Dissociable encoding of motivated behavior by parallel thalamo-striatal projections.

The successful pursuit of goals requires the coordinated execution and termination of actions that lead to positive outcomes. This process relies on motivational states that are guided by internal drivers, such as hunger or fear. However, the mechanisms by which the brain tracks motivational states to shape instrumental actions are not fully understood. The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus that shapes motivated behaviors via its projections to the nucleus accumbens (NAc)1,2,3,4,5,6,7,8 and monitors internal state via interoceptive inputs from the hypothalamus and brainstem.3,9,10,11,12,13,14 Recent studies indicate that the PVT can be subdivided into two major neuronal subpopulations, namely PVTD2(+) and PVTD2(-), which differ in genetic identity, functionality, and anatomical connectivity to other brain regions, including the NAc.4,15,16 In this study, we used fiber photometry to investigate the in vivo dynamics of these two distinct PVT neuronal types in mice performing a foraging-like behavioral task. We discovered that PVTD2(+) and PVTD2(-) neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVTD2(+) neuronal population mirrored motivation parameters such as vigor and satiety. Similarly, PVTD2(-) neurons also mirrored some of these parameters, but to a much lesser extent. Importantly, these features were largely preserved when activity in PVT projections to the NAc was selectively assessed. Collectively, our results highlight the existence of two parallel thalamo-striatal projections that participate in the dynamic regulation of goal pursuits and provide insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.

Electroacupuncture pretreatment mediates sympathetic nerves to alleviate myocardial ischemia-reperfusion injury via CRH neurons in the paraventricular nucleus of the hypothalamus.

BACKGROUND: Myocardial ischemia-reperfusion can further exacerbate myocardial injury and increase the risk of death. Our previous research found that the paraventricular nucleus (PVN) of the hypothalamus plays a crucial role in the improvement of myocardial ischemia-reperfusion injury (MIRI) by electroacupuncture (EA) pretreatment, but its mechanism of action is still unclear. CRH neurons exhibit periodic concentrated expression in PVN, but further research is needed to determine whether they are involved in the improvement of MIRI by EA pretreatment. Meanwhile, numerous studies have shown that changes in sympathetic nervous system innervation and activity are associated with many heart diseases. This study aims to investigate whether EA pretreatment improves MIRI through sympathetic nervous system mediated by PVNCRH neurons. METHODS: Integrated use of fiber-optic recording, chemical genetics and other methods to detect relevant indicators: ECG signals were acquired through Powerlab standard II leads, and LabChart 8 calculated heart rate, ST-segment offset, and heart rate variability (HRV); Left ventricular ejection fraction (LVEF), left ventricular short-axis shortening (LVFS), left ventricular end-systolic internal diameter (LVIDs) and interventricular septal thickness (IVSs) were measured by echocardiography; Myocardial infarct area (IA) and area at risk (AAR) were calculated by Evans-TTC staining. Pathological changes in cardiomyocytes were observed by HE staining; Changes in PVNCRH neuronal activity were recorded by fiber-optic photometry; Sympathetic nerve discharges were recorded for in vivo electrophysiology; NE and TH protein expression was assayed by Western blot. RESULTS: Our data indicated that EA pretreatment can effectively alleviate MIRI. Meanwhile, we found that in the MIRI model, the number and activity of CRH neurons co labeled with c-Fos in the PVN area of the rat brain increased, and the frequency of sympathetic nerve discharge increased. EA pretreatment could reverse this change. In addition, the results of chemical genetics indicated that inhibiting PVNCRH neurons has a similar protective effect on MIRI as EA pretreatment, and the activation of PVNCRH neurons can counteract this protective effect. CONCLUSION: EA pretreatment can inhibit PVNCRH neurons and improve MIRI by inhibiting sympathetic nerve, which offers fresh perspectives on the application of acupuncture in the management of cardiovascular disease.

Paraventricular thalamus to nucleus accumbens circuit activation decreases long-term relapse of alcohol-seeking behaviour in male mice.

