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Acta Pharmacologica Sinica Nov 2022The raphe nuclei comprise nearly all of 5-hydroxytryptaminergic (5-HTergic) neurons in the brain and are widely acknowledged to participate in the modulation of neural... (Review)
Review
The raphe nuclei comprise nearly all of 5-hydroxytryptaminergic (5-HTergic) neurons in the brain and are widely acknowledged to participate in the modulation of neural excitability. "Excitability-inhibition imbalance" results in a variety of brain disorders, including epilepsy. Epilepsy is a common neurological disorder characterized by hypersynchronous epileptic seizures accompanied by many psychological, social, cognitive consequences. Current antiepileptic drugs and other therapeutics are not ideal to control epilepsy and its comorbidities. Cumulative evidence suggests that the raphe nuclei and 5-HTergic system play an important role in epilepsy and epilepsy-associated comorbidities. Seizure activities propagate to the raphe nuclei and induce various alterations in different subregions of the raphe nuclei at the cellular and molecular levels. Intervention of the activity of raphe nuclei and raphe 5-HTergic system with pharmacological or genetic approaches, deep brain stimulation or optogenetics produces indeed diverse and even contradictory effects on seizure and epilepsy-associated comorbidities in different epilepsy models. Nevertheless, there are still many open questions left, especially regarding to the relationship between 5-HTergic neural circuit and epilepsy. Understanding of 5-HTergic network in a circuit- and molecule-specific way may not only be therapeutically relevant for increasing the drug specificity and precise treatment in epilepsy, but also provide critical hints for other brain disorders with abnormal neural excitability. In this review we focus on the roles of the raphe 5-HTergic system in epilepsy and epilepsy-associated comorbidities. Besides, further perspectives about the complexity and diversity of the raphe nuclei in epilepsy are also addressed.
Topics: Humans; Raphe Nuclei; Epilepsy; Brain; Seizures; Neurons
PubMed: 35614227
DOI: 10.1038/s41401-022-00918-2 -
Gray areas: Neuropeptide circuits linking the Edinger-Westphal and Dorsal Raphe nuclei in addiction.Neuropharmacology Oct 2021The circuitry of addiction comprises several neural networks including the midbrain - an expansive region critically involved in the control of motivated behaviors.... (Review)
Review
The circuitry of addiction comprises several neural networks including the midbrain - an expansive region critically involved in the control of motivated behaviors. Midbrain nuclei like the Edinger-Westphal (EW) and dorsal raphe (DR) contain unique populations of neurons that synthesize many understudied neuroactive molecules and are encircled by the periaqueductal gray (PAG). Despite the proximity of these special neuron classes to the ventral midbrain complex and surrounding PAG, functions of the EW and DR remain substantially underinvestigated by comparison. Spanning approximately -3.0 to -5.2 mm posterior from bregma in the mouse, these various cell groups form a continuum of neurons that we refer to collectively as the subaqueductal paramedian zone. Defining how these pathways modulate affective behavioral states presents a difficult, yet conquerable challenge for today's technological advances in neuroscience. In this review, we cover the known contributions of different neuronal subtypes of the subaqueductal paramedian zone. We catalogue these cell types based on their spatial, molecular, connectivity, and functional properties and integrate this information with the existing data on the EW and DR in addiction. We next discuss evidence that links the EW and DR anatomically and functionally, highlighting the potential contributions of an EW-DR circuit to addiction-related behaviors. Overall, we aim to derive an integrated framework that emphasizes the contributions of EW and DR nuclei to addictive states and describes how these cell groups function in individuals suffering from substance use disorders. This article is part of the special Issue on 'Neurocircuitry Modulating Drug and Alcohol Abuse'.
