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Tamas Kozicz - One of the best experts on this subject based on the ideXlab platform.
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Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal Nucleus.
Frontiers in neuroanatomy, 2014Co-Authors: Donny Janssen, Balazs Gaszner, Eric W. Roubos, Rebecca L. Leshan, Martin G. Myers, Noortje J. F. Van Der Knaap, Tamas KoziczAbstract:Leptin targets the brain to regulate feeding, neuroendocrine function and metabolism. The leptin receptor is present in hypothalamic centers controlling energy metabolism as well as in the centrally projecting Edinger-Westphal Nucleus (EWcp), a region implicated in the stress response and in various aspects of stress-related behaviors. We hypothesized that the stress response by cocaine- and amphetamine-regulated transcript (CART)-producing EWcp-neurons would depend on the animal’s energy state. To test this hypothesis, we investigated the effects of changes in energy state (mimicked by low, normal and high leptin levels, which were achieved by 24h fasting, normal chow and leptin injection, respectively) on the response of CART neurons in the EWcp of rats subjected or not to acute restraint stress. Our data show that leptin treatment alone significantly increases CART mRNA expression in the rat EWcp and that in leptin receptor deficient (db/db) mice, the number of CART producing neurons in this Nucleus is reduced. This suggests that leptin has a stimulatory effect on the production of CART in the EWcp under non-stressed condition. Under stressed condition, however, leptin blunts stress-induced activation of EWcp neurons and decreases their CART mRNA expression. Interestingly, fasting, does not influence the stress-induced activation of EWcp-neurons, and specifically EWcp-CART neurons are not activated. These results suggest that the stress response by the EWcp depends to some degree on the animal’s energy state, a mechanism that may contribute to a better understanding of the complex interplay between obesity and stress.
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Orexinergic innervation of urocortin1 and cocaine and amphetamine regulated transcript neurons in the midbrain centrally projecting Edinger-Westphal Nucleus.
Journal of chemical neuroanatomy, 2013Co-Authors: Tim L. Emmerzaal, Eric W. Roubos, R. H.a. Van Der Doelen, Tamas KoziczAbstract:Orexin is a neuropeptide that has been implicated in several processes, such as induction of appetite, arousal and alertness and sleep/wake regulation. Multiple lines of evidence also suggest that orexin is involved in the stress response. When orexin is administered intracerebroventricular it activates the hypothalamic pituitary adrenal (HPA)-axis, which is the main regulator of the stress response. The HPA-axis is not the only player in the stress response evidence suggests that urocortin 1 (Ucn1), a member of the corticotropin releasing factor (CRF) neuropeptide family, also plays an important role in the stress response adaptation. Ucn1 is primarily synthetized in the centrally projecting Edinger-Westphal Nucleus (EWcp), which also receives dense innervation by orexin terminals. In this study we tested the hypothesis that orexin would directly shape the response of EWcp-Ucn1 neurons to acute cold stress. To test this hypothesis, we first assessed whether orexinergic axon terminals would innervate EWcp-Ucn1/CART neurons, and next we exposed orexin deficient (orexin-KO) male mice and their male wild-type (WT) littermates to acute cold stress for 2h. We also assessed stress-associated changes in plasma corticosterone (CORT), as well as the activation of Ucn1/CART neurons in the EWcp Nucleus. We found that orexin immunoreactive axon terminals were juxtaposed to EWcp-Ucn1/CART neurons, which also expressed orexin receptor 1 mRNA. Furthermore, acute stress strongly activated the EWcp-Ucn1/CART neurons and increased plasma CORT in both WT littermates and orexin-KO mice, however no genotype effect was found on these indices. Taken together our data show that orexin in general is not involved in the animal's acute stress response (plasma CORT) and it does not play a direct role in shaping the response of EWcp-Ucn1 neurons to acute stress either.
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A subset of presympathetic-premotor neurons within the centrally projecting Edinger-Westphal Nucleus expresses urocortin-1.
Journal of chemical neuroanatomy, 2013Co-Authors: Najmul S. Shah, Balazs Gaszner, Tamas Kozicz, Diane C.w.a. Van Wijk, Phyllis C. Pugh, Hyungwoo Nam, Devin T. Rosenthal, Ilan A. KermanAbstract:Numerous motivated behaviors require simultaneous activation of somatomotor and autonomic functions. We have previously characterized the organization of brain circuits that may mediate this integration. Presympathetic premotor neurons (PSPMNs) that are part of such circuits are distributed across multiple brain regions, which mediate stress-elicited behavioral and physiological responses, including the Edinger-Westphal Nucleus (EW). Based on its connectivity and function, EW has recently been re-classified into a preganglionic (EWpg) and a centrally projecting (EWcp) population. Neurons within EWcp are the major source of urocortin 1 (Ucn-1), an analog of the corticotropin-releasing factor that binds the CRFR1 and CRFR2 receptors and has been implicated in mediating homeostatic responses to stress. We hypothesized that a subset of EWcp PSPMNs expresses Ucn-1. Utilizing dual-label immunofluorescence, we initially mapped the distribution of Ucn-1 and cholinergic neurons within EW in colchicine pre-treated rats. Based on this labeling we divided EWcp into three neuroanatomical levels. To examine connections of EWcp neurons to the gastrocnemius muscle and the adrenal gland, we next employed trans-synaptic tract-tracing in a second group of rats, utilizing two pseudorabies virus (PRV) recombinants that express unique reporter proteins. Using multi-label immunofluorescent staining, we identified the presence of Ucn-1-positive PSPMNs, dually labeled with PRV and present throughout the entire extent of EWcp and intermingled with Ucn-1 neurons infected with one or neither of the viral recombinants. Compared to rats pretreated with colchicine, we observed significantly fewer Ucn-1 neurons in animals that received PRV injections. Post hoc analyses revealed significantly fewer Ucn-1 neurons at the rostral level as compared to the caudal and middle levels. These data suggest functional and anatomic heterogeneity within EWcp; this organization may coordinate various aspects of stress-elicited and emotionally salient behaviors.
