stressors elicit a cascade of neuronal , endocrine , and behavioral responses that promote homoeostatic adaptation to changing or threatening environments .
stressors maintained over prolonged periods of time or perceived as extreme can lead to maladaptive responses within stress - integrative circuitry .
pathological neurochemical and behavioral mechanisms can then manifest in the form of stress - related psychiatric diseases including anxiety disorders , post - traumatic stress disorder ( ptsd ) , and depression .
neuropeptides have been shown to be influential neuromodulators of stress - related emotionality ( kormos and gaszner , 2013 ) .
a growing body of evidence supports a role for neuropeptide y ( npy ) as a protective neurochemical that mediates stress resilience .
npy is a 36-amino acid peptide derived from prepronpy and belonging to a family that also includes pancreatic polypeptide ( pp ) and peptide yy ( pyy ) ( larhammar et  al . , 1993 ) .
npy is highly conserved across mammalian species and is expressed throughout the central nervous system ( cns ) ( larhammar and et  al , 2001 , adrian and et  al , 1983 , allen and et  al , 1983 , lundberg and hokfelt , 1986 , hirsch and zukowska , 2012 ) . in the periphery , npy is expressed primarily in sympathetic ganglia , the adrenal medulla , and in platelets ( larhammar and et  al , 2001 , adrian and et  al , 1983 , allen and et  al , 1983 , lundberg and hokfelt , 1986 , hirsch and zukowska , 2012 ) .
npy is the most abundant and widely distributed neuropeptide in the human brain ( adrian et  al . , 1983 ) , and
has been shown to have a significant impact on brain activity . in the cns , npy and its receptors ( y1 , y2 , y4 , y5 )
play important roles in the control of food intake , energy homeostasis , pain , and many behavioral and physiological processes associated with stress and stress resilience ( hirsch and zukowska , 2012 , brothers and wahlestedt , 2010 ) . in this review
, we will discuss the role of npy in stress - related behaviors and its relevance to select psychiatric disorders .
npy immunopositive cell bodies and fibers are generally found in cortical , limbic , hypothalamic , and brainstem regions ( allen et  al . , 1983 ) .
expression of npy in the human and rodent brain is similar , with abundant npy mrna or immunoreactivity located in the neocortex , amygdala , hippocampus , basal ganglia , hypothalamus , periaqueductal grey , dorsal raphe nucleus , and the a1 - 3 and a6 noradrenergic cells groups in the brainstem ( adrian and et  al , 1983 , allen and et  al , 1983 , caberlotto et  al . ,
, 1989 , yamazoe and et  al , 1985 , de quidt and emson , 1986a , de quidt and emson , 1986b ) .
the effects of npy are mediated by at least four subtypes of g - protein coupled receptors termed y1 , y2 , y4 , and y5 .
y6 receptors are expressed in the mouse brain , but this isoform is absent in the rat and nonfunctional in human and non - human primates ( larhammar and salaneck , 2004 ) .
autoradiographic and immunohistochemical examinations indicate that y1 and y2 receptors ( y1r and y2r ) exhibit the greatest expression in the brain , whereas lower levels of y4 and y5 receptors ( y4r and y5r ) are also present ( dumont and et  al , 1993 , stanic and et  al , 2006 , stanic and et  al , 2011 , dumont and et  al , 1998 , kask and et  al , 2002 , wolak and et  al , 2003 ) .
significant differences in the distribution of npy receptors are detectable between the rodent and human brain , warranting caution in the generalization of the role of npy receptors from preclinical animal models to humans ( dumont et  al . , 1998 ) .
npy receptors can couple to various effectors systems by associating with inhibitory gi / o proteins ( see review ( sah and geracioti , 2013 ) ) .
npy receptors inhibit adenylyl cyclase and the accumulation of camp , mobilize calcium through phospholipase c and phosphatidylinositol 3-kinase activity , and have effects on multiple ion channels ( sah and geracioti , 2013 ) . within stress responsive brain regions such as the cortex , amygdala , hypothalamus , and locus coeruleus
, npy receptors are localized on or impact the function of neurons expressing gaba , glutamate , corticotropin - releasing factor ( crf ) , and norepinephrine ( ne ) ( grove and et  al , 2000 , dimitrov and et  al , 2007 , giesbrecht and et  al , 2010 , rostkowski and et  al , 2009 , illes et  al . , 1993 ,
it has been hypothesized that npy serves as a functional  brake  to tone down the excitatory effects of pro - stress neurotransmitters such as crf and ne ( sah and geracioti , 2013 , eaton et  al .