Topics: Animals; Gray Matter; Humans; Nerve Net; Neuropeptides; Periaqueductal Gray; Raphe Nuclei; Substance-Related Disorders
PubMed: 34481834
DOI: 10.1016/j.neuropharm.2021.108769 -
Brain Structure & Function Sep 2016Forebrain serotonin relevant for many psychological disorders arises in the hindbrain, primarily within the dorsal and median raphe nuclei (DR and MR). These nuclei are... (Review)
Review
Forebrain serotonin relevant for many psychological disorders arises in the hindbrain, primarily within the dorsal and median raphe nuclei (DR and MR). These nuclei are heterogeneous, containing several distinct groups of serotonin neurons. Here, new insight into the afferent and efferent connectivity of these areas is reviewed in correlation with their developmental origin. These data suggest that the caudal third of the DR, the area originally designated B6, may be misidentified as part of the DR as it shares many features of connectivity with the MR. By considering the rostral DR independently and affiliating the B6 to the MR, the diverse subgroups of serotonin neurons can be arranged with more coherence into two umbrella groups, each with distinctive domains of influence. Serotonin neurons within the rostral DR are uniquely interconnected with brain areas associated with emotion and motivation such as the amygdala, accumbens and ventral pallidum. In contrast serotonin neurons in the B6 and MR are characterized by their dominion over the septum and hippocampus. This distinction between the DR and B6/MR parallels their developmental origin and likely impacts their role in both behavior and psychopathology. Implications and further subdivisions within these areas are discussed.
Topics: Animals; Brain; Humans; Mice; Neural Pathways; Neuroanatomical Tract-Tracing Techniques; Raphe Nuclei; Serotonergic Neurons
PubMed: 26740230
DOI: 10.1007/s00429-015-1176-7 -
NeuroImage. Clinical 2023Accumulating evidence showed that major depressive disorder (MDD) is characterized by a dysfunction of serotonin neurotransmission. Raphe nuclei are the sources of most...
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.
Topics: Humans; Brain; Depressive Disorder, Major; Gyrus Cinguli; Magnetic Resonance Imaging; Raphe Nuclei
PubMed: 36878150
DOI: 10.1016/j.nicl.2023.103359 -
ELife Nov 2021The dorsal raphe nucleus (DR) and median raphe nucleus (MR) contain populations of glutamatergic and GABAergic neurons that regulate diverse behavioral functions....
The dorsal raphe nucleus (DR) and median raphe nucleus (MR) contain populations of glutamatergic and GABAergic neurons that regulate diverse behavioral functions. However, their whole-brain input-output circuits remain incompletely elucidated. We used viral tracing combined with fluorescence micro-optical sectioning tomography to generate a comprehensive whole-brain atlas of inputs and outputs of glutamatergic and GABAergic neurons in the DR and MR. We found that these neurons received inputs from similar upstream brain regions. The glutamatergic and GABAergic neurons in the same raphe nucleus had divergent projection patterns with differences in critical brain regions. Specifically, MR glutamatergic neurons projected to the lateral habenula through multiple pathways. Correlation and cluster analysis revealed that glutamatergic and GABAergic neurons in the same raphe nucleus received heterogeneous inputs and sent different collateral projections. This connectivity atlas further elucidates the anatomical architecture of the raphe nuclei, which could facilitate better understanding of their behavioral functions.
Topics: Animals; Connectome; Dorsal Raphe Nucleus; GABAergic Neurons; Mice; Midbrain Raphe Nuclei; Neurons
PubMed: 34792021
DOI: 10.7554/eLife.65502 -
PloS One 2022The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety...
OBJECTIVES
The pathogenesis of fibromyalgia syndrome (FMS) is unclear. Transcranial ultrasonography revealed anechoic alteration of midbrain raphe in depression and anxiety disorders, suggesting affection of the central serotonergic system. Here, we assessed midbrain raphe echogenicity in FMS.
METHODS
Sixty-six patients underwent transcranial sonography, of whom 53 were patients with FMS (27 women, 26 men), 13 patients with major depression and physical pain (all women), and 14 healthy controls (11 women, 3 men). Raphe echogenicity was graded visually as normal or hypoechogenic, and quantified by digitized image analysis, each by investigators blinded to the clinical diagnosis.
RESULTS
Quantitative midbrain raphe echogenicity was lower in patients with FMS compared to healthy controls (p<0.05), but not different from that of patients with depression and accompanying physical pain. Pain and FMS symptom burden did not correlate with midbrain raphe echogenicity as well as the presence and severity of depressive symptoms.
CONCLUSION
We found reduced echogenicity of the midbrain raphe area in patients with FMS and in patients with depression and physical pain, independent of the presence or severity of pain, FMS, and depressive symptoms. Further exploration of this sonographic finding is necessary before this objective technique may enter diagnostic algorithms in FMS and depression.