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The behavioral phenotype of pituitary adenylate-cyclase activating polypeptide-deficient mice in anxiety and depression tests is accompanied by blunted c-Fos expression in the bed Nucleus of the stria terminalis, central projecting Edinger-Westphal n
Neuroscience, 2012Co-Authors: Balazs Gaszner, V. Kormos, Dora Reglodi, Tamas Kozicz, H Hashimoto, Zsuzsanna HelyesAbstract:Pituitary adenylate-cyclase activating polypeptide (PACAP) has been implicated in the (patho)physiology of stress-adaptation. PACAP deficient (PACAP-/-) mice show altered anxiety levels and depression-like behavior, but little is known about the underlying mechanisms in stress-related brain areas. Therefore, we aimed at investigating PACAP-/-mice in light-dark box, marble burying, open field, and forced swim paradigms. We also analyzed whether the forced swim test-induced c-Fos expression would be affected by PACAP deficiency in the following stress-related brain areas: magno- and parvocellular paraventricular Nucleus of the hypothalamus (PVN); basolateral (BLA), medial (MeA), and central (CeA) amygdaloid nuclei; ventral (BSTv), dorsolateral (BSTdl), dorsomedial (BSTdm), and oval (BSTov) nuclei of the bed Nucleus of stria terminalis; dorsal (dLS) and ventral parts (vLS) of lateral septal Nucleus, central projecting Edinger-Westphal Nucleus (EWcp), dorsal (dPAG) and lateral (lPAG) periaqueductal gray matter, dorsal raphe Nucleus (DR). Our results revealed that PACAP-/-mice showed greatly reduced anxiety and increased locomotor activity compared with wildtypes. In forced swim test PACAP-/-mice showed increased depression-like behavior. Forced swim exposure increased c-Fos expression in all examined brain areas in wildtypes, whereas this was markedly blunted in the DR, EWcp, BSTov, BSTdl, BSTv, PVN, vLS, dPAG, and in the lPAG of PACAP-/-mice vs. wildtypes, strongly suggesting their involvement in the behavioral phenotype of PACAP-/-mice. PACAP deficiency did not influence the c-Fos response in the CeA, MeA, BSTdm, and dLS. Therefore, we propose that PACAP exerts a brain area-specific effect on stress-induced neuronal activation and it might contribute to stress-related mood disorders. © 2011 IBRO.
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Acute pain increases phosphorylation of DCLK-long in the Edinger-Westphal Nucleus but not in the hypothalamic paraventricular Nucleus of the rat
The journal of pain, 2010Co-Authors: T. Rouwette, Balazs Gaszner, Tamas Kozicz, Eric W. Roubos, Nicola F.m. Olde Loohuis, Erno Vreugdenhil, Gert Jan Scheffer, Kris Vissers, Wim J.j.m. ScheenenAbstract:Abstract The doublecortin-like kinase (DCLK) gene is crucially involved in neuronal plasticity and microtubule-guided retrograde transport of signaling molecules. We have explored the possibility that DCLK is involved in pain-induced signaling events in adult male Wistar rats. Our results show that both DCLK-short and DCLK-long splice variants are present in the cell body and proximal dendrites of neurons in stress-related nuclei, ie, the paraventricular Nucleus of the hypothalamus (PVN) and the non-preganglionic Edinger-Westphal Nucleus (npEW) in the rostroventral periaqueductal grey. We found that DCLK-long but not DCLK-short is phosphorylated in its serine/proline-rich domain. Furthermore, we demonstrate that phosphorylation of DCLK-long in the npEW is increased by acute pain, whereas DCLK-long phosphorylation in the PVN remains unaffected. This is the first report revealing that DCLK isoforms in the PVN and npEW occur in the adult mammalian brain and that pain differentially affects DCLK-long-mediated neuronal plasticity in these 2 stress-sensitive brain centers. Perspective Pain is a burden for society and the individual, and although the mechanisms underlying pain are relatively well known, its treatment remains difficult and incomplete. Pain stress can lead to diseases like chronic pain and depression. The differential DCLK-phosphorylation in stress-sensitive brain areas is a potential novel therapeutic target in pain research.
Eric W. Roubos - One of the best experts on this subject based on the ideXlab platform.
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Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal Nucleus.
Frontiers in neuroanatomy, 2014Co-Authors: Donny Janssen, Balazs Gaszner, Eric W. Roubos, Rebecca L. Leshan, Martin G. Myers, Noortje J. F. Van Der Knaap, Tamas KoziczAbstract:Leptin targets the brain to regulate feeding, neuroendocrine function and metabolism. The leptin receptor is present in hypothalamic centers controlling energy metabolism as well as in the centrally projecting Edinger-Westphal Nucleus (EWcp), a region implicated in the stress response and in various aspects of stress-related behaviors. We hypothesized that the stress response by cocaine- and amphetamine-regulated transcript (CART)-producing EWcp-neurons would depend on the animal’s energy state. To test this hypothesis, we investigated the effects of changes in energy state (mimicked by low, normal and high leptin levels, which were achieved by 24h fasting, normal chow and leptin injection, respectively) on the response of CART neurons in the EWcp of rats subjected or not to acute restraint stress. Our data show that leptin treatment alone significantly increases CART mRNA expression in the rat EWcp and that in leptin receptor deficient (db/db) mice, the number of CART producing neurons in this Nucleus is reduced. This suggests that leptin has a stimulatory effect on the production of CART in the EWcp under non-stressed condition. Under stressed condition, however, leptin blunts stress-induced activation of EWcp neurons and decreases their CART mRNA expression. Interestingly, fasting, does not influence the stress-induced activation of EWcp-neurons, and specifically EWcp-CART neurons are not activated. These results suggest that the stress response by the EWcp depends to some degree on the animal’s energy state, a mechanism that may contribute to a better understanding of the complex interplay between obesity and stress.