this hypothesis is supported by studies demonstrating that npy is frequently contained within the same neuroanatomical brain structures as crf and ne , and the function of npy is often physiologically and behaviorally opposite to pro - stress neurotransmitters ( reviewed in ( kask and et  al , 2002 , sah and geracioti , 2013 , sajdyk et  al . , 2004 ) ) .
although clear interactions between npy and pro - stress systems in the regulation of stress - related emotionality still need to be established , it is likely that the balance of these neuropeptides and transmitters in stress - related circuits plays a pivotal role in mediating resilience to stress - associated responses discussed in this review .
human studies have identified associations between npy and stress resilience . in healthy human subjects , plasma npy levels
have been shown to rise in response to stress ( morgan 3rd and et  al , 2001 , morgan 3rd and et  al , 2000 , morgan 3rd and et  al , 2002 ) .
for example , when military soldiers underwent an interrogation model of extreme psychological stress to mimic the captive experience of prisoners of war , higher levels of npy following interrogation were present in soldiers displaying lower psychological distress or belonging to special operations forces ( morgan 3rd and et  al , 2000 , morgan 3rd and et  al , 2002 ) .
npy levels were positively associated with feelings of dominance and self - confidence , and superior performance under interrogation stress ( morgan 3rd and et  al , 2001 , morgan 3rd and et  al , 2000 , morgan 3rd and et  al , 2002 ) .
genetic variants of the prepronpy gene have been associated with differential stress responses and emotionality ( mickey and et  al , 2011 , zhou and et  al , 2008 ) .
specific npy haplotypes have been correlated to postmortem levels of npy mrna in the brain , plasma npy concentrations , and brain activity in response to stressful challenges ( zhou et  al . , 2008 ) .
individuals possessing a genotype associated with low npy expression report more negative emotional experiences during a painful stressor , exhibit greater amygdalar reactivity in response to threat - related facial images , and exhibit low stress resilience compared to high npy genotype carriers ( mickey and et  al , 2011 , zhou and et  al , 2008 ) .
haplotype - driven npy expression is also inversely correlated to trait anxiety in healthy individuals ( zhou et  al . , 2008 ) .
studies in humans with stress - related psychiatric disorders have also revealed a role for npy in resilience ( eaton et  al .
, 2010 , sah and et  al , 2009 , rasmusson and et  al , 2000a , morgan 3rd and et  al , 2003 ) , although the evidence stems primarily from populations with ptsd and depression .
rodent studies have provided a wealth of evidence for npy in resilience to anxiety ( see below ) , but few human studies have been conducted to determine the profile of npy in generalized anxiety , obsessive compulsive , social anxiety , and panic disorders .
one study found an association between a single - nucleotide polymorphism of the npy gene and increased risk for generalized anxiety disorder in individuals exposed to high stress ( amstadter et  al . , 2010 ) .
genetic variants of the y5 receptor gene have been significantly associated with panic disorder ( domschke et  al . , 2008 ) .
elevated plasma npy was detected in a study of individuals with panic disorder , in which the authors suggest that an increase in npy may be compensatory to buffer enhanced sympathetic activation in this disorder ( boulenger et  al . , 1996 ) .
other studies have not detected differences in npy levels between healthy controls and persons with obsessive compulsive , social anxiety , or panic disorders ( stein and et  al , 1996 , altemus and et  al , 1999 ) , or have failed to identify genetic associations between npy and anxiety disorders ( lindberg et  al .
clinical investigations have revealed that the plasma and csf of depressed individuals contain decreased concentrations of npy compared to healthy controls ( hashimoto and et  al , 1996 , heilig and et  al , 2004 , hou and et  al , 2006 , nilsson and et  al , 1996 , widerlov and et  al , 1988 ) .
additional studies have shown lower npy in clinically depressed patients with a history of suicide attempts compared to healthy persons , and that npy levels are lowest in individuals with a recent suicide attempt ( westrin et  al . , 1999 ) . likewise , low npy immunoreactivity has been found in postmortem brain tissue of suicide victims , with the most robust reductions in npy occurring in the brains of persons with a history of depression ( widdowson et  al . , 1992 ) .
low levels of npy mrna expression are also found in persons with bipolar disorder ( caberlotto and hurd , 1999 , kuromitsu and et  al , 2001 ) .
genetic variants of the prepronpy gene have been associated with resilience or vulnerability to depression ( heilig and et  al , 2004 , wang and et  al , 2013 , sjoholm and et  al , 2009 ) .
for instance , a genetic polymorphism resulting in higher levels of mature npy appears to be protective against depression despite exposure to environmental risk factors ( sjoholm et  al . , 2009 ) ,
and the presence of this polymorphism is less frequent in depressed patients ( heilig et  al . , 2004 ) .
