Median Raphe Research Articles

A Case of Multiple Median Raphe Cysts with Pathologically Mixed Variants: A Rare Presentation

A Case of Multiple Median Raphe Cysts with Pathologically Mixed Variants: A Rare Presentation

Parallel streams of raphe VGLUT3-positive inputs target the dorsal and ventral hippocampus in each hemisphere.

The hippocampus (HP) receives neurochemically diverse inputs from the raphe nuclei, including glutamatergic axons characterized by the expression of the vesicular glutamate transporter type 3 (VGLUT3). These raphe-HP VGLUT3 projections have been suggested to play a critical role in HP functions, yet a complete anatomical overview of raphe VGLUT3 projections to the forebrain, and in particular to the HP, is lacking. Using anterograde viral tracing, we describe largely nonoverlapping VGLUT3-positive projections from the dorsal raphe (DR) and median raphe (MnR) to the forebrain, with the HP receiving inputs from the MnR. A limited subset of forebrain regions such as the amygdaloid complex, claustrum, and hypothalamus receives projections from both the DR and MnR that remain largely segregated. This highly complementary anatomical pattern suggests contrasting roles for DR and MnR VGLUT3 neurons. To further analyze the topography of VGLUT3 raphe projections to the HP, we used retrograde tracing and found that HP-projecting VGLUT3-positive neurons (VGLUT3HP ) distribute over several raphe subregions (including the MnR, paramedian raphe, and B9 cell group) and lack co-expression of serotonergic markers. Strikingly, double retrograde tracing experiments unraveled two parallel streams of VGLUT3-positive projections targeting the dorsal and ventral poles of the HP. These results demonstrate highly organized and segregated VGLUT3-positive projections to the HP, suggesting independent modulation of HP functions such as spatial memory and emotion-related behavior.

Aberrant serotonergic signaling contributes to the hyperexcitability of CA1 pyramidal neurons in a mouse model of Alzheimer’s disease

Hyperactivity of pyramidal neurons (PNs) in CA1 is an early event in Alzheimer's disease. However, factors accounting for the hyperactivity of CA1 PNs remain to be completely investigated. In the present study, we report that the serotonergic signaling is abnormal in the hippocampus of hAPP-J20 mice. Interestingly, chemogenetic activation of serotonin (5-hydroxytryptamine; 5-HT) neurons in the median raphe nucleus (MRN) attenuates the activity of CA1 PNs in hAPP-J20 mice by regulating the intrinsic properties or inhibitory synaptic transmission of CA1 PNs through 5-HT3aR and/or 5-HT1aR. Furthermore, activating MRN 5-HT neurons improves memory in hAPP-J20 mice, and this effect is mediated by 5-HT3aR and 5-HT1aR. Direct activation of 5-HT3aR and 5-HT1aR with their selective agonists also improves the memory of hAPP-J20 mice. Together, we identify the impaired 5-HT/5-HT3aR and/or 5-HT/5-HT1aR signaling as pathways contributing to the hyperexcitability of CA1 PNs and the impaired cognition in hAPP-J20 mice.

Median Raphe (Parameatal) Cyst of the Penis as Reversible Cause of Loss of Self-Esteem and Impaired Sexual Behaviour

Median Raphe (Parameatal) Cyst of the Penis as Reversible Cause of Loss of Self-Esteem and Impaired Sexual Behaviour

Sembrava un lombrico: la cisti del rafe mediano

The Authors describe the rare (and striking) case of a 4-year-old child with an infected median raphe cyst.

Median raphe cysts: A clinico-pathologic and immunohistochemical study of 52 cases.

Median raphe cysts (MRC) are epithelial-lined cystic lesions of the genital area that do not communicate with the urethra or the overlying epidermis. Immunohistochemically, MRC show positivity for cytokeratin (CK) 5-6, CK 7, carcinoembryonic antigen, p63 and uroplakin III (URO III). GATA3 and human milk fat globulin 1 (HMFG1) are immunohistochemical markers that have been not previously studied in MRC. We conducted a study of 52 patients diagnosed with MRC in the Pathology Departments of eight hospitals between 1990 and 2016. The monoclonal antibodies used were CK5-6, CK7, CK20, URO III, p63, GATA3, and HMFG1. HMFG1 was studied in five cases of apocrine hidrocystomas and compared with five cases of MRC from our series. CK 5-6, CK7, and p63 expression showed strong positivity in the urothelial epithelium of 48 cases. CK20 was focally positive in areas of mucinous differentiation in three cases. GATA3 showed intense nuclear staining in 30 cases. HMFG1 was positive in three cases of MRC and in three cases of apocrine hidrocystoma. Positivity of GATA3 and CK7 in MRC supports the urothelial origin of these cysts. We found no differences in HMFG1 expression between MRC and apocrine hidrocystomas.