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Orexinergic innervation of urocortin1 and cocaine and amphetamine regulated transcript neurons in the midbrain centrally projecting Edinger-Westphal Nucleus.
Journal of chemical neuroanatomy, 2013Co-Authors: Tim L. Emmerzaal, Eric W. Roubos, R. H.a. Van Der Doelen, Tamas KoziczAbstract:Orexin is a neuropeptide that has been implicated in several processes, such as induction of appetite, arousal and alertness and sleep/wake regulation. Multiple lines of evidence also suggest that orexin is involved in the stress response. When orexin is administered intracerebroventricular it activates the hypothalamic pituitary adrenal (HPA)-axis, which is the main regulator of the stress response. The HPA-axis is not the only player in the stress response evidence suggests that urocortin 1 (Ucn1), a member of the corticotropin releasing factor (CRF) neuropeptide family, also plays an important role in the stress response adaptation. Ucn1 is primarily synthetized in the centrally projecting Edinger-Westphal Nucleus (EWcp), which also receives dense innervation by orexin terminals. In this study we tested the hypothesis that orexin would directly shape the response of EWcp-Ucn1 neurons to acute cold stress. To test this hypothesis, we first assessed whether orexinergic axon terminals would innervate EWcp-Ucn1/CART neurons, and next we exposed orexin deficient (orexin-KO) male mice and their male wild-type (WT) littermates to acute cold stress for 2h. We also assessed stress-associated changes in plasma corticosterone (CORT), as well as the activation of Ucn1/CART neurons in the EWcp Nucleus. We found that orexin immunoreactive axon terminals were juxtaposed to EWcp-Ucn1/CART neurons, which also expressed orexin receptor 1 mRNA. Furthermore, acute stress strongly activated the EWcp-Ucn1/CART neurons and increased plasma CORT in both WT littermates and orexin-KO mice, however no genotype effect was found on these indices. Taken together our data show that orexin in general is not involved in the animal's acute stress response (plasma CORT) and it does not play a direct role in shaping the response of EWcp-Ucn1 neurons to acute stress either.
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Acute pain increases phosphorylation of DCLK-long in the Edinger-Westphal Nucleus but not in the hypothalamic paraventricular Nucleus of the rat
The journal of pain, 2010Co-Authors: T. Rouwette, Balazs Gaszner, Tamas Kozicz, Eric W. Roubos, Nicola F.m. Olde Loohuis, Erno Vreugdenhil, Gert Jan Scheffer, Kris Vissers, Wim J.j.m. ScheenenAbstract:Abstract The doublecortin-like kinase (DCLK) gene is crucially involved in neuronal plasticity and microtubule-guided retrograde transport of signaling molecules. We have explored the possibility that DCLK is involved in pain-induced signaling events in adult male Wistar rats. Our results show that both DCLK-short and DCLK-long splice variants are present in the cell body and proximal dendrites of neurons in stress-related nuclei, ie, the paraventricular Nucleus of the hypothalamus (PVN) and the non-preganglionic Edinger-Westphal Nucleus (npEW) in the rostroventral periaqueductal grey. We found that DCLK-long but not DCLK-short is phosphorylated in its serine/proline-rich domain. Furthermore, we demonstrate that phosphorylation of DCLK-long in the npEW is increased by acute pain, whereas DCLK-long phosphorylation in the PVN remains unaffected. This is the first report revealing that DCLK isoforms in the PVN and npEW occur in the adult mammalian brain and that pain differentially affects DCLK-long-mediated neuronal plasticity in these 2 stress-sensitive brain centers. Perspective Pain is a burden for society and the individual, and although the mechanisms underlying pain are relatively well known, its treatment remains difficult and incomplete. Pain stress can lead to diseases like chronic pain and depression. The differential DCLK-phosphorylation in stress-sensitive brain areas is a potential novel therapeutic target in pain research.
