The Roles of Neuropeptide Y in Respiratory Disease Pathogenesis via the Airway Immune Response.

The lungs are very complex organs, and the respiratory system performs the dual roles of repairing tissue while protecting against infection from various environmental stimuli. Persistent external irritation disrupts the immune responses of tissues and cells in the respiratory system, ultimately leading to respiratory disease. Neuropeptide Y (NPY) is a 36-amino-acid polypeptide and a neurotransmitter that regulates homeostasis. The NPY receptor is a seven-transmembrane-domain G-protein-coupled receptor with six subtypes (Y1, Y2, Y3, Y4, Y5, and Y6). Of these receptors, Y1, Y2, Y4, and Y5 are functional in humans, and Y1 plays important roles in the immune responses of many organs, including the respiratory system. NPY and the Y1 receptor have critical roles in the pathogenesis of asthma, chronic obstructive pulmonary disease, and idiopathic pulmonary fibrosis. The effects of NPY on the airway immune response and pathogenesis differ among respiratory diseases. This review focuses on the involvement of NPY in the airway immune response and pathogenesis of various respiratory diseases.

Mechanisms of Modulation of Adrenergic Regulation of Spontaneous Activity Rate and Atrial Myocardial Contractility in Early Postnatal Ontogeny in Rats.

We studied combined effect of the ß1,2-adrenoreceptor agonist isoproterenol and the Y1,5 receptor agonist [Leu31, Pro34]neuropeptide Y on the frequency of spontaneous activity and myocardial contractility in 21- and 100-day-old rats. Isoproterenol increased the frequency of spontaneous activity and reduced the main parameters of isometric contraction of the atrial myocardium. When [Leu31, Pro34]neuropeptide Y was added, the frequency of spontaneous activity and the negative inotropic and the positive chronotropic effects of isoproterenol were reduced in 100-day-old rats. In 21-day-olds rats, a tendency to a decrease in the effect of isoproterenol was observed.

Effect of depression and suicidal behavior on neuropeptide Y (NPY) and its receptors in the adult human brain: A postmortem study.

Neuropeptides are small proteinaceous molecules (3-100 amino acids) that are secreted by neurons and act on both neuronal and non-neuronal cells. Neuropeptide Y (NPY), a highly conserved and expressed neuropeptide in the central nervous system of mammals, plays a major role in stress response and resilience. Increasing evidence suggests that NPY and its receptors are altered in depression and suicide, pointing to their antidepressant-like nature. The objective of this study was to examine the role of NPY system in depression and suicidal behavior. Expression of NPY and its four receptors, NPY1R, NPY2R, NPY4R, and NPY5R was studied at the transcriptional and translational levels in the prefrontal cortex (PFC) and hippocampus regions of the postmortem brain of normal control (NC) (n = 24) and depressed suicide (DS) (n = 24) subjects. We observed a significant decrease in NPY mRNA and upregulation in NPY1R and NPY2R mRNA in both brain regions of DS subjects compared with NC subjects. We also observed a significant decrease in NPY protein expression in the PFC of subjects with DS. This study provides the first detailed evidence of alterations in the NPY system and the associated stress response in depression and suicidal behavior in humans. The outcomes of this study could be applied in the development of novel NPY system-targeted approaches for the treatment of depression.

Neuropeptide Y suppresses thermogenic and cardiovascular sympathetic nerve activity via Y1 receptors in the paraventricular nucleus and dorsomedial hypothalamus.

