neuropeptide-y and Memory-Disorders

Since its discovery in 1982, neuropeptide Y (NPY) has been shown to have numerous effects mediated by a growing number of NPY receptors in both the CNS and peripheral nervous system. Perhaps best appreciated is the role of NPY in the control of systemic blood pressure, together with its effects on feeding, anxiety and memory. However, recent evidence increasingly supports an important role for NPY in mediating analgesia and hyperalgesia by distinct central and peripheral mechanisms. In this review we concentrate on this important aspect of NPY pharmacology and consider mechanisms controlling the expression of NPY and its receptors. In addition, we also present the more recent data describing the other possible roles for NPY-NPY agonists and antagonists may be useful in the treatment of conditions as varied as anorexia, epilepsy, anxiety, depression, hypertension and heart failure.

Topics: Analgesics; Animals; Anti-Anxiety Agents; Antihypertensive Agents; Appetite Stimulants; Cardiovascular Diseases; Central Nervous System; Depression; Humans; Hyperalgesia; Memory Disorders; Neuropeptide Y; Peripheral Nervous System; Receptors, Neuropeptide Y; Schizophrenia

Memory is the ability to store, retrieve and use information that requires a progressive time-dependent stabilization process known as consolidation to be established. The hippocampus is essential for processing all the information that forms memory, especially spatial memory. Neuropeptide Y (NPY) affects memory, so in this study we investigated the participation and recruitment of NPY receptors during spatial memory consolidation in rats. Using the water maze test, we show that NPY (1 pmol) injected into the dorsal hippocampus impaired memory consolidation and that previous restraint stress (30 min) potentiates NPY effects, i.e. further impaired memory consolidation. Using selective antagonists for NPY Y

Topics: Animals; Arginine; Behavior, Animal; Benzazepines; Disease Models, Animal; Male; Memory Disorders; Neuropeptide Y; Rats; Rats, Wistar; Receptors, Neuropeptide Y; Restraint, Physical; Spatial Memory; Stress, Psychological

The present experiments reveal the alterations of the hippocampal neuronal populations in chronic epilepsy. The mice were injected with a single dose of pilocarpine. They had status epilepticus and spontaneously recurrent motor seizures. Three months after pilocarpine treatment, the animals were investigated with the Barnes maze to determine their learning and memory capabilities. Their hippocampi were analyzed 2 weeks later (at 3.5 months) with standard immunohistochemical methods and cell counting. Every animal displayed hippocampal sclerosis. The neuronal loss was evaluated with neuronal-N immunostaining, and the activation of the microglia was measured with Iba1 immunohistochemistry. The neuropeptide Y, parvalbumin, and calretinin immunoreactive structures were qualitatively and quantitatively analyzed in the hippocampal formation. The results were compared statistically to the results of the control mice. We detected neuronal loss and strongly activated microglia populations. Neuropeptide Y was significantly upregulated in the sprouting axons. The number of parvalbumin- and calretinin-containing interneurons decreased significantly in the Ammon's horn and dentate gyrus. The epileptic animals displayed significantly worse learning and memory functions. We concluded that degeneration of the principal neurons, a numerical decrease of PV-containing GABAergic neurons, and strong peptidergic axonal sprouting were responsible for the loss of the hippocampal learning and memory functions.

Topics: Aging; Animals; Calbindin 2; Cell Proliferation; Cell Survival; Densitometry; Epilepsy; Hippocampus; Interneurons; Maze Learning; Memory Disorders; Mice; Microglia; Neurons; Neuropeptide Y; Parvalbumins; Peptides; Pilocarpine; Reaction Time; Sclerosis; Spatial Learning; Status Epilepticus

