Histaminergic Neurons Research Articles

Alzheimer's Disease: An Attempt of Total Recall.

This review is an attempt to compile existing hypotheses on the mechanisms underlying the initiation and progression of Alzheimer's disease (AD), starting from sensory impairments observed in AD and concluding with molecular events that are typically associated with the disease. These events include spreading of amyloid plaques and tangles of hyperphosphorylated tau and formation of Hirano and Biondi bodies as well as the development of oxidative stress. We have detailed the degenerative changes that occur in several neuronal populations, including the cholinergic neurons in the nucleus basalis of Meynert, the histaminergic neurons in the tuberomammillary nucleus, the serotonergic neurons in the raphe nuclei, and the noradrenergic neurons in the locus coeruleus. Furthermore, we discuss the potential role of iron accumulation in the brains of subjects with AD in the disease progression which served as a basis for the idea that iron chelation in the brain may mitigate oxidative stress and decelerate disease development. We also draw attention to possible role of sympathetic system and, more specifically, noradrenergic neurons of the superior cervical ganglion in triggering of the disease. We also explore the alternative possibility of compensatory protective changes that may occur in these neurons to support cholinergic function in the forebrain of subjects with AD.

Structural Basis for Histaminergic Regulation of Neural Circuits in the Mouse Olfactory Bulb.

Odor information is modulated by centrifugal inputs from other brain regions to the olfactory bulb (OB). Neurons containing monoamines, such as serotonin, acetylcholine, and noradrenaline, are well known as centrifugal inputs; however, the role of histamine, which is also present in the OB, is not well understood. In this study, we examined the histaminergic neurons projecting from the hypothalamus to the OB. We used an antibody against histidine decarboxylase (HDC), a synthesizing enzyme of histamine, to identify histaminergic neurons and assess their localization within the OB and the ultrastructure of their fibers and synapses using multiple immunostaining laser microscopy, ultra-high voltage electron microscopy (EM), and EM to confirm their relationships with other neurons. To further identify the origin nucleus of the histaminergic neurons projecting to the OB, we injected the retrograde tracer FluoroGold and analyzed the pathway to the OB anterogradely. HDC-immunoreactive (-ir) fibers were abundant in the olfactory nerve (ON) layer compared to other monoamines. HDC-ir neurons received asymmetrical synapses from ONs and formed synapses containing pleomorphic vesicles with variable postsynaptic densities to non-ON elements, thus forming serial synapses. We also confirmed that histaminergic neurons project from the rostral ventral tuberomammillary nucleus to the granule cell layer of the OB and, for the first time, successfully visualized their axons from the hypothalamus to the OB. These findings indicate that histamine may regulate odor discrimination in the OB, suggesting a regulatory relationship between hypothalamic function and olfaction. We thus elucidate morphological mechanisms with tuberomammillary nucleus-derived histaminergic neurons involved in olfactory information.

Top-down modulation of the retinal code via histaminergic neurons of the hypothalamus.

The mammalian retina is considered an autonomous circuit, yet work dating back to Ramon y Cajal indicates that it receives inputs from the brain. How such inputs affect retinal processing has remained unknown. We confirmed brain-to-retina projections of histaminergic neurons from the mouse hypothalamus. Histamine application ex vivo altered the activity of various retinal ganglion cells (RGCs), including direction-selective RGCs that gained responses to high motion velocities. These results were reproduced in vivo with optic tract recordings where histaminergic retinopetal axons were activated chemogenetically. Such changes could improve vision of fast-moving objects (e.g., while running), which fits with the known increased activity of histaminergic neurons during arousal. An antihistamine drug reduced optomotor responses to high-speed moving stimuli in freely moving mice. In humans, the same antihistamine nonuniformly modulated visual sensitivity across the visual field, indicating an evolutionary conserved function of the histaminergic system. Our findings expose a previously unappreciated role for brain-to-retina projections in modulating retinal function.