BACKGROUND: Some studies have highlighted the crucial role of aversion in addiction treatment. The pathway from the anterior paraventricular thalamus (PVT) to the shell of the nucleus accumbens (NAc) has been reported as an essential regulatory pathway for processing aversion and is also closely associated with substance addiction. However, its impact on alcohol addiction has been relatively underexplored. Therefore, this study focused on the role of the PVT-NAc pathway in the formation and relapse of alcohol addiction-like behaviour, offering a new perspective on the mechanisms of alcohol addiction. RESULTS: The chemogenetic inhibition of the PVT-NAc pathway in male mice resulted in a notable decrease in the establishment of ethanol-induced conditioned place aversion (CPA), and NAc-projecting PVT neurons were recruited due to aversive effects. Conversely, activation of the PVT-NAc pathway considerably impeded the formation of ethanol-induced conditioned place preference (CPP). Furthermore, during the memory reconsolidation phase, activation of this pathway effectively disrupted the animals' preference for alcohol-associated contexts. Whether it was administered urgently 24 h later or after a long-term withdrawal of 10 days, a low dose of alcohol could still not induce the reinstatement of ethanol-induced CPP. CONCLUSIONS: Our results demonstrated PVT-NAc circuit processing aversion, which may be one of the neurobiological mechanisms underlying aversive counterconditioning, and highlighted potential targets for inhibiting the development of alcohol addiction-like behaviour and relapse after long-term withdrawal.

Male rat hypothalamic extraretinal photoreceptor Opsin3 is sensitive to osmotic stimuli and light.

The light-sensitive protein Opsin 3 (Opn3) is present throughout the mammalian brain; however, the role of Opn3 in this organ remains unknown. Since Opn3 encoded mRNA is modulated in the supraoptic and paraventricular nucleus of the hypothalamus in response to osmotic stimuli, we have explored by in situ hybridization the expression of Opn3 in these nuclei. We have demonstrated that Opn3 is present in the male rat magnocellular neurones expressing either the arginine vasopressin or oxytocin neuropeptides and that Opn3 increases in both neuronal types in response to osmotic stimuli, suggesting that Opn3 functions in both cell types and that it might be involved in regulating water balance. Using rat hypothalamic organotypic cultures, we have demonstrated that the hypothalamus is sensitive to light and that the observed light sensitivity is mediated, at least in part, by Opn3. The data suggests that hypothalamic Opn3 can mediate a light-sensitive role to regulate circadian homeostatic processes.

The temporal and spatial pattern of leptin receptor-expressing cells in the developing mouse hypothalamus.

The arcuate nucleus is a crucial hypothalamic brain region involved in regulating body weight homeostasis. Neurons within the arcuate nucleus respond to peripheral metabolic signals, such as leptin, and relay these signals via neuronal projections to brain regions both within and outside the hypothalamus, ultimately causing changes in an animal's behaviour and physiology. There is a substantial amount of evidence to indicate that leptin is intimately involved with the postnatal development of arcuate nucleus melanocortin circuitry. Further, it is clear that leptin signalling directly in the arcuate nucleus is required for circuitry development. However, as leptin receptor long isoform (Leprb) mRNA is expressed in multiple nuclei within the developing hypothalamus, including the postsynaptic target regions of arcuate melanocortin projections, this raises the possibility that leptin also signals in these nuclei to promote circuitry development. Here, we used RT-qPCR and RNAscope® to reveal the spatio-temporal pattern of Leprb mRNA in the early postnatal mouse hypothalamus. We found that Leprb mRNA expression increased significantly in the arcuate nucleus, ventromedial nucleus and paraventricular nucleus of the hypothalamus from P8, in concert with the leptin surge. In the dorsomedial nucleus of the hypothalamus, increases in Leprb mRNA were slightly later, increasing significantly from P12. Using duplex RNAscope®, we found Leprb co-expressed with Sim1, Pou3f2, Mc4r and Bdnf in the paraventricular nucleus at P8. Together, these data suggest that leptin may signal in a subset of neurons postsynaptic to arcuate melanocortin neurons, as well as within the arcuate nucleus itself, to promote the formation of arcuate melanocortin circuitry during the early postnatal period.

Chronic Intermittent Hypobaric Hypoxia Reduces Hypothalamic N-Methyl-d-Aspartate Receptor Activity and Sympathetic Outflow in Spontaneously Hypertensive Rats.