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Restraint stress alters the secretory activity of neurons co-expressing urocortin-1, cocaine- and amphetamine-regulated transcript peptide and nesfatin-1 in the mouse Edinger-Westphal Nucleus
Brain research, 2010Co-Authors: Bernard Okere, Eric W. Roubos, Dario Sonetti, Tamas KoziczAbstract:Abstract Central stress regulatory pathways utilize various neuropeptides, such as urocortin-1 (Ucn1) and cocaine- and amphetamine-regulated transcript peptide (CART). Ucn1 is most abundantly expressed in the non-preganglionic Edinger–Westphal Nucleus (npEW). In addition to Ucn1, CART and nesfatin-1 are highly expressed in neurons of the npEW, but the way these three neuropeptides act together in response to acute stress is not known. We hypothesized that Ucn1, CART and nesfatin-1 are colocalized in npEW neurons and that these neurons are recruited by acute stress. Using quantitative immunocytochemistry and the reverse transcriptase polymerase chain reaction (RT-PCR), we support this hypothesis, by showing in B6C3F1/Crl mice that Ucn1, CART and nesfatin-1 occur in the same neurons of the npEW Nucleus. More specifically, Ucn1 and CART revealed a complete colocalization in the same perikarya, while 90% of these neurons are also nesfatin-1-immunoreactive. Furthermore, acute (restraint) stress stimulates the general secretory activity of these npEW neurons (increased presence of Fos) and the production of Ucn1, CART and nesfatin-1: Ucn1, CART and nesfatin-1( NUCB2 ) mRNAs have been increased compared to controls by x1.8, x2.0 and x2.6, respectively ( p
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Sex-specific effects of fasting on urocortin 1, cocaine- and amphetamine-regulated transcript peptide and nesfatin-1 expression in the rat Edinger–Westphal Nucleus
Neuroscience, 2009Co-Authors: Bas R. Bloem, Balazs Gaszner, Eric W. Roubos, Tamas KoziczAbstract:Leptin is critical for normal food intake and energy metabolism. While leptin receptor (ObR) function has been well studied in hypothalamic feeding circuitries, the functional relevance of ObR in extrahypothalamic areas is largely unknown. Central regulatory pathways involved in food intake utilize various neuropeptides, such as urocortin 1 (Ucn1), cocaine- and amphetamine-regulated transcript peptide (CART) and nesfatin-1. Ucn1 is most abundantly expressed in the non-preganglionic Edinger-Westphal Nucleus (npEW). In addition to Ucn1, other satiety signals, such as CART and nesfatin-1, are highly expressed in neurons of the npEW. Using immunocytochemistry and reverse transcriptase polymerase chain reaction (RT-PCR), we here show the presence of short and long forms of ObR in the rat npEW. Then, we tested our hypothesis that a change in plasma leptin will modulate the activity of npEW neurons containing Ucn1, CART and nesfatin-1. First, by double-labeling immunocytochemistry, we observed that almost all npEW neurons colocalizing Ucn1, CART and nesfatin-1 also contain ObR. Fasting rats for two days caused a marked body weight loss and reduced leptin plasma level in both genders. Ucn1 mRNA and CART mRNA were upregulated after fasting in males (3.3 and 2.4 times, respectively; P
Kozicz L.t. - One of the best experts on this subject based on the ideXlab platform.
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Melanocortin 4 receptor ligands modulate energy homeostasis through urocortin 1 neurons of the centrally projecting Edinger-Westphal Nucleus
2017Co-Authors: Furedi N., Kozicz L.t., Nagy A., Miko A., Berta G., Petervari E., Balasko M., Gaszner B.Abstract:The role of the urocortin 1 (Ucn1) expressing centrally projecting Edinger-Westphal (EWcp) Nucleus in energy homeostasis and stress adaptation response has previously been investigated. Morphological and functional studies have proven that orexigenic and anorexigenic peptidergic afferents and receptors for endocrine messengers involved in the energy homeostasis are found in the EWcp. The central role of the hypothalamic melanocortin system in energy homeostasis is well known, however, no data have been published so far on possible crosstalk between melanocortins and EWcp-Ucn1. First, we hypothesized that members of the melanocortin system [i.e. alpha-melanocyte stimulating hormone (alpha-MSH), agouti-related peptide (AgRP), melanocortin 4 receptor (MC4R)] would be expressed in the EWcp. Second, we put forward, that alpha-MSH and AgRP contents as well as neuronal activity and Ucn1 peptide content of the EWcp would be affected by fasting. Third, we assumed that the intra-EWcp injections of exogenous MC4R agonists and antagonist would cause food intake-related and metabolic changes. Ucn1 neurons were found to carry MC4Rs, and they were contacted both by alpha-MSH and AgRP immunoreactive nerve fibers in the rat. The alpha-MSH immunosignal was reduced, while that of AgRP was increased upon starvation. These were associated with the elevation of FosB and Ucn1 expression. The intra-EWcp administration of MC4R blocker (i.e. HS024) had a similar, but enhanced effect on FosB and Ucn1. Furthermore, alpha-MSH injected into the EWcp had anorexigenic effect, increased oxygen consumption and caused peripheral vasodilation. We conclude that the melanocortin system influences the EWcp that contributes to energy-homeostasis
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Melanocortin 4 receptor ligands modulate energy homeostasis through urocortin 1 neurons of the centrally projecting Edinger-Westphal Nucleus
'Elsevier BV', 2017Co-Authors: Furedi N., Kozicz L.t., Nagy A., Miko A., Berta G., Petervari E., Balasko M., Gaszner B.Abstract:Contains fulltext : 174209.pdf (publisher's version ) (Closed access)The role of the urocortin 1 (Ucn1) expressing centrally projecting Edinger-Westphal (EWcp) Nucleus in energy homeostasis and stress adaptation response has previously been investigated. Morphological and functional studies have proven that orexigenic and anorexigenic peptidergic afferents and receptors for endocrine messengers involved in the energy homeostasis are found in the EWcp. The central role of the hypothalamic melanocortin system in energy homeostasis is well known, however, no data have been published so far on possible crosstalk between melanocortins and EWcp-Ucn1. First, we hypothesized that members of the melanocortin system [i.e. alpha-melanocyte stimulating hormone (alpha-MSH), agouti-related peptide (AgRP), melanocortin 4 receptor (MC4R)] would be expressed in the EWcp. Second, we put forward, that alpha-MSH and AgRP contents as well as neuronal activity and Ucn1 peptide content of the EWcp would be affected by fasting. Third, we assumed that the intra-EWcp injections of exogenous MC4R agonists and antagonist would cause food intake-related and metabolic changes. Ucn1 neurons were found to carry MC4Rs, and they were contacted both by alpha-MSH and AgRP immunoreactive nerve fibers in the rat. The alpha-MSH immunosignal was reduced, while that of AgRP was increased upon starvation. These were associated with the elevation of FosB and Ucn1 expression. The intra-EWcp administration of MC4R blocker (i.e. HS024) had a similar, but enhanced effect on FosB and Ucn1. Furthermore, alpha-MSH injected into the EWcp had anorexigenic effect, increased oxygen consumption and caused peripheral vasodilation. We conclude that the melanocortin system influences the EWcp that contributes to energy-homeostasis
