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Proceedings of the National Academy of... Jul 2023
PubMed: 37463219
DOI: 10.1073/pnas.2310935120 -
Biomedicine & Pharmacotherapy =... Sep 2023Sleep disturbances are commonly non-motor symptoms in Parkinson's diseases (PD). However, standard dopamine replacement therapies for the treatment of motor symptoms...
Sleep disturbances are commonly non-motor symptoms in Parkinson's diseases (PD). However, standard dopamine replacement therapies for the treatment of motor symptoms often prove inadequate in combating sleep disturbances. Previous studies conducted by our research group have reported the neuroprotective effects of tenuigenin, a natural extract from Polygala tenuifolia root, which has been traditionally employed in treating insomnia. The objective of this study was to investigate the potential of tenuigenin in modulating sleep-wake behaviors and elucidate the underlying mechanisms. We employed EEG/EMG recordings to evaluate the impact of tenuigenin on sleep-wake profiles. Furthermore, we utilized c-Fos immunostaining, whole-cell patch clamping and local field potentials (LFP) recording to explore the mechanisms involved in sleep-promoting effects of tenuigenin. Additionally, we examined the effects of tenuigenin on sleep-promoting in MPTP PD mice. Here, we found tenuigenin demonstrated a significant increase in NREM sleep and a reduction in sleep latency in mice, without altering the EEG power density. Moreover, tenuigenin increased c-Fos expression in the ventrolateral preoptic area (VLPO) and stimulated sleep-promoting neurons in VLPO. The sleep-promoting effects of tenuigenin were abolished when mice were pretreated with flumazenil, an antagonist at the benzodiazepine site of the GABA receptor. Furthermore, tenuigenin was found to ameliorate sleep disturbances in MPTP-induced mice. The results suggesting that tenuigenin facilitated a type of NREM sleep comparable to physiological NREM sleep through interaction with the GABA receptor. Additionally, tenuigenin demonstrated improvements in sleep disturbances in MPTP-induced PD mice, suggesting its potential as a sleep-promoting substance, particularly for PD patients experiencing sleep disturbances.
Topics: Mice; Animals; Receptors, GABA-A; Parkinson Disease; Eye Movements; Sleep; Electroencephalography
PubMed: 37531785
DOI: 10.1016/j.biopha.2023.115259 -
Endocrine Journal Jun 2024In the early 2000s, metastin, an endogenous ligand for G protein-coupled receptor 54 (GPR54), was discovered in human placental extracts. In 2003, GPR54 receptor...
In the early 2000s, metastin, an endogenous ligand for G protein-coupled receptor 54 (GPR54), was discovered in human placental extracts. In 2003, GPR54 receptor mutations were found in a family with congenital hypogonadotropic hypogonadism. Metastin was subsequently renamed kisspeptin after its coding gene, Kiss1. Since then, studies in mice and other animals have revealed that kisspeptin is located at the apex of the hypothalamic-pituitary-gonadal axis and regulates reproductive functions by modulating gonadotropin-releasing hormone (GnRH). In rodents, kisspeptin (Kiss1) neurons localize to two regions, the hypothalamic arcuate nucleus (ARC) and the anteroventral periventricular nucleus (AVPV). ARC Kiss1 neurons co-express neurokinin B (NKB) and dynorphin and are thus termed KNDy neurons. Kiss1 neurons in humans are concentrated in the infundibular nucleus (equivalent to the ARC), with few Kiss1 neurons localized to the preoptic area (equivalent to the AVPV), and the mechanisms underlying GnRH surge secretion in humans are poorly understood. However, peripheral administration of kisspeptin to humans promotes gonadotropin secretion, and administration of kisspeptin to patients with hypothalamic amenorrhea or congenital hypogonadotropic hypogonadism restores the pulsatile secretion of GnRH/luteinizing hormone. Thus, kisspeptin undoubtedly plays an important role in reproductive function in humans. Studies are currently underway to develop kisspeptin receptor agonists or antagonists for clinical application. Modification of KNDy neurons by NKB agonists/antagonists is also being attempted to develop therapeutic agents for various menstrual abnormalities, including polycystic ovary syndrome and menopausal hot flashes. Here, we review the role of kisspeptin in humans and its clinical applications.
PubMed: 38866494
DOI: 10.1507/endocrj.EJ24-0006 -
The Journal of Comparative Neurology Aug 2023Islet-1 (Isl1) is one of the most conserved transcription factors in the evolution of vertebrates, due to its continuing involvement in such important functions as the...