Guo, Xinqi, Hongyu Ma, Ziye Cui, Qiyue Zhao, Ying Zhang, Lu Jia, Liping Zhang, Hui Guo, Xiangjian Zhang, Yi Zhang, Yue Guan, and Huijie Ma. Chronic intermittent hypobaric hypoxia reduces hypothalamic N-Methyl-d-Aspartate Receptor activity and sympathetic outflow in spontaneously hypertensive rats. High Alt Med Biol. 25:77-88, 2024. Objective: This study aims to determine the role of hypothalamic renin-angiotensin system (RAS) in the antihypertensive effect of chronic intermittent hypobaric hypoxia (CIHH). Methods: Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs) received 35 days of hypobaric hypoxia simulating an altitude of 4,000 m, 5 h/day. The levels of RAS, blood pressure, and N-methyl-d-aspartate receptor (NMDAR) activities of hypothalamic paraventricular nucleus (PVN) presympathetic neurons from each group of rats were determined. Results: The systolic blood pressure, diastolic blood pressure, and mean arterial blood pressure (MAP) of SHRs significantly decreased from the third week of CIHH treatment. This blood pressure reduction effect could be maintained for at least 2 weeks after stopping the CIHH treatment. CIHH treatment also attenuated the decrease in MAP and renal sympathetic nerve activity induced by hexamethonium administration in SHRs, but not in WKY rats. Furthermore, CIHH reversed the increase in serum angiotensin (Ang)II concentration and the expression of PVN angiotensin-converting enzyme (ACE) and AngII type 1 (AT1) receptors, as well as the decrease in serum Ang1-7 concentration and the expression of PVN ACE2 and Mas receptors in SHRs. In addition, the administration of CIHH resulted in a reduction in the frequency of miniature excitatory postsynaptic currents and amplitude of NMDAR current in PVN presympathetic neurons of SHRs, which means that CIHH decreased the pre- and postsynaptic NMDAR activity of PVN presympathetic neurons in SHRs. However, pretreatment with A779 (a Mas receptor blocker) or AngII abrogated the above effects. Meanwhile, Ang1-7 pretreatment mimicked the CIHH effect on pre- and postsynaptic NMDAR activity of presympathetic neurons in SHRs. Conclusions: Our data indicate that CIHH reduces pre- and postsynaptic NMDAR activity of PVN presympathetic neurons, sympathetic outflow, and blood pressure by decreasing the activity of the ACE/AngII/AT1 axis and increasing the activity of ACE2/Ang1-7/Mas axis in the hypothalamus in hypertension.

Involvement of the ipsilateral-to-the-pain anterior-superior hypothalamic subunit in chronic cluster headache.

BACKGROUND: Despite hypothalamus has long being considered to be involved in the pathophysiology of cluster headache, the inconsistencies of previous neuroimaging studies and a limited understanding of the hypothalamic areas involved, impede a comprehensive interpretation of its involvement in this condition. METHODS: We used an automated algorithm to extract hypothalamic subunit volumes from 105 cluster headache patients (57 chronic and 48 episodic) and 59 healthy individuals; after correcting the measures for the respective intracranial volumes, we performed the relevant comparisons employing logist regression models. Only for subunits that emerged as abnormal, we calculated their correlation with the years of illness and the number of headache attacks per day, and the effects of lithium treatment. As a post-hoc approach, using the 7 T resting-state fMRI dataset from the Human Connectome Project, we investigated whether the observed abnormal subunit, comprising the paraventricular nucleus and preoptic area, shows robust functional connectivity with the mesocorticolimbic system, which is known to be modulated by oxytocin neurons in the paraventricular nucleus and that is is abnormal in chronic cluster headache patients. RESULTS: Patients with chronic (but not episodic) cluster headache, compared to control participants, present an increased volume of the anterior-superior hypothalamic subunit ipsilateral to the pain, which, remarkably, also correlates significantly with the number of daily attacks. The post-hoc approach showed that this hypothalamic area presents robust functional connectivity with the mesocorticolimbic system under physiological conditions. No evidence of the effects of lithium treatment on this abnormal subunit was found. CONCLUSIONS: We identified the ipsilateral-to-the-pain antero-superior subunit, where the paraventricular nucleus and preoptic area are located, as the key hypothalamic region of the pathophysiology of chronic cluster headache. The significant correlation between the volume of this area and the number of daily attacks crucially reinforces this interpretation. The well-known roles of the paraventricular nucleus in coordinating autonomic and neuroendocrine flow in stress adaptation and modulation of trigeminovascular mechanisms offer important insights into the understanding of the pathophysiology of cluster headache.

