Elsevier

Neuropeptides

Volume 55, February 2016, Pages 79-89
Neuropeptides

News and reviews
The role of NPY in learning and memory

https://doi.org/10.1016/j.npep.2015.09.010Get rights and content

Highlights

  • NPY affects memory differentially depending on type/phase of memory, dose, and receptor subtypes.

  • NPY impairs associative implicit memory after aversive events involving Y1 receptors.

  • NPY impairs acquisition but enhances retention in associative explicit memory involving Y2 receptors

Abstract

High levels of NPY expression in brain regions important for learning and memory together with its neuromodulatory and neurotrophic effects suggest a regulatory role for NPY in memory processes. Therefore it is not surprising that an increasing number of studies have provided evidence for NPY acting as a modulator of neuroplasticity, neurotransmission, and memory. Here these results are presented in relation to the types of memory affected by NPY and its receptors. NPY can exert both inhibitory and stimulatory effects on memory, depending on memory type and phase, dose applied, brain region, and NPY receptor subtypes. Thus NPY act as a resilience factor by impairing associative implicit memory after stressful and aversive events, as evident in models of fear conditioning, presumably via Y1 receptors in the amygdala and prefrontal cortex. In addition, NPY impairs acquisition but enhances consolidation and retention in models depending on spatial and discriminative types of associative explicit memory, presumably involving Y2 receptor-mediated regulations of hippocampal excitatory transmission. Moreover, spatial memory training leads to increased hippocampal NPY gene expression that together with Y1 receptor-mediated neurogenesis could constitute necessary steps in consolidation and long-term retention of spatial memory. Altogether, NPY-induced effects on learning and memory seem to be biphasic, anatomically and temporally differential, and in support of a modulatory role of NPY at keeping the system in balance. Obtaining further insight into memory-related effects of NPY could inspire the engineering of new therapeutics targeting diseases where impaired learning and memory are central elements.

Introduction

Learning and memory processes depend on electro-chemical signalling within the neuronal networks in the brain. This includes chemical signalling undertaken by amino acids, biogenic monoamines, acetylcholine, gasotransmitters, and peptides, with the neuropeptides and its more than 20 distinct gene families (http://www.neuropeptides.nl) being the largest and most diverse class. The neuropeptides are 3–100 amino acid residues long proteinaceous substances synthesized in neurons and often co-localized with other neuropeptides or neurotransmitters (Hökfelt et al., 2000). Due to the slow and more diffuse release of neuropeptides, they are generally regarded as second messengers with neurotrophic and neuromodulatory effects. One of the most abundantly expressed neuropeptides in the mammalian brain is the neuropeptide Y (NPY) (Tatemoto et al., 1982, De Quidt and Emson, 1986).

NPY is a 36-amino acid residue long peptide named after its C-terminally amidated tyrosine (Y), and belongs to the NPY hormone family, also including the gut peptides peptide YY (PYY) and pancreatic polypeptide (PP) (Berglund et al., 2003). NPY has been implicated in regulations of important biological and pathophysiological functions such as blood pressure, neuroendocrine secretions, feeding behaviour, circadian rhythms, seizures, neuronal excitability, neuroplasticity, and memory (Vezzani et al., 1999, Michalkiewicz et al., 2001, Hansel et al., 2001, Berglund et al., 2003, Magni, 2003, Hökfelt et al., 2008, Beck and Pourié, 2013, Loh et al., 2015). In the brain, NPY is predominantly expressed in and released from GABAergic interneurons upon sustained neuronal activity (Vezzani et al., 1999), but it is also detected in astrocytes (Ramamoorthy and Whim, 2008) and some projection neurons (Wahlestedt et al., 1989), or could enter the brain from the blood circulation by diffusion over the blood–brain barrier (Kastin and Åkerstrom, 1999). The biological effects of NPY have been ascribed to activation of several known and cloned pertussis-sensitive rhodopsin-like GPCRs (Y1, Y2, Y4, Y5, and y6) (reviewed in Berglund et al., 2003). In the brain, Y1, Y2, and Y5 are the most prominent (Cabrele and Beck-Sickinger, 2000) whereas Y4 is mainly expressed in the gastrointestinal tract and to a lesser extent in the central nervous system (CNS) (Babilon et al., 2013), and y6 that shares high sequence identity with Y1 (Larhammar et al., 2001) is functional in rabbits and mice (Starback et al., 2000) but not in primates and rats. The existence of additional receptors has been suggested (Lin et al., 2005, Dumont and Quirion, 2006), e.g., pharmacological studies pointed to the existence of a putative Y3 receptor subtype, characterized by NPY over PYY preference (Gehlert, 1998, Lee and Miller, 1998), but so far cloning of this putative receptor has been unsuccessful. Moderate to high NPY immunoreactivity and concentrated NPY binding has been shown in several brain regions including the lateral septum, hypothalamus, hippocampus, cortex, neocortex, striatum, amygdala, and thalamus (Chang et al., 1985, De Quidt and Emson, 1986, Lynch et al., 1989, Caberlotto et al., 1997, Ramamoorthy et al., 2011). NPY receptors primarily couple to Gi/o proteins, leading to decreased cAMP accumulation, due to inhibited adenylate cyclase, but also to modulations of Ca2 + and K+ channels as well as intracellular Ca2 + mobilization (Herzog et al., 1992, Larhammar et al., 1992, Gerald et al., 1995, Rimland et al., 1996, Cabrele and Beck-Sickinger, 2000, Holliday et al., 2004).

