HT activation of GirK channels in GABAergic presynaptic axon terminals. Equally important, after 14 days of treatment with fluoxetine, a widely used SSRI type antidepressant, the 5-HT inhibition of GABAergic inputs was downregulated. Furthermore, chronic fluoxetine treatment downregulated the 5-HT activation of the inhibitory GirK current in 5-HT neurons. Conclusions: Taken together, our results suggest that chronic fluoxetine treatment, by blocking 5-HT reuptake and hence increasing the extracellular 5-HT level, can downregulate the function of 5-HT1B receptors on the GABAergic afferent axon terminals synapsing onto 5-HT neurons, allowing extrinsic GABAergic neurons to more effectively influence 5-HT neurons; simultaneously, chronic fluoxetine treatment also downregulated somatic 5-HT autoreceptor-activated GirK channel-mediated hyperpolarization and decrease in input resistance, rendering 5-HT neurons resistant to autoinhibition and leading to increased 5-HT neuron activity. These neuroplastic changes in raphe 5-HT neurons and their GABAergic afferents may contribute to the behavioral effect of SSRIs. Full article

Agmatine is a naturally occurring biogenic amine that acts primarily as an inhibitor of neuronal nitric oxide synthase (nNOS). Previous studies have shown that both acute and chronic agmatine administration induced anxiolytic and antidepressant-like effects in rodents. In the dorsal raphe nucleus (DRN), nitric oxide (NO) donors inhibit serotonergic (5-HT) neuronal activity, with the nNOS-expressing 5-HT neurons showing lower baseline firing rates than the non-nNOS expressing neurons. Our study aimed to test the hypothesis that the psychoactive effects of agmatine are mediated, at least in part, via a mechanism involving the stimulation of the DRN 5-HT neurons, as well as to assess the molecular pathway allowing agmatine to modulate the excitability of 5-HT neurons. Using extracellular in vivo electrophysiology, we demonstrated that both acute (1–3 mg/kg, i.v.) and chronic (40 mg/kg/day, i.p., 14 days) agmatine administration significantly increased the firing rate of DRN 5-HT neurons. Quantitative PCR (qPCR) analysis revealed that chronic agmatine treatment selectively upregulated the expression of serotonin-1B (5-HT_1B) and serotonin-2A (5-HT_2A) receptor mRNA in the DRN. Previous studies have shown that DRN 5-HT_2A receptor activation stimulates 5-HT neurons and produces antidepressant-like effects; our findings suggest that agmatine’s excitatory effect on DRN 5-HT neurons may be partially 5-HT_2A receptor-dependent. Given that modulation of the 5-HT neuronal firing activity is critical for the proper antidepressant efficacy, nNOS inhibitors can be potential antidepressants by their own and/or effective adjuncts to other antidepressant drugs. Full article

Background/Objectives: Spinal cord injury (SCI) presents significant challenges in restoring motor function, with limited therapeutic options available. Recent advancements in neuromodulation technologies, such as brain-spine interface (BSI), epidural electrical stimulation (EES), and deep brain stimulation (DBS), offer promising solutions. This review article explores the integration of these approaches, focusing on their potential to restore function in SCI patients. Findings: DBS has shown efficacy in SCI treatment with several stimulation sites identified, including the nucleus raphe magnus (NRM) and periaqueductal gray (PAG). However, transitioning from animal to human studies highlights challenges, including the technical risks of targeting the NRM in humans instead of rodent models. Additionally, several other regions have shown potential for motor rehabilitation, including the midbrain locomotor region (MLR) pathways, cuneiform nucleus (CnF), pedunculopontine nucleus (PPN), and lateral hypothalamic. DBS with EES further supports motor recovery in SCI; however, this approach requires high-DBS amplitude, serotonergic pharmacotherapy, and cortical activity decoding to attenuate stress-associated locomotion. BSI combined with EES has recently emerged as a promising novel therapy. Although human studies are limited, animal models have provided evidence supporting its potential. Despite these advancements, the effectiveness of DBS and combined systems remains limited in cases of complete central denervation. Conclusions: The integration and combination of DBS, BSI, and EES represent a transformational approach to treating and restoring function in patients with SCI. While further research is needed to optimize these strategies, these advancements hold immense potential for improving the quality of life in SCI patients and advancing the field of neuromodulation. Full article

