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Neuropeptide S: Functional organization of a novel transmitter system regulating fear and anxiety
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Abstracts
lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Interestingly, peripheral application of the Y4 receptor agonist [K30(PEG2)]hPP2 -36 promoted fear extinction in fasted but not in fed wildtype mice, while it was ineffective in Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug-targets for treatment of anxiety disorders.
Acknowledgements: This research was supported by the Austrian Science Fund.
doi:10.1016/j.npep.2015.11.054
DPP4-DEFICIENT CONGENIC RATS DISPLAY BLUNTED STRESS RESPONSE, IMPROVED FEAR EXTINCTION AND INCREASED CENTRAL NPY Fabio Cannevaa,, Yulia Golubb, Eva M. Schildbachb, Joerg Distlera, Julia Dobnera, Sandra Meyera, Stephan von Hörstena; aDepartment of Experimental Therapy, Preclinical Experimental Center, University Clinic of Erlangen, 91054 Erlangen, Germany; bDepartment of Child and Adolescent Mental Health, University Clinic of Erlangen, 91054 Erlangen, Germany
Dipeptidyl peptidase 4 (DPP4, CD26) is a moonlighting enzyme responsible for the inactivation of a number of regulatory peptides including, glucagon-like protein 1 (GLP1), neuropeptide Y (NPY) and macrophage chemoattractant proteins (MCPs). Among all candidate substrates, DPP4 displays the highest affinity for NPY, whose endogenous anxiolytic properties are involved in stresscoping behaviors. Work recently published by our group (Canneva et al., 2015) has investigated the dimensions of the blunted stress response displayed by DPP4-deficient (DPP4mut) congenic rats: DPP4mut rats reveal a consistent stress-protective phenotype in both non-cognitive (i.e. stress-induced analgesia) and cognitive (i.e. fear extinction) tasks, while displaying overall normal behaviors (e.g. unaltered pain-perception, cognitive abilities, social skills etc.). On the molecular level, DPP4mut rats are characterized by significantly increased levels of central NPY (CSF), while NPY gene expression and number of NPY + neurons appear to be unchanged in most brain areas investigated (hypothalamus, septum, amygdala, hippocampus). Circulating corticosterone levels were found significantly decreased in DPP4mut rats; accordingly, new observations indicate that corticosteroid responsive receptors (GR) are significantly decreased in those areas of the brain involved in stressresponsive behaviors (amygdala and hypothalamus), while CRH-R1 expression was found significantly increased in the hippocampus of the same animals. NPY counteracts the effect of corticosterone and CRH, while contributing to the regulation of CRH release during stress activation. Further studies involving the pharmacological inhibition of DPP4 in genetically wild-type animals should confirm the value of our observations, while extending the therapeutic impact of DPP4 inhibition in stress- and anxiety-associated conditions (e.g. PTSD, depression).
doi:10.1016/j.npep.2015.11.055
SESSION 12 FEAR AND ANXIETY II NEUROPEPTIDE S: FUNCTIONAL ORGANIZATION OF A NOVEL TRANSMITTER SYSTEM REGULATING FEAR AND ANXIETY Hans-Christian Pape; Institute for Physiology I, Westfälische WilhelmsUniversität, Robert-Koch-Str. 27A, D-48149 Münster, Germany Fear is a crucial adaptive component of the behavioral repertoire that is generated in anticipation of or in response to stimuli which threaten to perturb homeostasis. Fear-relevant associations can be learned and consolidated as part of long term memory, and be extinguished through extinction learning. Acute or chronic stress can severely influence the balance of these processes, eventually leading to pathological alterations and anxiety disorders. Recent years have seen considerable progress in identifying relevant brain areas – such as the amygdala, the hippocampus and the prefrontal cortex – and key neuromodulatory mechanisms involved in balancing physiological and pathophysiological states of fear and anxiety. The recently discovered Neuropeptide S (NPS) and its cognate receptor represent such a system of neuromodulation. On one hand, NPS increases wakefulness and arousal. On the other, NPS produces anxiolytic-like effects by reducing acute fear responses and by modulating long-term aspects of fear memory, like contextual fear and fear extinction. Underlying mechanisms involve the presynaptic control of excitatory transmitter release, particularly in synaptic contacts to defined subsets of GABAergic interneurons in the amygdala. The availability of a NPS–EGFP transgenic mouse line has revealed that NPS-expressing neurons form neuronal clusters in the brainstem, respond in an excitatory fashion to corticotrophin releasing factor (CRF), and send axonal projections to defined targets in the