Central blockage of nesfatin-1 has anxiolytic effects but does not prevent corticotropin-releasing factor-induced anxiety in male rats.

Nesfatin-1, a pleotropic peptide, was recently implicated in the regulation of anxiety and depression-like behavior in rats. However, the underlying mechanisms remain unclear so far. Thus, this study aimed to investigate the role of endogenous nesfatin-1 in the mediation of anxiety and depression-like behavior induced by corticotropin-releasing factor (CRF). Therefore, normal weight male intracerebroventricularly (icv) cannulated Sprague Dawley rats received two consecutive icv injections of anti-nesfatin-1 antibody or IgG control antibody followed by CRF or saline, before being exposed to a behavioral test. In the elevated zero maze test, assessing anxiety and explorative behavior, blockade of nesfatin-1 using an anti-nesfatin-1 antibody under basal conditions increased the number of entries into the open arms compared to control antibody/vehicle (1.6-fold, p < 0.05) and the time in open arms compared to the other groups (p < 0.05). Control antibody/CRF-treated animals tended to spend less time in the open arms compared to control antibody/vehicle (0.7-fold, p = 0.17), an effect not altered by the nesfatin-1 antibody (control antibody/CRF-treated animals vs. nesfatin-1 antibody/CRF group, p = 1.00). In the novelty-induced hypophagia test, assessing anhedonia as part of depression-like behavior, no significant differences were observed between the four groups for the latency to the first bout, number of bouts and the amount of palatable snack eaten (p > 0.05). In summary, CRF tended to increase anxiety and explorative behavior an effect not altered by blockade of nesfatin-1, whereas no significant effect of CRF on anhedonia was observed. Blockade of endogenous nesfatin-1 significantly decreased anxiety-like behavior giving rise to a physiological role of brain nesfatin-1 in the mediation of anxiety.

Exercise prevents high-fat diet-induced impairment of flexible memory expression in the water maze and modulates adult hippocampal neurogenesis in mice.

Obesity is currently one of the most serious threats to human health in the western civilization. A growing body of evidence suggests that obesity is associated with cognitive dysfunction. Physical exercise not only improves fitness but it has also been shown in human and animal studies to increase hippocampus-dependent learning and memory. High-fat diet (HFD)-induced obesity and physical exercise both modulate adult hippocampal neurogenesis. Adult neurogenesis has been demonstrated to play a role in hippocampus-dependent learning and memory, particularly flexible memory expression. Here, we investigated the effects of twelve weeks of HFD vs. control diet (CD) and voluntary physical activity (wheel running; -R) vs. inactivity (sedentary; -S) on hippocampal neurogenesis and spatial learning and flexible memory function in female C57Bl/6 mice assessed in the Morris water maze. HFD was initiated either in adolescent mice combined with long-term concurrent exercise (preventive approach) or in young adult mice with 14days of subsequent exercise (therapeutic approach). HFD resulted in impaired flexible memory expression only when initiated in adolescent (HFD-S) but not in young adult mice, which was successfully prevented by concurrent exercise (HFD-R). Histological analysis revealed a reduction of immature neurons in the hippocampus of the memory-impaired HFD-S mice of the preventive approach. Long-term physical exercise also led to accelerated spatial learning during the acquisition period, which was accompanied by increased numbers of newborn mature neurons (HFD-R and CD-R). Short-term exercise of 14days in the therapeutic group was not effective in improving spatial learning or memory. We show that (1) alterations in learning and flexible memory expression are accompanied by changes in the number of neuronal cells at different maturation stages; (2) these neuronal cells are in turn differently affected by HFD; (3) adolescent mice are specifically susceptible to the negative effects of HFD. Thus, physical exercise, by modulating adult neurogenesis in the hippocampus, might represent a potential preventive approach for treating cognitive impairments associated with adolescent obesity.

Physical exercise counteracts MPTP-induced changes in neural precursor cell proliferation in the hippocampus and restores spatial learning but not memory performance in the water maze.

Parkinson's disease (PD) is characterized by a continuous loss of dopaminergic neurons in the substantia nigra, which not only leads to characteristic motor symptoms but also to cognitive impairments. Physical exercise has been shown to improve hippocampus-dependent cognitive functions in PD patients. Animal studies have demonstrated the involvement of adult hippocampal neurogenesis in exercise-induced improvements of visuo-spatial learning and memory. Here, we investigated the direct impact of voluntary wheel running on hippocampal neurogenesis and spatial learning and memory in the Morris water maze (MWM) using the1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. We also analyzed striatal and hippocampal dopamine transmission and mRNA expression levels of dopamine receptors. We show that MPTP-induced spatial learning deficits were alleviated by short-term physical exercise but not MPTP-induced spatial memory impairments in either exercise intervention group. Neural precursor proliferation was transiently altered in MPTP-treated mice, while the cell survival was increased by exercise. Dopamine was progressively depleted by MPTP and its turnover altered by exercise. In addition, gene expression of dopamine receptor D1/D5 was transiently upregulated following MPTP treatment but not affected by physical exercise. Our findings suggest that physical exercise benefits spatial learning but not memory performance in the MWM after MPTP-induced dopamine depletion by restoring precursor cell proliferation in the hippocampus and influencing dopamine transmission. This adds to the understanding of cognitive decline and mechanisms for potential improvements by physical exercise in PD patients.

NOMA-GAP/ARHGAP33 regulates synapse development and autistic-like behavior in the mouse.

Neuropsychiatric developmental disorders, such as autism spectrum disorders (ASDs) and schizophrenia, are typically characterized by alterations in social behavior and have been linked to aberrant dendritic spine and synapse development. Here we show, using genetically engineered mice, that the Cdc42 GTPase-activating multiadaptor protein, NOMA-GAP, regulates autism-like social behavior in the mouse, as well as dendritic spine and synapse development. Surprisingly, we were unable to restore spine morphology or autism-associated social behavior in NOMA-GAP-deficient animals by Cre-mediated deletion of Cdc42 alone. Spine morphology can be restored in vivo by re-expression of wild-type NOMA-GAP or a mutant of NOMA-GAP that lacks the RhoGAP domain, suggesting that other signaling functions are involved. Indeed, we show that NOMA-GAP directly interacts with several MAGUK (membrane-associated guanylate kinase) proteins, and that this modulates NOMA-GAP activity toward Cdc42. Moreover, we demonstrate that NOMA-GAP is a major regulator of PSD-95 in the neocortex. Loss of NOMA-GAP leads to strong upregulation of serine 295 phosphorylation of PSD-95 and moreover to its subcellular mislocalization. This is associated with marked loss of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and defective synaptic transmission, thereby providing a molecular basis for autism-like social behavior in the absence of NOMA-GAP.