Sudden unexpected death in epilepsy (SUDEP) is a critical concern for individuals suffering from epilepsy, with respiratory dysfunction playing a significant role in its pathology. Fatal seizures are often characterized by central apnea and hypercapnia (elevated CO₂ levels), indicating a failure in ventilatory control. Research has shown that both human epilepsy patients and animal models exhibit a reduced hypercapnic ventilatory response in the interictal (non-seizure) period, suggesting an impaired ability to regulate breathing in response to high CO₂ levels. This review examines the role of central chemoreceptors—specifically the retrotrapezoid nucleus, raphe nuclei, nucleus tractus solitarius, locus coeruleus, and hypothalamus in this pathology. These structures are critical for sensing CO₂ and maintaining respiratory homeostasis. Emerging evidence also implicates neuropeptidergic pathways within these chemoreceptive regions in SUDEP. Neuropeptides like galanin, pituitary adenylate cyclase-activating peptide (PACAP), orexin, somatostatin, and bombesin-like peptides may modulate chemosensitivity and respiratory function, potentially exacerbating respiratory failure during seizures. Understanding the mechanisms linking central chemoreception, respiratory control, and neuropeptidergic signaling is essential to developing targeted interventions to reduce the risk of SUDEP in epilepsy patients. Full article

Subcortical innervation of the hippocampus by the raphe nucleus is essential for emotional and cognitive control. The two major afferents from raphe to hippocampus originate from serotonergic and glutamatergic neurons, of which the serotonergic control of hippocampal inhibitory network, theta activity, and synaptic plasticity have been extensively explored in the growing body of literature, whereas those of glutamatergic circuits have received little attention. Notably, both serotonergic and glutamatergic circuits between raphe and hippocampus are disrupted in Alzheimer’s disease (AD), which may contribute to initiation and progression of behavioral and psychological symptoms of dementia. Thus, deciphering the mechanism underlying abnormal raphe–hippocampal circuits in AD is crucial to prevent dementia-associated emotional and cognitive symptoms. In this review, we summarize the anatomical, neurochemical, and electrophysiological diversity of raphe nuclei as well as the architecture of raphe–hippocampal circuitry. We then elucidate subcortical control of hippocampal activity by raphe nuclei and their role in regulation of emotion and cognition. Additionally, we present an overview of disrupted raphe–hippocampal circuits in AD pathogenesis and analyze the available therapies that can potentially be used clinically to alleviate the neuropsychiatric symptoms and cognitive decline in AD course. Full article

The gut–brain axis represents an important bidirectional communication network, with the vagus nerve acting as a central conduit for peripheral signals from the various gut organs to the central nervous system. Among the molecular mediators involved, serotonin (5-HT), synthesized predominantly by enterochromaffin cells in the gut, plays a pivotal role. Gut-derived serotonin activates vagal afferent fibers, transmitting signals to the nucleus tractus solitarius (NTS) and modulating serotonergic neurons in the dorsal raphe nucleus (DRN) as well as the norepinephrinergic neurons in the locus coeruleus (LC). This interaction influences emotional regulation, stress responses, and immune modulation. Emerging evidence also highlights the role of microbial metabolites, particularly short-chain fatty acids (SCFAs), in enhancing serotonin synthesis and vagal activity, thereby shaping gut–brain communication. This review synthesizes the current knowledge on serotonin signaling, vagal nerve pathways, and central autonomic regulation, with an emphasis on their implications for neuropsychiatric and gastrointestinal disorders. By elucidating these pathways, novel therapeutic strategies targeting the gut–brain axis may be developed to improve mental and physical health outcomes. Full article

