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The dorsal raphe nucleus (DRN) is a heterogeneous brainstem nucleus located in the midbrain and pons. Via widespread projections, which target a multitude of brain areas, its neurons utilize many transmitters to control various physiological functions, including learning, memory and affect. Accordingly, the DRN has been strongly associated with bra...
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Context 1
... precise number of GABAergic cells that project to a specific area within the dorsal raphe is unknown. The strength of a projection is divided into substantial, moderate and small using the above scale ( Gervasoni et al., 2000) (see Table 1, which is based on retrograde tracing experiments). ...Similar publications
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Evidence has shown that hypoxic episodes elicit hypoglossal neuroplasticity which depends on elevated serotonin (5-HT), in contrast to the rationale of obstructive sleep apnea (OSA) that deficient serotonergic input to HMs fails to keep airway patency. Therefore, understanding of the 5-HT dynamic changes at hypoglossal nucleus (HN) during chronic i...
The authors previously reported the development of the Wireless Instantaneous Neurotransmitter Concentration System (WINCS) for measuring dopamine and suggested that this technology may be useful for evaluating deep brain stimulation-related neuromodulatory effects on neurotransmitter systems. The WINCS supports fast-scan cyclic voltammetry (FSCV)...
Background
The serotonin (5-HT) system has long been implicated in autism spectrum disorder (ASD) as indicated by elevated whole blood and platelet 5-HT, altered platelet and brain receptor and transporter binding, and genetic linkage and association findings. Based upon work in genetically modified mice, 5-HT is known to influence several aspects...
Obesity, associated with the intake of a high-fat diet (HFD), and anxiety are common among those living in modern urban societies. Recent studies suggest a role of microbiome-gut-brain axis signaling, including a role for brain serotonergic systems in the relationship between HFD and anxiety. Evidence suggests the gut microbiome and the serotonergi...
Serotonin (5-hydroxytryptamine [5-HT]) is known to influence a wide range of behaviors and physiological processes, but relatively little is known about events that trigger 5-HT release. To address this issue, we recorded from neurons in the dorsal raphe nucleus (DRN) in rats performing an odor-guided spatial decision task. A large fraction of DRN...
Citations
... Various brain regions have been implicated in the pathogenesis of mood disorders [20], with the raphe nuclei of the upper brainstem thought to play a key role. Serotoninergic neurons of the raphe nuclei project widely, including to the forebrain, and are thought to regulate a variety of functions, including mood, memory and learning [21]. However, little is known about the changes in mitochondrial function and secretory activity of these nuclei during depression, and whether exercise or SSRIs might suppress or reverse any such changes. ...
... The DRN neurons extend their connections to various targets across the brain, employing multiple neurotransmitters. Among these, 5-HT is the most abundant and significant [45]. Dahlstrom and Fuxe (1964) were the first to detail the structure of the serotonergic system within the DRN in rats, employing the formaldehyde-induced fluorescence (FIF) technique. ...
... The LHb is strongly connected to the DRN, which is together with the serotonergic system a critical neuronal hub for the development and regulation of social behavior. 40,78 Behavioral changes are mediated by increased serotonergic activity, which can be triggered by uncontrollable stress. 79 The DRN receives glutamatergic inputs from the LHb. ...
Optogenetics has made substantial contributions to our understanding of the mechanistic underpinnings of depression. This systematic review employs quantitative analysis to investigate the impact of optogenetic stimulation in mice and rats on behavioral alterations in social interaction, sucrose consumption, and mobility. The review analyses optogenetic behavioral studies using standardized behavioral tests to detect behavioral changes induced via optogenetic stimulation in stressed or stress-naive mice and rats. Behavioral changes were evaluated as either positive, negative, or not effective. The analysis comprises the outcomes of 248 behavioral tests of 168 studies described in 37 articles, including negative and null results.
Test outcomes were compared for each behavior, depending on the animal cohort, applied type of stimulation and the stimulated neuronal circuit and cell type. The presented synthesis contributes toward a comprehensive picture of optogenetic behavioral research in the context of depression.
... The raphe nuclei (RN) are a cluster of nuclei found in the brain stem, consisting of serotonergic synthesizing neurons which assemble the major ascending serotonergic fibers projecting to the forebrain and descending fibers that extend to the medulla and spinal cord (Steinbusch and Nieuwenhuys, 1981;Commons, 2020). Through its ascending projections, the RN has an important role in the regulation of many physiological functions, including learning, cognition, and mood (Michelsen et al., 2008). ...
