Figure - available from: Frontiers in Neural Circuits
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Brain regions sending glutamate and GABA axon projections to the DRN. The cartoon summarizes the main sources of glutamate excitatory and GABAergic inhibitory inputs to the DRN. Glutamate cells (in red) are mainly located in the prefrontal cortex (PFC), lateral habenula (LHb), hypothalamus (Hyp), parabrachial nucleus (PB), laterodorsal tegmental nucleus (LDTg), paragigantocellular nucleus (PGi), prepositus hypoglossal nucleus (Pr) as well as the spinal trigeminal nucleus (Sp5), as well as in local sources including the DRN. GABAergic cells (in green) sending projections to the DRN are located mainly in the hypothalamus, substantia nigra (SN), ventral tegmental area (VTA), rostromedial tegmental nucleus (RMTg) and locally within the periaqueductal gray (PAG) and DRN.
Source publication
The dorsal raphe nucleus (DRN), representing the main source of brain's serotonin, is implicated in the pathophysiology and therapeutics of several mental disorders that can be debilitating and life-long including depression, anxiety and autism. The activity of DRN neurons is precisely regulated, both phasically and tonically, by excitatory glutama...
Citations
... For example, the brain 5-HT system/5-HT neurons may contribute critically to the induction and regulation of sleep; 5-HT neuron destruction can lead to insomnia (Jouvet 1999); and REM sleep is associated with inhibition of 5-HT neuron spike firing or decreased 5-HT release (Iwasaki et al. 2018;Jouvet 1999;Nitz and Siegel 1997;Sakai and Crochet 2001;Siegel 2004), or 5-HT neuron activity may inhibit REM sleep (Saper et al. 2010)-although this is not fully settled (Sakai 2011). This inhibition of 5-HT neuron activity may be mediated, at least partially, by GABAergic input from extrinsic sources such as the hypothalamus, lateral habenula nucleus, mesopontine rostromedial tegmental nucleus (RMTg), lateral preoptic area and the pontine ventral periaqueductal gray including the DRN, VTA, SNr (Bernard et al. 2012;Gervasoni et al. 2000;Kirouac et al. 2004;Lavezzi et al. 2012;Pollak et al. 2014;Reisine et al. 1982;Sego et al. 2014;Soiza-Reilly and Commons 2014;Taylor et al. 2014; Wang and Aghajanian 1977;Zhou et al. 2017). These GABAergic inputs can affect the spike firing of the raphe 5-HT neurons, which in turn affects the synaptic 5-HT level in 5-HT neuron projection areas and hence behaviors. ...
... Second, our data indicate that 5-HT reduced the GABAergic inputs to DRN 5-HT neurons, probably by activating presynaptic 5-HT1B receptors on GABA afferent terminals synapsing on 5-HT neurons based on the well established observation that 5-HT1B receptors are commonly on axon terminals (Boschert et al. 1994;Ding et al. 2013Lemos et al. 2006;Li and Bayliss 1998;Morikawa et al. 2000;Sari 2014), although in the present study we did not use 5-HT1B receptor-selective ligands to test this possibility. This mechanism serves to reduce the inhibitory influence of local GABA neurons and external GABAergic centers such as the hypothalamus, lateral habenula nucleus, RMTg, lateral preoptic area and the pontine ventral periaqueductal gray and VTA, SNr have on DRN 5-HT neurons (Gervasoni et al. 2000;Kirouac et al. 2004;Lavezzi et al. 2012;Pollak et al. 2014;Reisine et al. 1982;Sego et al. 2014;Soiza-Reilly and Commons 2014;Taylor et al. 2014;Zhou et al. 2017). This mechanism may contribute to the overall regulation of 5-HT neuron spiking activity that matches the animal's mental and behavioral status and needs. ...
... Thus, it appears that chronic exposure to high levels of extracellular 5-HT can desensitize the function and/or decrease the cell surface or de novo expression of both 5-HT1B autoreceptors and heteroreceptors. The reduced 5-HT inhibition indicates that after chronic fluoxetine treatment, 5-HT neurons can be more effectively influenced by outside GABAergic neurons in the hypothalamus, substantia nigra pars reticulata, ventral tegmental area, and other brain areas including the cerebral cortex and brainstem (Soiza-Reilly and Commons et al. 2014). ...
