Mejora de los déficits conductuales asociados con el envejecimiento fisiológico en roedores a través de la modulación de diversos sistemas de neurotransmisiónmecanismos de neuroprotección

Abstract

The aging process causes anatomical and physiological changes in the brain that induce deficits at the behavioral level, both in cognitive (memory and learning) and affective (susceptibility to late-life depression) functions. Prefrontal cortex (working memory) and hippocampus (declarative memory) are the most affected areas by the aging process and their cognitive deficits are clearly visible at the behavioral level. A previous study led by our research group demonstrated that brain levels of FADD protein (Fas-Associated protein with Death Domain), a key cell regulator (balance between cell death and survival) was decreased in elderly subjects with clinical dementia. Therefore, FADD protein was postulated as a putative biomarker for cognitive impairment. In this context, the first objective of this doctoral thesis was to characterize the emergence of behavioral deficits in rodents (rats and mice) during aging, both at the cognitive (Barnes maze, 8-arm radial maze) and affective (forced-swim test, sucrose preference test, open field test) levels, as well as the modifications in FADD protein expression. The results (Article I) confirmed the validity of using laboratory rodents to model the cognitive and affective deficits associated with aging and showed a region-specific decrease in FADD protein (hippocampus) with age. These results support a possible parallel regulation of FADD protein with the behavioral deficits observed during aging. The next objective of the doctoral thesis was to evaluate, through different pharmacological treatments (serotonergic, noradrenergic and imidazolinic drugs), the possible improvement of the age-related deficits characterized in rodents. Drugs were selected for their precognitive- and/or antidepressant-like potential and by their ability to modulate FADD protein in the brain. The results were diverse and are summarized as follows. The acute treatment with the 5-HT1A receptor agonist 8-OH-DPAT (Article I) improved cognitive performance at all ages studied, showed antidepressant-like effects in aged rats, and reduced FADD protein to levels even lower than those produced by aging. Altogether, these results support a beneficial role of 8-OH-DPAT treatment for a broad age range, including older animals. On the other hand, the repeated treatment with UK-14304, an 2 adrenergic receptor agonist, improved cognitive performance in rats. The magnitude of improvement was correlated with increases in hippocampal FADD levels (Article II). These results reinforce a possible role for FADD protein in the cognitive processes taking place during aging. Treatments with 2-BFI and tracizoline, two imidazoline I2 receptors ligands, did not improve the behavioral deficits observed in aged rats. Yet, the acute treatment with 2-BFI induced an antidepressant-like response in aged rats (Article III). Finally, results from an exploratory study with LSL 60101 (an I2 receptor ligand) in young adult rats did not improve affective-like behavior, nor did it induce any changes at the neurochemical level. These results add to the existing contradictory literature regarding the potential use of I2 ligands as effective modulators of affective-like behavior. Overall, the results presented in this thesis validated the use of laboratory rodents to model the behavioral deficits as well as the neurochemical affectations (decreased FADD protein) related with aging. Based on these results a different pharmacological modulation of FADD can be implied during aging. While its acute modulation (Article I) seemed to have a similar regulation in young adults and aged rats (decreased FADD as a neuroplasticity index), a differential modulation was observed following repeated treatments, since increasing FADD protein in aged rodents correlated with better cognitive scores (Article II). To conclude, these results support a role for FADD protein in the cognitive deterioration associated with aging, while present several pharmacological treatments with the potential to improve some of these deficits and FADD modulation, providing a starting point for future studies that aim at clarifying the role of FADD in aging.