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Ghrelin's Role in the Hypothalamic-Pituitary-Adrenal Axis Stress Response: Implications for Mood Disorders
'Elsevier BV', 2015Co-Authors: Spencer S.j., Kozicz L.t., Emmerzaal T.l., Andrews Z.b.Abstract:Contains fulltext : 155371.pdf (publisher's version ) (Closed access)Ghrelin is a stomach hormone normally associated with feeding behavior and energy homeostasis. Recent studies highlight that ghrelin targets the brain to regulate a diverse number of functions, including learning, memory, motivation, stress responses, anxiety, and mood. In this review, we discuss recent animal and human studies showing that ghrelin regulates the hypothalamic-pituitary-adrenal axis and affects anxiety and mood disorders, such as depression and fear. We address the neural sites of action through which ghrelin regulates the hypothalamic-pituitary-adrenal axis and associated stress-induced behaviors, including the centrally projecting Edinger-Westphal Nucleus, the hippocampus, amygdala, locus coeruleus, and the ventral tegmental area. Stressors modulate many behaviors associated with motivation, fear, anxiety, depression, and appetite; therefore, we assess the potential role for ghrelin as a stress feedback signal that regulates these associated behaviors. Finally, we briefly discuss important areas for future research that will help us move closer to potential ghrelin-based therapies to treat stress responses and related disorders
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Ghrelin's Role in the Hypothalamic-Pituitary-Adrenal Axis Stress Response: Implications for Mood Disorders
2015Co-Authors: Spencer S.j., Kozicz L.t., Emmerzaal T.l., Andrews Z.b.Abstract:Ghrelin is a stomach hormone normally associated with feeding behavior and energy homeostasis. Recent studies highlight that ghrelin targets the brain to regulate a diverse number of functions, including learning, memory, motivation, stress responses, anxiety, and mood. In this review, we discuss recent animal and human studies showing that ghrelin regulates the hypothalamic-pituitary-adrenal axis and affects anxiety and mood disorders, such as depression and fear. We address the neural sites of action through which ghrelin regulates the hypothalamic-pituitary-adrenal axis and associated stress-induced behaviors, including the centrally projecting Edinger-Westphal Nucleus, the hippocampus, amygdala, locus coeruleus, and the ventral tegmental area. Stressors modulate many behaviors associated with motivation, fear, anxiety, depression, and appetite; therefore, we assess the potential role for ghrelin as a stress feedback signal that regulates these associated behaviors. Finally, we briefly discuss important areas for future research that will help us move closer to potential ghrelin-based therapies to treat stress responses and related disorders
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Ghrelin's role in the hypothalamic-pituitary-adrenal axis in response to stress
Elsevier (United States), 2015Co-Authors: Spencer S, Kozicz L.t., Emmerzaal T, Andrews ZAbstract:Ghrelin is a stomach hormone normally associated with feeding behavior and energy homeostasis. Recent studies highlight that ghrelin targets the brain to regulate a diverse number of functions, including learning, memory, motivation, stress responses, anxiety, and mood. In this review, we discuss recent animal and human studies showing that ghrelin regulates the hypothalamic-pituitary-adrenal axis and affects anxiety and mood disorders, such as depression and fear. We address the neural sites of action through which ghrelin regulates the hypothalamic-pituitary-adrenal axis and associated stress-induced behaviors, including the centrally projecting Edinger-Westphal Nucleus, the hippocampus, amygdala, locus coeruleus, and the ventral tegmental area. Stressors modulate many behaviors associated with motivation, fear, anxiety, depression, and appetite; therefore, we assess the potential role for ghrelin as a stress feedback signal that regulates these associated behaviors. Finally, we briefly discuss important areas for future research that will help us move closer to potential ghrelin-based therapies to treat stress responses and related disorders
Balazs Gaszner - One of the best experts on this subject based on the ideXlab platform.
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Integration of stress and leptin signaling by CART producing neurons in the rodent midbrain centrally projecting Edinger-Westphal Nucleus.
Frontiers in neuroanatomy, 2014Co-Authors: Donny Janssen, Balazs Gaszner, Eric W. Roubos, Rebecca L. Leshan, Martin G. Myers, Noortje J. F. Van Der Knaap, Tamas KoziczAbstract:Leptin targets the brain to regulate feeding, neuroendocrine function and metabolism. The leptin receptor is present in hypothalamic centers controlling energy metabolism as well as in the centrally projecting Edinger-Westphal Nucleus (EWcp), a region implicated in the stress response and in various aspects of stress-related behaviors. We hypothesized that the stress response by cocaine- and amphetamine-regulated transcript (CART)-producing EWcp-neurons would depend on the animal’s energy state. To test this hypothesis, we investigated the effects of changes in energy state (mimicked by low, normal and high leptin levels, which were achieved by 24h fasting, normal chow and leptin injection, respectively) on the response of CART neurons in the EWcp of rats subjected or not to acute restraint stress. Our data show that leptin treatment alone significantly increases CART mRNA expression in the rat EWcp and that in leptin receptor deficient (db/db) mice, the number of CART producing neurons in this Nucleus is reduced. This suggests that leptin has a stimulatory effect on the production of CART in the EWcp under non-stressed condition. Under stressed condition, however, leptin blunts stress-induced activation of EWcp neurons and decreases their CART mRNA expression. Interestingly, fasting, does not influence the stress-induced activation of EWcp-neurons, and specifically EWcp-CART neurons are not activated. These results suggest that the stress response by the EWcp depends to some degree on the animal’s energy state, a mechanism that may contribute to a better understanding of the complex interplay between obesity and stress.