Dorsal raphe serotonin (5-hydroxytryptamine, 5-HT) neurons are spontaneously active and release 5-HT that is critical to normal brain function such 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 exert clinical benefits. The cellular mechanism underlying this delay was not fully understood. Here we show that the GABAergic inputs inhibit the spike firing of raphe 5-HT neurons; this GABAergic regulation was reduced by 5-HT, which was prevented by 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 of fluoxetine, a widely used SSRI type antidepressant, this 5-HT inhibition of GABAergic inputs was substantially downregulated. Furthermore, the chronic fluoxetine treatment substantially downregulated the 5-HT activation of the inhibitory Girk current in 5-HT neurons. Taken together, our results suggest that chronic fluoxetine administration, 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, behaviorally important GABA neurons to more effectively influence 5-HT neurons; simultaneously, chronic fluoxetine treatment also downregulate somatic 5-HT autoreceptor-activated Girk channel-mediated hyperpolarization and decrease in input resistance and intrinsic excitability, rendering 5-HT neurons resistant to autoinhibition and leading to increased 5-HT neuron activity, potentially contributing to the antidepressant effect of SSRIs.
... Mutations of multiple 5-HT related genes, such as In addition to 5-HT-ergic neurons, there are also a large number of GABAergic neurons in the DRN that can regulate their activity. GABAergic cells projecting to the DRN are mainly located in the hypothalamus, ventral tegmental area (VTA), and locally within the DRN (79). Studies have shown that SH3 and multiple Ankyrin repeat domains 3 (SHANK3) -deficient mice, a model of autism, had significantly lower levels of GABA synthesis in the hypothalamus and VTA compared to controls (80). ...
Background
The incidence of sleep disorders in children with autism spectrum disorder (ASD) is very high. Sleep disorders can exacerbate the development of ASD and impose a heavy burden on families and society. The pathological mechanism of sleep disorders in autism is complex, but gene mutations and neural abnormalities may be involved.
Methods
In this review, we examined literature addressing the genetic and neural mechanisms of sleep disorders in children with ASD. The databases PubMed and Scopus were searched for eligible studies published between 2013 and 2023.
Results
Prolonged awakenings of children with ASD may be caused by the following processes. Mutations in the MECP2, VGAT and SLC6A1 genes can decrease GABA inhibition on neurons in the locus coeruleus, leading to hyperactivity of noradrenergic neurons and prolonged awakenings in children with ASD. Mutations in the HRH1, HRH2, and HRH3 genes heighten the expression of histamine receptors in the posterior hypothalamus, potentially intensifying histamine’s ability to promote arousal. Mutations in the KCNQ3 and PCDH10 genes cause atypical modulation of amygdala impact on orexinergic neurons, potentially causing hyperexcitability of the hypothalamic orexin system. Mutations in the AHI1, ARHGEF10, UBE3A, and SLC6A3 genes affect dopamine synthesis, catabolism, and reuptake processes, which can elevate dopamine concentrations in the midbrain. Secondly, non-rapid eye movement sleep disorder is closely related to the lack of butyric acid, iron deficiency and dysfunction of the thalamic reticular nucleus induced by PTCHD1 gene alterations. Thirdly, mutations in the HTR2A, SLC6A4, MAOA, MAOB, TPH2, VMATs, SHANK3, and CADPS2 genes induce structural and functional abnormalities of the dorsal raphe nucleus (DRN) and amygdala, which may disturb REM sleep. In addition, the decrease in melatonin levels caused by ASMT, MTNR1A, and MTNR1B gene mutations, along with functional abnormalities of basal forebrain cholinergic neurons, may lead to abnormal sleep–wake rhythm transitions.
Conclusion
Our review revealed that the functional and structural abnormalities of sleep–wake related neural circuits induced by gene mutations are strongly correlated with sleep disorders in children with ASD. Exploring the neural mechanisms of sleep disorders and the underlying genetic pathology in children with ASD is significant for further studies of therapy.