Characterization of social hierarchy formation and maintenance in same-sex, group-housed male and female C57BL/6 J mice.

Social hierarchies are a prevalent feature of all animal groups, and an individual's rank within the group can significantly affect their overall health, typically at the greatest expense of the lowest-ranked individuals, or omegas. These subjects have been shown to exhibit various stress-related phenotypes, such as increased hypothalamic-pituitary axis activity and increased amygdalar corticotropin-releasing factor levels compared to higher-ranked subjects. However, these findings have been primarily characterized in males and in models requiring exhibition of severe aggression. The goals of the current study, therefore, were to characterize the formation and maintenance of social hierarchies using the tube test and palatable liquid competition in same-sex groups of male and female C57BL/6 J mice. We also aimed to examine the effects of tube test-determined social rank on plasma and hypothalamic oxytocin and vasopressin levels, peptides with established roles in social behaviors and the stress response. Lastly, we assessed the effects of environmental enrichment and length of testing on the measures outlined above. Overall, we demonstrated that males and females develop social hierarchies and that these hierarchies can be determined using the tube test. While we were unable to establish a consistent connection between peptide levels and social rank, we observed transient changes in these peptides reflecting complex interactions between social rank, sex, environment, and length of testing. We also found that many male and female omegas began to exhibit passive coping behavior after repeated tube test losses, demonstrating the potential of this assay to serve as a model of chronic, mild psychosocial stress.

Neonatal di-(2-ethylhexyl)phthalate exposure induces permanent alterations in secretory CRH neuron characteristics in the hypothalamus paraventricular region of adult male rats.

Corticotrophin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) play a critical role in the modulation of the hypothalamic-pituitary-adrenal (HPA) axis. Early-life exposure to di-(2-ethylhexyl) phthalate (DEHP) has been associated with an increased risk of developing psychiatric disorders in adulthood. The present work was designed to explore the impact of neonatal exposure to DEHP on adult PVN CRH neuronal activity. DEHP or vehicle was given to male rat pups from PND16 to PND22. Then, anxiety-like behaviors, serum corticosterone and testosterone, immunohistochemistry, western blotting, fluorescence in situ hybridization and acute ex vivo slice electrophysiological recordings were used to evaluate the influence of DEHP on adult PVN secretory CRH neurons. Neonatal DEHP-exposed rats exhibited enhanced anxiety-like behaviors in adults, with an increase in CORT. Secretory CRH neurons showed higher spontaneous firing activity but could be inhibited by GABAAR blockers. CRH neurons displayed fewer firing spikes, prolonged first-spike latency, depolarizing shifts in GABA reversal potential and strengthened GABAergic inputs, as indicated by increases in the frequency and amplitude of sIPSCs. Enhancement of GABAergic transmission was accompanied by upregulated expression of GAD67 and downregulated expression of GABABR1, KCC2 and GAT1. These findings suggest that neonatal exposure to DEHP permanently altered the characteristics of secretory CRH neurons in the PVN, which may contribute to the development of psychiatric disorders later in life.

Oxytocin neurons mediate stress-induced social memory impairment.

Oxytocin has long been thought to play a substantial role in social behaviors, such as social attachment and parenting behavior. However, how oxytocin neurons respond to social and non-social stimuli is largely unknown, especially in high temporal resolution. Here, we recorded the in vivo real-time responses of oxytocin neurons in the paraventricular nucleus of the hypothalamus (PVN) in freely behaving mice. Our results revealed that oxytocin neurons were activated more significantly by stressors than social stimuli. The activation of oxytocin neurons was precisely correlated with struggling behavior during stress. Furthermore, we found that oxytocin mediated stress-induced social memory impairment. Our results reveal an important role of PVN oxytocin neurons in stress-induced social amnesia.

Smith-Magenis syndrome protein RAI1 regulates body weight homeostasis through hypothalamic BDNF-producing neurons and neurotrophin downstream signalling.

Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. RAI1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (BDNF) and its downstream signalling are disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all BDNF-producing cells or from BDNF-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation decreased the intrinsic excitability of PVHBDNF neurons. Chronic treatment of SMS mice with LM22A-4 engages neurotrophin downstream signalling and delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that RAI1 regulates body weight and metabolic function through hypothalamic BDNF-producing neurons and that targeting neurotrophin downstream signalling might improve associated SMS phenotypes.

Distinctiveness and continuity in transcriptome and connectivity in the anterior-posterior axis of the paraventricular nucleus of the thalamus.

The paraventricular nucleus of the thalamus (PVT) projects axons to multiple areas, mediates a wide range of behaviors, and exhibits regional heterogeneity in both functions and axonal projections. Still, questions regarding the cell types present in the PVT and the extent of their differences remain inadequately addressed. We applied single-cell RNA sequencing to depict the transcriptomic characteristics of mouse PVT neurons. We found that one of the most significant variances in the PVT transcriptome corresponded to the anterior-posterior axis. While the single-cell transcriptome classified PVT neurons into five types, our transcriptomic and histological analyses showed continuity among the cell types. We discovered that anterior and posterior subpopulations had nearly non-overlapping projection patterns, while another population showed intermediate patterns. In addition, these subpopulations responded differently to appetite-related neuropeptides, with their activation showing opposing effects on food consumption. Our studies unveiled the contrasts and the continuity of PVT neurons that underpin their function.

Modulating activity of PVN neurons prevents atrial fibrillation induced circulation dysfunction by electroacupuncture at BL15.

BACKGROUND: Circulation dysfunction is a major contributing factor to thrombosis in patients with atrial fibrillation (AF) for which effective interventions are lacking. Growing evidence indicates that regulating the paraventricular nucleus (PVN), an autonomic control center, could offer a novel strategy for treating cardiovascular and circulatory diseases. Concurrently, electroacupuncture (EA) at Xinshu (BL15), a form of peripheral nerve stimulation, has shown efficacy in treating several cardiovascular conditions, although its specific mechanism remains unclear. This study aimed to assess the impact of EA at BL15 on circulatory dysfunction in a rat AF model and investigate the pivotal role of PVN neuronal activity. METHODS: To mimic the onset of AF, male SD rats received tail intravenous injection of ACh-CaCl2 and were then subjected to EA at BL15, sham EA, or EA at Shenshu (BL23). Macro- and micro-circulation function were evaluated using in vivo ultrasound imaging and laser doppler testing, respectively. Vasomotricity was assessed by measuring dimension changes during vascular relaxation and contraction. Vascular endothelial function was measured using myograph, and the activation of the autonomic nerve system was evaluated through nerve activity signals. Additionally, chemogenetic manipulation was used to block PVN neuronal activation to further elucidate the role of PVN activation in the prevention of AF-induced blood circulation dysfunction through EA treatment. RESULTS: Our data demonstrate that EA at BL15, but not BL23 or sham EA, effectively prevented AF-induced macro- and micro-circulation dysfunction. Furthermore, EA at BL15 restored AF-induced vasomotricity impairment. Additionally, EA treatment prevented abnormal activation of the autonomic nerve system induced by AF, although it did not address vascular endothelial dysfunction. Importantly, excessive activation of PVN neurons negated the protective effects of EA treatment on AF-induced circulation dysfunction in rats. CONCLUSION: These results indicate that EA treatment at BL15 modulates PVN neuronal activity and provides protection against AF-induced circulatory dysfunction.

Capsaicin improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the hypothalamic paraventricular nucleus.

