Neuropeptide Y (NPY) acting through Y1 receptors reduces anxiety-and depression-like behavior in rodents, whereas Y2 receptor stimulation has the opposite effect. This study addressed the implication of Y4 receptors in emotional behavior by comparing female germ line Y4 knockout (Y42/2) mice with control and germ line Y22/2 animals. Anxiety-and depression-like behavior was assessed with the open field (OF), elevated plus maze (EPM), stress-induced hyperthermia (SIH) and tail suspension tests (TST), respectively. Learning and memory were evaluated with the object recognition test (ORT). In the OF and EPM, both Y42/2 and Y22/2 mice exhibited reduced anxiety-related behavior and enhanced locomotor activity relative to control animals. Locomotor activity in a familiar environment was unchanged in Y42/2 but reduced in Y22/2 mice. The basal rectal temperature exhibited diurnal and genotype-related alterations. Control mice had temperature minima at noon and midnight, whereas Y42/2 and Y22/2 mice displayed only one temperature minimum at noon. The magnitude of SIH was related to time of the day and genotype in a complex manner. In the TST, the duration of immobility was significantly shorter in Y42/2 and Y22/2 mice than in controls. Object memory 6 h after initial exposure to the ORT was impaired in Y22/2 but not in Y42/2 mice, relative to control mice. These results show that genetic deletion of Y4 receptors, like that of Y2 receptors, reduces anxiety-like and depression-related behavior. Unlike Y2 receptor knockout, Y4 receptor knockout does not impair object memory. We propose that Y4 receptors play an important role in the regulation of behavioral homeostasis. There is evidence that both Y1 and Y2 receptors are relevant to emotional behavior. Intracerebroventricular injection of NPY reduces anxiety-and depression-related behavior in several animal models, this action being primarily mediated by Y1 receptors (Heilig 2004;Kask et al. 2002;Primeaux et al. 2005;Redrobe et al. 2002). Neuropeptide Y acting through Y2 receptors enhances anxiety-and depression-like behavior as deduced from the behavioral characterization of Y2 receptor knockout (Y2À/À) mice (Redrobe et al. 2003;Tschenett et al. 2003). In addition, Y2 receptors are relevant to cognitive functions, given that Y2À/À mice exhibit impaired performance in the Morris water maze and object recognition tests (ORT) (Redrobe et al. 2004b).The possible role of Y4 receptors in the control of affective behavior has not yet been examined. Albeit less widely distributed in the brain than Y1 and Y2 receptors, the presence of Y4 receptors in hypothalamus, limbic system and medullary brainstem (Dumont et al. 1998;Fetissov et al. 2004;Heilig 2004;Kask et al. 2002;Parker & Herzog, 1999;Stanic et al. 2006) is consistent with a putative role of Y4 receptors in emotional and stress-related behavior. As Y4 receptor-selective antagonists are not yet available, the first and major aim of the present study was to evaluate anxietylike and depression-related behavior in Y4 receptor kno...

Gastric acid challenge of the rat and mouse stomach is signalled to the brainstem as revealed by expression of c-Fos. The molecular sensors relevant to the detection of gastric mucosal acidosis are not known. Since the acid-sensing ion channels ASIC2 and ASIC3 are expressed by primary afferent neurons, we examined whether knockout of the ASIC2 or ASIC3 gene modifies afferent signalling of a gastric acid insult in the normal and inflamed stomach. The stomach of conscious mice (C57BL/6) was challenged with intragastric HCl; two hours later the activation of neurons in the nucleus tractus solitarii (NTS) of the brainstem was visualized by c-Fos immunocytochemistry. Mild gastritis was induced by addition of iodoacetamide (0.1 %) to the drinking water for 7 days. Exposure of the gastric mucosa to HCl (0.25 M) caused a 3-fold increase in the number of c-Fos-positive neurons in the NTS. This afferent input to the NTS remained unchanged by ASIC3 knockout, whereas ASIC2 knockout augmented the c-Fos response to gastric HCl challenge by 33 % (P<0.01). Pretreatment of wild-type mice with iodoacetamide induced mild gastritis, as revealed by increased myeloperoxidase activity, and enhanced the number of NTS neurons responding to gastric HCl challenge by 41 % (P<0.01). This gastric acid hyperresponsiveness was absent in ASIC3 knockout mice but fully preserved in ASIC2 knockout mice. The current data indicate that ASIC3 plays a major role in the acid hyperresponsiveness associated with experimental gastritis. In contrast, ASIC2 appears to dampen acid-evoked input from the stomach to the NTS. KeywordsAcid-sensing ion channels; gastric acid hyperresponsiveness; gastritis; expression of c-Fos; nucleus of the solitary tract; vagal afferent neurons