Distribution of the transcription factor islet-1 in the central nervous system of nonteleost actinopterygian fish: Relationship with cholinergic and catecholaminergic systems.
Islet-1 (Isl1) is one of the most conserved transcription factors in the evolution of vertebrates, due to its continuing involvement in such important functions as the differentiation of motoneurons, among other essential roles in cell fate in the forebrain. Although its functions are thought to be similar in all vertebrates, the knowledge about the conservation of its expression pattern in the central nervous system goes as far as teleosts, leaving the basal groups of actinopterygian fishes overlooked, despite their important phylogenetic position. In order to assess the extent of its conservation among vertebrates, we studied its expression pattern in the central nervous system of selected nonteleost actinopterygian fishes. By means of immunohistochemical techniques, we analyzed the Isl1 expression in the brain, spinal cord, and sensory ganglia of the cranial nerves of young adult specimens of the cladistian species Polypterus senegalus and Erpetoichthys calabaricus, the chondrostean Acipenser ruthenus, and the holostean Lepisosteus oculatus. We also detected the presence of the transcription factor Orthopedia and the enzymes tyrosine hydroxylase (TH) and choline acetyltransferase (ChAT) to better locate all the immunoreactive structures in the different brain areas and to reveal the possible coexpression with Isl1. Numerous conserved features in the expression pattern of Isl1 were observed in these groups of fishes, such as populations of cells in the subpallial nuclei, preoptic area, subparaventricular and tuberal hypothalamic regions, prethalamus, epiphysis, cranial motor nuclei and sensory ganglia of the cranial nerves, and the ventral horn of the spinal cord. Double labeling of TH and Isl1 was observed in cells of the preoptic area, the subparaventricular and tuberal hypothalamic regions, and the prethalamus, while virtually all motoneurons in the hindbrain and the spinal cord coexpressed ChAT and Isl1. Altogether, these results show the high degree of conservation of the expression pattern of the transcription factor Isl1, not only among fish, but in the subsequent evolution of vertebrates.
Topics: Animals; Phylogeny; Central Nervous System; Brain; Fishes; Choline O-Acetyltransferase; Prosencephalon; Cholinergic Agents; Transcription Factors
PubMed: 37071579
DOI: 10.1002/cne.25484 -
Frontiers in Endocrinology 2023The neuroendocrine control of ovulation is orchestrated by neuronal circuits that ultimately drive the release of gonadotropin-releasing hormone (GnRH) from the...
BACKGROUND
The neuroendocrine control of ovulation is orchestrated by neuronal circuits that ultimately drive the release of gonadotropin-releasing hormone (GnRH) from the hypothalamus to trigger the preovulatory surge in luteinizing hormone (LH) secretion. While estrogen feedback signals are determinant in triggering activation of GnRH neurons, through stimulation of afferent kisspeptin neurons in the rostral periventricular area of the third ventricle (RP3V neurons), many neuropeptidergic and classical neurotransmitter systems have been shown to regulate the LH surge. Among these, several lines of evidence indicate that the monoamine neurotransmitter serotonin (5-HT) has an excitatory, permissive, influence over the generation of the surge, activation of type 2 5-HT (5-HT) receptors. The mechanisms through which this occurs, however, are not well understood. We hypothesized that 5-HT exerts its influence on the surge by stimulating RP3V neurons in a 5-HT receptor-dependent manner.
METHODS
We tested this using kisspeptin neuron-specific calcium imaging and electrophysiology in brain slices obtained from male and female mice.
RESULTS
We show that exogenous 5-HT reversibly increases the activity of the majority of RP3V neurons. This effect is more prominent in females than in males, is likely mediated directly at RP3V neurons and requires activation of 5-HT receptors. The functional impact of 5-HT on RP3V neurons, however, does not significantly vary during the estrous cycle.
CONCLUSION
Taken together, these data suggest that 5-HT receptor-mediated stimulation of RP3V neuron activity might be involved in mediating the influence of 5-HT on the preovulatory LH surge.
Topics: Mice; Female; Male; Animals; Preoptic Area; Kisspeptins; Serotonin; Neurons; Gonadotropin-Releasing Hormone; Receptors, Serotonin; Neurotransmitter Agents
PubMed: 37900129
DOI: 10.3389/fendo.2023.1212854 -
Cell and Tissue Research May 2024The natriuretic peptide (NP) family consists of cardiac NPs (ANP, BNP, and VNP) and brain NPs (CNPs) in teleosts. In addition to CNP1-4, a paralogue of CNP4 (named...
