Age-related shifts in ghrelin responsiveness of dorsomedial and ventromedial hypothalamic neurons in rats

The hypothalamus is a unique neuro-endocrine center that is involved in the regulation of homeostasis, vital functions, and aging. The hormone ghrelin, acting via the growth hormone secretagogue receptor 1A (GHSR-1A), affects different hypothalamic nuclei, including the tuberal area, and may play an important role in the regulation of aging. The expression of GHSR-1A was studied in the dorsomedial (DMN) and ventromedial (VMN) hypothalamic nuclei of young (2 months), mature (12 months), and aged (24 months) male Wistar rats using immunohistochemistry and extracellular in vivo electrophysiology. By means of immunohistochemistry, only a small number of GHSR-1A-immunoreactive (IR) neurons were observed in the DMN (4.0 ± 1.5%) and VMN (2.3 ± 1.3%) in young rats, whereas the percentage of GHSR-1A-IR neurons significantly increased in mature (DMN - 22.1 ± 2.8%, VMN - 25.5 ± 4.4%) and aged rats (DMN - 24.8 ± 2.8%, VMN - 26.5 ± 3.8%). In all age groups, the median firing rate of DMN and VMN neurons did not change after ghrelin administration. In the DMN of young rats, ghrelin predominantly activated neurons (72%), whereas only a few neurons were inhibited by ghrelin (7%). In contrast, a large number of DMN neurons were inhibited by ghrelin in mature (50%) and aged rats (64%). In the VMN of young rats, the largest number of neurons were inhibited by ghrelin (52%), while the proportion of ghrelin-activated neurons increased, and the percentage of ghrelin-inhibited neurons decreased with aging in mature (40%) and aged rats (33%). However, shift in the responsiveness of VMN neurons to ghrelin during aging was not statistically significant. Thus, the sensitivity of hypothalamic neurons to ghrelin changes with aging, accompanied by elevation in the expression of GHS-R1A in the DMN and VMN, as well as deviations in neuronal responses to ghrelin. These alterations in hormone receptor sensitivity, along with changes in the types of responses to hormones, may contribute to the development of age-related diseases, particularly metabolic syndrome.