BACKGROUND: Hypertension has seriously affected a large part of the adult and elderly population. The complications caused by hypertension are important risk factors for cardiovascular disease accidents. Capsaicin, a pungent component of chili pepper has been revealed to improve hypertension. However, its potential mechanism in improving hypertension remains to be explored. PURPOSE: In the present study, we aimed to investigate whether capsaicin could attenuate the SIRT1/NF-κB/MAPKs pathway in the paraventricular nucleus of hypothalamus (PVN). METHODS: We used spontaneous hypertensive rats (SHRs) as animal model rats. Micro osmotic pump was used to give capsaicin through PVN for 28 days, starting from age12-week-old. RESULTS: The results showed that capsaicin significantly reduced blood pressure from the 16th day of infusion onward. At the end of the experimental period, we measured cardiac hypertrophy index and the heart rate (HR), and the results showed that the cardiac hypertrophy and heart rate of rats was significantly improved upon capsaicin chronic infusion. Norepinephrine (NE) and epinephrine (EPI) in plasma of SHRs treated with capsaicin were also decreased. Additionally, capsaicin increased the protein expression and number of positive cells of SIRT1 and the 67-kDa isoform of glutamate decarboxylase (GAD67), decreased the production of reactive oxygen species (ROS), number of positive cells of NOX2, those of Angiotensin Converting Enzyme (ACE) and p-IKKß, tyrosine hydroxylase (TH), the gene expression levels of NOX4 and pro-inflammatory cytokines. Capsaicin also decreased the relative protein expressions of protein in MAPKs pathway. CONCLUSION: Current data indicated that capsaicin within the PVN improves hypertension and cardiac hypertrophy via SIRT1/NF-κB/MAPKs pathway in the PVN of SHRs, supporting its potential as candidate drug for preventing and improving hypertension.

Effects of electroacupuncture at KI3 and ST36 on the hypothalamic paraventricular nucleus in a rat model of chronic glomerulonephritis.

OBJECTIVE: The hypothalamic paraventricular nucleus (PVN) acts as a critical integrating center of endocrine/autonomic responses and regulates visceral functional activities. However, its involvement in electroacupuncture (EA) treatment of chronic glomerulonephritis (CGN) remains unclear. METHODS: Over four experiments, we randomized 111 rats into: control, untreated model (CGN) or EA-treated model (CGN + EA) groups, a model group receiving EA after PVN damage (CGN + EA + Lesion) or untreated model groups injected with adeno-associated viral vectors encoding human M4 muscarinic receptor (CGN + hM4D) or enhanced green fluorescent protein (CGN + EGFP). CGN was modeled by intraperitoneal injection of bovine serum albumin for 2 weeks. Rats in the CGN + EA and CGN + EA + Lesion groups received EA at bilateral ST36 and KI3 for 14 days. Urine/serum samples were collected to evaluate inflammatory factors and changes in renal function. RESULTS: EA inhibited the release of interleukin (IL)-6, tumor necrosis factor (TNF)-α and IL-1ß, and decreased urine protein (PRO), creatinine (Cre) and blood urea nitrogen (BUN) levels. PVN damage influenced the effect of EA on the levels of these parameters. EA appeared to inhibit the firing frequency and spectral energy of PVN neurons. In the viral vector experiment, levels of PRO, Cre, IL-6, IL-1ß and TNF-α in the CGN group were increased in CGN versus control groups (p < 0.0001), decreased in CGN + hM4D versus CGN groups (p < 0.05) and did not differ between CGN + EGFP and control groups (p > 0.05). CONCLUSION: Our findings indicate that EA at ST36 and KI3 improves CGN in this rat model by weakening the activity of PVN neurons, alleviating impairment of renal function impairment and restricting the release of inflammatory factors.

ß-asarone prolongs sleep via regulating the level of glutamate in the PVN.

People of all ages could suffer from sleep disorders, which are increasingly recognized as common manifestations of neurologic disease. Acorus tatarinowii is a herb that has been used in traditional medicine to promote sleep. ß-asarone, as the main component of volatile oil obtained from Acorus tatarinowii, may be the main contributor to the sleeping-promoting efficacy of Acorus tatarinowii. In the study, adult male C57BL/6 mice were administered ß-asarone at 12.5 mg/kg, 25 mg/kg, and 50 mg/kg. Behavioral experiments showed that ß-asarone at 25 mg/kg could significantly improve sleep duration. It was also observed that the proportion of NREM (Non-Rapid Eye Movement) sleep increased considerably after administration of ß-asarone. In the PVN (paraventricular nucleus of hypothalamus) region of the hypothalamus, it was observed that the glutamate content decreased after ß-asarone treatment. At the same time, the expression of VGLUT2 (vesicular glutamate transporters 2) decreased while the expression of GAD65 (glutamic acid decarboxylase 65) and GABARAP (GABA Type A Receptor-Associated Protein) increased in the hypothalamus, suggesting that ß-asarone may suppress arousal by reducing glutamate and promoting transformation of glutamate to the inhibitory neurotransmitter GABA (γ-aminobutyric acid). This study is the first to focus on the association between ß-asarone and sleep, shedding perspectives for pharmacological applications of ß-asarone and providing a new direction for future research.