Light-responsive adipose-hypothalamus axis controls metabolic regulation

Light is fundamental for biological life, with most mammals possessing light-sensing photoreceptors in various organs. Opsin3 is highly expressed in adipose tissue which has extensive communication with other organs, particularly with the brain through the sympathetic nervous system (SNS). Our study reveals a new light-triggered crosstalk between adipose tissue and the hypothalamus. Direct blue-light exposure to subcutaneous white fat improves high-fat diet-induced metabolic abnormalities in an Opsin3-dependent manner. Metabolomic analysis shows that blue light increases circulating levels of histidine, which activates histaminergic neurons in the hypothalamus and stimulates brown adipose tissue (BAT) via SNS. Blocking central actions of histidine and denervating peripheral BAT blunts the effects of blue light. Human white adipocytes respond to direct blue light stimulation in a cell-autonomous manner, highlighting the translational relevance of this pathway. Together, these data demonstrate a light-responsive metabolic circuit involving adipose-hypothalamus communication, offering a potential strategy to alleviate obesity-induced metabolic abnormalities.

Chemogenetic activation or inhibition of histaminergic neurons bidirectionally modulates recognition memory formation and retrieval in male and female mice.

Several lines of evidence demonstrate that the brain histaminergic system is fundamental for cognitive processes and the expression of memories. Here, we investigated the effect of acute silencing or activation of histaminergic neurons in the hypothalamic tuberomamillary nucleus (TMNHA neurons) in vivo in both sexes in an attempt to provide direct and causal evidence of the necessary role of these neurons in recognition memory formation and retrieval. To this end, we compared the performance of mice in two non-aversive and non-rewarded memory tests, the social and object recognition memory tasks, which are known to recruit different brain circuitries. To directly establish the impact of inactivation or activation of TMNHA neurons, we examined the effect of specific chemogenetic manipulations during the formation (acquisition/consolidation) or retrieval of recognition memories. We consistently found that acute chemogenetic silencing of TMNHA neurons disrupts the formation or retrieval of both social and object recognition memory in males and females. Conversely, acute chemogenetic activation of TMNHA neurons during training or retrieval extended social memory in both sexes and object memory in a sex-specific fashion. These results suggest that the formation or retrieval of recognition memory requires the tonic activity of histaminergic neurons and strengthen the concept that boosting the brain histaminergic system can promote the retrieval of apparently lost memories.

The role of histamine H1 receptor in the anterior cingulate cortex on nociception level following acute restraint stress in male rats.

Considering the importance of pain and stress, we decided to investigate the intra-anterior cingulate cortex (ACC) microinjection of histamine and mepyramine alone and concurrently on acute pain induced by hot plate following restraint stress in male rats. 24-gauge, 10 mm stainless steel guide cannula was implanted over the ACC in the incised scalp of 4 groups. Restraint stress in healthy rats produced a significant increase (p < .05) in the pain threshold. The simultaneous microinjection of 4 μg/side histamine and 8 μg/side mepyramine as a histaminergic system inverse agonist in healthy nonrestraint animals did not affect the pain threshold. Although Histamine decreased the threshold of pain meaningfully, mepyramine elevated it in a significant manner (p < .05). In the restrained animals, intra-ACC microinjection of histamine produced no significant impact on the pain threshold. However, intra-ACC microinjection of mepyramine before histamine, significantly (p < .01) altered the result and enhanced the threshold of pain. The results of our study demonstrated that histaminergic neurons have an important role in the processing of pain in the ACC following restraint stress.

Organization of an ascending circuit that conveys flight motor state in Drosophila

Natural behaviors are a coordinated symphony of motor acts that drive reafferent (self-induced) sensory activation. Individual sensors cannot disambiguate exafferent (externally induced) from reafferent sources. Nevertheless, animals readily differentiate between these sources of sensory signals to carry out adaptive behaviors through corollary discharge circuits (CDCs), which provide predictive motor signals from motor pathways to sensory processing and other motor pathways. Yet, how CDCs comprehensively integrate into the nervous system remains unexplored. Here, we use connectomics, neuroanatomical, physiological, and behavioral approaches to resolve the network architecture of two pairs of ascending histaminergic neurons (AHNs) in Drosophila, which function as a predictive CDC in other insects. Both AHN pairs receive input primarily from a partially overlapping population of descending neurons, especially from DNg02, which controls wing motor output. Using Ca2+ imaging and behavioral recordings, we show that AHN activation is correlated to flight behavior and precedes wing motion. Optogenetic activation of DNg02 is sufficient to activate AHNs, indicating that AHNs are activated by descending commands in advance of behavior and not as a consequence of sensory input. Downstream, each AHN pair targets predominantly non-overlapping networks, including those that process visual, auditory, and mechanosensory information, as well as networks controlling wing, haltere, and leg sensorimotor control. These results support the conclusion that the AHNs provide a predictive motor signal about wing motor state to mostly non-overlapping sensory and motor networks. Future work will determine how AHN signaling is driven by other descending neurons and interpreted by AHN downstream targets to maintain adaptive sensorimotor performance.

