Omega-3 Fatty Acid Deficiency during Brain Maturation Reduces Neuronal and Behavioral Plasticity in Adulthood

Omega-3-fatty acid DHA is a structural component of brain plasma membranes, thereby crucial for neuronal signaling; however, the brain is inefficient at synthesizing DHA. We have asked how levels of dietary n-3 fatty acids during brain growth would affect brain function and plasticity during adult life. Pregnant rats and their male offspring were fed an n-3 adequate diet or n-3 deficient diets for 15 weeks. Results showed that the n-3 deficiency increased parameters of anxiety-like behavior using open field and elevated plus maze tests in the male offspring. Behavioral changes were accompanied by a level reduction in the anxiolytic-related neuropeptide Y-1 receptor, and an increase in the anxiogenic-related glucocorticoid receptor in the cognitive related frontal cortex, hypothalamus and hippocampus. The n-3 deficiency reduced brain levels of docosahexaenoic acid (DHA) and increased the ratio n-6/n-3 assessed by gas chromatography. The n-3 deficiency reduced the levels of BDNF and signaling through the BDNF receptor TrkB, in proportion to brain DHA levels, and reduced the activation of the BDNF-related signaling molecule CREB in selected brain regions. The n-3 deficiency also disrupted the insulin signaling pathways as evidenced by changes in insulin receptor (IR) and insulin receptor substrate (IRS). DHA deficiency during brain maturation reduces plasticity and compromises brain function in adulthood. Adequate levels of dietary DHA seem crucial for building long-term neuronal resilience for optimal brain performance and aiding in the battle against neurological disorders

Central neuropeptide Y receptors are involved in 3(rd )ventricular ghrelin induced alteration of colonic transit time in conscious fed rats

BACKGROUND: Feeding related peptides have been shown to be additionally involved in the central autonomic control of gastrointestinal functions. Recent studies have shown that ghrelin, a stomach-derived orexigenic peptide, is involved in the autonomic regulation of GI function besides feeding behavior. Pharmacological evidence indicates that ghrelin effects on food intake are mediated by neuropeptide Y in the central nervous system. METHODS: In the present study we examine the role of ghrelin in the central autonomic control of GI motility using intracerobroventricular and IP microinjections in a freely moving conscious rat model. Further the hypothesis that a functional relationship between NPY and ghrelin within the CNS exists was addressed. RESULTS: ICV injections of ghrelin (0.03 nmol, 0.3 nmol and 3.0 nmol/5 μl and saline controls) decreased the colonic transit time up to 43%. IP injections of ghrelin (0.3 nmol – 3.0 nmol kg(-1 )BW and saline controls) decreased colonic transit time dose related. Central administration of the NPY(1 )receptor antagonist, BIBP-3226, prior to centrally or peripherally administration of ghrelin antagonized the ghrelin induced stimulation of colonic transit. On the contrary ICV-pretreatment with the NPY(2 )receptor antagonist, BIIE-0246, failed to modulate the ghrelin induced stimulation of colonic motility. CONCLUSION: The results suggest that ghrelin acts in the central nervous system to modulate gastrointestinal motor function utilizing NPY(1 )receptor dependent mechanisms

Differential Susceptibility of Interneurons Expressing Neuropeptide Y or Parvalbumin in the Aged Hippocampus to Acute Seizure Activity

Acute seizure (AS) activity in old age has an increased predisposition for evolving into temporal lobe epilepsy (TLE). Furthermore, spontaneous seizures and cognitive dysfunction after AS activity are often intense in the aged population than in young adults. This could be due to an increased vulnerability of inhibitory interneurons in the aged hippocampus to AS activity. We investigated this issue by comparing the survival of hippocampal GABA-ergic interneurons that contain the neuropeptide Y (NPY) or the calcium binding protein parvalbumin (PV) between young adult (5-months old) and aged (22-months old) F344 rats at 12 days after three-hours of AS activity. Graded intraperitoneal injections of the kainic acid (KA) induced AS activity and a diazepam injection at 3 hours after the onset terminated AS-activity. Measurement of interneuron numbers in different hippocampal subfields revealed that NPY+ interneurons were relatively resistant to AS activity in the aged hippocampus in comparison to the young adult hippocampus. Whereas, PV+ interneurons were highly susceptible to AS activity in both age groups. However, as aging alone substantially depleted these populations, the aged hippocampus after three-hours of AS activity exhibited 48% reductions in NPY+ interneurons and 70% reductions in PV+ interneurons, in comparison to the young hippocampus after similar AS activity. Thus, AS activity-induced TLE in old age is associated with far fewer hippocampal NPY+ and PV+ interneuron numbers than AS-induced TLE in the young adult age. This discrepancy likely underlies the severe spontaneous seizures and cognitive dysfunction observed in the aged people after AS activity

NPY Neuron-Specific Y2 Receptors Regulate Adipose Tissue and Trabecular Bone but Not Cortical Bone Homeostasis in Mice

