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Neuropharmacology Nov 2022Nucleus incertus (NI) is a brainstem structure involved in the control of arousal, stress responses and locomotor activity. It was reported recently that NI neurons...
Nucleus incertus (NI) is a brainstem structure involved in the control of arousal, stress responses and locomotor activity. It was reported recently that NI neurons express the dopamine type 2 (D2) receptor that belongs to the D2-like receptor (D2R) family, and that D2R activation in the NI decreased locomotor activity. In this study, using multiplex in situ hybridization, we observed that GABAergic and glutamatergic NI neurons express D2 receptor mRNA, and that D2 receptor mRNA-positive neurons belong to partially overlapping relaxin-3- and cholecystokinin-positive NI neuronal populations. Our immunohistochemical and viral-based retrograde tract-tracing studies revealed a dense innervation of the NI area by fibers containing the catecholaminergic biosynthesis enzymes, tyrosine hydroxylase (TH) and dopamine β-hydroxylase (DBH), and indicated the major sources of the catecholaminergic innervation of the NI as the Darkschewitsch, raphe and hypothalamic A13 nuclei. Furthermore, using whole-cell patch clamp recordings, we demonstrated that D2R activation by quinpirole produced excitatory and inhibitory influences on neuronal activity in the NI, and that both effects were postsynaptic in nature. Moreover, the observed effects were cell-type specific, as type I NI neurons were either excited or inhibited, whereas type II NI neurons were mainly excited by D2R activation. Our results reveal that rat NI receives a strong catecholaminergic innervation and suggest that catecholamines acting within the NI are involved in the control of diverse processes, including locomotor activity, social interaction and nociceptive signaling. Our data also strengthen the hypothesis that the NI acts as a hub integrating arousal-related neuronal information.
Topics: Animals; Dopamine; Neurons; RNA, Messenger; Raphe Nuclei; Rats; Receptors, Dopamine D2
PubMed: 35973599
DOI: 10.1016/j.neuropharm.2022.109216 -
Journal of Neurophysiology Jul 2018Intermittent hypercapnia evokes prolonged depression of phrenic nerve activity (phrenic long-term depression, pLTD). This study was undertaken to investigate the role of...
Intermittent hypercapnia evokes prolonged depression of phrenic nerve activity (phrenic long-term depression, pLTD). This study was undertaken to investigate the role of 5-HT and α2-adrenergic receptors in the initiation of pLTD. Adult male urethane-anesthetized, vagotomized, paralyzed, and mechanically ventilated Sprague-Dawley rats were exposed to a protocol of acute intermittent hypercapnia (AIHc; 5 episodes of 15% CO in air, each episode lasting 3 min). The experimental group received microinjection of the selective 5-HT receptor agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT), the broad-spectrum 5-HT antagonist methysergide, or the α2-adrenergic antagonist yohimbine, whereas the control group received microinjection of 0.9% saline into the caudal raphe region. Peak phrenic nerve activity (pPNA) and burst frequency ( f) were analyzed during baseline (T0), during 5 hypercapnic episodes (THc1-THc5), and at 15, 30, and 60 min after the end of the last hypercapnic episode. In the control group, pPNA decreased 60 min after the end of the last hypercapnic episode compared with baseline values, i.e., pLTD developed ( P = 0.023). In the 8-OH-DPAT group, pPNA significantly decreased at T15, T30, and T60 compared with baseline values, i.e., pLTD developed ( P = 0.01). In the methysergide and yohimbine groups, AIHc did not evoke significant changes of the pPNA at T15, T30, and T60 compared with baseline values. In conclusion, activation of 5-HT receptors accentuated induction of pLTD, whereas blockade of α2-adrenergic receptors prevented development of pLTD following AIHc in anesthetized rats. These results suggest that chemical modulation of 5-HT and α2-adrenergic receptors in raphe nuclei affects hypercapnia-induced pLTD, offering important insights in understanding the mechanisms involved in development of respiratory plasticity. NEW & NOTEWORTHY Hypercapnia is a concomitant feature of many breathing disorders, including obstructive sleep apnea. In this study, acute intermittent hypercapnia evoked development of phrenic long-term depression (pLTD) 60 min after the last hypercapnic episode that was preserved if the selective 5-HT receptor agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide was microinjected in the caudal raphe region before the hypercapnic stimulus. This study highlights that both 5-HT and adrenergic receptor activation is needed for induction of pLTD in urethane-anesthetized rats following intermittent hypercapnia exposure.