The senescence-accelerated mouse prone 8 (SAMP8) strain is considered a neurodegeneration model showing age-related cognitive deficits with little physical impairment. Young SAMP8 mice, however, exhibit signs of disturbances in development such as marked hyperactivity and reduced anxiety well before the onset of cognitive impairment. As the key enzyme in local regulation of thyroid hormone (TH) signaling, type 2 deiodinase, was significantly reduced in the SAMP8 hippocampus relative to that of the normally aging SAM-resistant 1 (SAMR1), we used these two strains to compare the development of the hippocampal GABAergic system, which is known to be strongly affected by hypothyroidism. Among GABAergic components, neuronal K+ /Cl- co-transporter 2 was down-regulated in SAMP8 transiently at 2 weeks. Although distribution of total GABAergic neurons was similar in both strains, 22-30% reduction was observed in the neuropeptide Y (NPY)-positive subpopulation of GABAergic neurons in SAMP8. Electrophysiological studies on hippocampal slices obtained at 4 weeks revealed that epileptiform activity, induced by high-frequency stimulation, lasted four times longer in SAMP8 compared with SAMR1, indicating a dysregulation of excitability that may be linked to the behavioral abnormalities of young SAMP8 and to neurodegeneration later on in life. Local attenuation of TH signaling may thus impact the normal development of the GABAergic system.

Topics: Aging; Animals; Behavior, Animal; Cognition Disorders; Cyclic AMP Response Element-Binding Protein; Electrophysiological Phenomena; gamma-Aminobutyric Acid; Hippocampus; Iodide Peroxidase; K Cl- Cotransporters; Learning Disabilities; Male; Memory Disorders; Mice; Neurodegenerative Diseases; Neurons; Neuropeptide Y; Phosphorylation; Symporters; Thyroid Hormones

Hippocampal interneuron populations are reportedly vulnerable to normal aging. The relationship between interneuron network integrity and age-related memory impairment, however, has not been tested directly. That question was addressed in the present study using a well-characterized model in which outbred, aged, male Long-Evans rats exhibit a spectrum of individual differences in hippocampal-dependent memory. Selected interneuron populations in the hippocampus were visualized for stereological quantification with a panel of immunocytochemical markers, including glutamic acid decarboxylase-67 (GAD67), somatostatin, and neuropeptide Y. The overall pattern of results was that, although the numbers of GAD67- and somatostatin-positive interneurons declined with age across multiple fields of the hippocampus, alterations specifically related to the cognitive outcome of aging were observed exclusively in the hilus of the dentate gyrus. Because the total number of NeuN-immunoreactive hilar neurons was unaffected, the decline observed with other markers likely reflects a loss of target protein rather than neuron death. In support of that interpretation, treatment with the atypical antiepileptic levetiracetam at a low dose shown previously to improve behavioral performance fully restored hilar SOM expression in aged, memory-impaired rats. Age-related decreases in GAD67- and somatostatin-immunoreactive neuron number beyond the hilus were regionally selective and spared the CA1 field of the hippocampus entirely. Together these findings confirm the vulnerability of hippocampal interneurons to normal aging and highlight that the integrity of a specific subpopulation in the hilus is coupled with age-related memory impairment.

Topics: Aging; Animals; Antigens, Nuclear; Behavior, Animal; CA3 Region, Hippocampal; Cell Count; Cognition; Glutamate Decarboxylase; Hippocampus; Imaging, Three-Dimensional; Immunohistochemistry; Interneurons; Levetiracetam; Male; Memory Disorders; Nerve Tissue Proteins; Neuropeptide Y; Nootropic Agents; Perfusion; Piracetam; Rats; Rats, Long-Evans; Somatostatin

Neuropeptide Y (NPY) is a 36-amino acid peptide widely distributed in the central nervous system (CNS) that has been associated with the modulation of several functions including food intake, learning and memory, mood and neuroprotection. There is great interest in understanding the role of NPY in the deleterious effects induced by the central accumulation of amyloid-β (Aβ) peptides, a pathological hallmark of Alzheimer's disease (AD). Herein, we evaluated the effects of a single intracerebroventricular (i.c.v.) administration of NPY (0.0234 μmol/μL) 15 min prior to the i.c.v. injection of aggregated Aβ1-40 peptide (400 pmol/mouse) in behavioral and neurochemical parameters related to oxidative stress in mice. Pretreatment with NPY prevented Aβ1-40-induced depressive-like responses and spatial memory impairments evaluated in the tail suspension and object location tasks, respectively. The protective effects of NPY on spatial memory of Aβ1-40-treated mice were abolished by the pretreatment with the selective Y2 receptor antagonist BIIE0246. On the other hand, the administration of NPY and Aβ1-40 did not alter the performance of the animals in the elevated plus-maze and open field arena, indicating lack of effects on anxiety state and locomotor function. Although Aβ1-40 infusion did not change hippocampal and cortical glutathione peroxidase (GPx) activity and glutathione (GSH) levels, Aβ1-40-infused animals showed an increased lipid peroxidation in hippocampus and prefrontal cortex that were blunted by NPY administration. These findings indicate that central administration of NPY prevents Aβ1-40-induced depressive-like behavior and spatial memory deficits in mice and that this response is mediated, at least in part, by the activation of Y2 receptors and prevention of oxidative stress.