In hungry animals, neuropeptide Y (NPY) neurones in the arcuate nucleus (ArcN) are activated to suppress energy expenditure, in part by decreasing brown adipose tissue sympathetic nerve activity (BAT SNA); however, the NPY receptor subtype and brain neurocircuitry are unclear. In the present study, we investigated the inhibition of BAT SNA by exogenous and endogenous NPY via binding to Y1 receptors (NPY1R) in the hypothalamic paraventricular nucleus (PVN) and dorsomedial hypothalamus (DMH), in anaesthetised male rats. Downstream projections of PVN/DMH NPY1R-expressing neurones were identified using male Npy1r-cre mice and localised unilateral DMH or PVN injections of an adeno-associated virus, which allows for the cre-dependent expression of a fluorescent protein (mCherry) in the cell bodies, axon fibres and nerve terminals of NPY1R-containing neurones. Nanoinjections of NPY into the DMH of cooled rats decreased BAT SNA, as well as mean arterial pressure (MAP) and heart rate (HR), and these responses were reversed by subsequent injection of the selective NPY1R antagonist, BIBO3304. In warmed rats, with little to no BAT SNA, bilateral nanoinjections of BIBO3304 into the DMH or PVN increased BAT SNA, MAP and HR. DMH NPY1R-expressing neurones projected heavily to the raphe pallidus (RPa), which houses BAT presympathetic neurones, as well as the PVN. In anaesthetised mice, DMH BIBO3304 increased splanchnic SNA, MAP and HR, all of which were reversed by nonselective blockade of the PVN with muscimol, suggesting that DMH-to-PVN connections are involved in this DMH BIBO3304 disinhibition. PVN Y1R expressing neurones also projected to the RPa, as well as to the nucleus tractus solitarius. We conclude that NPY tonically released in the DMH and PVN suppresses BAT SNA, MAP and HR via Y1R. Downstream neuropathways for BAT SNA may utilise direct projections to the RPa. Release of tonic NPY inhibition of BAT SNA may contribute to feeding- and diet-induced thermogenesis.

Ninjin'yoeito modulates feeding and activity under negative energy balance conditions via the NPY system.

The central and peripheral neuropeptide Y (NPY) system is critically involved in feeding and energy homeostasis control. Disease conditions as well as aging can lead to reduced functionality of the NPY system and boosting it represents a promising option to improve health outcomes in these situations. Here we show that Ninjin-yoeito (NYT), a Japanese kampo medicine comprising twelve herbs, and known to be effective to treat anorexia and frailty, mediates part of its action via NPY/peptide YY (PYY) related pathways. Especially under negative energy homeostasis conditions NYT is able to promote feeding and reduces activity to conserve energy. These effects are in part mediated via signalling through the NPY system since lack of Y4 receptors or PYY leading to modification in these responses highlighting the possibility for combination treatment to improve aging related conditions on energy homeostasis control.

Neuropeptide Y and glutamatergic mechanisms in the amygdala and ventral hippocampus differentially mediate impaired social behavior in diabetic mice.

Though patients with diabetes mellitus are reported to show deficits in social interaction, the mechanisms of these impairments are unclear. The present study investigated the role of AMPA and neuropeptide Y (NPY) receptors in the ventral hippocampus (vHC) and basolateral amygdala (BLA) in the social behavior of diabetic mice. In the three-chamber test, streptozotocin (STZ)-induced diabetic mice showed impairment in social novelty preference, but not in sociability. Injection of the AMPA receptor antagonist NBQX into vHC or BLA each restored social novelty preference in STZ-induced diabetic mice. NPY content in amygdala, but not in vHC, of STZ-induced diabetic mice was increased relative to non-diabetic mice. In STZ-induced diabetic mice, injection of the NPY Y2 receptor antagonist BIIE 0246 into BLA restored social novelty preference, whereas injection of BIIE 0246 into vHC was without effect. Finally, in non-diabetic mice social novelty preference was impaired by the NPY Y2 receptor agonist NPY 13-36 injected into BLA and restored by co-injection of NBQX. These results indicate that in diabetic mice glutamatergic function is enhanced in both vHC and BLA, which impairs social novelty preference through AMPA receptors. In addition, they indicate that NPYergic function in BLA, but not vHC, is enhanced in diabetic mice, which impairs social novelty preference through NPY Y2 receptors.

NPY-Y1 receptors in dorsal periaqueductal gray modulate anxiety, alcohol intake, and relapse in Wistar rats.