Whole Brain Mapping of Orexin Receptor mRNA Expression Visualized by Branched In Situ Hybridization Chain Reaction.

Orexins, which are produced within neurons of the lateral hypothalamic area, play a pivotal role in the regulation of various behaviors, including sleep/wakefulness, reward behavior, and energy metabolism, via orexin receptor type 1 (OX1R) and type 2 (OX2R). Despite the advanced understanding of orexinergic regulation of behavior at the circuit level, the precise distribution of orexin receptors in the brain remains unknown. Here, we develop a new branched in situ hybridization chain reaction (bHCR) technique to visualize multiple target mRNAs in a semiquantitative manner, combined with immunohistochemistry, which provided comprehensive distribution of orexin receptor mRNA and neuron subtypes expressing orexin receptors in mouse brains. Only a limited number of cells expressing both Ox1r and Ox2r were observed in specific brain regions, such as the dorsal raphe nucleus and ventromedial hypothalamic nucleus. In many brain regions, Ox1r-expressing cells and Ox2r-expressing cells belong to different cell types, such as glutamatergic and GABAergic neurons. Moreover, our findings demonstrated considerable heterogeneity in Ox1r- or Ox2r-expressing populations of serotonergic, dopaminergic, noradrenergic, cholinergic, and histaminergic neurons. The majority of orexin neurons did not express orexin receptors. This study provides valuable insights into the mechanism underlying the physiological and behavioral regulation mediated by the orexin system, as well as the development of therapeutic agents targeting orexin receptors.

Network changes and compensation mechanisms of wake‐promoting neurons across AD continuum

AbstractBackgroundSleep is a complex process regulated by various neural mechanisms, including those promoting wakefulness, those promoting sleep, and those regulating the circadian clock. Recent research has revealed that wake‐promoting neurons, specifically those found in the noradrenergic locus ceruleus (LC), the orexinergic (ORX) neurons in the lateral hypothalamic area (LHA), and the histaminergic neurons in the hypothalamic tuberomammillary nucleus (TMN), are particularly vulnerable to the AD‐tau pathology found in the early stages of Alzheimer’s disease (AD). These studies have uncovered how these neurons accumulate AD‐tau, the extent to which they die in AD, and specific correlations with polysomnographic readings. Notably, a complex pattern of neuronal dysregulation within and among these wake‐promoting neurons has been observed, suggesting the existence of robust compensatory mechanisms in an attempt to overcome dysfunction. Thus, understanding the vulnerability of these nuclei to AD requires network‐based studies. These studies are crucial for informing disease‐specific treatment for sleep disturbance and identifying factors underlying the vulnerability of these neurons.MethodsResults from several ongoing experiments in the Grinberg Lab, including methods such as quantitative pathology, molecular profiling and clinicopathological correlationResultsFor example, the hypocretin (orexin) receptor 1 (HCRTR1) shows upregulation in orexin neurons from early AD stages, while no changes are observed in the LC or TMN. Additionally, while the LC shows an early pattern of upregulation of genes associated with neuroinflammation, early dysregulation in the ORX is related to synapse‐related genes. Furthermore, circadian genes such as CRY1 and CRY2 show upregulation in the ORX but downregulation in the TMN during AD progression.ConclusionThis talk will focus on current knowledge, including unpublished data, based on studies in humans, on the vulnerability of wake‐promoting neurons in AD, with a particular emphasis on similarities and contrasts in the patterns of dysregulation among these nuclei during AD progression, in conjunction with changes in the suprachiasmatic nucleus, the circadian clock, and regional expression of circadian genes.