Topics: Amyloid beta-Peptides; Animals; Arginine; Benzazepines; Cerebral Cortex; Depression; Glutathione; Glutathione Peroxidase; Hippocampus; Injections, Intraventricular; Lipid Peroxidation; Male; Maze Learning; Memory Disorders; Mice; Motor Activity; Neuropeptide Y; Neuroprotective Agents; Oxidative Stress; Peptide Fragments; Receptors, Neuropeptide Y

Methamphetamine (METH) is a psychostimulant drug that causes irreversible brain damage leading to several neurological and psychiatric abnormalities, including cognitive deficits. Neuropeptide Y (NPY) is abundant in the mammalian central nervous system (CNS) and has several important functions, being involved in learning and memory processing. It has been demonstrated that METH induces significant alteration in mice striatal NPY, Y(1) and Y(2) receptor mRNA levels. However, the impact of this drug on the hippocampal NPY system and its consequences remain unknown. Thus, in this study, we investigated the effect of METH intoxication on mouse hippocampal NPY levels, NPY receptors function, and memory performance. Results show that METH increased NPY, Y(2) and Y(5) receptor mRNA levels, as well as total NPY binding accounted by opposite up- and down-regulation of Y(2) and Y(1) functional binding, respectively. Moreover, METH-induced impairment in memory performance and AKT/mammalian target of rapamycin pathway were both prevented by the Y(2) receptor antagonist, BIIE0246. These findings demonstrate that METH interferes with the hippocampal NPY system, which seems to be associated with memory failure. Overall, we concluded that Y(2) receptors are involved in memory deficits induced by METH intoxication.

Topics: Animals; Central Nervous System Stimulants; Hippocampus; Male; Memory Disorders; Methamphetamine; Mice; Mice, Inbred C57BL; Neuropeptide Y; Proto-Oncogene Proteins c-akt; Receptors, Neuropeptide Y; Signal Transduction; TOR Serine-Threonine Kinases

Alzheimer's disease (AD) is characterized by three primary pathologies in the brain: amyloid plaques, neurofibrillary tangles, and neuron loss. Mouse models have been useful for studying components of AD but are limited in their ability to fully recapitulate all pathologies. We crossed the APPSwDI transgenic mouse, which develops amyloid beta (Abeta)-protein deposits only, with a nitric oxide synthase 2 (NOS2) knock-out mouse, which develops no AD-like pathology. APPSwDI/NOS2(-/-) mice displayed impaired spatial memory compared with the APPSwDI mice, yet they have unaltered levels of Abeta. APPSwDI mice do not show tau pathology, whereas APPSwDI/NOS2(-/-) mice displayed extensive tau pathology associated with regions of dense microvascular amyloid deposition. Also, APPSwDI mice do not have any neuron loss, whereas the APPSwDI/NOS2(-/-) mice have significant neuron loss in the hippocampus and subiculum. Neuropeptide Y neurons have been shown to be particularly vulnerable in AD. These neurons appear to be particularly vulnerable in the APPSwDI/NOS2(-/-) mice as we observe a dramatic reduction in the number of NPY neurons in the hippocampus and subiculum. These data show that removal of NOS2 from an APP transgenic mouse results in development of a much greater spectrum of AD-like pathology and behavioral impairments.