... neuroanatomical study, and it has already been demonstrated that the mPFC sends glutamatergic projections to the DRN. [55,56] Concerning glutamate release in the DRN, stimulation of glutamate receptors activates serotonergic neurons [57] and promotes serotonin release in forebrain structures. [58][59][60] When MY was microinjected into the PrL cortex, the firing rate of DRN neurons increased. ...
Depression has a high rate of comorbidity with neuropathic pain. This study aims to investigate the effect of Mygalin, an acylpolyamine synthesized from a natural molecule in the hemolymph of the Acanthoscurria gomesiana spider, injected into the prelimbic (PrL) region of the medial prefrontal cortex on chronic neuropathic pain and depression comorbidity in rats. To investigate that comorbidity, neuropathic pain was induced by chronic constriction injury (CCI) of the sciatic nerve in male Wistar rats. The biotinylated biodextran amine (BDA) bidirectional neural tract tracer was microinjected into the PrL cortex to study brain connections. Rodents were further subjected to von Frey (mechanical allodynia), acetone (cold allodynia), and forced swim (depressive-like behavior) tests. BDA neural tract tracer-labeled perikarya were found in the dorsal columns of the periaqueductal gray matter (dPAG) and the dorsal raphe nucleus (DRN). Neuronal activity of DRN neurons decreased in CCI rats. However, PrL cortex treatment with Mygalin increased the number of spikes on DRN neurons. Mygalin treatment in the PrL cortex decreased both mechanical and cold allodynia and immobility behavior in CCI rats. PrL cortex treatment with N-methyl-D-aspartate (NMDA) receptor receptors attenuated the analgesic and antidepressive effects caused by Mygalin. The PrL cortex is connected with the dPAG and DRN, and Mygalin administration into the PrL increased the activity of DRN neurons. Mygalin in the PrL cortex produced antinociceptive and antidepressive-like effects, and the NMDA agonist reversed these effects.
... ARC AgRP , LH GABA , and DR GABA neurons exert sophisticated regulation. 2,22,[34][35][36][37][38][39][40] Hormones regulate ARC AgRP neurons based on the energy state, 5,6 and leptin-receptor-expressing neurons in the dorsomedial hypothalamus (DMH LepR neurons) deliver food cues to ARC AgRP neurons, 36,41 making it possible for ARC AgRP neurons to detect and lead to restraint from ongoing non-feeding-related behaviors during hunger. GABAergic neurons in the septum and dopamine 1 recepter (D1R)expressing neurons in the accumbens can inhibit LH GABA neurons and reduce food intake. ...
Feeding requires sophisticated orchestration of neural processes to satiate appetite in natural, capricious settings. However, the complementary roles of discrete neural populations in orchestrating distinct behaviors and motivations throughout the feeding process are largely unknown. Here, we delineate the behavioral repertoire of mice by developing a machine-learning-assisted behavior tracking system and show that feeding is fragmented and divergent motivations for food consumption or environment exploration compete throughout the feeding process. An iterative activation sequence of agouti-related peptide (AgRP)-expressing neurons in arcuate (ARC) nucleus, GABAergic neurons in the lateral hypothalamus (LH), and in dorsal raphe (DR) orchestrate the preparation, initiation, and maintenance of feeding segments, respectively, via the resolution of motivational conflicts. The iterative neural processing sequence underlying the competition of divergent motivations further suggests a general rule for optimizing goal-directed behaviors.
... The excitatory afferents to the DRN originate in the prefrontal cortex and several subcortical sources [9,10]. Inhibitory synaptic inputs to DRN 5-HT projection neurons are provided mainly by local GABAergic interneurons [11,12], but the DRN also receives long-range GABAergic innervation from other brain structures [13]. Using an animal model of stress-induced depressionlike behavior in rodents-repeated corticosterone administration [14]-we had previously investigated the influence of corticosterone on inhibitory synaptic transmission in the DRN. ...