Perinatal Western-style diet alters serotonergic neurons in the macaque raphe nuclei.

The neurotransmitter serotonin is a key regulator of neurotransmission, mood, and behavior and is essential in neurodevelopment. Dysfunction in this important neurotransmitter system is connected to behavioral disorders such as depression and anxiety. We have previously shown that the developing serotonin system is sensitive to perinatal exposure to Western-style diet (WSD). To advance our hypothesis that perinatal WSD has a long-term impact on the serotonergic system, we designed a fluorescent immunohistochemistry experiment using antibodies against tryptophan hydroxylase 2 (TPH2) and vesicular glutamate transporter 3 (VGLUT3) to probe protein expression in the raphe subnuclei in 13-month-old Japanese macaques (Macaca fuscata; n = 22). VGLUT3 has been shown to be coexpressed in TPH2+ cells in the dorsal raphe (DR) and median raphe nucleus (MnR) of rodent raphe nuclei and may provide information about the projection site of serotonergic fibers into the forebrain. We also sought to improve scientific understanding of the heterogeneity of the serotonin production center for the central nervous system, the midbrain raphe nuclei. In this immunohistochemical study, we provide the most detailed characterization of the developing primate raphe to date. We utilize multi-level modeling (MLM) to simultaneously probe the contribution of WSD, offspring sex, and raphe anatomical location, to raphe neuronal measurements. Our molecular and morphological characterization revealed that the 13-month-old macaque DR is remarkably similar to that of adult macaques and humans. We demonstrate that vesicular glutamate transporter 3 (VGLUT3), which rodent studies have recently shown can distinguish raphe populations with distinct projection targets and behavioral functions, likewise contributes to the heterogeneity of the primate raphe. This study provides evidence that perinatal WSD has a long-term impact on the density of serotonin-producing neurons, potentially limiting serotonin availability throughout the brain. Due to the critical involvement of serotonin in development and behavior, these findings provide important insight into the mechanisms by which maternal nutrition and metabolic state influence offspring behavioral outcomes. Finally, these findings could inform future research focused on designing therapeutic interventions to optimize neural development and decrease a child's risk of developing a mental health disorder.

Resting-state functional connectivity of the raphe nuclei in major depressive Disorder: A Multi-site study

Accumulating evidence showed that major depressive disorder (MDD) is characterized by a dysfunction of serotonin neurotransmission. Raphe nuclei are the sources of most serotonergic neurons that project throughout the brain. Incorporating measurements of activity within the raphe nuclei into the analysis of connectivity characteristics may contribute to understanding how neurotransmitter synthesized centers are involved in thepathogenesisof MDD. Here, we analyzed the resting-state functional magnetic resonance imaging (RS-fMRI) dataset from 1,148 MDD patients and 1,079 healthy individuals recruited across nine centers. A seed-based analysis with the dorsal raphe and median raphe nuclei was performed to explore the functional connectivity (FC) alterations. Compared to controls, for dorsal raphe, the significantly decreased FC linking with the right precuneus and median cingulate cortex were found; for median raphe, the increased FC linking with right superior cerebellum (lobules V/VI) was found in MDD patients. In further exploratory analyzes, MDD-related connectivity alterations in dorsal and median raphe nuclei in different clinical factors remained highly similar to the main findings, indicating these abnormal connectivities are a disease-related alteration. Our study highlights a functional dysconnection pattern of raphe nuclei in MDD with multi-site big data. These findings help improve our understanding of the pathophysiology of depression and provide evidence of the theoretical foundation for the development of novel pharmacotherapies.

Neuroanatomical Localization of Rapid Eye Movement Sleep Behavior Disorder in Human Brain Using Lesion Network Mapping.