in another study , a genotype associated with low npy expression was found to be overrepresented in persons with major depression compared to healthy controls ( mickey et  al . , 2011 ) .
interestingly , antidepressant strategies are associated with parallel elevations in npy and decreases in corticotropin - releasing hormone ( crh ) , thereby supporting peptidergic interactions in the mechanisms underlying clinically efficacious treatments for depression .
for example , csf levels of npy are elevated in depressed patients following electroconvulsive therapy , while levels of corticotropin - releasing hormone decrease concurrently ( math and et  al , 1995 , nikisch and mathe , 2008 ) . increased npy after treatment with the selective serotonin reuptake inhibitor citalopram is associated with a reduction in depression severity and the levels of crh ( nikisch et  al . , 2005 ) . reduced concentrations of cerebrospinal and plasma npy
have been reported in both individuals with ptsd and those who have been exposed to traumatic stress ( sah and et  al , 2009 , rasmusson and et  al , 2000a , morgan 3rd and et  al , 2003 ) .
npy is inversely related to ptsd symptomology , with low npy correlating specifically to the presence of intrusion symptoms ( sah et  al . , 2014 ) .
higher npy is predicative of ptsd symptom improvement and shows a positive association with coping following a traumatic event ( yehuda et  al . ,
yohimbine , an antagonist of the presynaptic 2-adrenergic receptor that increases norepinephrine levels , elicits panic attacks and exacerbates the core symptoms of ptsd ( bremner et  al . ,
yohimbine has also been shown to stimulate increases in plasma npy and levels of the norepinephrine metabolite mhpg ( 3-methyl-4-hydroxy - phenyl - glycol ) in healthy subjects . however , yohimbine - stimulated increases in npy are significantly blunted in persons with ptsd ( rasmusson and et  al , 2000a , rasmusson and et  al , 1998 ) .
additionally , baseline concentrations of plasma npy correlated negatively to yohimbine - induced increases in mhpg in the same study ( rasmusson et  al . , 2000 ) .
this correlation suggests that low basal levels of npy were associated with an exaggerated increase in mhpg following yohimbine ( rasmusson et  al . , 2000 ) .
both basal and yohimbine - stimulated levels of npy were negatively correlated to scores on a combat - exposure scale , indicating that greater combat exposure was associated with blunted levels of npy ( rasmusson et  al . , 2000 ) .
pathological responses to stress manifest in behaviors that include enhanced anxiety , arousal , and fear . in this section
, we review the findings in animal models utilized to examine these three behavioral responses , as well as the effects of npy in rodent models of ptsd and depression - like behavior .
examples provided in the text are summarized in table  1 . genetic rodent models and pharmacological studies
have provided insight into the anxiolytic properties of npy in multiple paradigms of anxiety - like behavior ( kask and et  al , 2002 , sajdyk et  al . , 2004 ) .
npy deficiency is associated with an anxiogenic phenotype in rodents ( bannon et  al . , 2000 ) , and highly anxious rats are more sensitive to the anxiolytic actions of npy ( sudakov et  al . , 2001 ) .
intracerebroventricular ( i.c.v . ) administration of npy decreases anxiety - like behavior in the elevated plus maze , vogel 's drinking conflict test ( broqua and et  al , 1995 , heilig and et  al , 1989 ) , and other operant conflict tasks ( britton and et  al , 1997 , heilig and et  al , 1992 ) .
site specific - studies have revealed the amygdala , locus coeruleus , lateral septum , and hippocampus as regions that are involved in the anxiolytic properties of npy ( lin and et  al , 2010 , thorsell and et  al , 2000 , primeaux and et  al , 2005 , sajdyk et  al .
, 1999 , heilig and et  al , 1993 , kask et  al . , 1998a , kask et  al . ,
1998c , trent and menard , 2011 ) . for example , infusion of npy into the basolateral amygdala decreases social anxiety ( sajdyk et  al . , 1999 ) , produces anti - conflict effects via the central nucleus of the amygdala ( heilig et  al . , 1993 ) , and decreases anxiety upon injection into the locus coeruleus ( kask et  al . , 1998a , kask et  al .
the effects of npy may be related to interactions with crf signaling , as npy attenuates anxiety and avoidance behavior induced by crf and crf agonists upon i.c.v . or direct delivery into subregions of the amygdala ( ide and et  al , 2013 , sajdyk et  al . , 2006 ,
an interaction with norepinephrine systems has also been implicated , as pretreatment with idazoxan , an 2-adrenergic receptor antagonist , blocks the anxiolytic effects of npy ( heilig et  al . ,
studies largely support a role for the activation of y1r in the attenuation of anxiety - like behavior .
