neuropeptide-y and Cognitive-Dysfunction

Insulin is known to act in the central nervous system to regulate several physiological and behavioural outcomes, including energy balance, glucose homeostasis and cognitive functioning. However, the neuronal populations through which insulin enhances cognitive performance remain unidentified. Insulin receptors are found in neuropeptide-Y (NPY) expressing neurons, which are abundant in the hypothalamus and hippocampus; regions involved in feeding behaviour and spatial memory, respectively. Here we show that mice with a tissue specific knockout of insulin receptors in NPY expressing neurons (IRl⁢o⁢x/l⁢o⁢x; NPYC⁢r⁢e⁣/+) display an impaired performance in the probe trial of the Morris Water Maze compared with control mice at both the 6 and the 12, but not at the 24 months time point, consistent with a crucial role of insulin and NPY in cognitive functioning. By 24 months of age all groups demonstrated similar reductions in spatial memory performance. Together, these data suggest that the mechanisms through which insulin influences cognitive functioning are, at least in part, via insulin receptor signaling in NPY expressing neurons. These results also highlight that cognitive impairments observed in aging may be due to impaired insulin signaling.

Topics: Aging; Animals; Behavior, Animal; Cognitive Dysfunction; Disease Models, Animal; Hippocampus; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Knockout; Neurons; Neuropeptide Y; Receptor, Insulin; Spatial Memory

Neuropeptide Y (NPY) has a modulatory role in learning and memory, and is involved in the pathophysiology of neurodegenerative diseases. However, there was no population-based evidence on the relationship between NPY and post-stroke cognitive impairment (PSCI). We aimed to prospectively examine the association between plasma NPY and cognitive impairment among patients with acute ischemic stroke.. On the basis of samples from the China Antihypertensive Trial in Acute Ischemic Stroke, 593 patients with baseline plasma NPY levels were finally included in this study. The study outcome was cognitive impairment (Montreal Cognitive Assessment score < 26) at 3 months after ischemic stroke. Logistic regression models were used to estimate the risk of cognitive impairment.. After 3 months of follow-up, 422 participants (71.2 %) experienced cognitive impairment. Multivariable-adjusted odds ratio (95 % confidence interval) for the highest tertile of NPY was 0.58 (0.36-0.92) compared with the lowest tertile. Each 1-SD higher log-NPY was associated with a decreased risk of 20 % (95 % confidence interval 2 %-34 %) for PSCI. The addition of plasma NPY to the basic model with conventional risk factors improved the risk reclassification (continuous net reclassification index was 22.8 %, p = 0.01; integrated discrimination improvement was 0.9 %, p = 0.02) for PSCI.. We measured plasma NPY only once at baseline and failed to explore the association between NPY changes and PSCI.. Elevated plasma NPY levels were associated with a decreased risk of cognitive impairment, suggesting plasma NPY may serve as a predictive factor and potential therapeutic target for PSCI.

Topics: Antihypertensive Agents; Brain Ischemia; Clinical Trials as Topic; Cognitive Dysfunction; Humans; Ischemic Stroke; Neuropeptide Y; Stroke

Neuropeptide Y (NPY) is a 36-amino-acid peptide member of a family also including peptide YY and pancreatic polypeptide, which are all ligands to Gi/Go coupled receptors. NPY regulates several fundamental biologic functions including appetite/satiety, sex and reproduction, learning and memory, cardiovascular and renal function and immune functions. The mesenteric circulation is a major source of NPY in the blood in man and this peptide is considered a key regulator of gut-brain cross talk. A progressive increase in circulating NPY accompanies the progression of chronic kidney disease (CKD) toward kidney failure and NPY robustly predicts cardiovascular events in this population. Furthermore, NPY is suspected as a possible player in accelerated cognitive function decline and dementia in patients with CKD and in dialysis patients. In theory, interfering with the NPY system has relevant potential for the treatment of diverse diseases from cardiovascular and renal diseases to diseases of the central nervous system. Pharmaceutical formulations for effective drug delivery and cost, as well as the complexity of diseases potentially addressable by NPY/NPY antagonists, have been a problem until now. This in part explains the slow progress of knowledge about the NPY system in the clinical arena. There is now renewed research interest in the NPY system in psychopharmacology and in pharmacology in general and new studies and a new breed of clinical trials may eventually bring the expected benefits in human health with drugs interfering with this system.