Neuropeptide Y (NPY) is likely the main endogenous anxiolytic neuromodulator involved in alcohol intake. NPY-Y1, a receptor for NPY, is highly expressed in the periaqueductal gray (PAG), a mesencephalic structure involved in integrating nervous activity to the performance of active and passive defensive behaviors related to fear and anxiety. Interestingly, anxiety and fear are some of the prevailing emotional negative states during alcohol abstinence. Moreover, an inverse relationship between NPY activity and alcohol consumption has been frequently reported, mainly in the extended amygdala. Nevertheless, both the roles of NPY and that of the receptor involved in these actions have been scarcely studied. Thus, the aim of this study was to analyze the pharmacological effect of NPY and NPY-Y1 receptor blockade into the dorsal periaqueductal gray (D-PAG) in an alcohol consumption and relapse paradigm in adult male Wistar rats. Ninety-six rats at postnatal day 42 (PND-42) were classified as having low and high anxiety (LA and HA), respectively, through the elevated plus maze test (EPM). Then, those animals were randomly divided into alcohol naïve (AN) and forced alcohol consumption (FAC) groups. A cannula was implanted in D-PAG to microinject vehicle (VEH), NPY, or BIBP-3226 (a selective NPY-Y1 receptor antagonist). A defensive burying behavior test (DBB) was performed to assess the anxiety-like state during withdrawal, followed by a 24-hour free choice voluntary alcohol intake test. Under our experimental conditions, NPY microinjection decreased alcohol consumption in HA rats, whereas NPY-Y1 receptor blockade in D-PAG produced a notably anxiogenic effect and higher alcohol intake and relapse. In conclusion, NPY in the D-PAG, most likely acting on NPY-Y1 receptors, induced a significant anxiolytic effect and prominently inhibited alcohol consumption and relapse in Wistar rats.

Nuclear Factor I/A Controls A-fiber Nociceptor Development.

Noxious mechanical information is transmitted through molecularly distinct nociceptors, with pinprick-evoked sharp sensitivity via A-fiber nociceptors marked by developmental expression of the neuropeptide Y receptor 2 (Npy2r) and von Frey filament-evoked punctate pressure information via unmyelinated C fiber nociceptors marked by MrgprD. However, the molecular programs controlling their development are only beginning to be understood. Here we demonstrate that Npy2r-expressing sensory neurons are in fact divided into two groups, based on transient or persistent Npy2r expression. Npy2r-transient neurons are myelinated, likely including A-fiber nociceptors, whereas Npy2r-persistent ones belong to unmyelinated pruriceptors that co-express Nppb. We then showed that the transcription factors NFIA and Runx1 are necessary for the development of Npy2r-transient A-fiber nociceptors and MrgprD+ C-fiber nociceptors, respectively. Behaviorally, mice with conditional knockout of Nfia, but not Runx1 showed a marked attenuation of pinprick-evoked nocifensive responses. Our studies therefore identify a transcription factor controlling the development of myelinated nociceptors.

The involvement of NK1 and Y2 receptor in the development of laser-induced CNVs in C57Bl/6N mice.

PURPOSE: to explore whether the NK1 and Y2 receptors are involved in the pathogenesis of laser-induced CNV (choroidal neovascularization) in C57Bl/6N mice. METHODS: CNV was induced by laser damage of Bruch's membrane and the CNV volume was determined by OCT and/or flatmount preparation. First, the development of the CNV volume over time was evaluated. Second, the CNV development in NK1- and Y2 KO mice was analyzed. Third, the effect on the development as well as the regression of CNV by intravitreal injections of the NK1 antagonist SR140333 and the Y2 antagonist BIIEO246 separately and each in combination with Eylea®, was investigated. Furthermore, flatmount CNV volume measurements were correlated to volumes obtained by the in vivo OCT technique. RESULTS: CNV volume peak was observed at day 4 after laser treatment. Compared to wild type mice, NK1 and Y2 KO mice showed significantly smaller CNV volumes. Eylea® and the Y2 antagonist significantly reduced the volume of the developing CNV. In contrast to Eylea® there was no effect of either antagonist on the regression of CNV, additionally no additive effect upon combined Eylea®/antagonist treatment was observed. There was a strong positive correlation between CNV volumes obtained by OCT and flatmount. CONCLUSION: NK1 and Y2 receptors mediate the development of laser-induced CNVs in mice. They seem to play an important role at the developmental stage of CNVs, whereas VEGF via VEGF receptor may be an important mediator throughout the CNV existence. In vivo OCT correlates with flatmount CNV volume, representing a useful tool for in vivo evaluations of CNV over time.

FLP-18 Functions through the G-Protein-Coupled Receptors NPR-1 and NPR-4 to Modulate Reversal Length in Caenorhabditis elegans.