Dose-Related Effects of Ciproxifan on Brain Tissue in Rats with Cerebral Ischemia-Reperfusion

Cerebral ischemia is the result of decreased or interrupted blood flow to the brain. It is the third leading cause of death after cardiovascular disease and cancer. Cerebral ischemia is reversible or irreversible in neurons in the affected area, and subsequent free radical damage can be exacerbated if reperfusion occurs. Ciproxifan is used to study the involvement of histaminergic neurons in different phases such as wakefulness and cognition. We wanted to find out whether ciproxifan has a protective effect on the brain of rats with cerebral ischemia-reperfusion injury. A total of 64 adult rats (32 male and 32 female) were used for the experiment. Eight cages were formed with randomly selected rats. No substance was administered to the rats in group 1 and no surgical procedure was performed. The cerebral ischemia-reperfusion model (clamping of the left common carotid artery for 15 minutes followed by reperfusion for 24 hours) was applied to rats in group 2, group 3, and group 4 after 7 days/single dose of saline and ciproxifan (10mg/kg, 30mg/kg). After that, the activitymeter, forced swim test (FST), and Morris water maze (MWM) were performed in all animals. Rats treated with ciproxifan exhibit neurons and glial cells with histologic structures similar to those of the control group, and interestingly, these differences became more pronounced with increasing dose. Rats administered ciproxifan improved motor coordination, decreased total distance behavior, and improved learning ability. However, when the groups were compared by sex, no significant difference was found in the parameters. Thus, we could conclude that ciproxifan has a protective effect on the brain to a certain extent, regardless of the dose.

Effects of oral morphine on experimentally evoked itch and pain: a randomized, double-blind, placebo-controlled trial.

Pain and itch share similar neuronal networks; hence, it is difficult to explain why opioids can relieve painbut provoke itching. The present human volunteer study aimed to investigate the similarities and differences in responses to experimentally provoked pain and itching to explore the underlying fundamental mechanisms. Twenty-four healthy volunteers were enrolled in this single-center, randomized, double-blind, placebo-controlled, parallel-group trial. Three volar forearms and two mandibular areas were marked, and participants randomly received morphine (20 mg) or identical placebo tablets. Heat, cold, and pressure pain thresholds, and vasomotor responses were assessed at baseline and after oral morphine administration. Itch provocations were induced by intradermal application of 1 % histamine or a topical cowhage (non-histaminergic itch) to a marked area of theskin. The participants were subsequently asked to rate their itching and pain intensities. The assessments were repeated for all marked areas. Morphine caused analgesia, as assessed by the significant modulation of cold and pressure pain thresholds (p<0.05). There were no significant differences in histaminergic or non-histaminergic itch or pain intensity between the morphine and placebo groups. Superficial blood perfusion (vasomotor response) following histamine provocation wassignificantly increased by morphine (p<0.05) in both areas. No correlation was found between the provoked itch intensity and analgesic efficacy in any area or group. Oral administration of morphine caused analgesia without modulating itch intensities but increased neurogenic inflammation in response to histamine, suggesting that different opioid mechanisms in histaminergic and non-histaminergic neurons evoke neurogenic inflammation.

Larger hypothalamic volume in narcolepsy type 1.

Narcolepsy type 1 (NT1) is a neurological sleep disorder. Postmortem studies have shown 75%-90% loss of the 50 000-70 000 hypocretin-producing neurons and 64%-94% increase in the 64 000-120 000 histaminergic neurons and conflicting indications of gliosis in the hypothalamus of NT1 patients. The aim of this study was to compare MRI-based volumes of the hypothalamus in patients with NT1 and controls in vivo. We used a segmentation tool based on deep learning included in Freesurfer and computed the volume of the whole hypothalamus, left/right part of the hypothalamus, and 10 hypothalamic subregions. We included 54 patients with post-H1N1 NT1 (39 females, mean age 21.8 ± 11.0 years) and 114 controls (77 females, mean age 23.2 ± 9.0 years). Group differences were tested with general linear models using permutation testing in Permutation Analysis of Linear Models and evaluated after 10 000 permutations, yielding two-tailed P-values. Furthermore, a stepwise Bonferroni correction was performed after dividing hypothalamus into smaller regions. The analysis revealed larger volume for patients compared to controls for the whole hypothalamus (Cohen's d = 0.71, p = 0.0028) and for the left (d = 0.70, p = 0.0037) and right part of the hypothalamus (d = 0.65, p = 0.0075) and left (d = 0.72, p = 0.0036) and right tubular-inferior (d = 0.71, p = 0.0037) hypothalamic subregions. In conclusion, patients with post-H1N1 NT1 showed significantly larger hypothalamic volume than controls, in particular in the tubular-inferior subregions which could reflect several processes as previous studies have indicated neuroinflammation, gliosis, and changes in the numbers of different cell types.

