On the Role of Neuropeptide Y Receptor 1 (NPY1R)-Galanin Receptor 2 (GALR2) Heteroreceptor Complexes in Enhancing Adult Hippocampal Neurogenesis and Cognitive Function

Laburpena

This PhD thesis investigates the roles of Neuropeptide Y receptor 1 (NPY1R) homo- and heteroreceptor complexes, specifically NPY1R- galanin receptor 2 (GALR2) heteroreceptor complexes, within the Central Nervous System (CNS), focusing on hippocampal neuronal cells and their implications for neurogenesis, mood regulation, and cognitive functions. These receptor complexes introduce a novel dimension to molecular neuroscience, as allosteric receptor-receptor interactions can modify receptor function, signaling pathways, and pharmacological responses. The research explores how these complexes influence hippocampal neurogenesis and cognition under physiological and pathological conditions, with two primary objectives. First, the study aims to examine whether intranasal administration of GALR2 and NPY1R agonists stimulates adult neurogenesis in the ventral hippocampus and induces antidepressant-like effects. By analyzing the activation of the ventral hippocampus through c-Fos and PCNA expression and the formation of NPY1R-GALR2 heteroreceptor complexes using in situ proximity ligation assays (PLA), the research highlights increased cell proliferation, particularly in neuroblasts, without affecting quiescent progenitors or astrocytes. The study reveals that these effects are mediated by increased BDNF expression, a crucial neurotrophic factor involved in neurogenesis and mood regulation. Furthermore, behavioral tests, including the forced swimming test (FST), confirm enhanced antidepressant-like responses, supporting the therapeutic potential of targeting NPY1R-GALR2 complexes for depression. This study also underscores the efficacy of intranasal administration as a non-invasive method to bypass the blood-brain barrier, minimizing peripheral side effects and improving compliance. Second, the thesis investigates the role of Galanin (GAL) and NPY interactions on hippocampal neurogenesis, focusing on memory and potential applications for age-related cognitive decline, including Alzheimer's disease models. The research demonstrates that intranasal co-administration of GALR2 and NPY1R agonists significantly enhances spatial memory, neuronal survival, and differentiation in the adult hippocampus. The synergistic effects of these agonists, which were not observed when administered individually, are evidenced by increased neurogenesis, as shown by the rise in BrdU-positive cells in the dentate gyrus, and enhanced neuronal maturation, as indicated by doublecortin (DCX)-positive cells with mature dendritic structures. These findings suggest that newly generated neurons integrate into hippocampal circuits, potentially enhancing cognitive functions. Overall, this thesis provides compelling evidence for the therapeutic potential of targeting NPY1R-GALR2 heteroreceptor complexes to enhance hippocampal neurogenesis, mood regulation, and cognitive function, with significant implications for developing treatments for depression and age-related cognitive decline.