Repeated exposure to novelty promotes resilience against the amyloid-beta effect through dopaminergic stimulation

• Published in: Psychopharmacology 2025, Vol.242 (1), p.85-100
• Main Authors: Velázquez-Delgado, Cintia, Hernández-Ortiz, Eduardo, Landa-Navarro, Lucia, Tapia-Rodríguez, Miguel, Moreno-Castilla, Perla, Bermúdez-Rattoni, Federico
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Biomedical and Life Sciences; Biomedicine; Catecholamines; Cognitive Dysfunction - metabolism; Disease Models, Animal; Dopamine; Dopamine - metabolism; Dopamine receptors; Exploratory Behavior - drug effects; Exploratory Behavior - physiology; Forebrain; Hippocampus; Hippocampus - drug effects; Hippocampus - metabolism; Male; Maze Learning - drug effects; Maze Learning - physiology; Memory; Mice; Mice, Inbred C57BL; Microdialysis; Neurodegenerative diseases; Neurosciences; Novelty; Original Investigation; Peptide Fragments - metabolism; Pharmacology/Toxicology; Psychiatry; Social Interaction - drug effects; Spatial memory; Spatial Memory - drug effects; Spatial Memory - physiology; Toxicity; Tyrosine 3-monooxygenase; β-Amyloid
• ISSN: 0033-3158; 1432-2072; 1432-2072
• DOI: 10.1007/s00213-024-06650-5

Rationale The accumulation of beta-amyloid peptide (Aβ) in the forebrain leads to cognitive dysfunction and neurodegeneration in Alzheimer's disease. Studies have shown that individuals with a consistently cognitively active lifestyle are less vulnerable to Aβ toxicity. Recent research has demonstrated that intrahippocampal Aβ can impact catecholaminergic release and spatial memory. Interestingly, exposure to novelty stimuli has been found to stimulate the release of catecholamines in the hippocampus. However, it remains uncertain whether repeated enhancing catecholamine activity can effectively alleviate cognitive impairment in individuals with Alzheimer's disease. Objectives Our primary aim was to investigate whether repeated exposure to novelty could enable cognitive resilience against Aβ. This protection could be achieved by modulating catecholaminergic activity within the hippocampus. Methods To investigate this hypothesis, we subjected mice to three different conditions—standard housing (SH), repeated novelty (Nov), or daily social interaction (Soc) for one month. We then infused saline solution (SS) or Aβ (Aβ 1-42 ) oligomers intrahippocampally and measured spatial memory retrieval in a Morris Water Maze (MWM). Stereological analysis and extracellular baseline dopamine levels using in vivo microdialysis were assessed in independent groups of mice. Results The mice that received Aβ 1-42 intrahippocampal infusions and remained in SH or Soc conditions showed impaired spatial memory retrieval. In contrast, animals subjected to the Nov protocol demonstrated remarkable resilience, showing strong spatial memory expression even after Aβ 1-42 intrahippocampal infusion. The stereological analysis indicated that the Aβ 1-42 infusion reduced the tyrosine hydroxylase axonal length in SH or Soc mice compared to the Nov group. Accordingly, the hippocampal extracellular dopamine levels increased significantly in the Nov groups. Conclusions These compelling results demonstrate the potential for repeated novelty exposure to strengthen the dopaminergic system and mitigate the toxic effects of Aβ 1-42 . They also highlight new and promising therapeutic avenues for treating and preventing AD, especially in its early stages.