Animal behavior is critically dependent on the activity of neuropeptides. Reversals, one of the most conspicuous behaviors in Caenorhabditis elegans, plays an important role in determining the navigation strategy of the animal. Our experiments on hermaphrodite C. elegans show the involvement of a neuropeptide FLP-18 in modulating reversal length in these hermaphrodites. We show that FLP-18 controls the reversal length by regulating the activity of AVA interneurons through the G-protein-coupled neuropeptide receptors, NPR-4 and NPR-1. We go on to show that the site of action of these receptors is the AVA interneuron for NPR-4 and the ASE sensory neurons for NPR-1. We further show that mutants in the neuropeptide, flp-18, and its receptors show increased reversal lengths. Consistent with the behavioral data, calcium levels in the AVA neuron of freely reversing C. elegans were significantly higher and persisted for longer durations in flp-18, npr-1, npr-4, and npr-1 npr-4 genetic backgrounds compared with wild-type control animals. Finally, we show that increasing FLP-18 levels through genetic and physiological manipulations causes shorter reversal lengths. Together, our analysis suggests that the FLP-18/NPR-1/NPR-4 signaling is a pivotal point in the regulation of reversal length under varied genetic and environmental conditions.SIGNIFICANCE STATEMENT In this study, we elucidate the circuit and molecular machinery required for normal reversal behavior in hermaphrodite Caenorhabditis elegans We delineate the circuit and the neuropeptide receptors required for maintaining reversal length in C. elegans Our work sheds light on the importance of a single neuropeptide, FLP-18, and how change in levels in this one peptide could allow the animal to change the length of its reversal, thereby modulating how the C. elegans explores its environment. We also go on to show that FLP-18 functions to maintain reversal length through the neuropeptide receptors NPR-4 and NPR-1. Our study will allow for a better understanding of the complete repertoire of behaviors shown by freely moving animals as they explore their environment.

Islet neuropeptide Y receptors are functionally conserved and novel targets for the preservation of beta-cell mass.

AIMS: Two unmet therapeutic strategies for diabetes treatment are prevention of beta-cell death and stimulation of beta-cell replication. Our aim was to characterize the role of neuropeptide Y receptors in the control of beta-cell mass. MATERIALS AND METHODS: We used endogenous and selective agonists of the NPY receptor system to explore its role in the prevention of beta-cell apoptosis and proliferation in islets isolated from both mouse and human donors. We further explored the intra-cellular signalling cascades involved, using chemical inhibitors of key signalling pathways. As proof of principle we designed a long-acting analogue of [Leu31 Pro34 ]-NPY, an agonist of the islet-expressed Y receptors, to determine if targeting this system could preserve beta-cell mass in vivo. RESULTS: Our data reveal that NPY Y1, 4 and 5 receptor activation engages a generalized and powerful anti-apoptotic pathway that protects mouse and human islets from damage. These anti-apoptotic effects were dependent on stimulating a Gαi-PLC-PKC signalling cascade, which prevented cytokine-induced NFkB signalling. NPY receptor activation functionally protected islets by restoring glucose responsiveness following chemically induced injury in both species. NPY receptor activation attenuated beta-cell apoptosis, preserved functional beta-cell mass and attenuated the hyperglycaemic phenotype in a low-dose streptozotocin model of diabetes. CONCLUSION: Taken together, our observations identify the islet Y receptors as promising targets for the preservation of beta-cell mass. As such, targeting these receptors could help to maintain beta-cell mass in both type 1 and type 2 diabetes, and may also be useful for improving islet transplantation outcomes.

Neuropeptide Y and its Involvement in Chronic Pain.

Chronic pain is a serious condition that significantly impairs the quality of life, affecting an estimate of 1.5 billion people worldwide. Despite the physiological, emotional and financial burden of chronic pain, there is still a lack of efficient treatments. Neuropeptide Y (NPY) is a highly conserved endogenous peptide in the central and peripheral nervous systems of all mammals, which has been implicated in both pro- and antinociceptive effects. NPY is expressed in the superficial laminae of the dorsal horn of the spinal cord, where it appears to mediate its antinociceptive actions via the Y1 and Y2 receptors. Intrathecal administration of NPY in animal models of neuropathic, inflammatory or postoperative pain has been shown to cause analgesia, even though its exact mechanisms are still unclear. It remains to be seen whether these promising central antinociceptive effects of NPY can be transferred into a future treatment for chronic pain.

Dipeptidyl peptidase IV (DPP-IV) inhibition prevents fibrosis in adipose tissue of obese mice.