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A subset of presympathetic-premotor neurons within the centrally projecting Edinger-Westphal Nucleus expresses urocortin-1.
Journal of chemical neuroanatomy, 2013Co-Authors: Najmul S. Shah, Balazs Gaszner, Tamas Kozicz, Diane C.w.a. Van Wijk, Phyllis C. Pugh, Hyungwoo Nam, Devin T. Rosenthal, Ilan A. KermanAbstract:Numerous motivated behaviors require simultaneous activation of somatomotor and autonomic functions. We have previously characterized the organization of brain circuits that may mediate this integration. Presympathetic premotor neurons (PSPMNs) that are part of such circuits are distributed across multiple brain regions, which mediate stress-elicited behavioral and physiological responses, including the Edinger-Westphal Nucleus (EW). Based on its connectivity and function, EW has recently been re-classified into a preganglionic (EWpg) and a centrally projecting (EWcp) population. Neurons within EWcp are the major source of urocortin 1 (Ucn-1), an analog of the corticotropin-releasing factor that binds the CRFR1 and CRFR2 receptors and has been implicated in mediating homeostatic responses to stress. We hypothesized that a subset of EWcp PSPMNs expresses Ucn-1. Utilizing dual-label immunofluorescence, we initially mapped the distribution of Ucn-1 and cholinergic neurons within EW in colchicine pre-treated rats. Based on this labeling we divided EWcp into three neuroanatomical levels. To examine connections of EWcp neurons to the gastrocnemius muscle and the adrenal gland, we next employed trans-synaptic tract-tracing in a second group of rats, utilizing two pseudorabies virus (PRV) recombinants that express unique reporter proteins. Using multi-label immunofluorescent staining, we identified the presence of Ucn-1-positive PSPMNs, dually labeled with PRV and present throughout the entire extent of EWcp and intermingled with Ucn-1 neurons infected with one or neither of the viral recombinants. Compared to rats pretreated with colchicine, we observed significantly fewer Ucn-1 neurons in animals that received PRV injections. Post hoc analyses revealed significantly fewer Ucn-1 neurons at the rostral level as compared to the caudal and middle levels. These data suggest functional and anatomic heterogeneity within EWcp; this organization may coordinate various aspects of stress-elicited and emotionally salient behaviors.
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The behavioral phenotype of pituitary adenylate-cyclase activating polypeptide-deficient mice in anxiety and depression tests is accompanied by blunted c-Fos expression in the bed Nucleus of the stria terminalis, central projecting Edinger-Westphal n
Neuroscience, 2012Co-Authors: Balazs Gaszner, V. Kormos, Dora Reglodi, Tamas Kozicz, H Hashimoto, Zsuzsanna HelyesAbstract:Pituitary adenylate-cyclase activating polypeptide (PACAP) has been implicated in the (patho)physiology of stress-adaptation. PACAP deficient (PACAP-/-) mice show altered anxiety levels and depression-like behavior, but little is known about the underlying mechanisms in stress-related brain areas. Therefore, we aimed at investigating PACAP-/-mice in light-dark box, marble burying, open field, and forced swim paradigms. We also analyzed whether the forced swim test-induced c-Fos expression would be affected by PACAP deficiency in the following stress-related brain areas: magno- and parvocellular paraventricular Nucleus of the hypothalamus (PVN); basolateral (BLA), medial (MeA), and central (CeA) amygdaloid nuclei; ventral (BSTv), dorsolateral (BSTdl), dorsomedial (BSTdm), and oval (BSTov) nuclei of the bed Nucleus of stria terminalis; dorsal (dLS) and ventral parts (vLS) of lateral septal Nucleus, central projecting Edinger-Westphal Nucleus (EWcp), dorsal (dPAG) and lateral (lPAG) periaqueductal gray matter, dorsal raphe Nucleus (DR). Our results revealed that PACAP-/-mice showed greatly reduced anxiety and increased locomotor activity compared with wildtypes. In forced swim test PACAP-/-mice showed increased depression-like behavior. Forced swim exposure increased c-Fos expression in all examined brain areas in wildtypes, whereas this was markedly blunted in the DR, EWcp, BSTov, BSTdl, BSTv, PVN, vLS, dPAG, and in the lPAG of PACAP-/-mice vs. wildtypes, strongly suggesting their involvement in the behavioral phenotype of PACAP-/-mice. PACAP deficiency did not influence the c-Fos response in the CeA, MeA, BSTdm, and dLS. Therefore, we propose that PACAP exerts a brain area-specific effect on stress-induced neuronal activation and it might contribute to stress-related mood disorders. © 2011 IBRO.
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Acute pain increases phosphorylation of DCLK-long in the Edinger-Westphal Nucleus but not in the hypothalamic paraventricular Nucleus of the rat
The journal of pain, 2010Co-Authors: T. Rouwette, Balazs Gaszner, Tamas Kozicz, Eric W. Roubos, Nicola F.m. Olde Loohuis, Erno Vreugdenhil, Gert Jan Scheffer, Kris Vissers, Wim J.j.m. ScheenenAbstract:Abstract The doublecortin-like kinase (DCLK) gene is crucially involved in neuronal plasticity and microtubule-guided retrograde transport of signaling molecules. We have explored the possibility that DCLK is involved in pain-induced signaling events in adult male Wistar rats. Our results show that both DCLK-short and DCLK-long splice variants are present in the cell body and proximal dendrites of neurons in stress-related nuclei, ie, the paraventricular Nucleus of the hypothalamus (PVN) and the non-preganglionic Edinger-Westphal Nucleus (npEW) in the rostroventral periaqueductal grey. We found that DCLK-long but not DCLK-short is phosphorylated in its serine/proline-rich domain. Furthermore, we demonstrate that phosphorylation of DCLK-long in the npEW is increased by acute pain, whereas DCLK-long phosphorylation in the PVN remains unaffected. This is the first report revealing that DCLK isoforms in the PVN and npEW occur in the adult mammalian brain and that pain differentially affects DCLK-long-mediated neuronal plasticity in these 2 stress-sensitive brain centers. Perspective Pain is a burden for society and the individual, and although the mechanisms underlying pain are relatively well known, its treatment remains difficult and incomplete. Pain stress can lead to diseases like chronic pain and depression. The differential DCLK-phosphorylation in stress-sensitive brain areas is a potential novel therapeutic target in pain research.