... Moreover, recent studies show no support for, and even refute, the idea that depression is caused by lowered serotonin levels or less effective serotonin signaling (Moncrieff et al., 2022;Albert et al., 2012;Albert and Benkelfat, 2013;Kendrick and Collinson, 2022). This study focused on the RN, which consist of clusters of serotonergic neurons (Hornung, 2003) that project to almost all cortico-limbic regions and regulate many physiological functions (Michelsen et al., 2008;Hamon and Blier, 2013). ...
... Alzheimer's disease (AD) is a devastating age-related neurodegenerative disease that afflicts a large proportion of individuals aged 65 and older [1]. Recent evidence suggests that neurofibrillary tangles (NFT) develop in brainstem nuclei including the dorsal raphe nucleus (DRN) and locus coeruleus (LC) before the hippocampus and cortex, which may lead to loss of monoaminergic neurons and neuropsychiatric symptoms (NPS) in the prodromal stages of AD [2][3][4][5][6][7][8][9][10][11][12][13]. The DRN contains a large population of serotonin neurons that project to the forebrain and regulate mood, sleep, and reward-seeking behaviors, all of which are perturbed in AD [14][15][16][17][18][19]. ...
Alzheimer’s disease (AD) poses an ever-increasing public health concern as the population ages, affecting more than 6 million Americans. AD patients present with mood and sleep changes in the prodromal stages that may be partly driven by loss of monoaminergic neurons in the brainstem, but a causal relationship has not been firmly established. This is due in part to a dearth of animal models that recapitulate early AD neuropathology and symptoms. The goal of the present study was to evaluate depressive and anxiety-like behaviors in a mouse model of AD that overexpresses human wild-type tau (htau) prior to the onset of cognitive impairments and assess these behavior changes in relationship to tau pathology, neuroinflammation, and monoaminergic dysregulation in the dorsal raphe nucleus (DRN) and locus coeruleus (LC). We observed depressive-like behaviors at 4 months in both sexes and hyperlocomotion in male htau mice. Deficits in social interaction persisted at 6 months and were accompanied by an increase in anxiety-like behavior in males. The behavioral changes at 4 months coincided with a lower density of serotonergic (5-HT) neurons, downregulation of 5-HT markers, reduced excitability of 5-HT neurons, and hyperphosphorylated tau in the DRN. Inflammatory markers were also upregulated in the DRN along with protein kinases and transglutaminase 2, which may promote tau phosphorylation and aggregation. Loss of 5-HT innervation to the entorhinal cortex and dentate gyrus of the hippocampus was also observed and may have contributed to depressive-like behaviors. There was also reduced expression of noradrenergic markers in the LC along with elevated phospho-tau expression, but this did not translate to a functional change in neuronal excitability. In total, these results suggest that tau pathology in brainstem monoaminergic nuclei and the resulting loss of serotonergic and/or noradrenergic drive may underpin depressive- and anxiety-like behaviors in the early stages of AD.
... The dorsal raphe nucleus is a heterogeneous brainstem nucleus located in the ventral part of the midbrain aqueduct between the upper end of the pontine and the upper and lower colliculus of the midbrain. Its neurons use a variety of transmitters to control a variety of physiological functions, including learning, memory, and emotion, and it is closely associated with brain dysfunction (50). This whole nucleus mass is roughly divided into three parts: the ventral part, the lateral part, and the dorsal part (51). ...
The efficacy of acupuncture and moxibustion in the treatment of depression has been fully recognized internationally. However, its central mechanism is still not developed into a unified standard, and it is generally believed that the central mechanism is regulation of the cortical striatum thalamic neural pathway of the limbic system. In recent years, some scholars have applied functional magnetic resonance imaging (fMRI) to study the central mechanism and the associated brain effects of acupuncture and moxibustion treatment for depression. This study reviews the acupuncture and moxibustion treatment of depression from two aspects: (1) fMRI study of the brain function related to the acupuncture treatment of depression: different acupuncture and moxibustion methods are summarized, the fMRI technique is elaborately explained, and the results of fMRI study of the effects of acupuncture are analyzed in detail, and (2) fMRI associated “brain functional network” effects of acupuncture and moxibustion on depression, including the effects on the hippocampus, the amygdala, the cingulate gyrus, the frontal lobe, the temporal lobe, and other brain regions. The study of the effects of acupuncture on brain imaging is not adequately developed and still needs further improvement and development. The brain function networks associated with the acupuncture treatment of depression have not yet been adequately developed to provide a scientific and standardized mechanism of the effects of acupuncture. For this purpose, this study analyzes in-depth the clinical studies on the treatment of anxiety and depression by acupuncture and moxibustion, by depicting how the employment of fMRI technology provides significant imaging changes in the brain regions. Therefore, the study also provides a reference for future clinical research on the treatment of anxiety and depression.