Topics: 8-Hydroxy-2-(di-n-propylamino)tetralin; Adrenergic alpha-2 Receptor Antagonists; Animals; Hypercapnia; Long-Term Synaptic Depression; Male; Methysergide; Phrenic Nerve; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptors, Adrenergic; Receptors, Serotonin; Serotonin Antagonists; Yohimbine
PubMed: 29617215
DOI: 10.1152/jn.00776.2017 -
Psychiatry and Clinical Neurosciences Sep 2022The association between psychiatric symptoms in Lewy body disease (LBD) and the noradrenergic and serotonergic systems is still controversial. This study investigated...
AIM
The association between psychiatric symptoms in Lewy body disease (LBD) and the noradrenergic and serotonergic systems is still controversial. This study investigated the quantitative relationships of depression and delusion with these systems.
METHODS
We studied 24 postmortem tissues from individuals with a pathological diagnosis of LBD with sufficient clinical history. The numbers of neurons and Lewy bodies (LBs) in the locus coeruleus (LC) and dorsal raphe nucleus (DRN) were counted, and the density of neurons in the DRN was analyzed. In addition, the densities of tryptophan hydroxylase-positive neurites and norepinephrine transporter-positive neurites in the amygdala and dorsal prefrontal cortex were measured. Finally, we divided the cases into two groups: with or without depressive mood, and with or without delusion. Quantitative histological data were compared between the groups.
RESULTS
The group with depressive mood had a significantly smaller number of neurons in the LC compared with the group without depressive mood. The group with delusion had a significantly larger number of LBs in the DRN compared with the group without delusion. The density of norepinephrine transporter-positive neurites in the dorsal prefrontal cortex was significantly correlated with the number of neurons in the LC.
CONCLUSIONS
The accumulation of LBs in the DRN of individuals with LBD was associated with delusion, whereas a decrease in the number of neurons in the LC was associated with depressive mood. These neurodegenerative changes involved the serotonergic and noradrenergic systems and may be associated with the formation of delusion and depression, respectively, in LBD.
Topics: Delusions; Depression; Dorsal Raphe Nucleus; Humans; Lewy Body Disease; Norepinephrine; Norepinephrine Plasma Membrane Transport Proteins
PubMed: 35695782
DOI: 10.1111/pcn.13436 -
Neuropharmacology Sep 2011The median (MR) and dorsal raphe (DR) nuclei contain the majority of the 5-hydroxytryptamine (5-HT, serotonin) neurons that project to limbic forebrain regions, are...