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Sex-specific effects of fasting on urocortin 1, cocaine- and amphetamine-regulated transcript peptide and nesfatin-1 expression in the rat Edinger–Westphal Nucleus
Neuroscience, 2009Co-Authors: Bas R. Bloem, Balazs Gaszner, Eric W. Roubos, Tamas KoziczAbstract:Leptin is critical for normal food intake and energy metabolism. While leptin receptor (ObR) function has been well studied in hypothalamic feeding circuitries, the functional relevance of ObR in extrahypothalamic areas is largely unknown. Central regulatory pathways involved in food intake utilize various neuropeptides, such as urocortin 1 (Ucn1), cocaine- and amphetamine-regulated transcript peptide (CART) and nesfatin-1. Ucn1 is most abundantly expressed in the non-preganglionic Edinger-Westphal Nucleus (npEW). In addition to Ucn1, other satiety signals, such as CART and nesfatin-1, are highly expressed in neurons of the npEW. Using immunocytochemistry and reverse transcriptase polymerase chain reaction (RT-PCR), we here show the presence of short and long forms of ObR in the rat npEW. Then, we tested our hypothesis that a change in plasma leptin will modulate the activity of npEW neurons containing Ucn1, CART and nesfatin-1. First, by double-labeling immunocytochemistry, we observed that almost all npEW neurons colocalizing Ucn1, CART and nesfatin-1 also contain ObR. Fasting rats for two days caused a marked body weight loss and reduced leptin plasma level in both genders. Ucn1 mRNA and CART mRNA were upregulated after fasting in males (3.3 and 2.4 times, respectively; P
Andrey E. Ryabinin - One of the best experts on this subject based on the ideXlab platform.
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contribution of urocortin to the development of excessive drinking
International Review of Neurobiology, 2017Co-Authors: Andrey E. Ryabinin, William J. GiardinoAbstract:The corticotropin-releasing factor (CRF) system plays a role in alcohol consumption, and its dysregulation can contribute to alcohol use disorder. This system includes four peptide ligands: CRF, urocortin (Ucn)1, Ucn2, and Ucn3. Historically, attention focused on CRF, however, Ucn1 also plays a critical role in excessive alcohol use. This review covers evidence for this contribution and contrasts the role of Ucn1 with CRF. While CRF can promote binge consumption, this regulation occurs through generalized mechanisms that are not specific for alcohol. In contrast, inhibition of Ucn1 action specifically blunts escalation of alcohol drinking. Lesions, genetic knockout, and RNA interference experiments indicate that the centrally projecting Edinger-Westphal Nucleus is the neuroanatomical source of Ucn1 critical for alcohol drinking. We propose that the contributions of Ucn1 to excessive drinking likely occur through enhancing rewarding properties of alcohol and symptoms of alcohol withdrawal, whereas CRF drives dependence-induced drinking at later stages of alcohol use. The transition from occasional binge drinking to dependence intricately depends on CRF system plasticity and coordination of CRF and Ucn1.
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Characterization of genetic differences within the centrally-projecting Edinger-Westphal Nucleus of C57BL/6J and DBA/2J mice by expression profiling
Frontiers Media S.A., 2012Co-Authors: William J. Giardino, Dawn M. Cote, Ju Eli, Andrey E. RyabininAbstract:Detailed examinations of the midbrain Edinger-Westphal Nucleus (EW) revealed the existence of two distinct nuclei. One population of preganglionic neurons was found to control oculomotor functions (EWpg), and a separate population of centrally-projecting neurons was found to contain stress- and feeding-related neuropeptides thought to be important for drug and alcohol addiction (EWcp). Although we and others have shown that neurons of the EWcp are highly responsive to drugs of abuse and behavioral stress, a thorough genetic characterization of the EWcp was needed. In order to identify genetic differences in the EWcp between mouse strains that differ in behaviors relevant to EWcp function, we used publicly-available tools from the Allen Brain Atlas to identify 68 genes that were selectively-expressed in the EWcp, and examined their expression within tissue punch microdissection samples containing the EWcp of adult male C57BL/6J (B6) and DBA/2J (D2) mice. Using 96-well quantitative real-time PCR (qPCR) arrays that included the EWcp-specific genes, several other genes of interest, and five housekeeping genes, we found strain differences in expression of eleven EWcp-specific genes (BC023892, Btg3, Bves, Cart, Cck, Ghsr, Neto1, Postn, Ptprn, Rcn1, and Ucn), two immediate early genes (Egr1 and Fos), and one dopamine-related gene (Drd5). All significant expression differences were greater in B6 vs. D2 mice, and several of these were verified at the protein level using immunohistochemical (IHC) protocols. These results demonstrate a significant advance in our understanding of the EWcp on three levels. First, we generated a list of EWcp-specific genes (most of which had not yet been reported within the EWcp in the literature) that will be informative for future studies of EWcp function. Second, due to similarity in results from qPCR and IHC, we revealed that strain differences in basal EWcp neuropeptide content are accounted for by differential transcription and by the numb
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Urocortin-1 within the Centrally-Projecting Edinger- Westphal Nucleus Is Critical for Ethanol Preference