... Previous studies have indicated that STN-DBS inhibits serotonergic neuron activity in the DRN in PD and naive animals [19,28,29]. Ample evidence suggests that the disruption of the serotonergic raphe system plays a key role in mood disorders [30]. As aforementioned, changes in the activity of the serotonergic system are critical, as it plays an important role in not only the therapeutic but also the adverse effects of DBS. ...
Background:
Deep brain stimulation (DBS) is commonly used to alleviate motor symptoms in several movement disorders. However, the procedure is invasive, and the technology has remained largely stagnant since its inception decades ago. Recently, we have shown that wireless nanoelectrodes may offer an alternative approach to conventional DBS. However, this method is still in its infancy, and more research is required to characterize its potential before it can be considered as an alternative to conventional DBS.
Objectives:
Herein, we aimed to investigate the effect of stimulation via magnetoelectric nanoelectrodes on primary neurotransmitter systems that have implications for DBS in movement disorders.
Methods:
Mice were injected with either magnetoelectric nanoparticles (MENPs) or magnetostrictive nanoparticles (MSNPs, as a control) in the subthalamic nucleus (STN). Mice then underwent magnetic stimulation, and their motor behavior was assessed in the open field test. In addition, magnetic stimulation was applied before sacrifice and post-mortem brains were processed for immunohistochemistry (IHC) to assess the co-expression of c-Fos with either tyrosine hydroxylase (TH), tryptophan hydroxylase-2 (TPH2) or choline acetyltransferase (ChAT).
Results:
Stimulated animals covered longer distances in the open field test when compared to controls. Moreover, we found a significant increase in c-Fos expression in the motor cortex (MC) and paraventricular region of the thalamus (PV-thalamus) after magnetoelectric stimulation. Stimulated animals showed fewer TPH2/c-Fos double-labelled cells in the dorsal raphe nucleus (DRN), as well as TH/c-Fos double-labelled cells in the ventral tegmental area (VTA), but not in the substantia nigra pars compacta (SNc). There was no significant difference in the number of ChAT/ c-Fos double-labelled cells in the pedunculopontine nucleus (PPN).
Conclusions:
Magnetoelectric DBS in mice enables selective modulation of deep brain areas and animal behavior. The measured behavioral responses are associated with changes in relevant neurotransmitter systems. These changes are somewhat similar to those observed in conventional DBS, suggesting that magnetoelectric DBS might be a suitable alternative.
... DRN neurons innervate a multitude of targets throughout the brain and use many neurotransmitters, of which serotonin is the most abundant and important one (Michelsen et al., 2008). These targets include the IL cortex and the BLA, which are strongly involved in the pathophysiology of anxiety and depression (Van Bockstaele et al., 1993;Petrov et al., 1994). ...
Metam sodium-based pesticide (MS-BP) is widely used in agriculture and public health. We have previously demonstrated that maternal exposure to MS-BP resulted in sensorimotor alterations in mice offspring with long-lasting deficits including anxiety- and depression-like behaviors. Here, we project to verify whether these two neurobehavioral effects occur during adulthood following direct exposure to MS-BP and whether it results in changes in the serotoninergic system and gut microbiota. Our findings showed that chronic exposure to MS-BP increased anxiety- and depression-like behaviors, accompanied by a depletion of serotonin-like neurons within the dorsal raphe nucleus and a reduction in serotoninergic terminals in the infralimbic cortex and the basolateral amygdala. In addition, all MS-BP-exposed animals exhibited a reduced total bacterial number and diversity of gut microbiota. Taken together, our data demonstrated that MS-BP-induced behavioral changes could be related to the impairment of the serotoninergic system and gut microbiota dysbiosis.