for example , the anxiolytic effects of npy are absent in mice lacking the y1r ( karlsson and et  al , 2008 , heilig , 1995 ) , and y1r knockout mice exhibit an anxiogenic phenotype ( karl et  al .
selective knockout of y1r from excitatory forebrain neurons also results in increased anxiety ( bertocchi et  al . , 2011 ) .
centrally administered y1r agonists are anxiolytic in a number of behavioral paradigms ( britton and et  al , 1997 , sorensen and et  al , 2004 ) , while site - specific examinations implicate the central nucleus of the amygdala and hippocampus as regions of y1r - mediated anxiolysis ( heilig and et  al , 1993 , olesen and et  al , 2012 , lyons and thiele , 2010 ) .
administration of y1r antagonists centrally or into the periaqueductal grey produces anxiogenic effects ( kask et  al .
, 1998b , kask et  al . , 1998c ) , but has no reported effects when delivered into the locus coeruleus , hypothalamus , or central nucleus of the amygdala ( kask et  al . , 1998a , kask et  al . , 1998b , kask et  al .
. the lack of effect in these regions may be due to their low level of expression of y1r ( kask et  al . , 2002 ) .
central blockade of y1r is also sufficient to elicit conditioned place aversion , supporting the notion that y1r are necessary for endogenous anxiolytic actions of npy ( kask et  al .
y1r are found to be preferentially expressed on pyramidal cells in the basolateral amygdala ( rostkowski et  al . , 2009 ) , therefore it is likely that y1r mediate anxiolysis here by influencing glutamatergic input to the central nucleus of the amygdala and subsequent output to the brainstem ( gilpin et  al . , 2011 ) .
the function of y2r in anxiety is allegedly opposite of the y1r subtype ; however conflicting reports demonstrating both anxiogenic and anxiolytic effects mediated by y2r make the role of this subtype in anxiety less clear .
y2r are generally considered npy autoreceptors and evidence for their pre - synaptic localization has been demonstrated in humans and rodents ( stanic and et  al , 2011 , caberlotto and et  al , 1998 ) .
central administration of y2r agonists have failed to alter anxiety - like behavior in a number of studies ( broqua and et  al , 1995 , heilig and et  al , 1989 , britton and et  al , 1997 , sorensen and et  al , 2004 ) . however , agonism of y2r in the locus coeruleus and lateral septum produces anxiolytic effects , whereas y2r are required for npy - mediated anxiolysis in the hippocampus ( kask et  al .
, 1998a , kask et  al . , 1998b , kask et  al .
, 1998c , trent and menard , 2013 , smialowska and et  al , 2007 ) . y2r
agonism in the basolateral amygdala has bidirectional effects on anxiety in the social interaction test , with low agonist doses generating anxiety and high doses decreasing anxiety ( sajdyk et  al . , 2002 ) .
a recent study indicates that knockout of the y2r in gabaergic neurons located in the central nucleus of the amygdala was anxiogenic specifically in female mice ( mccall et  al . , 2013 ) .
contrasting reports indicate that y2r antagonism in the central nucleus of the amygdala is anxiolytic ( kallupi et  al . , 2013 ) , and that ablation of y2r in either the basolateral or central nucleus of the amygdala produces an anxiolytic phenotype ( tasan et  al . , 2010 ) .
dark , open - field , and marble burying tests ( tasan and et  al , 2009 , painsipp et  al .
, 2008 , painsipp and et  al , 2008 , tschenett and et  al , 2003 ) , and y2r deficient mice exhibit reduced neuronal activation upon exposure to an anxiogenic environment ( nguyen et  al . , 2009 ) .
taken together , this evidence suggests that y2r may function in a regionally specific and neurochemically selective fashion .
similar to y2r mutant mice , deletion of the y4r also reduces anxiety - like behavior in a number of rodent paradigms ( tasan and et  al , 2009 , painsipp and et  al , 2008 ) .
knockout of the y4r with the y2r enhances the anxiolytic phenotype observed following deletion of either receptor alone ( tasan et  al . , 2009 ) .
a y5r antagonist blocked the anxiolytic effects of a y2r agonist in the basolateral amygdala ( sajdyk et  al . , 2002 ) , while i.c.v .
y5r can form heterodimers with y1r ( gehlert et  al . , 2007 ) , and these receptor subtypes are colocalized in the basolateral amygdala , hippocampus , and hypothalamus ( wolak and et  al , 2003 , longo and et  al , 2014 , oberto and et  al , 2007 , fetissov et  al . , 2004 ) . y1 and y5 receptors act synergistically in the regulation of energy homeostasis ( mashiko et  al .