Topics: Alzheimer Disease; Animals; Cerebral Amyloid Angiopathy; Disease Models, Animal; Disease Progression; Hippocampus; Immunohistochemistry; Memory Disorders; Mice; Mice, Transgenic; Neurons; Neuropeptide Y; Nitric Oxide Synthase Type II

Recombinant adeno-associated viral (rAAV) vector-induced neuropeptide Y (NPY) overexpression in the hippocampus exerts powerful antiepileptic and antiepileptogenic effects in rats. Such gene therapy approach could be a valuable alternative for developing new antiepileptic treatment strategies. Future clinical progress, however, requires more detailed evaluation of possible side effects of this treatment. Until now it has been unknown whether rAAV vector-based NPY overexpression in the hippocampus alters normal synaptic transmission and plasticity, which could disturb learning and memory processing. Here we show, by electrophysiological recordings in CA1 of the hippocampal formation of rats, that hippocampal NPY gene transfer into the intact brain does not affect basal synaptic transmission, but slightly alters short-term synaptic plasticity, most likely via NPY Y2 receptor-mediated mechanisms. In addition, transgene NPY seems to be released during high frequency neuronal activity, leading to decreased glutamate release in excitatory synapses. Importantly, memory consolidation appears to be affected by the treatment. We found that long-term potentiation (LTP) in the CA1 area is partially impaired and animals have a slower rate of hippocampal-based spatial discrimination learning. These data provide the first evidence that rAAV-based gene therapy using NPY exerts relative limited effect on synaptic plasticity and learning in the hippocampus, and therefore this approach could be considered as a viable alternative for epilepsy treatment.

Topics: Animals; Arginine; Benzazepines; Dependovirus; Discrimination, Psychological; Excitatory Postsynaptic Potentials; Genetic Therapy; Genetic Vectors; Hippocampus; Injections; Long-Term Potentiation; Male; Memory Disorders; Neuronal Plasticity; Neuropeptide Y; Rats; Rats, Sprague-Dawley; Receptors, Neuropeptide Y; Recombinant Fusion Proteins; Transduction, Genetic; Transgenes

Neuropeptide Y (NPY) and, in particular, the Y2 receptor subtype, has been suggested to be involved in learning and memory processing. However, the precise role of Y2 receptors in learning and memory remains unclear. In the present study, mice lacking NPY Y2-type receptors were assessed in two animal models of learning and memory processing. We found that NPY Y2-/- mice displayed a deficit on the probe trial in the Morris water maze task, whereas acquisition performance, swim speed, and visible platform performance did not differ significantly between groups. In addition, NPY Y2-/- mice exhibited a marked deterioration in object memory 6 h, but not 1 h, following initial exposure in the object recognition test. Both groups of mice showed similar locomotor activity profiles in a low-stress, open field test. These data support the hypothesis that Y2 receptors are involved in the regulation of learning and memory processing.

Topics: Animals; Brain; Brain Chemistry; Learning; Learning Disabilities; Male; Maze Learning; Memory; Memory Disorders; Mice; Mice, Knockout; Models, Animal; Motor Activity; Neuropeptide Y; Receptors, Neuropeptide Y; Recognition, Psychology

In this study, effects of acupuncture at Zusanli acupoint on cell proliferation and expression of neuropeptide Y (NPY) in the dentate gyrus (DG) of streptozotocin-induced diabetic rats were investigated. Sprague-Dawley rats were divided into six groups: the control group, the non-diabetic and Zusanli-acupunctured group, the non-diabetic and non-acupoint-acupunctured group, the streptozotocin-induced-diabetes group, the streptozotocin-induced-diabetes and Zusanli-acupunctured group, and the streptozotocin-induced-diabetes and non-acupoint-acupunctured group. In the streptozotocin-induced diabetes group, the mean 5-bromo-2'-deoxyuridine-positive and NPY-positive cell counts in the DG were significantly decreased compared to the control group. Stimulation of the Zusanli resulted in increased cell proliferation and neuropeptide Y levels in the diabetic group. In the present results, it can be suggested that acupuncture may affect cell proliferation in the DG of streptozotocin-induced diabetic rats by regulating neuropeptide Y expression.

Topics: Acupuncture; Animals; Antimetabolites; Bromodeoxyuridine; Cell Count; Cell Division; Dentate Gyrus; Diabetes Mellitus, Experimental; Male; Memory Disorders; Neuropeptide Y; Rats; Rats, Sprague-Dawley