To localize the neuroanatomical substrate of rapid eye movement sleep behavior disorder (RBD) and to investigate the neuroanatomical locational relationship between RBD and α-synucleinopathy neurodegenerative diseases. Using a systematic PubMed search, we identified 19 patients with lesions in different brain regions that caused RBD. First, lesion network mapping was applied to confirm whether the lesion locations causing RBD corresponded to a common brain network. Second, the literature-based RBD lesion network map was validated using neuroimaging findings and locations of brain pathologies at post-mortem in patients with idiopathic RBD (iRBD) who were identified by independent systematic literature search using PubMed. Finally, we assessed the locational relationship between the sites of pathological alterations at the preclinical stage in α-synucleinopathy neurodegenerative diseases and the brain network for RBD. The lesion network mapping showed lesions causing RBD to be localized to a common brain network defined by connectivity to the pons (including the locus coeruleus, dorsal raphe nucleus, central superior nucleus, and ventrolateral periaqueductal gray), regardless of the lesion location. The positive regions in the pons were replicated by the neuroimaging findings in an independent group of patients with iRBD and it coincided with the reported pathological alterations at post-mortem in patients with iRBD. Furthermore, all brain pathological sites at preclinical stages (Braak stages 1-2) in Parkinson's disease (PD) and at brainstem Lewy body disease in dementia with Lewy bodies (DLB) were involved in the brain network identified for RBD. The brain network defined by connectivity to positive pons regions might be the regulatory network loop inducing RBD in humans. In addition, our results suggested that the underlying cause of high phenoconversion rate from iRBD to neurodegenerative α-synucleinopathy might be pathological changes in the preclinical stage of α-synucleinopathy located at the regulatory network loop of RBD.

Effects of juvenile stress on membrane potential properties of mouse medial prefrontal cortex and dorsal raphe nucleus neurons.

Effects of juvenile stress on membrane potential properties of mouse medial prefrontal cortex and dorsal raphe nucleus neurons.

3-D assessment of skeletal and dentoalveolar bilateral dimensions in unilateral impacted palatal canine cases - A CBCT study.

The aim of this study was to compare skeletal and dentoalveolar dimensions in subjects with maxillary unilateral impacted palatal canines versus the unaffected contralateral side using CBCT. Skeletal and dentoalveolar variables (Anterior alveolar ridge height, Anterior dentoalveolar height , nasal cavity width, basal nasal width, Lateral angulation of long axis of the incisors and canines with respect to the nasal horizontal plane, premolar to median raphe width, dimensions of lateral incisor and canine, root resorption of lateral incisors, crown-root angulation of lateral incisor, and sector classification of canine) were compared between the impacted and the contralateral sides. As the data had normal distribution, means were compared using students t test. The significance was set at p<0.05. The root resorption in lateral incisor was compared using Chi square test. Lateral angulation of long axis of canines, nasal cavity width, basal lateral width, and premolar to median raphe width were found to be significantly different. Maximum number fell in sector 4 (n = 23, 38.3%) in sector classification. Root resorption of lateral incisor on impacted side was insignificant. Skeletal and dento-alveolar dimensions vary between the impacted and non-impacted sides in unilateral palatal canine impaction cases. Canines on the impacted side were more mesially angulated compared to the non-impacted side. The nasal cavity width, basal lateral width and premolar to median raphe width were significantly less on the impacted side compared to the non- impacted side. Key words:Impacted canine, CBCT, skeletal dimensions, diagnosis, orthodontic treatment.

Role of median raphe serotonergic neurons in reward and aversive information processing

Role of median raphe serotonergic neurons in reward and aversive information processing

Aberrant filling of the retinal vein on fluorescein angiography in branch and hemi-central retinal artery occlusion.