subiculum, intralaminar thalamus and amygdala. “Fear” neurons in the amygdala in turn project back to NPS neurons in the brainstem, forming a functional feedback loop. The NPS system is activated in stressful situations, controls hyperexcitability in the amygdala and can thereby overcome stress-induced impairment of fear extinction. Furthermore, genetic variation of NPS receptor subtypes in humans has been associated with over-interpretation of learned fear (“catastrophizing reactions”), increases in stress sensitivity and panic disorders. Overall, the NPS system is a “novel” transmitter system that is critically involved in state-setting properties of network functions, providing a state aimed at enhancing the chances to respond to threatening situations. This word was supported by the Deutsche Forschungsgemeinschaft (SFBTRR58), Max-Planck-Gesellschaft, Alexander von Humboldt-Stiftung, and Interdisziplinaeres Zentrum für Klinische Forschung Münster. doi:10.1016/j.npep.2015.11.056
SINGLE INTRANASAL NEUROPEPTIDE Y INFUSION ATTENUATES DEVELOPMENT OF PTSD-LIKE SYMPTOMS TO TRAUMATIC STRESS IN RATS Esther L. Sabban, Lidia I. Serova, Marcela Laukova, Lishay Alaluf, Andrej Tillinger; New York Medical College, Valhalla, NY, USA The NPYergic system is associated with resilience, or improved recovery, from harmful effects of stress. However, peripheral NPY is not delivered to the brain very effectively and can elicit undesirable side effects, such as vasoconstriction. Thus, Sprague Dawley male rats were administered several doses of NPY by intranasal infusion. Dose of 100 μg/rat increased CSF NPY to range found anxiolytic when given icv,
Abstracts
lost in Y4KO mice. Fasting before extinction learning, however, resulted in specific activation of the medial intercalated neurons and re-established the enhancement of feed-forward inhibition in this amygdala microcircuit of Y4KO mice. Interestingly, peripheral application of the Y4 receptor agonist [K30(PEG2)]hPP2 -36 promoted fear extinction in fasted but not in fed wildtype mice, while it was ineffective in Y4KO mice. Hence, consolidation of fear and extinction memories is differentially regulated by hunger suggesting that fasting and modification of feeding-related genes could augment the effectiveness of exposure therapy and provide novel drug-targets for treatment of anxiety disorders.
Acknowledgements: This research was supported by the Austrian Science Fund.
doi:10.1016/j.npep.2015.11.054
DPP4-DEFICIENT CONGENIC RATS DISPLAY BLUNTED STRESS RESPONSE, IMPROVED FEAR EXTINCTION AND INCREASED CENTRAL NPY Fabio Cannevaa,, Yulia Golubb, Eva M. Schildbachb, Joerg Distlera, Julia Dobnera, Sandra Meyera, Stephan von Hörstena; aDepartment of Experimental Therapy, Preclinical Experimental Center, University Clinic of Erlangen, 91054 Erlangen, Germany; bDepartment of Child and Adolescent Mental Health, University Clinic of Erlangen, 91054 Erlangen, Germany
Dipeptidyl peptidase 4 (DPP4, CD26) is a moonlighting enzyme responsible for the inactivation of a number of regulatory peptides including, glucagon-like protein 1 (GLP1), neuropeptide Y (NPY) and macrophage chemoattractant proteins (MCPs). Among all candidate substrates, DPP4 displays the highest affinity for NPY, whose endogenous anxiolytic properties are involved in stresscoping behaviors. Work recently published by our group (Canneva et al., 2015) has investigated the dimensions of the blunted stress response displayed by DPP4-deficient (DPP4mut) congenic rats: DPP4mut rats reveal a consistent stress-protective phenotype in both non-cognitive (i.e. stress-induced analgesia) and cognitive (i.e. fear extinction) tasks, while displaying overall normal behaviors (e.g. unaltered pain-perception, cognitive abilities, social skills etc.). On the molecular level, DPP4mut rats are characterized by significantly increased levels of central NPY (CSF), while NPY gene expression and number of NPY + neurons appear to be unchanged in most brain areas investigated (hypothalamus, septum, amygdala, hippocampus). Circulating corticosterone levels were found significantly decreased in DPP4mut rats; accordingly, new observations indicate that corticosteroid responsive receptors (GR) are significantly decreased in those areas of the brain involved in stressresponsive behaviors (amygdala and hypothalamus), while CRH-R1 expression was found significantly increased in the hippocampus of the same animals. NPY counteracts the effect of corticosterone and CRH, while contributing to the regulation of CRH release during stress activation. Further studies involving the pharmacological inhibition of DPP4 in genetically wild-type animals should confirm the value of our observations, while extending the therapeutic impact of DPP4 inhibition in stress- and anxiety-associated conditions (e.g. PTSD, depression).