Topics: Male; Humans; Female; Midbrain Raphe Nuclei; Fibromyalgia; Raphe Nuclei; Ultrasonography; Pain
PubMed: 36395116
DOI: 10.1371/journal.pone.0277316 -
Synapse (New York, N.Y.) Nov 2013Oscillations in brain activities with periods of minutes to hours may be critical for normal mood behaviors. Ultradian (faster than circadian) rhythms of mood behaviors... (Review)
Review
Oscillations in brain activities with periods of minutes to hours may be critical for normal mood behaviors. Ultradian (faster than circadian) rhythms of mood behaviors and associated central nervous system activities are altered in depression. Recent data suggest that ultradian rhythms in serotonin (5HT) function also change in depression. In two separate studies, 5HT metabolites in cerebrospinal fluid (CSF) were measured every 10 min for 24 h before and after chronic antidepressant treatment. Antidepressant treatments were associated with enhanced ultradian amplitudes of CSF metabolite levels. Another study used resting-state functional magnetic resonance imaging (fMRI) to measure amplitudes of dorsal raphé activation cycles following sham or active dietary depletions of the 5HT precursor (tryptophan). During depletion, amplitudes of dorsal raphé activation cycles increased with rapid 6 s periods (about 0.18 Hz) while functional connectivity weakened between dorsal raphé and thalamus at slower periods of 20 s (0.05 Hz). A third approach studied MDMA (ecstasy, 3,4-methylenedioxy-N-methylamphetamine) users because of their chronically diminished 5HT function compared with non-MDMA polysubstance users (Karageorgiou et al., 2009). Compared with a non-MDMA using cohort, MDMA users showed diminished fMRI intra-regional coherence in motor regions along with altered functional connectivity, again suggesting effects of altered 5HT oscillatory function. These data support a hypothesis that qualities of ultradian oscillations in 5HT function may critically influence moods and behaviors. Dysfunctional 5HT rhythms in depression may be a common endpoint and biomarker for depression, linking dysfunction of slow brain network oscillators to 5HT mechanisms affected by commonly available treatments. 5HT oscillatory dysfunction may define illness subtypes and predict responses to serotonergic agents. Further studies of 5HT oscillations in depression are indicated.
Topics: Circadian Rhythm; Depressive Disorder; Humans; Magnetic Resonance Imaging; Raphe Nuclei; Serotonin; Serotonin Agents
PubMed: 23592367
DOI: 10.1002/syn.21675 -
Philosophical Transactions of the Royal... Sep 2012The serotonin (5-HT) system is generally considered as a single modulatory system, with broad and diffuse projections. However, accumulating evidence points to the... (Review)
Review
The serotonin (5-HT) system is generally considered as a single modulatory system, with broad and diffuse projections. However, accumulating evidence points to the existence of distinct cell groups in the raphe. Here, we review prior evidence for raphe cell heterogeneity, considering different properties of 5-HT neurons, from metabolism to anatomy, and neurochemistry to physiology. We then summarize more recent data in mice and zebrafish that support a genetic diversity of 5-HT neurons, based on differential transcription factor requirements for the acquisition of the 5-HT identity. In both species, PET1 plays a major role in the acquisition and maintenance of 5-HT identity in the hindbrain, although some 5-HT neurons do not require PET1 for their differentiation, indicating the existence of several transcriptional routes to become serotoninergic. In mice, both PET1-dependent and -independent 5-HT neurons are located in the raphe, but have distinct anatomical features, such as the morphology of axon terminals and projection patterns. In zebrafish, all raphe neurons express pet1, but Pet1-independent 5-HT cell groups are present in the forebrain. Overall, these observations support the view that there are a number of distinct 5-HT subsystems, including within the raphe nuclei, with unique genetic programming and functions.