Topics: Cognitive Dysfunction; Humans; Hypertension, Renal; Neuropeptide Y; Receptors, Neuropeptide Y; Renal Dialysis; Renal Insufficiency, Chronic; Risk Factors

Though patients with diabetes mellitus are reported to show deficits in social interaction, the mechanisms of these impairments are unclear. The present study investigated the role of AMPA and neuropeptide Y (NPY) receptors in the ventral hippocampus (vHC) and basolateral amygdala (BLA) in the social behavior of diabetic mice. In the three-chamber test, streptozotocin (STZ)-induced diabetic mice showed impairment in social novelty preference, but not in sociability. Injection of the AMPA receptor antagonist NBQX into vHC or BLA each restored social novelty preference in STZ-induced diabetic mice. NPY content in amygdala, but not in vHC, of STZ-induced diabetic mice was increased relative to non-diabetic mice. In STZ-induced diabetic mice, injection of the NPY Y

Topics: Animals; Arginine; Basolateral Nuclear Complex; Behavior, Animal; Benzazepines; Cognitive Dysfunction; Diabetes Complications; Diabetes Mellitus, Experimental; Excitatory Amino Acid Antagonists; Hippocampus; Male; Mice; Mice, Inbred ICR; Neuropeptide Y; Receptors, AMPA; Receptors, Neuropeptide Y; Social Behavior

Cannabinoid consumption during pregnancy has been increasing on the wave of the broad-based legalisation of cannabis in Western countries, raising concern about the putative detrimental outcomes on foetal neurodevelopment. Indeed, since the endocannabinoid system regulates synaptic plasticity, emotional and cognitive processes from early stages of life interfering with it and other excitability endogenous modulators, such as neuropeptide Y (NPY), might contribute to the occurrence of a vulnerable phenotype later in life.. This research investigated whether in utero exposure to Δ9-tetrahydrocannabinol (THC) may induce deficits in emotional/cognitive processes and alcohol vulnerability in adolescent offspring. NPY and excitatory postsynaptic density (PSD) machinery were measured as markers of neurobiological vulnerability.. Following in utero THC exposure (2 mg/kg delivered subcutaneously), preadolescent male rat offspring were assessed for: behavioural reactivity in the open field test, neutral declarative memory and aversive limbic memory in the Novel Object and Emotional Object Recognition tests, immunofluorescence for NPY neurons and the PSD proteins Homer-1, 1b/c and 2 in the prefrontal cortex, amygdala and nucleus accumbens at adolescence (cohort 1); and instrumental learning, alcohol taking, relapse and conflict behaviour in the operant chamber throughout adolescence until early adulthood (cohort 2).. In utero THC-exposed adolescent rats showed: (a) increased locomotor activity; (b) no alteration in neutral declarative memory; (c) impaired aversive limbic memory; (d) decreased NPY-positive neurons in limbic regions; (e) region-specific variations in Homer-1, 1b/c and 2 immunoreactivity; (f) decreased instrumental learning and increased alcohol drinking, relapse and conflict behaviour in the operant chamber.. Gestational THC impaired the formation of memory traces when integration between environmental encoding and emotional/motivational processing was required and promoted the development of alcohol-addictive behaviours. The abnormalities in NPY signalling and PSD make-up may represent the common neurobiological background, suggesting new targets for future research.

Topics: Alcohol Drinking; Animals; Behavior, Animal; Brain; Cognitive Dysfunction; Conflict, Psychological; Dronabinol; Female; Male; Memory; Motor Activity; Neuropeptide Y; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar

Epilepsy is marked by seizures that are a manifestation of excessive brain activity and is symptomatically treatable by anti-epileptic drugs (AEDs). Unfortunately, the older AEDs have many side effects, with cognitive impairment being a major side effect that affects the daily lives of people with epilepsy. Thus, this study aimed to determine if newer AEDs (Zonisamide, Levetiracetam, Perampanel, Lamotrigine and Valproic Acid) also cause cognitive impairment, using a zebrafish model. Acute seizures were induced in zebrafish using pentylenetetrazol (PTZ) and cognitive function was assessed using the T-maze test of learning and memory. Neurotransmitter and gene expression levels related to epilepsy as well as learning and memory were also studied to provide a better understanding of the underlying processes. Ultimately, impaired cognitive function was seen in AED treated zebrafish, regardless of whether seizures were induced. A highly significant decrease in γ-Aminobutyric Acid (GABA) and glutamate levels was also discovered, although acetylcholine levels were more variable. The gene expression levels of Brain-Derived Neurotrophic Factor (BDNF), Neuropeptide Y (NPY) and Cyclic Adenosine Monophosphate (CAMP) Responsive Element Binding Protein 1 (CREB-1) were not found to be significantly different in AED treated zebrafish. Based on the experimental results, a decrease in brain glutamate levels due to AED treatment appears to be at least one of the major factors behind the observed cognitive impairment in the treated zebrafish.