An α-hemoglobin-derived peptide (m)VD-hemopressin (α) promotes NREM sleep via the CB1 cannabinoid receptor.

Hemopressin and related peptides have shown to function as the endogenous ligands or the regulator of cannabinoid receptors. The previous studies demonstrated that the endocannabinoid system played important roles in modulating several physiological functions such as sleep, olfaction, emotion, learning and memory, and reward behaviors. Mouse VD-hemopressin (α) [(m)VD-HPα], an 11-residue peptide derived from the α1 chain of hemoglobin, was recently presumed as a selective agonist of the CB1 receptor. The present study was undertaken to investigate the effects of (m)VD-HPα on the sleep-wake cycle and power spectrum of cortical EEG in freely moving rats and the potential neurons in the brain activated by (m)VD-HPα. The results showed that 20.1nmol of (m)VD-HPα i.c.v. administration increased non-rapid eye movement (NREM) sleep in the first 2h section accompanied by an increase in EEG delta (0.5-4Hz) activity. The (m)VD-HPα-induced NREM sleep enhancement was due to extended episode duration instead of the episode number. In addition, the effect of (m)VD-HPα (20.1nmol) on sleep-wake states was significantly attenuated by an antagonist of the CB1 receptor, AM251 (20nmol, i.c.v.) but not by the CB2 receptor antagonist, AM630 (20nmol, i.c.v.). In comparison with vehicle, (m)VD-HPα increased Fos-immunoreactive (-ir) neurons in the ventrolateral preoptic nucleus (VLPO), but reduced Fos-ir neurons in the lateral hypothalamus (LH), tuberomammillary nucleus (TMN), and locus coeruleus (LC). These findings suggest that (m)VD-HPα promotes NREM sleep via the CB1 cannabinoid receptor to probably activate VLPO GABAergic neurons, but inactivates the LH orexinergic, LC noradrenergic, and TMN histaminergic neurons.

Histaminergic regulation of food intake.

Histamine is a biogenic amine that acts as a neuromodulator within the brain. In the hypothalamus, histaminergic signaling contributes to the regulation of numerous physiological and homeostatic processes, including the regulation of energy balance. Histaminergic neurons project extensively throughout the hypothalamus and two histamine receptors (H1R, H3R) are strongly expressed in key hypothalamic nuclei known to regulate energy homeostasis, including the paraventricular (PVH), ventromedial (VMH), dorsomedial (DMH), and arcuate (ARC) nuclei. The activation of different histamine receptors is associated with differential effects on neuronal activity, mediated by their different G protein-coupling. Consequently, activation of H1R has opposing effects on food intake to that of H3R: H1R activation suppresses food intake, while H3R activation mediates an orexigenic response. The central histaminergic system has been implicated in atypical antipsychotic-induced weight gain and has been proposed as a potential therapeutic target for the treatment of obesity. It has also been demonstrated to interact with other major regulators of energy homeostasis, including the central melanocortin system and the adipose-derived hormone leptin. However, the exact mechanisms by which the histaminergic system contributes to the modification of these satiety signals remain underexplored. The present review focuses on recent advances in our understanding of the central histaminergic system's role in regulating feeding and highlights unanswered questions remaining in our knowledge of the functionality of this system.

The activation of GABAergic neurons in the hypothalamic tuberomammillary nucleus attenuates sevoflurane and propofol-induced anesthesia in mice.