although the combined effects of y1 and y5 receptor agonists have not been tested in the context of anxiety thus far , the notion of co - activating these receptors could be valuable in the development of pharmacotherapeutics for enhanced anxiolytic effects .
hypervigilance is a characteristic symptom of stress - related psychiatric disorders that may reflect dysregulation of brain arousal systems .
startle responses can be measured in rodents using loud acoustic tones , and can be enhanced in fear - potentiated startle , a paradigm in which startle is tested in an environment previously paired with footshocks .
central administration of npy inhibits both basal acoustic startle and fear - potentiated startle in rodents ( broqua and et  al , 1995 , gilpin and et  al , 2011 , gutman and et  al , 2008 ) .
another study demonstrated that npy infusion into the basolateral , but not central nucleus , of the amygdala mimics the effects of npy on acoustic startle and fear - potentiated responses ( gutman et  al . , 2008 ) .
fear - potentiated startle , whereas a y2r agonist was reported to have no effect ( broqua et  al . , 1995 ) . in genetically modified rodents , knockout of npy or y2r
enhances acoustic startle ( bannon et  al . , 2000 ) , whereas deletion of the y1r yields impaired habituation of startle responses ( karl et  al . , 2010 ) .
these studies indicate a role for npy in the modulation of startle and potential for npy as a therapeutic for hyperarousal in stress - related psychiatric disorders .
however the receptor subtypes and brain regions dictating npy - induced resilience to this behavioral response remain unclear .
the ne system originating in the locus coeruleus ( lc ) is a brainstem region contributing to arousal responses ( samuels and szabadi , 2008 , sara and bouret , 2012 ) , thus npy may mediate arousal behavior by directly acting in the lc or by influencing brain regions upstream .
1 demonstrates putative neurochemical interactions and circuitry that may influence the function of the lc - ne system and arousal behavior .
npy inhibits the firing rate of ne neurons in the lc , and potentiates the effect of ne on presynaptic autoinhibition of neuronal firing ( illes et  al . , 1993 ,
this electrophysiological evidence suggests that npy may act to restrain the activity of noradrenergic neurons , which may have important implications for stress - psychiatric diseases in which the lc - ne system is disrupted . in combination with anatomical evidence demonstrating rich npy innervation of the lc ( smialowska , 1988 ) ( shown in fig . 
2),these studies suggest that npy may play an important role in the regulation of noradrenergic stress responses and arousal via ne circuitry .
recent rodent studies suggest that npy may be useful in the treatment of psychiatric diseases such as ptsd , which is heavily characterized by behavioral sequelae associated with fear .
npy has been found to influence multiple fear - related behaviors including the acquisition , incubation , expression , and extinction of conditioned fear .
administration of npy or a y1r agonist inhibits freezing behavior in both the acquisition and consolidation phases of fear conditioning , and these effects are blocked by pretreatment with a y1r antagonist ( lach de lima , 2013 ) .
y1r may not be necessary for the cued - expression of fear , as intra - amygdalar administration of npy robustly decreases the expression of conditioned fear , but these effects are not replicated by y1r agonists and are not blocked by pretreatment with a y1r antagonist ( fendt et  al .
in this particular study , y1r knockout mice showed slight elevations in freezing behavior during fear conditioning , but did not show an enhanced phenotype upon testing for the cued - expression of fear compared to wildtype mice ( fendt et  al .
in addition , npy was still capable of reducing the cued - expression of fear in these y1r deficient mice , suggesting that the y1r may not be involved in this phase ( fendt et  al . , 2009 ) .
npy can suppress the long - term incubation of conditioned fear , while delivery of npy prior to extinction training attenuates freezing and enhances retention of extinguished fear memories ( gutman and et  al , 2008 , lach and de lima , 2013 , pickens and et  al , 2009 ) .
y1r antagonism blocks npy - induced reductions in freezing and blockade of amygdalar y1r leads to deficient extinction retention ( gutman and et  al , 2008 , lach and de lima , 2013 ) .
consistent with pharmacological studies , npy knockout mice display accelerated acquisition of conditioned fear , excessive recall of fear , and impaired fear extinction ( verma et  al . , 2012 ) .
interestingly , deletion of the y1r has moderately similar effects , whereas knockout of the y2r has no effect on fear ( verma et  al . , 2012 ) .
