Aged Brains Express Less Melanocortin Receptors, Which Correlates with Age-Related Decline of Cognitive Functions

Abstract

Brain G-protein coupled receptors have been hypothesized to be potential targets for maintaining or restoring cognitive function in normal aged individuals or in patients with neurodegenerative disease. A number of recent reports suggest that activation of melanocortin receptors (MCRs) in the brain can significantly improve cognitive functions of normal rodents and of different rodent models of the Alzheimer’s disease. However, the potential impact of normative aging on the expression of MCRs and their potential roles for modulating cognitive function remains to be elucidated. In the present study, we first investigated the expression of these receptors in six different brain regions of young (6 months) and aged (23 months) rats following assessment of their cognitive status. Correlation analysis was further performed to reveal potential contributions of MCR subtypes to spatial learning and memory. Our results revealed statistically significant correlations between the expression of several MCR subtypes in the frontal cortex/hypothalamus and the hippocampus regions and the rats’ performance in spatial learning and memory only in the aged rats. These findings support the hypothesis that aging has a direct impact on the expression and function of MCRs, establishing MCRs as potential drug targets to alleviate aging-induced decline of cognitive function.

Type 1 melanocortin receptors in pro‐opiomelanocortin‐, vasopressin‐, and oxytocin‐immunopositive neurons in different areas of mouse brain

“…Using real‐time PCR, the expression of the Mc1R gene was studied in different brain regions, including the midbrain, where, according to other authors, the Mc1R expression is significant (Xia et al, 1995; Zhou et al, 2021). The expression of Mc1R gene was demonstrated in the cerebral cortex, midbrain, hypothalamus, NTS, and dorsal hippocampus, and it was significantly higher in the cortex than in the other brain regions (Figure 8).…”

“…These results were confirmed by us using real‐time PCR, which showed mRNA expression in these brain regions (Figure 8). Prior to our studies, there was only one immunochemical study on the detection of MC1Rs in the substantia nigra in mice (X. Chen et al, 2017), and the data on the identification of mRNA transcripts for MC1Rs in some regions of the brain in rats (Xia et al, 1995; Zhou et al, 2021). At the same time, Zhou et al (2021) determined the following order of Mc1R mRNA expression for the rat: midbrain > cerebellum ≈ hippocampus ≈ occipital lobe of the cerebral cortex > parietal cortex > frontal cortex and hypothalamus.…”

“…Prior to our studies, there was only one immunochemical study on the detection of MC1Rs in the substantia nigra in mice (X. Chen et al, 2017), and the data on the identification of mRNA transcripts for MC1Rs in some regions of the brain in rats (Xia et al, 1995; Zhou et al, 2021). At the same time, Zhou et al (2021) determined the following order of Mc1R mRNA expression for the rat: midbrain > cerebellum ≈ hippocampus ≈ occipital lobe of the cerebral cortex > parietal cortex > frontal cortex and hypothalamus. In our case, the order of Mc1R mRNA expression in brain areas of mouse was slightly different: cerebral cortex > midbrain ≈ hypothalamus ≈ NTS of the medulla oblongata ≥ dorsal hippocampus (Figure 8).…”

“…Only recent studies by Zhou et al (2021) revealed mRNA for MC1R in the frontal cortex, hypothalamus, hippocampus, midbrain, and rat cerebellum of rats, although the MC1R expression was significantly lower than that of MC3R and MC4R. The authors showed that with increasing age, the expression of the Mc1R gene was decreased, which, on one hand, demonstrates the effect of age on the functional activity of the brain MC1R system and, on the other hand, may indicate the relationship between MC1R expression and the weakening of cognitive functions during aging (Zhou et al, 2021). This work, which was carried out simultaneously with our studies, confirmed the importance of MC1Rs for the functioning of the CNS, but it remained unclear in which brain cells (neurons, glial cells, or endothelial cells) MC1Rs are localized.…”

Melanocortin-5 Receptor: Pharmacology and Its Regulation of Energy Metabolism

“…MC5R, widely expressed in central and peripheral tissues, has multiple physiological functions ( Figure 1 ). In the brain, MC5R is involved in the stress response [ 37 ], cognitive function [ 38 ], and fetal brain development [ 39 ]. MC5R in the perifornical lateral hypothalamus might mediate physical activity in lean rats [ 40 ].…”