Section snippets

Memory classifications

Memory can be classified according to the focus of interest, i.e., based on function (working or reference memory), temporal duration (short- or long-term memory), content (implicit or explicit memory), and nature (associative or non-associative) (Anderson, 1976, Squire and Cohen, 1984, Graf and Schacter, 1985). In addition, memory can be classified according to the involved, sequential memory phases including acquisition, consolidation, retention, and retrieval of experience-based information.

Neuroanatomy of learning and memory

By the time it was recognized that learning and memory could be classified into different types, it also became clear that the different kinds of memory are supported by distinct brain systems. Most of the knowledge comes from lesion studies from patients or animal models, but have subsequently gained further support with the emergence of functional imaging techniques. Under normal conditions, learning is a multimodal process not limited to engagement of a single brain-memory system, but more

NPY memory studies

An increasing number of studies have indicated a role for NPY in different functions of learning and memory using acute or chronic administration of NPY ligands and receptor agonists/antagonists as well as the employment of transgenic overexpression or knockout animals. Here we attempt to give an overall description of the role of the NPY system, but it should be noted that results from pharmacological and transgenic approaches are not always comparable. Most studies have been on the

Conclusions

There is compiling evidence that NPY acts as a modulator of neuroplasticity, synaptic transmission, and several types of memory. NPY can exert both inhibitory and stimulatory effects on memory, depending on the memory type, temporal memory step (i.e., acquisition, consolidation, retention, or retrieval), dose applied, NPY receptor subtype distribution, and the neuroanatomical brain systems involved. Thus NPY impairs acquisition in cued and contextual fear conditioning and step-down passive

Author information

D.P.D.W. is shareholder of CombiGene AB. The authors declare no other competing financial interests.

References (126)

  • M.S. Fanselow et al.

    Are the dorsal and ventral hippocampus functionally distinct structures?

    Neuron

    (2010)
  • J.F. Flood et al.

    Dissociation of the effects of neuropeptide Y on feeding and memory: evidence for pre- and postsynaptic mediation

    Peptides

    (1989)
  • J.F. Flood et al.

    Modulation of memory processing by neuropeptide Y

    Brain Res.

    (1987)
  • J.F. Flood et al.

    Modulation of memory processing by neuropeptide Y varies with brain injection site

    Brain Res.

    (1989)
  • C. Gerald et al.

    Expression cloning and pharmacological characterization of a human hippocampal neuropeptide Y/peptide YY Y2 receptor subtype

    J. Biolumin. Chemilumin.

    (1995)
  • B. Greco et al.

    Reduced attention and increased impulsivity in mice lacking NPY Y2 receptors: relation to anxiolytic-like phenotype

    Behav. Brain Res.

    (2006)
  • K. Grill-Spector et al.

    Repetition and the brain: neural models of stimulus-specific effects

    Trends Cogn. Sci.

    (2006)
  • M. Heilig et al.

    Intracerebroventricular neuropeptide Y suppresses open field and home cage activity in the rat

    Regul. Pept.

    (1987)
  • T. Hökfelt et al.

    Neuropeptides — an overview

    Neuropharmacology

    (2000)
  • T. Hökfelt et al.

    NPY and its involvement in axon guidance, neurogenesis, and feeding

    Nutrition

    (2008)
  • H. Husum et al.

    Extracellular levels of neuropeptide Y are markedly increased in the dorsal hippocampus of freely moving rats during kainic acid-induced seizures

    Brain Res.

    (1998)
  • H. Husum et al.

    Extracellular levels of NPY in the dorsal hippocampus of freely moving rats are markedly elevated following a single electroconvulsive stimulation, irrespective of anticonvulsive Y1 receptor blockade

    Neuropeptides

    (2002)
  • T. Karl et al.