BACKGROUND: During the development of obesity the expansion of white adipose tissue (WAT) leads to a dysregulation and an excessive remodeling of extracellular matrix (ECM), leading to fibrosis formation. These ECM changes have high impact on WAT physiology and may change obesity progression. Blocking WAT fibrosis may have beneficial effects on the efficacy of diet regimen or therapeutical approaches in obesity. Since dipeptidyl peptidase IV (DPP-IV) inhibitors prevent fibrosis in tissues, such as heart, liver and kidney, the objective of this study was to assess whether vildagliptin, a DPP-IV inhibitor, prevents fibrosis in WAT in a mouse model of obesity, and to investigate the mechanisms underlying this effect. METHODS: We evaluated the inhibitory effect of vildagliptin on fibrosis markers on WAT of high-fat diet (HFD)-induced obese mice and on 3T3-L1 cell line of mouse adipocytes treated with a fibrosis inducer, transforming growth factor beta 1 (TGFß1). RESULTS: Vildagliptin prevents the increase of fibrosis markers in WAT of HFD-fed mice and reduces blood glucose, serum triglycerides, total cholesterol and leptin levels. In the in vitro study, the inhibition of DPP-IV with vildagliptin, neuropeptide Y (NPY) treatment and NPY Y1 receptor activation prevents ECM deposition and fibrosis markers increase induced by TGFß1 treatment. CONCLUSIONS: Vildagliptin prevents fibrosis formation in adipose tissue in obese mice, at least partially through NPY and NPY Y1 receptor activation. GENERAL SIGNIFICANCE: This study highlights the importance of vildagliptin in the treatment of fibrosis that occur in obesity.

The metabolic syndrome in mice overexpressing neuropeptide Y in noradrenergic neurons.

A gain-of-function polymorphism in human neuropeptide Y (NPY) gene (rs16139) associates with metabolic disorders and earlier onset of type 2 diabetes (T2D). Similarly, mice overexpressing NPY in noradrenergic neurons (OE-NPYDBH) display obesity and impaired glucose metabolism. In this study, the metabolic syndrome-like phenotype was characterized and mechanisms of impaired hepatic fatty acid, cholesterol and glucose metabolism in pre-obese (2-month-old) and obese (4-7-month-old) OE-NPYDBH mice were elucidated. Susceptibility to T2D was assessed by subjecting mice to high caloric diet combined with low-dose streptozotocin. Contribution of hepatic Y1-receptor to the phenotype was studied using chronic treatment with an Y1-receptor antagonist, BIBO3304. Obese OE-NPYDBH mice displayed hepatosteatosis and hypercholesterolemia preceded by decreased fatty acid oxidation and accelerated cholesterol synthesis. Hyperinsulinemia in early obese state inhibited pyruvate- and glucose-induced hyperglycemia, and deterioration of glucose metabolism of OE-NPYDBH mice developed with aging. Furthermore, streptozotocin induced T2D only in OE-NPYDBH mice. Hepatic inflammation was not morphologically visible, but upregulated hepatic anti-inflammatory pathways and increased 8-isoprostane combined with increased serum resistin and decreased interleukin 10 pointed to increased NPY-induced oxidative stress that may predispose OE-NPYDBH mice to insulin resistance. Chronic treatment with BIBO3304 did not improve the metabolic status of OE-NPYDBH mice. Instead, downregulation of beta-1-adrenoceptors suggests indirect actions of NPY via inhibition of sympathetic nervous system. In conclusion, changes in hepatic fatty acid, cholesterol and glucose metabolism favoring energy storage contribute to the development of NPY-induced metabolic syndrome, and the effect is likely mediated by changes in sympathetic nervous system activity.

Inactivity periods and postural change speed can explain atypical postural change patterns of Caenorhabditis elegans mutants.

BACKGROUND: With rapid advances in genome sequencing and editing technologies, systematic and quantitative analysis of animal behavior is expected to be another key to facilitating data-driven behavioral genetics. The nematode Caenorhabditis elegans is a model organism in this field. Several video-tracking systems are available for automatically recording behavioral data for the nematode, but computational methods for analyzing these data are still under development. RESULTS: In this study, we applied the Gaussian mixture model-based binning method to time-series postural data for 322 C. elegans strains. We revealed that the occurrence patterns of the postural states and the transition patterns among these states have a relationship as expected, and such a relationship must be taken into account to identify strains with atypical behaviors that are different from those of wild type. Based on this observation, we identified several strains that exhibit atypical transition patterns that cannot be fully explained by their occurrence patterns of postural states. Surprisingly, we found that two simple factors-overall acceleration of postural movement and elimination of inactivity periods-explained the behavioral characteristics of strains with very atypical transition patterns; therefore, computational analysis of animal behavior must be accompanied by evaluation of the effects of these simple factors. Finally, we found that the npr-1 and npr-3 mutants have similar behavioral patterns that were not predictable by sequence homology, proving that our data-driven approach can reveal the functions of genes that have not yet been characterized. CONCLUSION: We propose that elimination of inactivity periods and overall acceleration of postural change speed can explain behavioral phenotypes of strains with very atypical postural transition patterns. Our methods and results constitute guidelines for effectively finding strains that show "truly" interesting behaviors and systematically uncovering novel gene functions by bioimage-informatic approaches.