Exogenous corticosterone administration reduces GABAergic transmission and impairs its 5-HT7 receptor-dependent modulation in the rat dorsal raphe nucleus (DRN), but it is largely unknown how neuronal functions of the DRN are affected by repeated physical and psychological stress. This study compared the effects of repeated restraint stress and corticosterone injections on DRN neuronal excitability, spontaneous synaptic transmission, and its 5-HT7 receptor-dependent modulation. Male Wistar rats received corticosterone injections for 7 or 14 days or were restrained for 10 min twice daily for 3 days. Repeated restraint stress and repeated corticosterone administration evoked similar changes in performance in the forced swim test. They increased the frequency of spontaneous excitatory postsynaptic currents (sEPSCs) recorded from DRN neurons. In contrast to the treatment with corticosterone, restraint stress-induced changes in sEPSC kinetics and decreased intrinsic excitability of DRN neurons did not modify inhibitory transmission. Repeated injections of the 5-HT7 receptor antagonist SB 269970 ameliorated the effects of restraint on excitability and sEPSC frequency but did not restore the altered kinetics of sEPSCs. Thus, repeated restraint stress and repeated corticosterone administration differ in consequences for the intrinsic excitability of DRN projection neurons and their excitatory and inhibitory synaptic inputs. Effects of repeated restraint stress on DRN neurons can be partially abrogated by blocking the 5-HT7 receptor.
... Neuropil is a fundamental form of tissue organization within the brain 1 , in which densely packed neurons synaptically interconnect into precise circuit architecture 2,3 . However, the structural and developmental principles that govern this nanoscale precision remain largely unknown 4,5 . Here we use an iterative data coarse-graining algorithm termed 'diffusion condensation' 6 to identify nested circuit structures within the Caenorhabditis elegans neuropil, which is known as the nerve ring. ...
Neuropil is a fundamental form of tissue organization within the brain¹, in which densely packed neurons synaptically interconnect into precise circuit architecture2,3. However, the structural and developmental principles that govern this nanoscale precision remain largely unknown4,5. Here we use an iterative data coarse-graining algorithm termed ‘diffusion condensation’⁶ to identify nested circuit structures within the Caenorhabditis elegans neuropil, which is known as the nerve ring. We show that the nerve ring neuropil is largely organized into four strata that are composed of related behavioural circuits. The stratified architecture of the neuropil is a geometrical representation of the functional segregation of sensory information and motor outputs, with specific sensory organs and muscle quadrants mapping onto particular neuropil strata. We identify groups of neurons with unique morphologies that integrate information across strata and that create neural structures that cage the strata within the nerve ring. We use high resolution light-sheet microscopy7,8 coupled with lineage-tracing and cell-tracking algorithms9,10 to resolve the developmental sequence and reveal principles of cell position, migration and outgrowth that guide stratified neuropil organization. Our results uncover conserved structural design principles that underlie the architecture and function of the nerve ring neuropil, and reveal a temporal progression of outgrowth—based on pioneer neurons—that guides the hierarchical development of the layered neuropil. Our findings provide a systematic blueprint for using structural and developmental approaches to understand neuropil organization within the brain.
... Nissl stained cells, of 33,008 [± 2,345] obtained in juvenile rats by King et al. (2002). This is problematic, given that the DRN consists primarily of neuropil, having a high density of glial, dopaminergic, GABAergic, and glutamatergic cells, on top of 5-HT cells (Adell et al., 2002;Allers and Sharp, 2003;Belin et al., 1979;Commons, 2009;Fu et al., 2010;Hioki et al., 2010;Jacobs and Azmitia, 1992;Jahanshahi et al., 2013;Jolas and Aghajanian, 1997;Molliver, 1987;Soiza-Reilly and Commons, 2014). One other stereological study was identified, reporting an estimate of roughly 18,500 5-HT cells in the DRN of Wistar rats, with relatively high CEs ranging from 0.07 to 0.09 for various DRN sub-regions (Maia et al., 2016). ...