doi:10.1016/j.npep.2015.11.055
SESSION 12 FEAR AND ANXIETY II NEUROPEPTIDE S: FUNCTIONAL ORGANIZATION OF A NOVEL TRANSMITTER SYSTEM REGULATING FEAR AND ANXIETY Hans-Christian Pape; Institute for Physiology I, Westfälische WilhelmsUniversität, Robert-Koch-Str. 27A, D-48149 Münster, Germany Fear is a crucial adaptive component of the behavioral repertoire that is generated in anticipation of or in response to stimuli which threaten to perturb homeostasis. Fear-relevant associations can be learned and consolidated as part of long term memory, and be extinguished through extinction learning. Acute or chronic stress can severely influence the balance of these processes, eventually leading to pathological alterations and anxiety disorders. Recent years have seen considerable progress in identifying relevant brain areas – such as the amygdala, the hippocampus and the prefrontal cortex – and key neuromodulatory mechanisms involved in balancing physiological and pathophysiological states of fear and anxiety. The recently discovered Neuropeptide S (NPS) and its cognate receptor represent such a system of neuromodulation. On one hand, NPS increases wakefulness and arousal. On the other, NPS produces anxiolytic-like effects by reducing acute fear responses and by modulating long-term aspects of fear memory, like contextual fear and fear extinction. Underlying mechanisms involve the presynaptic control of excitatory transmitter release, particularly in synaptic contacts to defined subsets of GABAergic interneurons in the amygdala. The availability of a NPS–EGFP transgenic mouse line has revealed that NPS-expressing neurons form neuronal clusters in the brainstem, respond in an excitatory fashion to corticotrophin releasing factor (CRF), and send axonal projections to defined targets in the subiculum, intralaminar thalamus and amygdala. “Fear” neurons in the amygdala in turn project back to NPS neurons in the brainstem, forming a functional feedback loop. The NPS system is activated in stressful situations, controls hyperexcitability in the amygdala and can thereby overcome stress-induced impairment of fear extinction. Furthermore, genetic variation of NPS receptor subtypes in humans has been associated with over-interpretation of learned fear (“catastrophizing reactions”), increases in stress sensitivity and panic disorders. Overall, the NPS system is a “novel” transmitter system that is critically involved in state-setting properties of network functions, providing a state aimed at enhancing the chances to respond to threatening situations. This word was supported by the Deutsche Forschungsgemeinschaft (SFBTRR58), Max-Planck-Gesellschaft, Alexander von Humboldt-Stiftung, and Interdisziplinaeres Zentrum für Klinische Forschung Münster. doi:10.1016/j.npep.2015.11.056
SINGLE INTRANASAL NEUROPEPTIDE Y INFUSION ATTENUATES DEVELOPMENT OF PTSD-LIKE SYMPTOMS TO TRAUMATIC STRESS IN RATS Esther L. Sabban, Lidia I. Serova, Marcela Laukova, Lishay Alaluf, Andrej Tillinger; New York Medical College, Valhalla, NY, USA The NPYergic system is associated with resilience, or improved recovery, from harmful effects of stress. However, peripheral NPY is not delivered to the brain very effectively and can elicit undesirable side effects, such as vasoconstriction. Thus, Sprague Dawley male rats were administered several doses of NPY by intranasal infusion. Dose of 100 μg/rat increased CSF NPY to range found anxiolytic when given icv,