The natriuretic peptide (NP) family consists of cardiac NPs (ANP, BNP, and VNP) and brain NPs (CNPs) in teleosts. In addition to CNP1-4, a paralogue of CNP4 (named CNP4b) was recently discovered in basal teleosts including Japanese eel. Mammals have lost most Cnps during the evolution, but teleost cnps were conserved and diversified, suggesting that CNPs are important hormones for maintaining brain functions in teleost. The present study evaluated the potency of each Japanese eel CNP to their NP receptors (NPR-A, NPR-B, NPR-C, and NPR-D) overexpressed in CHO cells. A comprehensive brain map of cnps- and nprs-expressing neurons in Japanese eel was constructed by integrating the localization results obtained by in situ hybridization. The result showed that CHO cells expressing NPR-A and NPR-B induced strong cGMP productions after stimulation by cardiac and brain NPs, respectively. Regarding brain distribution of cnps, cnp1 is engaged in the ventral telencephalic area and periventricular area including the parvocellular preoptic nucleus (Pp), anterior/posterior tuberal nuclei, and periventricular gray zone of the optic tectum. cnp3 is found in the habenular nucleus and prolactin cells in the pituitary. cnp4 is expressed in the ventral telencephalic area, while cnp4b is expressed in the motoneurons in the medullary area. Such CNP isoform-specific localizations suggest that function of each CNP has diverged in the eel brain. Furthermore, the Pp lacking the blood-brain barrier expressed both npra and nprb, suggesting that endocrine and paracrine NPs interplay for regulating the Pp functions in Japanese eels.
Topics: Animals; Brain; Natriuretic Peptides; CHO Cells; Cricetulus; Receptors, Atrial Natriuretic Factor; Paracrine Communication; Ligands; Anguilla; Endocrine System
PubMed: 38369645
DOI: 10.1007/s00441-024-03873-y -
BMC Neuroscience Aug 2023Song performed in flocks by European starlings (Sturnus vulgaris), referred to here as gregarious song, is a non-sexual, social behavior performed by adult birds....
BACKGROUND
Song performed in flocks by European starlings (Sturnus vulgaris), referred to here as gregarious song, is a non-sexual, social behavior performed by adult birds. Gregarious song is thought to be an intrinsically reinforced behavior facilitated by a low-stress, positive affective state that increases social cohesion within a flock. The medial preoptic area (mPOA) is a region known to have a role in the production of gregarious song. However, the neurochemical systems that potentially act within this region to regulate song remain largely unexplored. In this study, we used RNA sequencing to characterize patterns of gene expression in the mPOA of male and female starlings singing gregarious song to identify possibly novel neurotransmitter, neuromodulator, and hormonal pathways that may be involved in the production of gregarious song.
RESULTS
Differential gene expression analysis and rank rank hypergeometric analysis indicated that dopaminergic, cholinergic, and GABAergic systems were associated with the production of gregarious song, with multiple receptor genes (e.g., DRD2, DRD5, CHRM4, GABRD) upregulated in the mPOA of starlings who sang at high rates. Additionally, co-expression network analyses identified co-expressing gene clusters of glutamate signaling-related genes associated with song. One of these clusters contained five glutamate receptor genes and two glutamate scaffolding genes and was significantly enriched for genetic pathways involved in neurodevelopmental disorders associated with social deficits in humans. Two of these genes, GRIN1 and SHANK2, were positively correlated with performance of gregarious song.
CONCLUSIONS
This work provides new insights into the role of the mPOA in non-sexual, gregarious song in starlings and highlights candidate genes that may play a role in gregarious social interactions across vertebrates. The provided data will also allow other researchers to compare across species to identify conserved systems that regulate social behavior.
Topics: Animals; Humans; Male; Female; Starlings; Vocalization, Animal; Singing; Preoptic Area; Gene Expression
PubMed: 37537543
DOI: 10.1186/s12868-023-00813-4 -
Cerebral Cortex (New York, N.Y. : 1991) Jun 2024Biological motion, the typical movement of vertebrates, is perceptually salient for many animal species. Newly hatched domestic chicks and human newborns show a...