The median (MR) and dorsal raphe (DR) nuclei contain the majority of the 5-hydroxytryptamine (5-HT, serotonin) neurons that project to limbic forebrain regions, are important in regulating homeostatic functions and are implicated in the etiology and treatment of mood disorders and schizophrenia. The primary synaptic inputs within and to the raphe are glutamatergic and GABAergic. The DR is divided into three subfields, i.e., ventromedial (vmDR), lateral wings (lwDR) and dorsomedial (dmDR). Our previous work shows that cell characteristics of 5-HT neurons and the magnitude of the 5-HT(1A) and 5-HT(1B) receptor-mediated responses in the vmDR and MR are not the same. We extend these observations to examine the electrophysiological properties across all four raphe subfields in both 5-HT and non-5-HT neurons. The neurochemical topography of glutamatergic and GABAergic cell bodies and nerve terminals were identified using immunohistochemistry and the morphology of the 5-HT neurons was measured. Although 5-HT neurons possessed similar physiological properties, important differences existed between subfields. Non-5-HT neurons were indistinguishable from 5-HT neurons. GABA neurons were distributed throughout the raphe, usually in areas devoid of 5-HT neurons. Although GABAergic synaptic innervation was dense throughout the raphe (immunohistochemical analysis of the GABA transporters GAT1 and GAT3), their distributions differed. Glutamate neurons, as defined by vGlut3 anti-bodies, were intermixed and co-localized with 5-HT neurons within all raphe subfields. Finally, the dendritic arbor of the 5-HT neurons was distinct between subfields. Previous studies regard 5-HT neurons as a homogenous population. Our data support a model of the raphe as an area composed of functionally distinct subpopulations of 5-HT and non-5-HT neurons, in part delineated by subfield. Understanding the interaction of the cell properties of the neurons in concert with their morphology, local distribution of GABA and glutamate neurons and their synaptic input, reveals a more complicated and heterogeneous raphe. These results provide an important foundation for understanding how specific subfields modulate behavior and for defining which aspects of the circuitry are altered during the etiology of psychological disorders.
Topics: Animals; Brain Chemistry; Dendrites; Electric Impedance; GABA Plasma Membrane Transport Proteins; Glucose Transporter Type 3; Glutamate Decarboxylase; Immunohistochemistry; Male; Membrane Potentials; Neurons; Patch-Clamp Techniques; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A; Receptor, Serotonin, 5-HT1B; Synaptic Transmission; Tryptophan Hydroxylase
PubMed: 21530552
DOI: 10.1016/j.neuropharm.2011.04.008 -
The Journal of Neuroscience : the... Mar 2021Brainstem median raphe (MR) neurons expressing the serotonergic regulator gene send collateralized projections to forebrain regions to modulate affective,... (Comparative Study)
Comparative Study
Brainstem median raphe (MR) neurons expressing the serotonergic regulator gene send collateralized projections to forebrain regions to modulate affective, memory-related, and circadian behaviors. Some neurons express a surprisingly incomplete battery of serotonin pathway genes, with somata lacking transcripts for tryptophan hydroxylase 2 () encoding the rate-limiting enzyme for serotonin [5-hydroxytryptamine (5-HT)] synthesis, but abundant for vesicular glutamate transporter type 3 () encoding a synaptic vesicle-associated glutamate transporter. Genetic fate maps show these nonclassical, putatively glutamatergic neurons in the MR arise embryonically from the same progenitor cell compartment-hindbrain rhombomere 2 (r2)-as serotonergic TPH2 MR neurons. Well established is the distribution of efferents en masse from r2-derived, -neurons; unknown is the relationship between these efferent targets and the specific constituent source-neuron subgroups identified as r2- versus r2- Using male and female mice, we found r2- axonal boutons segregated anatomically largely by serotonin versus VGLUT3 identity. The former present in the suprachiasmatic nucleus, paraventricular nucleus of the thalamus, and olfactory bulb; the latter are found in the hippocampus, cortex, and septum. Thus r2- and r2- neurons likely regulate distinct brain regions and behaviors. Some r2- boutons encased interneuron somata, forming specialized presynaptic "baskets" of VGLUT3 or VGLUT3/5-HT identity; this suggests that some r2- neurons may regulate local networks, perhaps with differential kinetics via glutamate versus serotonin signaling. Fibers from other neurons (non-r2-derived) were observed in many of these same baskets, suggesting multifaceted regulation. Collectively, these findings inform brain organization and new circuit nodes for therapeutic considerations. Our findings match axonal bouton neurochemical identity with distant cell bodies in the brainstem raphe. The results are significant because they suggest that disparate neuronal subsystems derive from precursor cells of the embryonic progenitor compartment rhombomere 2 (r2). Of these r2- neuronal subsystems, one appears largely serotonergic, as expected given expression of the serotonergic regulator PET1, and projects to the olfactory bulb, thalamus, and suprachiasmatic nucleus. Another expresses VGLUT3, suggesting principally glutamate transmission, and projects to the hippocampus, septum, and cortex. Some r2- boutons-those that are VGLUT3 or VGLUT3/5-HT co-positive-comprise "baskets" encasing interneurons, suggesting that they control local networks perhaps with differential kinetics via glutamate versus serotonin signaling. Results inform brain organization and circuit nodes for therapeutic consideration.