Peptide YY (PYY) and neuropeptide Y (NPY) have been proposed to participate in the control of energy homeostasis. Since these activities show circadian variations, we explored the circadian pattern of locomotor, exploratory and ingestive behaviour in male and/or female mice with disrupted genes for PYY (PYY−/−), NPY (NPY−/−) as well as PYY plus NPY (PYY+NPY−/−). The effect of bacterial lipopolysaccharide (LPS, 0.1 mg/kg intraperitoneally) on these behaviours was also examined. The animals were housed singly in cages fitted with sensors for water and food intake and two infrared frames for recording ambulation and rearing under a 12 h light/dark cycle for 4 days. Locomotor and exploratory behaviour was decreased in female NPY−/− as well as male and female PYY+NPY−/− mice during the photo-and scotophase, and in male PYY−/− mice during the scotophase. Significant decreases in water and food intake were seen in female NPY−/− as well as male and female PYY+NPY−/− mice during the photophase. The effect of LPS to attenuate ingestive behaviour during the light and/or dark phase was most pronounced in PYY −/− and NPY−/− mice. These findings attest to a circadian cycle-and gender-related role of NPY and PYY in the control of behaviours that balance energy intake and energy expenditure. Both peptides stimulate feeding and drinking to balance the energy demand that they generate by enforcing the circadian pattern of locomotion and exploration. In addition, they counteract the anorectic and antidipsogenic effects of immune challenge.

There is a gender-related comorbidity of pain-related and inflammatory bowel diseases with psychiatric diseases. Since the impact of experimental gastrointestinal inflammation on the emotional-affective behaviour is little known, we examined whether experimental gastritis modifies anxiety, stress coping and circulating corticosterone in male and female Him:OF1 mice. Gastritis was induced by adding iodoacetamide (0.1 %) to the drinking water for at least 7 days. Inflammation was assessed by gastric histology and myeloperoxidase activity, circulating corticosterone determined by enzyme immunoassay, anxiety-related behaviour evaluated with the elevated plus maze and stress-induced hyperthermia tests, and depression-like behaviour estimated with the tail suspension test. Iodoacetamide-induced gastritis was associated with gastric mucosal surface damage and an increase in gastric myeloperoxidase activity, this increase being significantly larger in female mice than in male mice. The rectal temperature of male mice treated with iodoacetamide was enhanced, whereas that of female mice was diminished. The circulating levels of corticosterone were reduced by 65 % in female mice treated with iodoacetamide but did not significantly change in male mice. On the behavioural level, iodoacetamide treatment caused a decrease in nocturnal homecage activity, drinking and feeding. While depression-related behaviour remained unaltered following induction of gastritis, behavioural indices of anxiety were significantly enhanced in female but not male mice. There was no correlation between the oestrous cycle and anxiety as well as circulating corticosterone. Radiotracer experiments revealed that iodoacetamide did not readily enter the brain, the blood-brain ratio being 20:1. Collectively, these Correspondence: Peter Holzer, Ph.D., Institute of Experimental and Clinical Pharmacology, Medical University of Graz, Universitätsplatz 4, A-8010 Graz, Austria; telephone: +43 316 3804500; fax: +43 316 3809645; peter.holzer@meduni-graz.at. Europe PMC Funders Group Europe PMC Funders Author ManuscriptsEurope PMC Funders Author Manuscripts data show that iodoacetamide treatment causes gastritis in a gender-related manner, its severity being significantly greater in female than in male mice. The induction of gastritis in female mice is associated with a reduction of circulating corticosterone and an enforcement of behavioural indices of anxiety. Gastric inflammation thus has a distinct gender-dependent influence on emotional-affective behaviour and its neuroendocrine control. KeywordsIodoacetamide-induced gastritis; anxiety; elevated plus maze test; tail suspension test; myeloperoxidase activity; corticosterone Population-based surveys show that a history of gastroenteritis as well as neurotic and psychiatric disorders are risk factors for developing pain-related (functional) bowel disorders such as functional dyspepsia and irritable bowel syndrome . Accordingly, there is a considerable comorbidity of inflammatory bowel disease (IBD) and pa...

Members of the neuropeptide Y (NPY) family acting via Y2 and/or Y4 receptors have been proposed to participate in the control of ingestive behaviour and energy homeostasis. Since these processes vary between day and night, we explored the circadian patterns of locomotor, exploratory and ingestive behaviour in mice with disrupted genes for Y2 (Y2−/−) or Y4 (Y4−/−) receptors. To this end, the LabMaster system was used and its utility for the analysis of changes in circadian activity and ingestion caused by gene knockout evaluated. Female animals, aged 27 weeks on average, were housed singly in cages fitted with sensors for water and food intake and two infrared frames for recording ambulation and rearing under a 12 h light/dark cycle for 4 days. Relative to WT animals, diurnal locomotion, exploration, drinking and feeding were reduced, whereas nocturnal locomotion was enhanced in Y2−/− mice. In contrast, Y4−/− mice moved more but ate and drank less during the photophase, while they ate more and explored less during the scotophase. Both Y2−/− and Y4−/− mice weighed more than WT mice. These findings attest to a differential role of Y2 and Y4 receptor signalling in the circadian control of behaviours that balance energy intake and energy expenditure. These phenotypic traits can be sensitively and continuously recorded by the LabMaster system.