Biological motion, the typical movement of vertebrates, is perceptually salient for many animal species. Newly hatched domestic chicks and human newborns show a spontaneous preference for simple biological motion stimuli (point-light displays) at birth prior to any visual learning. Despite evidence of such preference at birth, neural studies performed so far have focused on a specialized neural network involving primarily cortical areas. Here, we presented newly hatched visually naïve domestic chicks to either biological or rigid motion stimuli and measured for the first time their brain activation. Immediate Early Gene (c-Fos) expression revealed selective activation in the preoptic area of the hypothalamus and the nucleus taeniae of the amygdala. These results suggest that subpallial/subcortical regions play a crucial role in biological motion perception at hatching, paving the way for future studies on adult animals, including humans.
Topics: Animals; Animals, Newborn; Motion Perception; Chickens; Brain; Proto-Oncogene Proteins c-fos; Photic Stimulation
PubMed: 38918076
DOI: 10.1093/cercor/bhae262 -
BioRxiv : the Preprint Server For... May 2024Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and...
Obese subjects often exhibit hypersomnia accompanied by severe sleep fragmentation, while emerging evidence suggests that poor sleep quality promotes overeating and exacerbates diet-induced obesity (DIO). However, the neural circuit and signaling mechanism underlying the reciprocal control of appetite and sleep is yet not elucidated. Here, we report a neural circuit where prokineticin receptor 2 (PROKR2)-expressing neurons within the parabrachial nucleus (PBN) of the brainstem received direct projections from neuropeptide Y receptor Y2 (NPY2R)-expressing neurons within the lateral preoptic area (LPO) of the hypothalamus. The RNA-Seq results revealed in the PBN is the most regulated GPCR signaling gene that is responsible for comorbidity of obesity and sleep dysfunction. Furthermore, those NPY2R neurons are minimally active during NREM sleep and maximally active during wakefulness and REM sleep. Activation of the NPY2R →PBN circuit or the postsynaptic PROKR2 neurons suppressed feeding of a high-fat diet and abrogated morbid sleep patterns in DIO mice. Further studies showed that genetic ablation of the PROKR2 signaling within PROKR2 neurons alleviated the hyperphagia and weight gain, and restored sleep dysfunction in DIO mice. We further discovered pterostilbene, a plant-derived stilbenoid, is a powerful anti-obesity and sleep-improving agent, robustly suppressed hyperphagia and promoted reconstruction of a healthier sleep architecture, thereby leading to significant weight loss. Collectively, our results unveil a neural mechanism for the reciprocal control of appetite and sleep, through which pterostilbene, along with a class of similarly structured compounds, may be developed as effective therapeutics for tackling obesity and sleep disorders.
PubMed: 38746393
DOI: 10.1101/2024.04.30.591948 -
Scientific Reports Oct 2023Diabetes mellitus (DM) is a chronic metabolic disease, characterized by persistent hyperglycemia resulting from diminished insulin secretion or insulin resistance. The...
Diabetes mellitus (DM) is a chronic metabolic disease, characterized by persistent hyperglycemia resulting from diminished insulin secretion or insulin resistance. The present study evaluated the ameliorative effects of Withaferin-A (WA) on DM-induced reproductive dysfunction in mice. For the same, mice were intraperitoneally injected with Streptozotocin (STZ), (40 mg/kg/day) for 5 consecutive days to induce DM. Mice were then treated with WA (8 mg/kg/day) in normal and diabetic conditions (STZ + WA). Next, blood glucose levels, oral glucose tolerance, intraperitoneal insulin tolerance, oxidative stress and reproductive parameters were estimated. For reproductive performance, immunofluorescent localization of gonadotropin-releasing hormone (GnRH-I) and estrogen receptor alpha (ERα) in the preoptic area and paraventricular nucleus region of hypothalamus and ERα in testes was performed. STZ-induced diabetes triggered reproductive dysfunctions as mediated by low GnRH-I and ERα in the brain and ERα in the testes along with declined testosterone and estradiol levels. Treatment with WA significantly reduced the blood glucose levels and enhanced glucose clearance accompanied by reduced oxidative stress in the brain, pancreas and testes as indicated by the low levels of HO and MDA in diabetic mice treated with WA (STZ + WA). This study reports, for the first time, that WA can efficiently ameliorate DM-induced reproductive dysfunctions by enhancing endogenous testosterone, estrogen and increased GnRH-I and ERα in the brain and ERα in the testes of DM-induced male mice.
Topics: Animals; Male; Mice; Blood Glucose; Brain; Diabetes Mellitus, Experimental; Estrogen Receptor alpha; Gonadotropin-Releasing Hormone; Hydrogen Peroxide; Streptozocin; Testis; Testosterone; Withanolides
PubMed: 37848702
DOI: 10.1038/s41598-023-44904-y