however , double y1r and y2r knockout mice exhibit a remarkably similar phenotype to npy deficient mice , indicating that both receptor subtypes do play a role in aspects of fear conditioning ( verma et  al . ,
interactions between the npy and crf systems were evident as increased amygdalar crfr1 and decreased y1r mrna were found concurrently in animals displaying enhanced freezing time , and all of these effects were reversed in parallel following re - exposure to the footshock - paired environment ( hendriksen et  al . , 2012 ) .
indirect evidence for npy interactions with norepinephrine was obtained using auditory fear conditioning , in which centrally administered npy and a y1r agonist blunted fear - induced tachycardia ( tovote et  al . , 2004 ) .
these effects were blocked by a y1r antagonist ( tovote et  al . , 2004 ) .
for example , central administration of npy dose - dependently reduces immobility and increases swimming time in the forced swim test ( redrobe and et  al , 2005 , stogner and holmes , 2000 , redrobe and et  al , 2002 ) , a screening paradigm for pharmacological anti - depressant activity .
y1r agonists and y2r antagonists also produce anti - depressant effects in forced swim ( redrobe et  al . , 2002 ) , whereas y1r antagonists block the anti - depressant effects of npy ( redrobe et  al . , 2002 ) .
intra - hippocampal infusion of npy has anti - depressant properties in a learned helplessness paradigm , which is blocked by co - administration of a y1r , but not a y2r antagonist ( ishida et  al . , 2007 ) .
y1r knockout mice display increased immobility in the forced swim test , indicative of a depression - like phenotype ( karlsson et  al .
, 2008 ) . both y2r and y4r knockout mice exhibit reduced depression - like behavior in the tail suspension test , another common screening assay for antidepressant potential ( tasan and et  al , 2009 , painsipp et  al
knockout of both y2r and y4r results in augmented anti - depressant effects compared to single - knockout of either receptor ( tasan et  al . , 2009 ) .
anti - depressant strategies including imipramine and electroconvulsive stimuli increase npy immunoreactivity or receptor mrna and binding sites , respectively ( heilig and et  al , 1988 , madsen and et  al , 2000 ) .
the anti - depressant properties of npy may be mediated through interactions with the serotonin system , as administration of a tryptophan hydroxylase inhibitor blocked the anti - depressant effects of npy in the forced swim test ( redrobe et  al . , 2005 ) .
the flinders - sensitive line ( fsl ) is a transgenic model of depression in which abnormalities in npy , serotonin , and catecholaminergic systems have been identified ( overstreet and et  al , 2005 , serova and et  al , 1998 ) .
depression - like behavior has been associated with impaired hippocampal neurogenesis , and enhanced npy and serotonin activities been shown to increase cell proliferation in the dentate gyrus of the hippocampus ( husum et  al . , 2006 ) .
hippocampal and amygdalar npy immunoreactivity is lower in fsl rats compared to flinders - resistant controls ( jimenez vasquez and et  al , 2000 , jimenez - vasquez et  al . , 2000 ,
zambello and et  al , 2008 ) , and aging is associated with exacerbated loss of hippocampal npy immunoreactivity in the fsl line ( husum et  al . ,
, y5r antagonism produces anti - depressant effects in the forced swim test ( walker et  al . , 2009 ) .
electroconvulsive stimuli and the selective serotonin reuptake inhibitor fluoxetine increase npy mrna or immunoreactivity in the hippocampus and hypothalamus , and upregulate amygdalar y1r binding sites in fsl rats ( caberlotto and et  al , 1998 , caberlotto and et  al , 1999 ) . exercise and escitalopram
are associated with similar alterations in hippocampal npy and y1 receptor mrna ( bjornebekk et  al . , 2010 ) .
npy has also been examined in olfactory bulbectomized rats ( obx ) , which are utilized as a rodent model due to depression - like disruptions in behavior , physiology , and neurochemistry ( song and leonard , 2005 , kelly et  al . , 1997 ) .
anti - depressant effects are observed following chronic treatment with npy , a y1r agonist , and a y2r antagonist in obx rats ( goyal and et  al , 2009 , morales - medina and et  al , 2012a ) .
in contrast , chronic administration of a y2r agonist enhanced depression - like behavior in obx rats in the forced swim test ( morales - medina et  al . , 2012 ) .
future studies investigating the efficacy of npy in depression - like behavior induced by chronic psychosocial stress using the resident - intruder model of social defeat would be interesting .
social defeat reproduces behavioral and physiological indices of depression including disruption of crf and ne systems ( wood and et  al , 2010 , wood , 2014 , chaijale and et  al , 2014 , chaijale and et  al , 2013 , russo and et  al , 2012 ) , and would likely yield important information regarding the role of npy in depressive behavior and disorders .