Reduced NPY Y1 receptor hippocampal expression and signs of decreased vagal modulation of heart rate in mice.

Central neuropeptide Y (NPY) signaling participates in the regulation of cardiac autonomic outflow, particularly via activation of NPY-Y1 receptors (Y1Rs). However, the specific brain areas and neural pathways involved have not been completely identified yet. Here, we evaluate the role of hippocampal Y1Rs in the modulation of the autonomic control of cardiac function using a conditional knockout mouse model. Radiotelemetric transmitters were implanted in 4-month-old male mice exhibiting reduced forebrain expression (rfb) of the Y1R (Npy1rrfb, n=10) and their corresponding controls (Npy1r2lox, n=8). ECG signals were recorded (i) during resting conditions, (ii) under selective pharmacological manipulation of cardiac vagal activity, and (iii) during acute and chronic psychosocial stress challenges, and analyzed via time- and frequency-domain analysis of heart rate variability. Npy1rrfb mice showed a lower Npy1r mRNA density in the dentate gyrus and in the CA1 region of the hippocampus. Under resting undisturbed conditions, Npy1rrfb mice exhibited (i) a higher heart rate, (ii) a reduced overall heart rate variability, and (iii) lower values of the indices of vagal modulation compared to Npy1r2lox counterparts. Following pharmacological vagal inhibition, heart rate was higher in control but not in Npy1rrfb mice compared to their respective baseline values, suggesting that tonic vagal influences on heart rate were reduced in Npy1rrfb mice. The magnitude of the heart rate response to acute stressors was smaller in Npy1rrfb mice compared to Npy1r2lox counterparts, likely due to a concurrent lower vagal withdrawal. These findings suggest that reduced Y1R expression leads to a decrease in resting vagal modulation and heart rate variability, which, in turn, may determine a reduced cardiac autonomic responsiveness to acute stress challenges.

Pancreatic polypeptide stimulates mouse gastric motor activity through peripheral neural mechanisms.

BACKGROUND: Pancreatic polypeptide (PP) is supposed to be one of the major endogenous agonists of the neuropeptide Y4 receptor. Pancreatic polypeptide can influence gastrointestinal motility, acting mainly through vagal mechanisms, but whether PP acts directly on the stomach has not been explored yet. The aims of this study were to investigate the effects of PP on mouse gastric emptying, on spontaneous tone of whole stomach in vitro and to examine the mechanism of action. METHODS: Gastric emptying was measured by red phenol method after i.p. PP administration (1-3 nmol per mouse). Responses induced by PP (1-300 mmol L-1 ) on gastric endoluminal pressure were analyzed in vitro in the presence of different drugs. Gastric genic expression of Y4 receptor was verified by RT-PCR. KEY RESULTS: Pancreatic polypeptide dose-dependently increased non-nutrient liquid gastric emptying rate. In vitro, PP produced a concentration-dependent contraction that was abolished by tetrodotoxin, a neural blocker of Na+ voltage-dependent channels. The contractile response was significantly reduced by atropine, a muscarinic receptor antagonist, and by SR48968, an NK2 receptor antagonist, while it was potentiated by neostigmine, an inhibitor of acetylcholinesterase. The joint application of atropine and SR48968 fully abolished PP contractile effect. Reverse transcriptase-polymerase chain reaction analysis revealed the presence of Y4 receptor mRNA in mouse stomach with a greater expression in antrum than in fundus. CONCLUSIONS & INFERENCES: The present findings demonstrate that exogenous PP stimulates mouse gastric motor activity, by acting directly on the stomach. This effect appears due to the activation of enteric excitatory neurons releasing acetylcholine and tachykinins.

Evidence for the involvement of neuropeptide Y in the antidepressant effect of imipramine in type 2 diabetes.