Serotonin (5-HT) is a common neurotransmitter in mammals, playing a central role in the regulation of various processes such as sleep, perception, cognitive and autonomic functions in the nervous system. Previous studies have demonstrated that 5-HT type 3 (5-HT3) receptors are expressed in either or both the substantia nigra (SN) and the dorsal raphe nucleus (DRN) in humans, marmosets, rats and Syrian hamsters. Here, we quantify the distribution of 5-HT3 receptors across these regions in the adult rat. Fluorescent immunohistochemistry was performed on sections of rat brain covering the entire rostro-caudal extent of the SN and DRN with antibodies specific to the 5-HT3A receptor subunit, as well as others targeting the monoaminergic markers tyrosine hydroxylase (TH) and the 5-HT transporter (SERT). The number of 5-HT3A receptor-positive, TH-positive (n = 28,428 ± 888, Gundersen’s m = 1 coefficient of error [CE] = 0.05) and SERT-positive (n = 12,852 ± 462, CE = 0.06) cells were estimated in both the SN and the DRN using stereology. We found that 5-HT3A receptor-positive cells are present in the SNr (n = 1250 ± 64, CE = 0.24), but they did not co-localise with TH-positive cells, nor were they present in the SNc. In contrast, no 5-HT3A receptor-positive cells were found in the DRN. These results support the presence of 5-HT3 receptors in the SN, but not in the DRN, and do not support their expression on monoaminergic cells within these two brain areas.
... Cortical afferents to the DRN arise mainly from the PFC [39][40][41]. Because of this, VGLUT1 immunolabelling can be used as a readout of PFC synaptic afferents, together with the co-labeling of synapsin 1a, a general marker for synaptic boutons [37,42]. Additionally, tryptophan hydroxylase (TPH) immunolabeling determines the presence of morphological contacts of synaptic boutons to 5-HT neurons [37,42] (Figure 2a,b). ...
... Because of this, VGLUT1 immunolabelling can be used as a readout of PFC synaptic afferents, together with the co-labeling of synapsin 1a, a general marker for synaptic boutons [37,42]. Additionally, tryptophan hydroxylase (TPH) immunolabeling determines the presence of morphological contacts of synaptic boutons to 5-HT neurons [37,42] (Figure 2a,b). Array tomography quantitative analyses of VGLUT1/synapsin double labeled puncta in 5-HTR7 -/mice (38,900 puncta analyzed) showed a significant reduction of 18% (t 8 = 2.680; p<0.03) compared to littermate controls (5-HTR7 -/+ mice; 29,938 puncta analyzed) (Figure 2c,d) To further interrogate the role of 5-HTR7 in the development of PFC neurons we selectively over-expressed the full length 5-HTR7 with the C-terminal fused to GFP under the control of the synapsin promoter [33]. ...
Altered development of prefrontal cortex (PFC) circuits can have long-term consequences on adult emotional behavior. Changes in serotonin homeostasis during critical periods produced by genetic or pharmacological inactivation of the serotonin transporter (SERT, or Slc6a4), have been involved in such developmental effects. In mice, serotonin selective reuptake inhibitors (SSRIs), administered during postnatal development cause exuberant synaptic connectivity of the PFC to brainstem dorsal raphe nucleus (DRN) circuits, and increase adult risk for developing anxiety and depressive symptoms. SERT is transiently expressed in the glutamate neurons of the mouse PFC, that project to the DRN. Here, we find that 5-HTR7 is transiently co-expressed with SERT by PFC neurons, and it plays a key role in the maturation of PFC-to-DRN synaptic circuits during early postnatal life. 5-HTR7-KO mice show reduced PFC-to-DRN synaptic density (as measured by array-tomography and VGLUT1/synapsin immunocytochemistry). Conversely, 5-HTR7 over-expression in the developing PFC increased PFC-to-DRN synaptic density. Long-term consequences on depressive-like and anxiogenic behaviors were observed in adults. 5-HTR7 over-expression in the developing PFC, results in depressive-like symptoms in adulthood. Importantly, the long-term depressive-like and anxiogenic effects of SSRIs (postnatal administration of fluoxetine from P2 to P14) were not observed in 5-HTR7-KO mice, and were prevented by co-administration of the selective inhibitor of 5-HTR7, SB269970. This study identifies a new role 5-HTR7 in the postnatal maturation of prefrontal descending circuits. Furthermore, it shows that 5-HTR7 in the PFC is crucially required for the detrimental emotional effects caused by SSRI exposure during early postnatal life.