several rodent models of ptsd indicate that npy expression in the brain following stress may be associated with susceptibility to ptsd - associated impairments . for example ,
rats displaying extreme anxiety and arousal following exposure to predator scent stress ( pss ) had lower npy protein levels in the cortex , amygdala , hippocampus , and periaqueductal grey compared to rodents that were less impaired or to unstressed controls ( cohen et  al . , 2012 ) .
injection of npy into the hippocampus 1  h after pss reduced the development of anxiety - like behavior , hyperarousal , and cue - elicited freezing .
additionally , npy administration reduced the prevalence of an extreme behavioral response ( cohen et  al . , 2012 ) .
delivery of npy to the brain by intranasal ( in ) infusion has been used to examine its efficacy in the single prolonged stress ( sps ) model of ptsd ( serova and et  al , 2013 , laukova and et  al , in press , serova and et  al , 2014 ) .
intranasal npy can elevate csf concentrations to a range that reduces anxiety behavior after i.c.v .
administration , while also reaching multiple stress responsive brain regions and leaving plasma npy levels unchanged ( serova and et  al , 2013 , laukova and et  al , in press ) . pretreatment with in npy slowed the development of immobility during the forced swim portion of sps , and reduced the induction of gene expression of the ne biosynthetic enzymes , tyrosine hydroxylase and dopamine beta hydroxylase , in the locus coeruleus shortly after sps ( serova et  al . , 2013 ) .
sps - induced increases in plasma corticosterone and acth were also attenuated by in npy , suggesting either less activation or more rapid recovery of the hypothalamic - pituitary - adrenal ( hpa ) axis ( serova et  al . ,
intranasal npy administered prior to or immediately after sps led to pronounced and long - lasting effects on the development of behavioral , neuroendocrine , and molecular impairments associated with ptsd .
npy greatly attenuated , and in many cases prevented , increases in anxiety , hyperarousal , and depression - like behavior observed 12 weeks after exposure to traumatic stress ( serova et  al . , 2013 ) .
npy prevented sps - triggered induction of crf , glucocorticoid receptor ( gr ) , and fkbp5 mrnas and the reduction in phosphorylated - gr in the mediobasal hypothalamus ( laukova et  al .
npy also increased the expression and phosphorylation of gr in the hippocampus ( laukova et  al .
these studies suggest that early intervention with intranasal npy may prevent dysregulation of the hpa axis by restoring proper negative feedback inhibition by gr .
intranasal npy also attenuated long - term changes in the central noradrenergic system induced by sps , including the development of increased sensitization of the lc to re - experiencing the forced swim ( serova et  al . , 2013 ) .
taken together , pss and sps studies indicate that a single treatment with npy near the time of the traumatic stress could provide long - lasting resilience to the development of ptsd and co - morbid impairments such as depression .
moreover , recent work also suggests that npy may be efficacious as a treatment once ptsd - like symptoms have already manifested .
rats given in npy one week after sps , when ptsd - like symptoms have manifested , exhibit anxiety - like behavior similar to unstressed controls up to 2 days later ( serova et  al . , 2014 ) .
rats administered npy after sps also had reduced depression - like behavior ( serova et  al . , 2014 ) .
further studies are necessary to determine if intranasal npy reverses other impairments associated with ptsd , as well as the duration and sustainability of the improvements .
the examples presented herein demonstrate that pharmacological interventions targeting the npy system display much promise for the treatment of numerous stress - related psychiatric disorders .
future pharmacotherapeutic studies should consider targeting the central npy system in stress - related emotionality and resilience .
the preponderance of data suggests that npy itself has significant therapeutic potential as a mediator of stress resilience .
there are two major challenges associated with the development of npy as a drug for psychiatric disorders ; it is a peptide and it has a broad range of activities that may result in undesirable side - effects .
the attractiveness and challenges of peptide therapeutics for cns disorders has recently been reviewed ( mcgonigle , 2012 ) .
peptides do not accumulate in tissues and are effectively metabolized by endogenous enzymes ; therefore they have limited potential for drug  drug interactions .
however , peptides have short half - lives and several methods have been introduced to prolong their stability in  vivo .
encouragingly , as demonstrated in rodent models ( serova and et  al , 2013 , laukova and et  al , in press , serova and et  al , 2014 ) , npy may confer long - lasting benefits for stress resilience despite its short half - life .
although this review has concentrated on the beneficial effects of npy in the cns , npy also has multiple actions in the periphery ( hirsch and zukowska , 2012 , held and et  al , 2006 , pedrazzini et  al . , 2003 ) .
for example , npy is a co - transmitter in sympathetic nerves , plays a role in vascular tone , and contributes to cardiovascular remodeling ( zukowska - grojec , 1995 , edvinsson and et  al , 1984 , schuerch and et  al , 1998 , abe et  al . , 2007 ) .