To study aberrant filling of the retinal vessels on fluorescein angiography (FA) images in patients with branch (BRAO) or hemi-central retinal artery occlusions (hemi-CRAO) and correlate with associated changes on optical coherence tomography (OCT). Cases of acute BRAO or hemi-CRAO having FA and OCT images at presentation between June 2017 to May 2022 were included. Comparisons were made between the cases with and without aberrant filling of the retinal vessel. Thirty-nine eyes of 39 patients with acute retinal artery occlusions underwent FA and OCT imaging. Seven of the ten cases with either BRAO or hemi-CRAO showed aberrant filling of the retinal vein on FA. No case with CRAO showed aberrant filling on FA. The cases with aberrant filling showed a better presenting visual acuity and lesser severity of retinal ischemia on OCT. Shunts between the retinal artery in the unaffected region and the retinal vein in the affected segment was seen in two eyes. The remaining five eyes showed no arteriovenous anastomosis. Cases with aberrant filling had a better visual function even at the last visit. Aberrant retinal vein filling across the horizontal median raphe in the affected region in BRAO or hemi-CRAO eyes had less severity of retinal ischemia and better presenting and final visual acuities. Reduced perfusion in retinal capillaries with altered retinal vascular anatomy or arteriovenous shunts could be probable reasons for the development of this FA finding. Presence of aberrant filling of the retinal vein could indicate better final visual prognosis.

Median raphe serotonergic neurons projecting to the interpeduncular nucleus control preference and aversion

Appropriate processing of reward and aversive information is essential for survival. Although a critical role of serotonergic neurons in the dorsal raphe nucleus (DRN) in reward processing has been shown, the lack of rewarding effects with selective serotonin reuptake inhibitors (SSRIs) implies the presence of a discrete serotonergic system playing an opposite role to the DRN in the processing of reward and aversive stimuli. Here, we demonstrated that serotonergic neurons in the median raphe nucleus (MRN) of mice process reward and aversive information in opposite directions to DRN serotonergic neurons. We further identified MRN serotonergic neurons, including those projecting to the interpeduncular nucleus (5-HTMRN→IPN), as a key mediator of reward and aversive stimuli. Moreover, 5-HT receptors, including 5-HT2A receptors in the interpeduncular nucleus, are involved in the aversive properties of MRN serotonergic neural activity. Our findings revealed an essential function of MRN serotonergic neurons, including 5-HTMRN→IPN, in the processing of reward and aversive stimuli.

Increased Serotonin Synthesis Capacity is Associated with Longitudinal Cortical Atrophy and Worsening Depressive Symptoms

AbstractBackgroundSerotonin‐producing raphe nuclei are sites of age and Alzheimer’s disease‐related alterations in structure and function.MethodWe used [18F]Fluoro‐m‐tyrosine ([18F]FMT) positron emission tomography (PET) to measure serotonin synthesis capacity in younger (mean age = 22.08, n = 62) and older adults (mean age = 77.8, n = 49). [18F]FMT net tracer influx (Ki) was higher in older adults in both the dorsal and median raphe nuclei (both p &lt; 0.001). To examine the functional relevance of higher raphe [18F]FMT Ki in older adults, we tested relationships with β‐amyloid status as defined by [11C]Pittburgh compound B ([11C]PiB) PET, retrospective longitudinal declines in cortical thickness, and retrospective longitudinal changes in depression symptoms measured using the geriatric depression scale (GDS).Result[11C]PiB positive (n=14) older adults showed trend‐level elevation in dorsal and median raphe [18F]FMT Ki relative to [11C]PiB negative older adults (n = 35; both p &lt; 0.09). Higher dorsal raphe [18F]FMT Ki was associated with decreasing cortical thickness over time in the banks of the superior temporal sulcus (BanksSTS) (Monte Carlo, p &lt; 0.05, r = ‐0.513), consistent with the interpretation that serotonin synthesis may be upregulated in response to neural losses. Decreasing cortical thickness was also associated with increasing GDS. We did not find evidence that higher dorsal raphe [18F]FMT Ki had a beneficial impact on affective function. Instead, interaction analyses revealed relationships between atrophy and increasing GDS were strongest in individuals with highest dorsal raphe [18F]FMT Ki (t = ‐2.056, p = 0.049; adjusting for age, sex, and [11C]PiB status).ConclusionTogether, these findings suggest serotonin synthesis capacity increases with age, and appears to signal poor aging trajectories. Most elevated serotonin synthesis capacity was associated with greatest cortical atrophy and drove relationships between atrophy and worsening depressive symptoms over time.

Robot-assisted radical prostatectomy using a novel urethral reconstruction technique vs standard vesicourethral anastomosis. A retrospective cohort study.

