SAT600 Absent LH Signaling Rescues The Anxiety Phenotype In Aging Female Mice

Disclosure: S. Sims: None. O. Barak: None. V. Ryu: None. S. Miyashita: None. H.S. Kannangara: None. F. Korkmaz: None. A. Macdonald: None. A. Gumerova: None. K. Goosens: None. M. Zaidi: None. T. Yuen: None. D. Lizneva: None. T. Frolinger: None. Clinical studies and experimental data together support a role for pituitary gonadotropins, including luteinizing hormone (LH), otherwise considered solely as a fertility hormones, in age-related cognitive decline. Furthermore, rising levels of LH in post-menopausal women have been implicated in the high prevalence of mood disorders. This study was designed to examine the effect of deficient LH signaling, using the global Lhcgr(-/-) mouse, on both cognitive and emotional behavior in 12-month-old mice. For this, we established and validated a battery of five tests, including Dark-Light Box (DLB), Y-Maze Spontaneous Alternation, Novel Object Recognition (NOR) and contextual and cued Fear Conditioning (FCT) tests. We found that 12-month-old female mice display a prominent anxiety phenotype on DLB and FCT. This phenotype was not seen in female Lhcgr(-/-) mice, indicating full phenotypic rescue. Furthermore, there was no effect of depleting LHCGRs on recognition memory or working spatial memory on NOR and Y-maze testing, respectively, in 12-month-old mice, notwithstanding the absence of a basal phenotype in wild type littermates. The latter data do not exclude an effect of LH on cognition documented in previous studies. Finally, male mice and 3-month-old male and female mice did not consistently display deficits on any test. The data collectively document, for the first time, that loss of LH signaling reverses age-related emotional disturbances, a prelude to future targeted therapies that block LH action. Presentation: Saturday, June 17, 2023