Background: The histaminergic neurons in the hypothalamic tuberomammillary nucleus (TMN) have been suggested to play a vital role in maintaining a rising state. But the neuronal types of the TMN are in debate and the role of GABAergic neurons remains unclear. Methods: In the present study, we examined the role of TMN GABAergic neurons in general anesthesia using chemogenetics and optogenetics strategies to regulate the activity of TMN GABAergic neurons. Results: The results indicated that either chemogenetic or optogenetic activation of TMN GABAergic neurons in mice decreased the effect of sevoflurane and propofol anesthesia. In contrast, inhibition of the TMN GABAergic neurons facilitates the sevoflurane anesthesia effect. Conclusion: Our results suggest that the activity of TMN GABAergic neurons produces an anti-anesthesia effect in loss of consciousness and analgesia.

Insights into the mechanism of histamine synthesis and recycling disruption induced by exposure to CdO NPs in the fruit fly (Drosophila melanogaster).

Exposure to a sublethal concentration of CdO nanoparticles impairs the vision of the fruit fly (Drosophila melanogaster) by disrupting histamine (HA) synthesis and recycling mechanisms. To gain more insights, we measured HA titer using HPLC in CdO NP-treated vs. non-treated adults in the current study and found that CdO NPs caused an increase in the level of HA in the head and the decapitated body. We asked whether HA accumulation (increase) is a response of photoreceptors or CNS histaminergic neurons, and whether there is any difference in the expression levels of HA recycling and transport encoding genes (Lovit, CarT, Ebony, Tan, BalaT) between the adult fly head and decapitated body that could explain this HA accumulation. We used GAL4/UAS system tool with three GAL4 drivers: ubiquitous tubP-GAL4, nervous system driver (elav Gal4), and compound eye drivers (sev Gal4 and GMR Gal4) to silence HA synthesis in site specific manner followed by detecting the expression level of genes involved in HA recycling and transport in both the heads and the decapitated bodies of CdO treated and non-treated flies. We found an increase in Lovit expression in the heads of treated adults, which is responsible for HA loading into synaptic vesicles and release from photoreceptors, as well as a decrease in catalytic enzymes involved in HA recycling, which leads to HA accumulation without increasing the real signal. To conclude, both photoreceptors and CNS histaminergic neurons are responsible for the increase in HA in CdO NP-treated flies, but through different mechanisms. Our results provide more insights on the underlying molecular mechanism of vision impairment because of nano-sized cadmium particles exposure.

1532-P: A Novel Light-Responsive Adipose–Hypothalamus Axis in Metabolic Regulation

Light plays an essential role in life. Animals and humans possess light-sensing photoreceptors in visual and non-visual organs. We and others recently showed a non-visual role for Opsin3 (Opn3) in regulating adipose function. In this study, we discovered that direct blue light exposure to subcutaneous white adipose tissue (WAT) could reduce lipids accumulation in WAT and improve high-fat diet-induced metabolic abnormalities in an Opn3-dependent manner. Adipose tissue is an orchestrated matrix comprising high innervation that can engage in crosstalk with other organs. Particularly, it communicates with the brain via the sympathetic nervous system (SNS). Using the metabolomic approach, we found that blue light increased circulating levels of histidine, which then triggered the activation of histaminergic neurons in the hypothalamus and turned on brown adipose tissue via SNS. The administration of histidine decarboxylase antagonist blunted the effects of blue light. Taken together, these data demonstrate a novel light-responsive adipose-hypothalamus axis in metabolic regulation and provide a potential light-based therapeutic approach for obesity. Disclosure T.Tsuji: None. T.Huang: None. Y.Zhang: None. M.Lynes: None. G.Profeta: None. N.Narain: None. M.Kiebish: None. Y.Tseng: Consultant; Cellarity, LyGenesis. Funding American Heart Association (903968)

Histamine signaling in the bed nucleus of the stria terminalis modulates stress-induced anxiety