Depression is a major comorbidity factor of diabetes and the outcome of one disorder influences the other. Our aim is to scrutinize the link between the two, if any. Since neuropeptide Y (NPY) system plays an important role in regulating central glucose sensing mechanisms, and also depression-related behavior, we test the involvement of NPY in the modulation of depression in type 2 diabetic mice. The mice were fed on high-fat diet and administered with low dose of streptozotocin to induce type 2 diabetes. These animals showed augmented plasma glucose and increased immobility time in tail suspension test (TST) suggesting induction of diabetes and depression. Intracerebroventricular (icv) treatment with NPY or NPY Y1 receptor agonist [Leu(31), Pro(34)]-NPY and intraperitoneal treatment with imipramine decreased immobility time. However, opposite effect was produced by NPY Y1 receptor antagonist BIBP3226 (icv). Moreover, reduced immobility time by imipramine was potentiated by NPY and [Leu(31), Pro(34)]-NPY, but attenuated by BIBP3226. Immunohistochemical analysis of the different nuclei of the extended amygdala, the region primarily involved in affective disorders, was undertaken. A significant reduction in NPY immunoreactivity in the central nucleus of amygdala, nucleus accumbens shell and lateral division of bed nucleus of stria terminalis of the diabetic mice was noticed; the response was ameliorated in imipramine treated animals. The results suggest that decreased NPY expression in the extended amygdala might be causally linked with the depression induced following type 2 diabetes and that the antidepressant action of imipramine in diabetic mice might be mediated by NPY-NPY Y1 receptor system.

Structure and function of the amygdaloid NPY system: NPY Y2 receptors regulate excitatory and inhibitory synaptic transmission in the centromedial amygdala.

The amygdala is essential for generating emotional-affective behaviors. It consists of several nuclei with highly selective, elaborate functions. In particular, the central extended amygdala, consisting of the central amygdala (CEA) and the bed nucleus of the stria terminalis (BNST) is an essential component actively controlling efferent connections to downstream effectors like hypothalamus and brain stem. Both, CEA and BNST contain high amounts of different neuropeptides that significantly contribute to synaptic transmission. Among these, neuropeptide Y (NPY) has emerged as an important anxiolytic and fear-reducing neuromodulator. Here, we characterized the expression, connectivity and electrophysiological function of NPY and Y2 receptors within the CEA. We identified several NPY-expressing neuronal populations, including somatostatin- and calretinin-expressing neurons. Furthermore, in the main intercalated nucleus, NPY is expressed primarily in dopamine D1 receptor-expressing neurons but also in interspersed somatostatin-expressing neurons. Interestingly, NPY neurons did not co-localize with the Y2 receptor. Retrograde tract tracing experiments revealed that NPY neurons reciprocally connect the CEA and BNST. Functionally, the Y2 receptor agonist PYY3-36, reduced both, inhibitory as well as excitatory synaptic transmission in the centromedial amygdala (CEm). However, we also provide evidence that lack of NPY or Y2 receptors results in increased GABA release specifically at inhibitory synapses in the CEm. Taken together, our findings suggest that NPY expressed by distinct populations of neurons can modulate afferent and efferent projections of the CEA via presynaptic Y2 receptors located at inhibitory and excitatory synapses.

Neuropeptide Y system in the retina: From localization to function.

The retina is a highly complex structure where several types of cells communicate through countless different molecules to codify visual information. Each type of cells plays unique roles in the retina, presenting a singular expression of neurotransmitters. Some neurotransmitter systems in the retina are well understood, while others need to be better explored to unravel the intricate signaling system involved. Neuropeptide Y (NPY), a 36 amino acid peptide, is one of the most common peptide neurotransmitter in the CNS and a highly conserved peptide among species. We review the localization of NPY and NPY receptors (mainly NPY Y1, Y2, Y4 and Y5) in retinal cells. Common features of the expression of NPY and NPY receptors in mammalian and non-mammalian species indicate universal roles of this system in the retina. In the present review, we highlight the putative roles of NPY receptor activation in the retina, discussing, in particular, their involvement in retinal development, neurotransmitter release modulation, neuroprotection, microglia and Muller cells function, retinal pigmented epithelium changes, retinal endothelial physiology and proliferation of retinal progenitor cells. Further studies are needed to confirm that targeting the NPY system might be a potential therapeutic strategy for retinal degenerative diseases.