... Sodium retention is an important factor that can lead to hypertension, and immunosuppression increases the risk of various infections [6,7]. Serotonin is known to mediate the feeling of happiness, and the lower level of serotonin can cause a shift from a calm, happy, and energized state to that of tension, anxiety, depression, and fatigue [8,9]. ...
Background
Fameyes (a mixture of Clematis mandshurica Rupr. extract (CMRE) and Erigeron annuus (L.) Pers. extract (EAPE)) containing scutellarin and chlorogenic acid as major components has been reported to relieve mental stress in human subjects, which is reflected in improved scores in psychometric tests measuring levels of depression, anxiety, well-being, and mental fitness. The aim of this study was to examine the anti-stress activity of Fameyes and to investigate the mechanisms of the anti-stress activity using in vitro and in vivo models of stresses.
Results
First, we tested the effect of Fameyes on corticosterone-induced cytotoxicity in SH-SY5Y cells (human neurofibroma cell lines). Corticosterone induced apoptosis and decreased cell viability and mitochondrial membrane potential, but treatment with Fameyes inhibited these cytotoxic effects in a dose-dependent manner. However, CMRE and EAPE (components of Fameyes) did not inhibit the cytotoxic effect of corticosterone individually. Next, we tested the effects of Fameyes on rats that were exposed to different kinds of stresses for four weeks. When the stressed rats were treated with Fameyes, their immobility time in forced swim and tail suspension tests decreased. A reduction was also observed in the serum levels of adrenocorticotropic hormone (ACTH) and corticosterone. Furthermore, upon oral administration of Fameyes, serum serotonin levels increased. These in vitro and in vivo results support the anti-stress effects of Fameyes.
Conclusions
In vitro experiments showed anti-stress effects of Fameyes in cell viability, apoptosis, and mitochondrial membrane potential. In addition, in vivo experiments using rats showed anti-stress effects of Fameyes in blood and tissue levels of ACTH, corticosterone, and serotonin, as well as the immobility time in the forced swim and tail suspension tests. However, we did not specifically investigate which ingredient or ingredients showed anti-stress effects, although we reported that Fameyes contained chlorogenic acid and scutellarin major ingredients.
... There is no cure for AD, but identification of biomarkers of prodromal AD is a high priority for research that may enable earlier diagnosis and intervention to improve quality of life and prevent mortality. Neuropsychiatric symptoms (NPS), such as depression and anxiety, have been reported in the early stages of AD and may be a useful indicator of underlying neuropathology and imminent cognitive decline [19,41,47,63,70]. While the neural circuits underlying NPS are currently unknown, several lines of evidence suggest that the dorsal raphe nucleus (DRN) may be critically involved. ...
Protein aggregation in brainstem nuclei is thought to occur in the early stages of Alzheimer's disease (AD), but its specific role in driving prodromal symptoms and disease progression is largely unknown. The dorsal raphe nucleus (DRN) contains a large population of serotonin (5-hydroxytryptamine; 5-HT) neurons that regulate mood, reward-related behavior, and sleep, all of which are disrupted in AD. We report here that tau pathology is present in the DRN of cognitively intact individuals 54-80 years of age, whereas synuclein and TDP-43 are relatively absent. Almost all AD cases had tau pathology in the DRN, whereas only a subset contained TDP-43 or synuclein, but not both. Mice overexpressing human P301L-tau in the DRN also exhibited depressive-like behaviors and hyperactivity without any deficits in spatial memory. There was a negative correlation between the density of Tph2-expressing neurons and phospho-tau (ptau) optical density in P301L-tau DRN mice, although mean Tph2 expression did not differ significantly from the controls. 5-HT neurons were hyperexcitable in P301L-tau DRN mice, and there was an increase in the amplitude of excitatory post-synaptic currents (EPSCs) which is suggestive of increased glutamatergic transmission. Astrocytic density was also elevated in the DRN and accompanied by an increase in GFAP expression, as well as changes in Htr2a, Htr2c, and Htr3a gene expression. Additionally, tau pathology was detected in axonal processes in the thalamus, hypothalamus, amygdala, and caudate putamen, suggesting that tau may spread in an anterograde manner to regions outside the DRN. Together, these results suggest that tau pathology accumulates in the DRN in a subset of individuals over 50 years and may lead to prodromal AD symptoms, 5-HT neuronal dysfunction, and activation of local astrocytes. The presence of tau pathology in the DRN combined with psychiatric assessments for depression may be a useful screening tool for individuals at risk for AD.