BackgroundAnxiety disorder is one of the most prevalent psychiatric disorders. Intriguingly, dysfunction of the central histaminergic system, which is recognized as a general regulator for whole-brain activity, may result in anxiety, suggesting an involvement of the central histaminergic signaling in the modulation of anxiety. However, the neural mechanisms involved have not been fully identified. MethodsHere, we examined the effect of histaminergic signaling in the bed nucleus of the stria terminalis (BNST) on anxiety-like behaviors both in normal and acute restraint stressed male rats by using anterograde tracing, immunofluorescence, qPCR, neuropharmacology, molecular manipulation and behavioral tests. ResultsWe found that histaminergic neurons in the hypothalamus send direct projections to the BNST, which forms a part of the circuitry involved in stress and anxiety. Infusion of histamine into the BNST produced anxiogenic effect. Moreover, histamine H1 and H2 receptors are expressed and distributed in the BNST neurons. Blockade of histamine H1 or H2 receptors in the BNST did not affect anxiety-like behaviors in normal rats, but ameliorated anxiogenic effect induced by acute restraint stress. Furthermore, knockdown of H1 or H2 receptors in the BNST induced anxiolytic effect in acute restraint stressed rats, which confirmed the pharmacological results. LimitationsA single dose of histamine receptor antagonist was used. ConclusionsTogether, these findings demonstrate a novel mechanism for the central histaminergic system in the regulation of anxiety, and suggest that inhibition of histamine receptors may be a useful strategy for treating anxiety disorder.

Brain mapping: topography of neurons and their transmitters involved in various brain functions.

Use of the demanding techniques microdialysis or push-pull superfusion makes it possible to identify neurons in distinct brain areas involved in central control of peripheral functions, thus enabling brain mapping. Investigations with the push-pull superfusion technique have shown that mainly catecholaminergic neurons of the posterior and anterior hypothalamus, the locus coeruleus, and the nucleus of the solitary tract are of crucial importance for blood pressure regulation. Experimentally induced blood pressure changes also modify the release of histamine, glutamate, and taurine in the posterior hypothalamus and of serotonin in the locus coeruleus. Furthermore, histaminergic neurons of the nucleus accumbens are involved in memory, serotonergic neurons of the locus coeruleus in response to noxious stimuli, while nitric oxide of striatum has been implicated in neurotoxicity elicited by amphetamines. The involvement of several neurons in one brain function is discussed.

Galanin inhibition of wake-active histaminergic neurons

Histaminergic neurons are a population of wake-active neurons confined to the tuberomammillary nucleus (TMN) in the posterior hypothalamus. They form a crucial component of the ‘sleep switch’ in the brain and promote arousal when activated. The histaminergic neurons are strongly innervated by ventrolateral preoptic area (VLPO) neurons expressing galanin, a neuropeptide associated with sleep promotion. While recent studies have confirmed the importance of VLPO projections to the TMN in initiating and maintaining sleep, the ability of galanin to modulate the activity of the wake-promoting histaminergic neurons of the TMN has largely been overlooked. Therefore, we aimed to determine the mechanisms by which galanin alters the electrical excitability of genetically identified histaminergic neurons. We hypothesized that galanin inhibits histaminergic neuron activity via direct post-synaptic activation of galanin 1 receptors (GalR1). Whole-cell patch-clamp electrophysiology was performed on hypothalamic brain slices from mice expressing tdTomato fluorescence in cells expressing histidine decarboxylase (HDC), the sole enzyme required for histamine synthesis (HDCCre::tdTomato mice). RNAscope ® in situ hybridization was used to explore Gal1R mRNA expression in HDC expressing neurons. Whole-cell current-clamp recordings in male mice revealed that galanin (100nM) inhibits the majority of HDC neurons. The galanin-induced inhibition was associated with a hyperpolarization of the membrane potential and a decrease in firing frequency. Consistent with our hypothesis, a selective galanin 2 receptor (Gal2R) agonist (M1145 - 200nM) had no effect on male HDC neuron activity. RNAscope ® studies in male mice revealed co-expression of Gal1R mRNA in a large proportion of HDC-expressing neurons. Interestingly, the galanin-induced inhibition of HDC neuron electrical excitability was less pronounced in female mice. Overall, our data point to an important role of post-synaptic Gal1Rs expressed on histaminergic neurons in mediating galanin’s inhibitory effects in the TMN. Our data also suggest that sex differences exist in histaminergic neuron responsiveness to galanin. These findings are consistent with the idea that some of the sleep promoting effects of VLPO neuron activation occur through galanin’s ability to inhibit the wake-active histaminergic neurons. Sleep Research Society (SRS), Canada First Research Excellence Fund (Sentinel North Partnered Research Chair in Sleep Pharmacometabolism), Fondation Institut Universitaire de Cardiologie et de Pneumologie de Quebec (FIUCPQ), Fonds de recherche de Quebec - Sante (FRQS). This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.