Topics: Amino Acid Transport Systems, Acidic; Animals; Brain Chemistry; Female; Male; Mice; Mice, Inbred C57BL; Mice, Transgenic; Raphe Nuclei; Rhombencephalon; Serotonin; Transcription Factors
PubMed: 33547164
DOI: 10.1523/JNEUROSCI.1667-20.2021 -
Experimental Physiology Jan 1997
Review
Topics: Animals; Autonomic Nervous System; Humans; Medulla Oblongata; Motor Cortex; Raphe Nuclei; Somatosensory Cortex
PubMed: 9023504
DOI: 10.1113/expphysiol.1997.sp004013 -
The Journal of Neuroscience : the... Feb 2002The recently described two-pore-domain K+ channels, TASK-1 and TASK-3, generate currents with a unique set of properties; specifically, the channels produce...
The recently described two-pore-domain K+ channels, TASK-1 and TASK-3, generate currents with a unique set of properties; specifically, the channels produce instantaneous open-rectifier (i.e., "leak") K+ currents that are modulated by extracellular pH and by clinically useful anesthetics. In this study, we used histochemical and in vitro electrophysiological approaches to determine that TASK channels are expressed in serotonergic raphe neurons and to show that they confer a pH and anesthetic sensitivity to these neurons. By combining in situ hybridization for TASK-1 or TASK-3 with immunohistochemical localization of tryptophan hydroxylase, we found that a majority of serotonergic neurons in both dorsal and caudal raphe cell groups contain TASK channel transcripts (approximately 70-90%). Whole-cell voltage-clamp recordings were obtained from raphe cells that responded to 5-HT in a manner characteristic of serotonergic neurons (i.e., with activation of an inwardly rectifying K+ current). In those cells, we isolated an endogenous K+ conductance that had properties expected of TASK channel currents; raphe neurons expressed a joint pH- and halothane-sensitive open-rectifier K+ current. The pH sensitivity of this current (pK approximately 7.0) was intermediate between that of TASK-1 and TASK-3, consistent with functional expression of both channel types. Together, these data indicate that TASK-1 and TASK-3 are expressed and functional in serotonergic raphe neurons. The pH-dependent inhibition of TASK channels in raphe neurons may contribute to ventilatory and arousal reflexes associated with extracellular acidosis; on the other hand, activation of raphe neuronal TASK channels by volatile anesthetics could play a role in their immobilizing and sedative-hypnotic effects.
Topics: Acidosis; Animals; Dose-Response Relationship, Drug; Halothane; Hydrogen-Ion Concentration; Immunohistochemistry; In Situ Hybridization; In Vitro Techniques; Membrane Potentials; Nerve Tissue Proteins; Neurons; Patch-Clamp Techniques; Potassium; Potassium Channels; Potassium Channels, Tandem Pore Domain; RNA, Messenger; Raphe Nuclei; Rats; Rats, Sprague-Dawley; Rats, Wistar; Serotonin
PubMed: 11850453
DOI: 10.1523/JNEUROSCI.22-04-01256.2002 -
PloS One 2018Serotonin (5-HT) acts as both a morphogenetic factor during early embryonic development and a neuromodulator of circuit plasticity in the mature brain. Dysregulation of...
