News and reviewsThe role of NPY in learning and memory
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.
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