    Effect of Y1 receptor deficiency on motor activity, exploration, and anxiety

    Behav. Brain Res.

    (2006)
  • T. Karl et al.

    Schizophrenia-relevant behaviours in a genetic mouse model for Y2 deficiency

    Behav. Brain Res.

    (2010)
  • R.M. Karlsson et al.

    Anxiolytic-like actions of centrally-administered neuropeptide Y, but not galanin, in C57BL/6J mice

    Pharmacol. Biochem. Behav.

    (2005)
  • A. Kask et al.

    The neurocircuitry and receptor subtypes mediating anxiolytic-like effects of neuropeptide Y

    Neurosci. Biobehav. Rev.

    (2002)
  • E. Koponen et al.

    Overexpression of the full-length neurotrophin receptor regulates the expression of plasticity-related genes in mouse brain

    Mol. Brain Res.

    (2004)
  • G. Lach et al.

    Role of NPY Y1 receptor on acquisition, consolidation and extinction on contextual fear conditioning: Dissociation between anxiety, locomotion and non-emotional memory behavior

    Neurobiol. Learn. Mem.

    (2013)
  • D. Larhammar et al.

    Cloning and functional expression of a human neuropeptide Y/peptide YY receptor of the Y1 type

    J. Biolumin. Chemilumin.

    (1992)
  • D. Larhammar et al.

    Origins of the many NPY-family receptors in mammals

    Peptides

    (2001)
  • C.C. Lee et al.

    Is there really an NPY Y3 receptor?

    Regul. Pept.

    (1998)
  • S. Lin et al.

    Compensatory changes in [125I]-PYY binding in Y receptor knockout mice suggest the potential existence of further Y receptor(s)

    Neuropeptides

    (2005)
  • D. Lindner et al.

    Molecular recognition of the NPY hormone family by their receptors

    Nutrition

    (2008)
  • K. Loh et al.

    Regulation of energy homeostasis by the NPY system

    Trends Endocrinol. Metab.

    (2015)
  • A. Longo et al.

    Conditional inactivation of neuropeptide Y Y1 receptors unravels the role of Y1 and Y5 receptors coexpressing neurons in anxiety

    Biol. Psychiatry

    (2014)
  • J. Mikkelsen et al.

    Accumulated increase in neuropeptide Y and somatostatin gene expression of the rat in response to repeated electroconvulsive stimulation

    J. Psychiatr. Res.

    (2006)
  • J.C. Morales-Medina et al.

    A possible role of neuropeptide Y in depression and stress

    Brain Res.

    (2010)
  • D.S. Olton et al.

    Attention and the frontal coretex as examined by simultaneous temporal processing

    Neuropsychologia

    (1988)
  • C.L. Pickens et al.

    Effect of pharmacological manipulations of neuropeptide Y and corticotropin-releasing factor neurotransmission on incubation of conditioned fear

    Neuroscience

    (2009)
  • R.J. Rangani et al.

    Nicotine evoked improvement in learning and memory is mediated through NPY Y1 receptors in rat model of Alzheimer's disease

    Peptides

    (2012)
  • J.P. Redrobe et al.

    Multiple receptors for neuropeptide Y in the hippocampus: putative roles in seizures and cognition

    Brain Res.

    (1999)
  • J.P. Redrobe et al.

    The neuropeptide Y (NPY) Y1 receptor subtype mediates NPY-induced antidepressant-like activity in the mouse forced swimming test

    Neuropsychopharmacology

    (2002)
  • D.L. Schacter et al.

    Reductions in cortical activity during priming

    Curr. Opin. Neurobiol.

    (2007)
  • K.S. Smith et al.

    A dual operator view of habitual behavior reflecting cortical and striatal dynamics

    Neuron

    (2013)
  • F. Agasse et al.

    Neuropeptide Y promotes neurogenesis in murine subventricular zone

    Stem Cells

    (2008)
  • J.R. Anderson

    Language, Memory, and Thought

    (1976)
  • S.K. Asinof et al.

    The 5-choice serial reaction time task: a task of attention and impulse control for rodents

    J. Vis. Exp.

    (2014)
  • S. Babilon et al.

    Towards improved receptor targeting: anterograde transport, internalization and postendocytotic trafficking of neuropeptide Y receptors

    Biol. Chem.

    (2013)
  • B. Beck et al.

    Ghrelin, neuropeptide Y, and other feeding-regulatory peptides active in the hippocampus: role in learning and memory

    Nutr. Rev.

    (2013)
  • M.M. Berglund et al.

    Recent developments in our understanding of the physiological role of PP-fold peptide receptor subtypes

    Exp. Biol. Med.

    (2003)
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