2011Co-Authors: William J. Giardino, Davelle L. Cocking, Simranjit Kaur, Christopher L. Cunningham, Andrey E. RyabininAbstract:Converging lines of evidence point to the involvement of neurons of the centrally projecting Edinger-Westphal Nucleus (EWcp) containing the neuropeptide Urocortin-1 (Ucn1) in excessive ethanol (EtOH) intake and EtOH sensitivity. Here, we expanded these previous findings by using a continuous-access, two-bottle choice drinking paradigm (3%, 6%, and 10% EtOH vs. tap water) to compare EtOH intake and EtOH preference in Ucn1 genetic knockout (KO) and wild-type (WT) mice. Based on previous studies demonstrating that electrolytic lesion of the EWcp attenuated EtOH intake and preference in high-drinking C57BL/6J mice, we also set out to determine whether EWcp lesion would differentially alter EtOH consumption in Ucn1 KO and WT mice. Finally, we implemented well-established place conditioning procedures in KO and WT mice to determine whether Ucn1 and the corticotropin-releasing factor type-2 receptor (CRF-R2) were involved in the rewarding and aversive effects of EtOH (2 g/kg, i.p.). Results from these studies revealed that (1) genetic deletion of Ucn1 dampened EtOH preference only in mice with an intact EWcp, but not in mice that received lesion of the EWcp, (2) lesion of the EWcp dampened EtOH intake in Ucn1 KO and WT mice, but dampened EtOH preference only in WT mice expressing Ucn1, and (3) genetic deletion of Ucn1 or CRF-R2 abolished the conditioned rewarding effects of EtOH, but deletion of Ucn1 had no effect on the conditioned aversive effects of EtOH. The current findings provide strong support for the hypothesi
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Lesions of the Edinger–Westphal Nucleus in C57BL/6J mice disrupt ethanol-induced hypothermia and ethanol consumption
2004Co-Authors: Ryan K Bachtell, Adam Z Weitemier, Andrey E. RyabininAbstract:Abstract The Edinger-Westphal Nucleus (EW) is a brain region that has recently been implicated as an important novel neural target for ethanol. Thus, the EW is the only brain region consistently showing elevated c-Fos expression following both voluntary and involuntary ethanol administration. Ethanol-induced c-Fos expression in the EW has been shown to occur in urocortin I-positive neurons. Moreover, previous reports using several genetic models have demonstrated that differences in the EW urocortin I system are correlated with ethanol-mediated behaviours such as ethanol-induced hypothermia and ethanol consumption. The aim of this study was to confirm these relationships using a more direct strategy. Thus, ethanol responses were measured following electrolytic lesions of the EW in male C57BL ⁄ 6J mice. Both EW-lesioned and sham-operated animals were tested for several ethanol sensitivity measures and ethanol consumption in a two-bottle choice test. The results show that lesions of the EW significantly disrupted ethanol-induced hypothermia, while having no effect on pupillary dilation, locomotor activity or ethanol-induced sedation. In addition, EW-lesioned animals showed significantly lower ethanol preference and total ethanol dose consumed in the two-bottle choice test. EW-lesioned animals also consumed less sucrose than sham-operated animals, but did not have altered preferences for sucrose or quinine in a two-bottle choice test. These data support previously observed genetic correlations between EW urocortin I expression and both ethanol-induced hypothermia and ethanol consumption. Taken together, the findings suggest that the EW may function as a sensor for ethanol, which can influence ethanol consumption and preference
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high alcohol sucrose consumption during dark circadian phase in c57bl 6j mice involvement of hippocampus lateral septum and urocortin positive cells of the Edinger Westphal Nucleus
Psychopharmacology, 2003Co-Authors: Andrey E. Ryabinin, Agustin Galvanrosas, Ryan K Bachtell, Fred O RisingerAbstract:Abstract Rationale. Identification of the neuroanatomical substrates regulating alcohol consumption is important for the understanding of alcoholism. Previous studies mapping changes in brain activity used rodent models of alcohol drinking with relatively low alcohol intakes. Objectives. This study was aimed to identify brain regions changing activity after high voluntary intake of alcohol-containing solutions. Methods. Adult male C57BL/6J mice were trained to drink a 10% ethanol/10% sucrose solution in daily 30-min limited-access sessions during the dark phase of the circadian cycle. Control groups of animals consumed 10% sucrose or water. Analysis of c-Fos immunohistochemistry (as a marker for neuronal activity) was performed at 90 min after the last alcohol drinking session. Results. The limited access procedure led to high intakes (2.9±0.3 g/kg) and blood alcohol concentrations of 251±46 mg%. Expression of c-Fos was significantly higher in the alcohol/sucrose group than both the water and sucrose groups in the Edinger-Westphal Nucleus, and significantly lower in the alcohol/sucrose group than two control groups in hippocampal subregions, posterior hypothalamus and dorsal lateral septum. Double immunohistochemistry showed that alcohol-induced c-Fos-positive cells in the Edinger-Westphal Nucleus co-localized with the neuropeptide urocortin. In addition, intake and/or blood alcohol concentrations correlated with c-Fos expression in specific subregions of the hippocampus, hypothalamus, prefrontal cortex, lateral septum and midbrain. Conclusions. The dark phase voluntary limited-access procedure in mice leads to intakes of alcohol-containing solutions that are considered highly intoxicating. Brain regions showing alcohol-specific changes in c-Fos expression after this procedure can be connected into a novel neurocircuit, including lateral septum, hippocampus, hypothalamus, and the Edinger-Westphal Nucleus.