BACKGROUND: Y2 receptor signalling is known to be important in neuropeptide Y (NPY)-mediated effects on energy homeostasis and bone physiology. Y2 receptors are located post-synaptically as well as acting as auto receptors on NPY-expressing neurons, and the different roles of these two populations of Y2 receptors in the regulation of energy homeostasis and body composition are unclear. METHODOLOGY/PRINCIPAL FINDINGS: We thus generated two conditional knockout mouse models, Y2(lox/lox) and NPYCre/+;Y2(lox/lox), in which Y2 receptors can be selectively ablated either in the hypothalamus or specifically in hypothalamic NPY-producing neurons of adult mice. Specific deletion of hypothalamic Y2 receptors increases food intake and body weight compared to controls. Importantly, specific ablation of hypothalamic Y2 receptors on NPY-containing neurons results in a significantly greater adiposity in female but not male mice, accompanied by increased hepatic triglyceride levels, decreased expression of liver carnitine palmitoyltransferase (CPT1) and increased expression of muscle phosphorylated acetyl-CoA carboxylase (ACC). While food intake, body weight, femur length, bone mineral content, density and cortical bone volume and thickness are not significantly altered, trabecular bone volume and number were significantly increased by hypothalamic Y2 deletion on NPY-expressing neurons. Interestingly, in situ hybridisation reveals increased NPY and decreased proopiomelanocortin (POMC) mRNA expression in the arcuate nucleus of mice with hypothalamus-specific deletion of Y2 receptors in NPY neurons, consistent with a negative feedback mechanism between NPY expression and Y2 receptors on NPY-ergic neurons. CONCLUSIONS/SIGNIFICANCE: Taken together these data demonstrate the anti-obesogenic role of Y2 receptors in the brain, notably on NPY-ergic neurons, possibly via inhibition of NPY neurons and concomitant stimulation of POMC-expressing neurons in the arcuate nucleus of the hypothalamus, reducing lipogenic pathways in liver and/or skeletal muscle in females. These data also reveal as an anti-osteogenic effect of Y2 receptors on hypothalamic NPY-expressing neurons on trabecular but not on cortical bone

Nociceptin receptor antagonists display antidepressant-like properties in the mouse forced swimming test

The present study investigated the effects of nociceptin, the peptide nociceptin receptor antagonist, [Nphe(1)]-nociceptin (1-13)-NH(2), and the non-peptide antagonist, J-113397, in the mouse forced swimming test, an animal model used for the screening of potential antidepressant drugs. Additional studies were performed with naloxone to exclude effects on traditional opioid receptors. Intracerebroventricular (ICV) administration of nociceptin (0.01-1 nmole) was devoid of any activity in the mouse forced swimming test, as was intraperitoneal (i.p.) administration of naloxone (1-10 mg/kg). ICV treatment with [Nphe(1)]-nociceptin (1-13)-NH(2) (25 nmole and 50 nmole) induced significant antidepressant-like activity ( P<0.01), as did administration of J-113397 (20 mg/kg, i.p; P<0.05). Open field analysis revealed that acute treatment with these molecules did not induce significant changes in locomotor activity at the doses tested. These results suggest that nociceptin, and its receptor, may play a role in depressive disorders and that the nociceptin system could represent a novel target for the development of new antidepressant drugs

Nociceptin receptor antagonists display antidepressant-like properties in the mouse forced swimming test

The present study investigated the effects of nociceptin, the peptide nociceptin receptor antagonist, [Nphe(1)]-nociceptin (1-13)-NH(2), and the non-peptide antagonist, J-113397, in the mouse forced swimming test, an animal model used for the screening of potential antidepressant drugs. Additional studies were performed with naloxone to exclude effects on traditional opioid receptors. Intracerebroventricular (ICV) administration of nociceptin (0.01-1 nmole) was devoid of any activity in the mouse forced swimming test, as was intraperitoneal (i.p.) administration of naloxone (1-10 mg/kg). ICV treatment with [Nphe(1)]-nociceptin (1-13)-NH(2) (25 nmole and 50 nmole) induced significant antidepressant-like activity ( P<0.01), as did administration of J-113397 (20 mg/kg, i.p; P<0.05). Open field analysis revealed that acute treatment with these molecules did not induce significant changes in locomotor activity at the doses tested. These results suggest that nociceptin, and its receptor, may play a role in depressive disorders and that the nociceptin system could represent a novel target for the development of new antidepressant drugs

[Nphe(1)]-Nociceptin (1-13)-NH2, a nociceptin receptor antagonist, reverses nociceptin-induced spatial memory impairments in the Morris water maze task in rats

1 The present study was undertaken to investigate the e ects of the novel nociceptin receptor antagonist, [Nphe1]-Nociceptin (1-13)-NH2 (bilateral intrahippocampal injection, 50 nmole rat71) on purported nociceptin-induced (bilateral intrahippocampal injection, 5 nmole rat71) de\uaecits in spatial learning in the rat Morris water maze task. In addition, experiments were performed in an `open \uaeeld' to investigate possible peptide-induced changes in exploratory behaviour. 2 Nociceptin signi\uaecantly impaired the ability of the animal to locate the hidden platform throughout training (P50.001 versus control group). 3 Pretreatment with [Nphe1]-Nociceptin (1-13)-NH2 signi\uaecantly blocked nociceptin-induced impairment of spatial learning (P50.001 versus nociceptin group). 4 A probe trial revealed that vehicle-treated animals spent more time in the quadrant that had previously contained the hidden platform, whereas nociceptin-treated animals did not spend more time in any one quadrant. 5 Learning impairments were not attributable to non-speci\uaec de\uaecits in motor performance or change in exploratory behaviour. 6 Taken together, our results reveal that [Nphe1]-Nociceptin (1-13)-NH2 represents an e ective and useful in vivo antagonist at the nociceptin receptors involved in learning and memory