Female reproductive decline is characterized by a gradual loss of estrous cyclicity due in part to age-related changes in several hypothalamic neurotransmitter systems known to regulate reproductive function. Previously, we have demonstrated that in middle-aged rats that exhibited no changes in the regularity of their estrous cycles, the proestrous LH surge is markedly attenuated. To determine whether these age-related deficits involve alterations in GnRH neuronal activation, we examined expression of the immediate early gene products, c-fos and Jun, in GnRH neurons of young and middle-aged proestrous animals. Regularly cycling young (3- to 4-month-old) and middle-aged (10- to 12-month-old) animals were perfused transcardially at 2300 h on diestrus or at 0230, 0530, 0900, 1400, 1630, 1930, or 2300 h on proestrus, and the brains were processed for dual immunocytochemistry of c- fos or Jun and GnRH. In agreement with earlier studies in young rats, 34 ± 4% of the GnRH neurons expressed c-fos and 40 ± 3% expressed Jun during the proestrous LH surge (1630 and 1930 h). However, in the middle-aged animals, there was a dramatic decline in the number of GnRH neurons that expressed c- fos (9 ± 1%) and Jun (14 ± 1%) during the LH surge. There were no changes in the number of GnRH neurons between the two age groups. Furthermore, the strong correlation that existed between c-fos expression and serum LH in young animals was lost by the time the animals reached middle age. These data demonstrate that by the time animals reach middle age, there is a significant decline in the number of activated GnRH neurons, which may account for the decrease in the amplitude of the LH surge that precedes the onset of irregular estrous cycles. This could be due to either age-related changes in the GnRH neuron itself or in the neuronal circuitry involved in activation of these neurons.
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