Serotonin (5-HT) acts as both a morphogenetic factor during early embryonic development and a neuromodulator of circuit plasticity in the mature brain. Dysregulation of serotonin signaling during critical periods is involved in developmental neurological disorders, such as schizophrenia and autism. In this study we focused on the consequences of defect reelin signaling for the development of the brainstem serotonergic raphe system. We observed that reelin signaling components are expressed by serotonergic neurons during the critical period of their lateral migration. Further, we found that reelin signaling is important for the normal migration of rostral, but not caudal hindbrain raphe nuclei and that reelin deficiency results in the malformation of the paramedian raphe nucleus and the lateral wings of the dorsal raphe nuclei. Additionally, we showed that serotonergic neurons projections to laminated brain structures were severely altered. With this study, we propose that the perturbation of canonical reelin signaling interferes with the orientation of tangentially, but not radially, migrating brainstem 5-HT neurons. Our results open the window for further studies on the interaction of reelin and serotonin and the pathogenesis of neurodevelopmental disorders.
Topics: Animals; Blotting, Western; Brain Stem; Cell Adhesion Molecules, Neuronal; Extracellular Matrix Proteins; Mice; Mice, Knockout; Nerve Tissue Proteins; Neuronal Plasticity; Raphe Nuclei; Reelin Protein; Serine Endopeptidases; Serotonergic Neurons; Serotonin; Signal Transduction
PubMed: 30001399
DOI: 10.1371/journal.pone.0200268 -
Neuron May 2020The brain dopamine (DA) system participates in forming and expressing memory. Despite a well-established role of DA neurons in the ventral tegmental area in memory...
The brain dopamine (DA) system participates in forming and expressing memory. Despite a well-established role of DA neurons in the ventral tegmental area in memory formation, the exact DA circuits that control memory expression remain unclear. Here, we show that DA neurons in the dorsal raphe nucleus (DRN) and their medulla input control the expression of incentive memory. DRN DA neurons are activated by both rewarding and aversive stimuli in a learning-dependent manner and exhibit elevated activity during memory recall. Disrupting their physiological activity or DA synthesis blocks the expression of natural appetitive and aversive memories as well as drug memories associated with opioids. Moreover, a glutamatergic pathway from the lateral parabrachial nucleus to the DRN selectively regulates the expression of reward memories associated with opioids or foods. Our study reveals a specialized DA subsystem important for memory expression and suggests new targets for interventions against opioid addiction.
Topics: Animals; Dopamine; Dopaminergic Neurons; Female; Glutamic Acid; Male; Memory; Mice; Mice, Inbred C57BL; Morphine; Narcotics; Raphe Nuclei; Reward
PubMed: 32145184
DOI: 10.1016/j.neuron.2020.02.009 -
Brain Research Feb 2010Accumulating evidence suggests that the neuropeptide substance P (SP) and its principal receptor neurokinin 1 (NK1) play a specific role in the behavioral response to... (Review)
Review
Accumulating evidence suggests that the neuropeptide substance P (SP) and its principal receptor neurokinin 1 (NK1) play a specific role in the behavioral response to opioids and stress that may help to initiate and maintain addictive behavior. In animal models, the NK1 receptor is required for opioids to produce their rewarding and motivational effects. SP neurotransmission is also implicated in the behavioral response to stress and in the process of drug sensitization, potentially contributing to vulnerability to addiction or relapse. However, SP neurotransmission only plays a minor role in opioid-mediated antinociception and the development of opioid tolerance. Moreover, the effects of SP on addiction-related behavior are selective for opioids and evidence supporting a role in the response to cocaine or psychostimulants is less compelling. This review will summarize the effects of SP neurotransmission on opioid-dependent behaviors and correlate them with potential contributing neural pathways. Specifically, SP neurotransmission within components of the basal forebrain particularly the nucleus accumbens and ventral pallidum as well as actions within the ascending serotonin system will be emphasized. In addition, cellular- or network-level interactions between opioids and SP signaling that may underlie the specificity of their relationship will be reviewed.
Topics: Analgesics, Opioid; Animals; Brain; Comorbidity; Humans; Neural Pathways; Nucleus Accumbens; Opioid-Related Disorders; Raphe Nuclei; Stress, Psychological; Substance P; Substance-Related Disorders
PubMed: 19913520
DOI: 10.1016/j.brainres.2009.11.014