... Neuropil is a fundamental form of tissue organization within brains 1 . In neuropils, densely packed neurons synaptically interconnect into precise circuit architecture 2,3 , yet the structural and developmental principles governing nanoscale precision in bundled neuropil assembly remain largely unknown [4][5][6] . Here we use diffusion condensation, a coarsegraining clustering algorithm 7 , to identify nested circuit structures within the C. elegans cerebral neuropil (called the nerve ring). ...
Neuropil is a fundamental form of tissue organization within brains. In neuropils, densely packed neurons synaptically interconnect into precise circuit architecture, yet the structural and developmental principles governing nanoscale precision in bundled neuropil assembly remain largely unknown. Here we use diffusion condensation, a coarse-graining clustering algorithm, to identify nested circuit structures within the C. elegans cerebral neuropil (called the nerve ring). We determine that the nerve ring neuropil is organized into four tightly bundled strata composed of related behavioral circuits. We demonstrate that the stratified architecture of the neuropil is a geometrical representation of the functional segregation of sensory information and motor outputs, with specific sensory organs and muscle quadrants mapping onto particular neuropil strata. We identify groups of neurons with unique morphologies that integrate information across strata and that create a sophisticated honeycomb-shaped scaffold that encases the strata within the nerve ring. We resolve the developmental sequence leading to stratified neuropil organization through the integration of lineaging and cell tracking algorithms with high resolution light-sheet microscopy, and reveal principles of cell position, migration and hierarchical outgrowth that guide neuropil organization. Our results uncover conserved design principles underlying nerve ring neuropil architecture and function, and a pioneer neuron-based, temporal progression of outgrowth that guides the hierarchical development of the layered neuropil. Our findings provide a blueprint for using structural and developmental approaches to systematically understand neuropil organization within brains.
... In the raphe, PFC synaptic inputs are directed to both 5-HT and non-5-HT GABAergic neurons [32,53]. The latter play a crucial role in feed-forward inhibitory modulation of 5-HT neuron activity [20,65] and on PFC glutamate terminals [34,66]. Our observations indicate that when Slc6a4/SERT is invalidated genetically or pharmacologically, the supernumerary PFC synapses are not exclusively associated with 5-HT neurons but are also largely on non-5-HT neurons, possibly GABA neurons, thus being in a position to either enhance or inhibit 5-HT output. ...
Antidepressants that block the serotonin transporter, (Slc6a4/SERT), selective serotonin reuptake inhibitors (SSRIs) improve mood in adults but have paradoxical long-term effects when administered during developmental periods, increasing the risk to develop anxiety and depression. The basis for this developmental effect is not known. In a previous study, we identified a subpopulation of layer 5–6 pyramidal neurons of the prefrontal cortex (PFC) that transiently expressed Slc6a4/SERT during an early postnatal period in mice (P0–P10). These PFC-SERT+ neurons establish glutamatergic synapses with subcortical targets, including the dorsal raphe nucleus (DRN). PFC-to-DRN circuits develop postnatally, coinciding with the period of PFC Slc6a4/SERT expression. Genetic ablation of SERT or early-life exposure to the SSRI, fluoxetine (from P2 to P14), increases the number of functional PFC glutamate synapses (hyperinnervation) on both 5-HT and GABA neurons in the DRN which also causes anxiety/ depressive-like symptoms. From our transcriptomic profiling of these PFC-SERT+ neurons at a developmental age of P7, we identified the Htr7 gene which could be mediating the developmental effects of SERT ablation. In this thesis, using anatomical and behavioural assays, I showed that pharmacological blockade of the 5-HT7 receptor using specific antagonist was sufficient to prevent the hyperinnervation to the DRN and the anxiety/depressive-like symptoms. In addition, we showed that the 5-HT7 knockout mice have no morphological and behavioural deficits. Furthermore, overexpression of 5-HT7 in the developing PFC, was sufficient to reproduce the anxiety/depressive-like symptoms observed in the absence of PFC-SERT. In conclusion activation of the PFC 5-HT7 receptor during development, could be responsible for the hyperinnervation of glutamatergic synapses to DRN and therefore precipitates the depressive-like behaviours.
