Ovariectomy Alters Gene Expression of the Hippocampal Formation in Middle-Aged Rats

Ovarian hormones regulate the transcriptome of the hippocampus and modulate its functions. During 29 menopause, this complex signaling declines, leading to impaired learning and memory. This study was 30 undertaken to clarify the effects of long-term, surgical ovariectomy (OVX) on the rat hippocampal 31 transcriptome. At age of 13 months, intact control and ovariectomized groups were formed. All animals 32 were sacrificed 5 weeks after gonadectomy, hippocampal formations were dissected and processed for 33 transcriptome analysis. Microarray and PCR studies identified 252 and 61 genes, respectively, whose 34 expression was altered in the lack of ovarian hormones. Pathway analysis revealed impact on 35 neuroactive ligand-receptor interaction, endocannabinoid and estrogen signaling, among others. 36 Network and interaction analyses of proteins encoded by OVX-regulated genes revealed upregulation 37 of growth/ troph/transcription factor signaling assembly (Mdk, Fgf1, Igf2, Ngf, Ngfr, Ntf3, Ntrk1, Otx2, 38 Hif1a, Esr1, Nr4a3), peptides/peptide receptors (Cartp, Kl, Ttr, Gnrhr), neurotransmission (Grm1, 39 Gria4, Gls, Slc18a2, Kcj6) and genes serving immune functions (C3, Ccl2, Itgam, Il1b). Downregulated 40 clusters included neuropeptides and their receptors (Adcyap1, Cbln2, Cck, Cckbr, Crhr1 and 2, Oprd1, 41 Nts, Penk, Sstr1, Vip), neurotransmitter signaling (Htr2c, hrna3, Chrm4, Grm8, Hrh3, Slc17a6) and 42 potassium channels (Kcnk9, Kcnj9, Kcnma1, Kcnc2). Several transcription factors (Rxra, Thrb), solute 43 carriers and defense molecules (Apitd1, Bcl2, Clql3, Ilr3a, Sod1, Sncb) also underwent downregulation. 44 The findings indicate that surgical gonadectomy carried out at middle-age robustly changes the 45 hippocampal transcriptome that alters neurogenesis, synaptic plasticity, immune modulation causing 46 cognitive dysfunctions