Elsevier

Neuropeptides

Volume 55, February 2016, Pages 111-126
Neuropeptides

News and reviews
The role of Neuropeptide Y in fear conditioning and extinction

https://doi.org/10.1016/j.npep.2015.09.007Get rights and content
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Highlights

  • Role of Neuropeptide Y in fear conditioning and extinction

  • Role of Pancreatic polypeptide in fear conditioning and extinction

  • Distribution and connectivity of NPY neurons in amygdala and hippocampus

  • Electrophysiology of NPY in amygdala and hippocampus

Abstract

While anxiety disorders are the brain disorders with the highest prevalence and constitute a major burden for society, a considerable number of affected people are still treated insufficiently. Thus, in an attempt to identify potential new anxiolytic drug targets, neuropeptides have gained considerable attention in recent years. Compared to classical neurotransmitters they often have a regionally restricted distribution and may bind to several distinct receptor subtypes. Neuropeptide Y (NPY) is a highly conserved neuropeptide that is specifically concentrated in limbic brain areas and signals via at least 5 different G-protein-coupled receptors. It is involved in a variety of physiological processes including the modulation of emotional-affective behaviors. An anxiolytic and stress-reducing property of NPY is supported by many preclinical studies. Whether NPY may also interact with processing of learned fear and fear extinction is comparatively unknown. However, this has considerable relevance since pathological, inappropriate and generalized fear expression and impaired fear extinction are hallmarks of human post-traumatic stress disorder and a major reason for its treatment-resistance. Recent evidence from different laboratories emphasizes a fear-reducing role of NPY, predominantly mediated by exogenous NPY acting on Y1 receptors. Since a reduction of fear expression was also observed in Y1 receptor knockout mice, other Y receptors may be equally important. By acting on Y2 receptors, NPY promotes fear extinction and generates a long-term suppression of fear, two important preconditions that could support cognitive behavioral therapies in human patients. A similar effect has been demonstrated for the closely related pancreatic polypeptide (PP) when acting on Y4 receptors. Preliminary evidence suggests that NPY modulates fear in particular by activation of Y1 and Y2 receptors in the basolateral and central amygdala, respectively. In the basolateral amygdala, NPY signaling activates inhibitory G protein-coupled inwardly-rectifying potassium channels or suppresses hyperpolarization-induced I(h) currents in a Y1 receptor-dependent fashion, favoring a general suppression of neuronal activity. A more complex situation has been described for the central extended amygdala, where NPY reduces the frequency of inhibitory and excitatory postsynaptic currents. In particular the inhibition of long-range central amygdala output neurons may result in a Y2 receptor-dependent suppression of fear. The role of NPY in processes of learned fear and fear extinction is, however, only beginning to emerge, and multiple questions regarding the relevance of endogenous NPY and different receptor subtypes remain elusive. Y2 receptors may be of particular interest for future studies, since they are the most prominent Y receptor subtype in the human brain and thus among the most promising therapeutic drug targets when translating preclinical evidence to potential new therapies for human anxiety disorders.

Abbreviations

[D-Arg25]hNPY
Y1 receptor agonist
[D-Arg25]hNPY
Y1 receptor agonist
AAV vector
Adeno-associated viral vector
AStr
Amygdala-striatal transition zone
ATP
Adenosine triphosphate
BAC
Bed nucleus of the anterior commissure
BF
Basal forebrain
BIBO 3304
Y1 receptor antagonist
BIBP 3226
Y1 receptor antagonist
BIIE 0246
Y2 receptor antagonist
BLA
Basolateral amygdala
BNST
Bed nucleus of the stria terminalis
CA1, CA3
Cornu amonis 1, 3
cAMP
Cyclic adenosine monophosphate
CCK
Cholecystokinin
CEA
Central amygdala
CEc
Centro-capsular amygdala
CEl
Centro-lateral amygdala
CEm
Centro-medial amygdala
CNS
Central nervous system
CR
Calretinin
CS
Conditioned stimulus
CSF
Cerebrospinal fluid
D-Trp32 NPY
Y5 receptor agonist
D1R
Dopamine 1 receptor
DG
Dentate gyrus
DPPIV
Dipeptidylpeptidase IV
EN
Entorhinal cortex
Epac
Exchange protein activated by cyclic adenosine monophosphate
F7P34NPY
Y1 receptor agonist
GABA
Gamma-amino butyric acid
GIRK
G protein-coupled inwardly-rectifying potassium
HC
Hippocampus
HPA
Hypothalamic pituitary adrenal
icv
Intracerebroventricular
IL
Infralimbic cortex
Im
Main intercalated nucleus
ip
Intraperitoneal
IR
Immunoreactivity
JNJ-31,020,028
Brain-penetrant Y2 receptor antagonist
L152,804
Y5 receptor antagonist
LC
Locus coeruleus
Leu31Pro34-NPY
Y1 (Y4, Y5) receptor agonist
LTP
Long-term potentiation
MEA
Medial amygdala
NPY
Neuropeptide Y
NPY13-36
Y2 receptor agonist
NPY3-36
Y2/Y5 receptor agonist
NPYKO, Y1KO, Y2KO, Y4KO
NPY, Y1, Y2, Y4 receptor KO mouse
PAG
Periaqueductal gray
PBN
Parabrachial nucleus
PC-1, PC-2
Prohormone convertase1, 2
Pir
Piriform cortex
PKA
Proteinkinase A
PL
Prelimbic cortex
PP
Pancreatic polypeptide
PTSD
Post traumatic stress disorder
PV
Parvalbumin
PYY
Peptide YY
PYY3-36
Y2/Y5 receptor agonist
RT
Reticular nucleus of the thalamus
SST
Somatostatin
st
Stria terminalis
US
Unconditioned stimulus
VIP
Vasoactive intestinal peptide
Y-28 (Des-AA11–18 [Cys7,21, d-Lys9 (Ac), d-His26, Pro34]-NPY)
Y1 receptor agonist
Y-36 ([d-Arg25, d-His26]-NPY)
Y1 receptor agonist
Y1R, Y2R, Y4R, Y5R, y6R
NPY Y1, Y2, Y4, Y5, y6 receptor

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