Background/Objectives: Medication-overuse headache (MOH) is a disabling condition affecting patients with chronic migraine resulting from excessive use of acute headache medication. It is characterized by both pain modulation and addiction-like mechanisms involving the brainstem raphe, a region critical to serotonergic signaling. This study investigates whether alterations in the brainstem raphe, assessed via transcranial sonography (TCS), are associated with MOH and independent of depressive symptoms, aiming to explore their utility as a biomarker. Methods: This prospective case-control study included 60 migraine patients (15 with MOH) and 7 healthy controls. Comprehensive clinical and psychometric assessments were performed to evaluate headache burden, medication use, and depressive symptoms. TCS was used to assess brainstem raphe echogenicity, with findings analyzed using generalized linear models adjusted for depression. Results: Non-visibility of the brainstem raphe was significantly associated with MOH, with an unadjusted odds ratio (OR) of 6.88 (95% CI: 1.32–36.01, p = 0.02). After adjusting for depressive symptoms, this association remained significant, with an adjusted OR of 1.85 (95% CI: 1.02–3.34, p = 0.041). TCS demonstrated good intraclass correlation, highlighting its reproducibility and ability to detect changes relevant to MOH pathophysiology. Conclusions: Brainstem raphe alterations are associated with MOH and may serve as a potential biomarker for its diagnosis and management. TCS offers a non-invasive, cost-effective tool for identifying MOH-specific mechanisms, which could improve clinical decision-making and support personalized care in chronic headache disorders. Further studies are needed to validate these findings and refine the clinical applications of brainstem-focused diagnostics. Full article

Transcatheter aortic valve replacement (TAVR) in patients with severe aortic stenosis and raphe-type bicuspid aortic valve (BAV) is still associated with poor outcomes in terms of increased risk of paravalvular regurgitation, stroke, and permanent pacemaker implantation. There is no definitive consensus on the optimal sizing method for prosthesis selection in this setting. The LIRA method is a supra-annular tailored sizing method specifically designed for bicuspid anatomy that might increase accuracy of prosthesis choice in BAV patients and improve TAVR outcomes. This is the first report of the combination of the novel LIRA method for prosthesis sizing together with the adoption of the technological improvements introduced by the Evolut FX prosthesis as a useful tool for improving outcomes in this high risk subgroup of patients. Full article

Causal graph discovery (CGD) is the process of estimating the underlying probabilistic graphical model that represents the joint distribution of features of a dataset. CGD algorithms are broadly classified into two categories: (i) constraint-based algorithms, where the outcome depends on conditional independence (CI) tests, and (ii) score-based algorithms, where the outcome depends on optimized score function. Because sensitive features of observational data are prone to privacy leakage, differential privacy (DP) has been adopted to ensure user privacy in CGD. Adding the same amount of noise in this sequential-type estimation process affects the predictive performance of algorithms. Initial CI tests in constraint-based algorithms and later iterations of the optimization process of score-based algorithms are crucial; thus, they need to be more accurate and less noisy. Based on this key observation, we present CURATE (CaUsal gRaph AdapTivE privacy), a DP-CGD framework with adaptive privacy budgeting. In contrast to existing DP-CGD algorithms with uniform privacy budgeting across all iterations, CURATE allows for adaptive privacy budgeting by minimizing error probability (constraint-based), maximizing iterations of the optimization problem (score-based) while keeping the cumulative leakage bounded. To validate our framework, we present a comprehensive set of experiments on several datasets and show that CURATE achieves higher utility compared to existing DP-CGD algorithms with less privacy leakage. Full article

The dorsal raphe nucleus (DRN) has gained attention owing to its involvement in various physiological functions, such as sleep–awake, feeding, and emotion, with its analgesic role being particularly significant. It is described as the “pain inhibitory nucleus” in the brain. The DRN has diverse projections from hypothalamus, midbrain, and pons. In turn, the DRN is a major source of projections to diverse cortex, limbic forebrain thalamus, and the midbrain and contains highly heterogeneous neuronal subtypes. The activation of DRN neurons in mice prevents the establishment of neuropathic, chronic pain symptoms. Chemogenetic or optogenetic inhibition neurons in the DRN are sufficient to establish pain phenotypes, including long-lasting tactile allodynia, that scale with the extent of stimulation, thereby promoting nociplastic pain. Recent progress has been made in identifying the neural circuits and cellular mechanisms in the DRN that are responsible for sensory modulation. However, there is still a lack of comprehensive review addressing the specific neuron types in the DRN involved in pain modulation. This review summarizes the function of specific cell types within DRN in the pain regulation, and aims to improve understanding of the mechanisms underlying pain regulation in the DRN, ultimately offering insights for further exploration. Full article

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. Full article

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. Full article