Topics: Animals; Axons; Brain; Electrophysiological Phenomena; Genetic Variation; Mice; Mice, Knockout; Raphe Nuclei; Serotonergic Neurons; Serotonin; Synaptic Transmission; Transcription Factors; Zebrafish; Zebrafish Proteins
PubMed: 22826339
DOI: 10.1098/rstb.2011.0378 -
Journal of Chemical Neuroanatomy Jul 2011The caudal serotonergic (5-HT) system is a critical component of a medullary "homeostatic network" that regulates protective responses to metabolic stressors such as... (Review)
Review
The caudal serotonergic (5-HT) system is a critical component of a medullary "homeostatic network" that regulates protective responses to metabolic stressors such as hypoxia, hypercapnia, and hyperthermia. We define anatomically the caudal 5-HT system in the human medulla as 5-HT neuronal cell bodies located in the raphé (raphé obscurus, raphé magnus, and raphé pallidus), extra-raphé (gigantocellularis, paragigantocellularis lateralis, intermediate reticular zone, lateral reticular nucleus, and nucleus subtrigeminalis), and ventral surface (arcuate nucleus). These 5-HT neurons are adjacent to all of the respiratory- and autonomic-related nuclei in the medulla where they are positioned to modulate directly the responses of these effector nuclei. In the following review, we highlight the topography and development of the caudal 5-HT system in the human fetus and infant, and its inter-relationships with nicotinic, GABAergic, and cytokine receptors. We also summarize pediatric disorders in early life which we term "developmental serotonopathies" of the caudal (as well as rostral) 5-HT domain and which are associated with homeostatic imbalances. The delineation of the development and organization of the human caudal 5-HT system provides the critical foundation for the neuropathologic elucidation of its disorders directly in the human brain.
Topics: Animals; Arcuate Nucleus of Hypothalamus; Autonomic Nervous System; Cats; Child Development Disorders, Pervasive; Cytokines; Depressive Disorder, Major; Embryo, Mammalian; Female; Fetal Alcohol Spectrum Disorders; Fetus; Homeostasis; Humans; Infant; Infant, Newborn; Male; Medulla Oblongata; Nervous System Diseases; Neural Pathways; Neurons; Pregnancy; Raphe Nuclei; Rats; Receptors, Serotonin; Reticular Formation; Serotonin; Spinal Cord; Sudden Infant Death
PubMed: 21640183
DOI: 10.1016/j.jchemneu.2011.05.004 -
Progress in Neurobiology Aug 1997The serotonergic system, because of very diffuse projections throughout the central nervous system, has been implicated in numerous functions including nociception,... (Review)
Review
The serotonergic system, because of very diffuse projections throughout the central nervous system, has been implicated in numerous functions including nociception, analgesia, sleep-wakefulness and autonomic regulation. Despite an abundant literature indicating the presence of neurotensin-containing (neurotensinergic) neurons, fibres and terminals in most areas containing serotonergic neurons, little is known about the possible relationship between serotonergic and neurotensinergic systems. The purpose of this review is (i) to summarize current knowledge on the anatomical relation between neurotensinergic and serotonergic system, (ii) to summarize current knowledge on the action of neurotensin on serotonergic neurons and (iii) to discuss the possible physiological relevance of this action. Neurotensin-containing cell bodies can be found in the most rostral raphe nuclei. There are neurotensin-containing fibres and terminals in all raphe nuclei. Raphe nuclei have also been shown to contain neurotensin-receptor binding sites. In the dorsal raphe nucleus, neurotensin induces a concentration-dependent increase in the firing rate of a subpopulation of serotonergic neurons. The neurotensin-induced excitation, which is selectively blocked by the non-peptide neurotensin receptor antagonist SR 48692, is observed mainly in the ventral part of the nucleus. Most serotonergic neurons show marked desensitization to neurotensin, even at low concentrations. In intracellular experiments, neurotensin induces an inward current, associated in some cases with a decrease in apparent input conductance, which is occluded by supramaximal concentrations of the alpha 1-adrenoceptor agonist phenylephrine. In rare cases, neurotensin induces an excitation of GABAergic or glutamatergic neurons. Since the neurotensinergic system has also been implicated in nociception, analgesia, sleep-wakefulness, and autonomic regulation, the review discusses the possibility that part of this regulation could involve the activation of the serotonergic system.
Topics: Animals; Electrophysiology; Humans; Neurons; Neurotensin; Raphe Nuclei; Serotonin
PubMed: 9316156
DOI: 10.1016/s0301-0082(97)00025-7