Life Without Neuropeptide Y
ABSTRACT Neuropeptide Y (NPY), a 36 amino acid neuromodulator that is secreted by neurons throughout the peripheral and central nervous system, has been implicated in the control of many physiological processes. We have begun to examine its role in regulation of appetite, behavior, and excitotoxicity by examining mice that are unable to produce NPY as a consequence of gene inactivation. These mutant mice are remarkably normal when reared under standard vivarium conditions. Despite considerable evidence that NPY plays a central role in stimulating appetite, NPY-deficient mice eat normally, grow normally, and refeed after a fast normally. Furthermore, all of their endocrine responses to fasting are normal. The response of NPY-null mice to diet-induced obesity, chemically induced obesity (monosodium glutamate and gold thioglucose), and genetic-based obesity (lethal yellow agouti, Ay; uncoupling protein-diphtheria toxin transgenics, UCP-DT) were all normal. However, NPY deficiency does partially ameliorate the obesity and all of the adverse endocrine effects of leptin deficiency in ob/ob mice. NPY-null mice as well as mice deficient in both NPY and leptin are more sensitive to leptin, suggesting that NPY may normally have a tonic inhibitory action on leptin-mediated satiety signals. NPY-null mice display the normal voracious feeding response to injected NPY. Thus, the only condition where we have observed a role for NPY in body-weight regulation is in the context of complete leptin deficiency--where absence of NPY is beneficial. The activity and general behavior of NPY-null mice are normal. They appear to have normal spatial and contextual learning ability; however, they manifest more anxiety under some conditions. NPY-null mice occasionally display spontaneous, seizure-like events. They also are less able to terminate seizures induced by GABA receptor antagonists or glutamate receptor agonists. These observations are consistent with previous data suggesting that NPY plays an important role in dampening excitotoxicity.
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- "is critical for the positive modulation of feeding behavior. Constitutive knockouts of Agrp and Npy genes or downstream NPY receptors in mice failed to produce feeding or body weight deficits, and these mice responded normally with compensatory increased feeding behavior in response to food-restriction (Palmiter et al., 1998; Qian et al., 2002; Thorsell and Heilig, 2002; Corander et al., 2011). Knock-in mice harboring Npy alleles with a tetracyclineoff (Tet-Off) regulatory domain and a minimal promoter inserted into exon 1 were developed to examine the necessity of NPY to promote feeding behavior (Ste Marie et al., 2005). "
ABSTRACT: Central proopiomelanocortin (POMC) neurons form a potent anorexigenic network, but our understanding of the integration of this hypothalamic circuit throughout the central nervous system (CNS) remains incomplete. POMC neurons extend projections along the rostrocaudal axis of the brain, and can signal with both POMC-derived peptides and fast amino acid neurotransmitters. Although recent experimental advances in circuit-level manipulation have been applied to POMC neurons, many pivotal questions still remain: how and where do POMC neurons integrate metabolic information? Under what conditions do POMC neurons release bioactive molecules throughout the CNS? Are GABA and glutamate or neuropeptides released from POMC neurons more crucial for modulating feeding and metabolism? Resolving the exact stoichiometry of signals evoked from POMC neurons under different metabolic conditions therefore remains an ongoing endeavor. In this review, we analyze the anatomical atlas of this network juxtaposed to the physiological signaling of POMC neurons both in vitro and in vivo. We also consider novel genetic tools to further characterize the function of the POMC circuit in vivo. Our goal is to synthesize a global view of the POMC network, and to highlight gaps that require further research to expand our knowledge on how these neurons modulate energy balance.Frontiers in Neuroscience 02/2013; 7(7):19. DOI:10.3389/fnins.2013.00019 · 3.66 Impact Factor
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- "However, in DAT over-expressing mice, although amphetamine-induced locomotion is increased, cocaine-induced hyperactivity is not significantly elevated (Salahpour et al., 2008). Another more plausible explanation for increased sensitivity to cocaine in NPY-KO mice could be increased anxiogenic-like behavior (Palmiter et al., 1998), a phenotype associated with higher motivation for cocaine self-administration in rodents (Dilleen et al., 2012; Homberg et al., 2002). Thus the present NPY-KO data could reflect compensatory effects, such as increased anxiety, rather than direct involvement of NPY in reward-related processes. "
ABSTRACT: There is increasing data implicating neuropeptide Y (NPY) in the neurobiology of addiction. This study explored the possible role of NPY in cocaine-induced behavior using NPY knockout mice. The transgenic mice showed a hypersensitive response to cocaine in three animal models of cocaine addiction. Whether this is due to an observed compensatory increase in striatal dopamine transporter binding or an anxiogenic phenotype of the transgenic mice remains to be determined.Synapse 09/2012; 66(9):840-3. DOI:10.1002/syn.21568 · 2.13 Impact Factor
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- "Indeed, central administration of NPY in rodents exerts anxiolytic-like effects in the open field, elevated plus maze, and light/dark transition tests (Heilig et al., 1989; Sørensen et al., 2004; Karlsson et al., 2005), and antidepressant-like effects in the forced swim test and learned helplessness paradigm (Redrobe et al., 2002b; Ishida et al., 2007). Likewise, rats overexpressing NPY show anxiolytic-like behaviour (Thorsell et al., 2000), whereas NPY knockout mice display anxiogenic-like behaviour in the elevated plus maze (Palmiter et al., 1998; Karl et al., 2008). Central nervous system effects of NPY are predominantly mediated via the G-protein coupled receptors Y1, Y2, and Y5 (Xapelli et al., 2006) and Y1 receptors appear to be centrally involved in mediating anxiety-and antidepressantlike effects of NPY (Heilig et al., 1993; Ishida et al., 2007; Karlsson et al., 2008). "
ABSTRACT: Neuropeptide Y (NPY) has been implicated in anxiolytic- and antidepressant-like behaviour as well as seizure-suppressant effects in rodents. Although these effects appear to be predominantly mediated via other NPY receptors (Y1 and/or Y2), several studies have also indicated a role for Y5 receptors. Gene therapy using recombinant viral vectors to induce overexpression of NPY, Y1 or Y2 receptors in the hippocampus or amygdala has previously been shown to modulate emotional behaviour and seizures in rodents. The present study explored the potential effects of gene therapy with the Y5 receptor, by testing effects of recombinant adeno-associated viral vector (rAAV) encoding Y5 (rAAV-Y5) in anxiety- and depression-like behaviour as well as in kainate-induced seizures in adult mice. The rAAV-Y5 vector injected into the hippocampus and amygdala induced a pronounced and sustained increase in Y5 receptor mRNA expression and functional Y5 receptor binding, but no significant effects were found with regard to anxiety- and depression-like behaviours or seizure susceptibility. Instead, rAAV-mediated Y5 receptor transgene overexpression resulted in moderate hyperactivity in the open field test. These results do not support a potential role for single transgene overexpression of Y5 receptors for modulating anxiety-/depression-like behaviours or seizures in adult mice. Whether the induction of hyperactivity by rAAV-Y5 could be relevant for other conditions remains to be studied.Neuropeptides 02/2012; 46(2):71-9. DOI:10.1016/j.npep.2012.01.002 · 2.64 Impact Factor