Topics: Acetylcholine; Animals; Anticonvulsants; Brain; Brain-Derived Neurotrophic Factor; Cognitive Dysfunction; Cyclic AMP; Cyclic AMP Response Element-Binding Protein; Drug Interactions; gamma-Aminobutyric Acid; Gene Expression; Glutamic Acid; Locomotion; Maze Learning; Neuropeptide Y; Pentylenetetrazole; Seizures; Zebrafish

Memory deficits are characteristic of HIV-associated neurocognitive disorders (HAND) and co-occur with hippocampal pathology. The HIV-1 transactivator of transcription (Tat), a regulatory protein, plays a significant role in these events, but the cellular mechanisms involved are poorly understood. Within the hippocampus, diverse populations of interneurons form complex networks; even subtle disruptions can drastically alter synaptic output, resulting in behavioral dysfunction. We hypothesized that HIV-1 Tat would impair cognitive behavior and injure specific hippocampal interneuron subtypes. Male transgenic mice that inducibly expressed HIV-1 Tat (or non-expressing controls) were assessed for cognitive behavior or had hippocampal CA1 subregions evaluated via interneuron subpopulation markers. Tat exposure decreased spatial memory in a Barnes maze and mnemonic performance in a novel object recognition test. Tat reduced the percentage of neurons expressing neuronal nitric oxide synthase (nNOS) without neuropeptide Y immunoreactivity in the stratum pyramidale and the stratum radiatum, parvalbumin in the stratum pyramidale, and somatostatin in the stratum oriens, which are consistent with reductions in interneuron-specific interneuron type 3 (IS3), bistratified, and oriens-lacunosum-moleculare interneurons, respectively. The findings reveal that an interconnected ensemble of CA1 nNOS-expressing interneurons, the IS3 cells, as well as subpopulations of parvalbumin- and somatostatin-expressing interneurons are preferentially vulnerable to HIV-1 Tat. Importantly, the susceptible interneurons form a microcircuit thought to be involved in feedback inhibition of CA1 pyramidal cells and gating of CA1 pyramidal cell inputs. The identification of vulnerable CA1 hippocampal interneurons may provide novel insight into the basic mechanisms underlying key functional and neurobehavioral deficits associated with HAND.

Topics: Animals; CA1 Region, Hippocampal; Cognition; Cognitive Dysfunction; Gene Expression Regulation; Interneurons; Male; Maze Learning; Mice; Mice, Transgenic; Neuropeptide Y; Nitric Oxide Synthase Type I; Parvalbumins; Signal Transduction; Somatostatin; tat Gene Products, Human Immunodeficiency Virus; Transgenes

Pain is a critical component hindering recovery and regaining of function after surgery, particularly in the elderly. Understanding the role of pain signaling after surgery may lead to novel interventions for common complications such as delirium and postoperative cognitive dysfunction. Using a model of tibial fracture with intramedullary pinning in male mice, associated with cognitive deficits, we characterized the effects on the primary somatosensory system. Here we show that tibial fracture with pinning triggers cold allodynia and up-regulates nerve injury and inflammatory markers in dorsal root ganglia (DRGs) and spinal cord up to 2 wk after intervention. At 72 h after surgery, there is an increase in activating transcription factor 3 (ATF3), the neuropeptides galanin and neuropeptide Y (NPY), brain-derived neurotrophic factor (BDNF), as well as neuroinflammatory markers including ionized calcium-binding adaptor molecule 1 (Iba1), glial fibrillary acidic protein (GFAP), and the fractalkine receptor CX3CR1 in DRGs. Using an established model of complete transection of the sciatic nerve for comparison, we observed similar but more pronounced changes in these markers. However, protein levels of BDNF remained elevated for a longer period after fracture. In the hippocampus, BDNF protein levels were increased, yet there were no changes in Bdnf mRNA in the parent granule cell bodies. Further, c-Fos was down-regulated in the hippocampus, together with a reduction in neurogenesis in the subgranular zone. Taken together, our results suggest that attenuated BDNF release and signaling in the dentate gyrus may account for cognitive and mental deficits sometimes observed after surgery.

Topics: Activating Transcription Factor 3; Animals; Brain-Derived Neurotrophic Factor; Calcium-Binding Proteins; Cognitive Dysfunction; CX3C Chemokine Receptor 1; Dentate Gyrus; Fracture Fixation, Intramedullary; Galanin; Ganglia, Spinal; Gene Expression Regulation; Glial Fibrillary Acidic Protein; Hyperalgesia; Male; Mice; Mice, Inbred C57BL; Microfilament Proteins; Neuropeptide Y; Pain; Proto-Oncogene Proteins c-fos; Sciatic Nerve; Signal Transduction; Spinal Cord; Tibial Fractures