Urinary incontinence is a common postoperative complication of radical prostatectomy (RP). In order to improve postoperative urinary continence rate, we proposed a urethral reconstruction technique which can prevent functional urethra retracting and maintain urethral stability. This study aims to describe the novel technique of robotic-assisted radical prostatectomy (RARP) and compare it with standard vesicourethral anastomosis (VUA) in the early postoperative urinary continence. Based on the anatomy study, we proposed our novel urethral reconstruction technique. The technique is a continuous suture of the outer urethral rhabdosphincter and the levator ani muscle, the medial dorsal raphe and Denonvilliers fascia. A retrospective, single-center cohort of 75 patients undergoing RARP between August 2020 and February 2022 was analyzed, including 38 patients in the study group undergoing the novel urethral reconstruction technique and 37 patients in the control group undergoing the standard VUA. The two groups were comparable in all baseline characteristics. The continence rates in the study group were significantly higher than that in the control group at the day catheter was removed, 1st month and 3rd month after the catheter removal (71.1% vs 37.8%, p = 0.004; 76.3% vs 43.2%, p = 0.003; and 94.7% vs 78.4%, p = 0.037; respectively). No significant difference was observed in operation time (p = 0.241). Meantime, no increase in complications rate was observed in the study group. Our novel urethral reconstruction technique contributes to the early urinary continence after RARP effectively and safely.

Dopaminergic nuclei in the chick midbrain express serotonin receptor subfamily genes.

Serotonin (5-hydroxytryptamine, 5-HT) is a phylogenetically conserved modulator of numerous aspects of neural functions. Serotonergic neurons in the dorsal and median raphe nucleus provide ascending innervation to the entire forebrain and midbrain. Another important neural modulatory system exists in the midbrain, the dopaminergic system, which is associated to reward processing and motivation control. Dopaminergic neurons are distributed and clustered in the brain, classically designated as groups A8-A16. Among them, groups A8-A10 associated with reward processing and motivation control are located in the midbrain and projected to the forebrain. Recently, midbrain dopaminergic neurons were shown to be innervated by serotonergic neurons and modulated by 5-HT, with the crosstalk between serotonergic and dopaminergic systems attracting increased attention. In birds, previous studies revealed that midbrain dopaminergic neurons are located in the A8-A10 homologous clusters. However, the detailed distribution of dopaminergic neurons and the crosstalk between serotonergic and dopaminergic systems in the bird are poorly understood. To improve the understanding of the regulation of the dopaminergic by the serotonergic system, we performed in situ hybridization in the chick brainstem. We prepared RNA probes for chick orthologues of dopaminergic neuron-related genes; tyrosine hydroxylase (TH) and dopa decarboxylase (DDC), noradrenaline related genes; noradrenaline transporter (NAT) and dopamine beta-hydroxylase (DBH), and serotonin receptor genes; 5-HTR1A, 5-HTR1B, 5-HTR1D, 5-HTR1E, 5-HTR1F, 5-HTR2A, 5-HTR2B, 5-HTR2C, 5-HTR3A, 5-HTR4, 5-HTR5A, and 5-HTR7. We confirmed that the expression of tyrosine hydroxylase (TH) and NAT was well matched in all chick dopaminergic nuclei examined. This supported that the compensation of the function of dopamine transporter (DAT) by NAT is a general property of avian dopaminergic neurons. Furthermore, we showed that 5-HTR1A and 5-HTR1B were expressed in midbrain dopaminergic nuclei, suggesting the serotonergic regulation of the dopaminergic system via these receptors in chicks. Our findings will help us understand the interactions between the dopaminergic and serotonergic systems in birds at the molecular level.

Common and unique dysconnectivity profiles of dorsal and median raphe in Parkinson's disease.