Alterations in pituitary adenylate cyclase-activating polypeptide in major depressive disorder, bipolar disorder, and comorbid depression in Alzheimer's disease in the human hypothalamus and prefrontal cortex.

BACKGROUND: Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) is involved in the stress response and may play a key role in mood disorders, but no information is available on PACAP for the human brain in relation to mood disorders. METHODS: PACAP-peptide levels were determined in a major stress-response site, the hypothalamic paraventricular nucleus (PVN), of people with major depressive disorder (MDD), bipolar disorder (BD) and of a unique cohort of Alzheimer's disease (AD) patients with and without depression, all with matched controls. The expression of PACAP-(Adcyap1mRNA) and PACAP-receptors was determined in the MDD and BD patients by qPCR in presumed target sites of PACAP in stress-related disorders, the dorsolateral prefrontal cortex (DLPFC) and anterior cingulate cortex (ACC). RESULTS: PACAP cell bodies and/or fibres were localised throughout the hypothalamus with differences between immunocytochemistry and in situ hybridisation. In the controls, PACAP-immunoreactivity-(ir) in the PVN was higher in women than in men. PVN-PACAP-ir was higher in male BD compared to the matched male controls. In all AD patients, the PVN-PACAP-ir was lower compared to the controls, but higher in AD depressed patients compared to those without depression. There was a significant positive correlation between the Cornell depression score and PVN-PACAP-ir in all AD patients combined. In the ACC and DLPFC, alterations in mRNA expression of PACAP and its receptors were associated with mood disorders in a differential way depending on the type of mood disorder, suicide, and psychotic features. CONCLUSION: The results support the possibility that PACAP plays a role in mood disorder pathophysiology.

Oxytocin promotes prefrontal population activity via the PVN-PFC pathway to regulate pain.

Neurons in the prefrontal cortex (PFC) can provide top-down regulation of sensory-affective experiences such as pain. Bottom-up modulation of sensory coding in the PFC, however, remains poorly understood. Here, we examined how oxytocin (OT) signaling from the hypothalamus regulates nociceptive coding in the PFC. In vivo time-lapse endoscopic calcium imaging in freely behaving rats showed that OT selectively enhanced population activity in the prelimbic PFC in response to nociceptive inputs. This population response resulted from the reduction of evoked GABAergic inhibition and manifested as elevated functional connectivity involving pain-responsive neurons. Direct inputs from OT-releasing neurons in the paraventricular nucleus (PVN) of the hypothalamus are crucial to maintaining this prefrontal nociceptive response. Activation of the prelimbic PFC by OT or direct optogenetic stimulation of oxytocinergic PVN projections reduced acute and chronic pain. These results suggest that oxytocinergic signaling in the PVN-PFC circuit constitutes a key mechanism to regulate cortical sensory processing.

Elucidating the central anorexigenic mechanism of glucagon-like peptide 1 in Japanese quail (Coturnix japonica).

Glucagon-like peptide 1 (GLP-1) elicits a potent reduction in food intake, although the central mechanism mediating this appetite-suppressive effect is not fully understood in all species. To begin to elucidate the molecular mechanisms in quail, we administered GLP-1 via intracerebroventricular (ICV) injection to 7-day-old Japanese quail (Coturnix japonica) and determined effects on food and water intake, behavior, and brain nucleus activation. We observed a reduction in food and water intake, with the lowest effective dose being 0.01 nmol. Quail injected with GLP-1 displayed fewer steps, feeding pecks, exploratory pecks, and jumps, while time spent sitting increased. We quantified c-Fos immunoreactivity at 60 min post-injection in hypothalamic and brainstem nuclei that mediate food intake and determined that the hypothalamic paraventricular nucleus (PVN), and nucleus of the solitary tract and area postrema of the brainstem were activated in response to GLP-1. In conclusion, these results suggest that GLP-1 induces anorexigenic effects that are likely mediated at the level of the PVN and brainstem.