rodent studies have demonstrated npy - induced disruption of metabolic homeostasis , as chronic npy administration in rodents leads to abnormal baroreflex sensitivity , abdominal obesity , and dyslipidemia ( xie et  al . , 2012 ) .
npy release from sympathetic nerves also stimulates fat angiogenesis , macrophage infiltration , and proliferation and differentiation of new adipocytes leading to abdominal obesity and a metabolic syndrome in rodents ( kuo et  al . , 2007 ) .
npy also plays a role in bone physiology , gastrointestinal function , and cancer progression ( brothers and wahlestedt , 2010 ) .
peripheral administration of npy may result in undesirable side effects on these physiological processes , increasing the value and necessity for strategies of npy administration to the brain .
although no such transporter is known to exist for npy , studies have shown that npy can enter the brain to some extent ( kastin and akerstrom , 1999 ) .
intranasal ( in ) infusion represents a clinically relevant and non - invasive approach for the delivery of npy to the brain . in administration
allows peptides to rapidly and directly enter the cns via intracellular neuronal olfactory and extracellular trigeminal - associated pathways bypassing the blood 
, 2010 , ionescu and et  al , 2012 , thorne and et  al , 1995 , thorne and et  al , 2004 ) .
as demonstrated in rodent models ( serova and et  al , 2013 , laukova and et  al , in press , serova and et  al , 2014 ) , npy delivered to the brain by in infusion has beneficial effects on stress - related emotionality and pathology , which is likely achieved by influencing npy responsive systems in all regions regulating stress responses . a potential disadvantage of in infusion is the lack of selective targeting and potential for cns - mediated side effects .
for example , npy is also a powerful orexigenic agent and regulates circadian rhythms ( brothers and wahlestedt , 2010 , gehlert , 1999 ) .
although not used for stress - related implications , studies have administered npy by in infusion in humans ( lacroix and mosimann , 1996 , lacroix and et  al , 1996 , cervin and et  al , 1999 , hallschmid and et  al , 2003 , hallschmid and et  al , 2004 ) . one small clinical trial aimed to test the effect of in npy on mood and anxiety ( nct 00748956 ) ( u.s .
, 2000b ) while another is currently underway to investigate the safety of in npy using a dose escalation in ptsd ( nct 01533519 ) ( u.s .
the viability of this route of administration makes it much more feasible to consider clinical proof of concept studies for severe stress - related disorders such as ptsd , for which there are no truly effective treatments and the initiating stress is often known . in the event that cns - mediated side effects prove to be significant obstacles to the chronic use of npy as a therapeutic , it is possible
that the selective activation or inhibition of individual receptor subtypes may be a safer yet still effective alternative .
there is already considerable preclinical data demonstrating the therapeutic potential of y1r agonists and y2r antagonists for the treatment of stress - related disorders and these targets clearly merit additional study .
elucidating the neuroanatomical interactions of the npy system with other neurotransmitters and peptides within stress - integrative circuitry would greatly advance our knowledge regarding the role of npy in stress resilience and emotionality in future studies .
in addition , future studies should consider the impact of sex differences on npy - mediated effects .
human and rodent studies indicate that females may be more vulnerable to stress and stress - related psychiatric diseases than males ( bangasser and valentino , 2014 ) .
psychiatric symptomology and treatments responses also vary based on sex ( kokras and dalla , 2014 ) .
future studies examining the efficacy of npy on stress and emotionality in females with direct comparisons to males would advance our understanding of sex differences in stress resilience .
neuroanatomical and molecular studies conducted across sexes would reveal potential mechanisms underlying effective coping to stress and intervention strategies for stress - induced psychiatric diseases .
 repeated , extreme , or traumatic stressors can elicit pathological effects leading to many negative physical and psychological outcomes . 
 stressors can precipitate the onset of psychiatric diseases , or exacerbate pre - existing disorders including various anxiety and mood disorders . as stressors can negatively impact human psychiatric health , 
 it is essential to identify neurochemicals that may confer protection from the negative sequelae of repeated or extreme stress exposure . elucidating the neurobiological underpinnings of stress resilience will enhance our ability to promote resilience to , or recovery from , stress - related psychiatric disease . herein , we will review the evidence for neuropeptide y as an endogenous mediator of resilience and its potential relevance for the treatment of stress - related psychiatric diseases . 
Introduction
Neuropeptide Y (NPY)
NPY in stress-related psychiatric disorders: insight from human studies
Potential therapeutic applications of NPY: evidence from animal models
Therapeutic implications
Future directions