The serotonergic (5-HT) system, which undergoes degeneration in Parkinson's disease (PD), is involved in the pathogenesis of motor and nonmotor symptoms. The dorsal raphe (DR) and median raphe (MR) nuclei are the main source of 5-HT neurons, however, brain connectivity changes in these two nuclei have not been delineated in PD. Here we used resting-state fMRI (rs-fMRI) to characterize functional connectivity profiles of DR and MR and further examine the associations between dysconnectivity of raphe nuclei and clinical phenotypes of PD. We found that DR and MR commonly hypo-connected with the sensorimotor, temporal, and occipital cortex, limbic system, left thalamus, putamen, and cerebellum in PD. DR had unique decreased connectivity with the bilateral prefrontal and cingulate cortices, while MR had lower connectivity with the pons. Moreover, reduced connectivity of DR correlated with depression, drowsiness, and anxiety, whereas dysconnectivity of MR correlated with depression, cognitive deficits, sleep disturbances, and pain. Our findings highlight the complex roles of raphe nuclei in motor and nonmotor symptoms, providing novel insights into the neurophysiological mechanisms underlying pathogenesis of PD.

Postnatal development of hippocampal CA2 structure and function during the emergence of social recognition of peers.

It is now well-established that the hippocampal CA2 region plays an important role in social recognition memory in adult mice. The CA2 is also important for the earliest social memories, including those that mice have for their mothers and littermates, which manifest themselves as a social preference for familiarity over novelty. The role of the CA2 in the development of social memory for recently encountered same-age conspecifics, that is, peers, has not been previously reported. Here, we used a direct social interaction test to characterize the emergence of novelty preference for peers during development and found that at the end of the second postnatal week, pups begin to significantly prefer novel over familiar peers. Using chemogenetic inhibition at this time, we showed that CA2 activity is necessary for the emergence of novelty preference and for the ability to distinguish never encountered fromrecently encountered peers. In adulthood, the CA2 region is known to integrate a large number of inputs from various sources, many of which participate in social recognition memory, but previous studies have not determined whether these afferents are present at adult levels by the end of the second postnatal week. To explore the development of CA2 inputs, we used immunolabeling and retrograde adenovirus circuit tracing and found that, by the end of the second postnatal week, the CA2 is innervated by many regions, including the dentate gyrus, supramammillary nucleus of the hypothalamus, the lateral entorhinal cortex, and the median raphe nucleus. Using retroviral labeling of postnatally generated granule cells in the dentate gyrus, we found that mossy fiber projections to the CA2 mature faster during development than those generated in adulthood. Together, our findings indicate that the CA2 is partially mature in afferent connectivity by the end of the second postnatal week, connections that likely facilitate the emergence of social recognition memory and preference for novel peers.

Smegma remains a diagnostic dilemma

A healthy, uncircumcised, two-year-old male presented with a six-month history of an asymptomatic, mobile, yellowish nodule near the base of the glans penis. An examination revealed a 1 × 0.5 cm, yellowish-white, soft, and mobile nodule between the glans and the foreskin of the penis (Fig. 1). No signs of infection or irritation were noted and the rest of the body was free of lesions. Ultrasound revealed soft tissue thickening, excluded a solid formation. The urine dipstick test was negative. Based on the clinical features, the diagnosis of a smegma cyst was reached. A smegma cyst is composed of epithelial debris, fat, and proteins and is covered by a well-formed, epithelial wall [1]. When there is no covering sac of lump, it is called the smegma pearl. Frequently located on the ventral surface of the glans, within the subpreputial space, the urethral meatus is not affected and the prepuce is partially retractable. It develops in uncircumcised patients. As phimosis resolves the inner foreskin, adhesions begin to undergo a gradual process of separation from the glans penis. Smegma may become entrapped during this process, forming smooth, palpable pearls [2]. It is neither damaging nor irritating. The differential diagnosis concerns either acquired or congenital penile cysts (e.g., trichilemmal cysts, preputial Epstein pearls, dermoid cysts, median raphe cysts, para meatal cysts, mucoid cysts, epidermoid cysts, pilosebaceous cysts, juvenile xanthogranuloma) [3]. Given the paucity of published reports, these collections are a diagnostic challenge for clinicians unfamiliar with this entity and a source of concern for parents. Smegma pearls are a benign entity. Bimanual retraction or gentle expression may be performed with a risk of paraphimosis, irritation, and recurrence [2,3]. Thus, these techniques must be discussed with the parents considering the spontaneous resolution. In the case of chronic evolution, smegma may evolve to preputial stones in adults and the elderly. No investigations or treatments are required. Only monitoring and parental reassurance are recommended.