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Absent LH signaling rescues the anxiety phenotype in aging female mice

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Abstract

Clinical studies and experimental data together support a role for pituitary gonadotropins, including luteinizing hormone (LH), otherwise considered solely as 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 on both cognitive and emotional behavior in 12–month–old Lhcgr−/− 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 wild type mice display a prominent anxiety phenotype on DLB and FCT. This phenotype was not seen in 12–month–old female Lhcgr−/− mice, indicating full phenotypic rescue. Furthermore, there was no effect of LHCGR depletion 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, 12–month–old 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.

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Fig. 1: Behavioral test battery.
Fig. 2: 12–month–old female Lhcgr−/− mice displayed lower anxiety in the Dark-Light Box test.
Fig. 3: Lhcgr−/− and WT mice displayed no short-term spatial memory differences in Y-Maze spontaneous alternation test.
Fig. 4: 12–month–old female mice displayed long-term recognition memory decline in the Novel Object Recognition test.
Fig. 5: The increased anxiety was reversed in 12–month–old Lhcgr−/− female mice in the Fear Conditioning test.

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References

  1. Rannevik G, Jeppsson S, Johnell O, Bjerre B, Laurell-Borulf Y, Svanberg L. A longitudinal study of the perimenopausal transition: altered profiles of steroid and pituitary hormones, SHBG and bone mineral density. Maturitas. 1995;21:103–13.

    Article  CAS  PubMed  Google Scholar 

  2. Wiacek M, Hagner W, Zubrzycki IZ. Measures of menopause driven differences in levels of blood lipids, follicle-stimulating hormone, and luteinizing hormone in women aged 35 to 60 years: national health and nutrition examination survey III and national health and nutrition examination survey 1999-2002 study. Menopause. 2011;18:60–6.

    Article  PubMed  Google Scholar 

  3. Morley JE, Kaiser FE, Perry HM III, Patrick P, Morley PM, Stauber PM, et al. Longitudinal changes in testosterone, luteinizing hormone, and follicle-stimulating hormone in healthy older men. Metabolism. 1997;46:410–13.

    Article  CAS  PubMed  Google Scholar 

  4. Sherwin BB. Hormones, mood, and cognitive functioning in postmenopausal women. Obstet Gynecol. 1996;87:20S–6S.

    Article  CAS  PubMed  Google Scholar 

  5. Arfa-Fatollahkhani P, Nahavandi A, Abtahi H, Anjidani S, Borhani S, Jameie SB, et al. The effect of luteinizing hormone reducing agent on anxiety and novel object recognition memory in gonadectomized rats. Basic Clin Neurosci. 2017;8:113–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG. Estrogen replacement therapy in older women. Comparisons between Alzheimer’s disease cases and nondemented control subjects. Arch Neurol. 1994;51:896–900.

    Article  CAS  PubMed  Google Scholar 

  7. Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de Andrade M, et al. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007;69:1074–83.

    Article  CAS  PubMed  Google Scholar 

  8. Casadesus G, Milliken EL, Webber KM, Bowen RL, Lei Z, Rao CV, et al. Increases in luteinizing hormone are associated with declines in cognitive performance. Mol Cell Endocrinol. 2007;269:107–11.

    Article  CAS  PubMed  Google Scholar 

  9. Berry A, Tomidokoro Y, Ghiso J, Thornton J. Human chorionic gonadotropin (a luteinizing hormone homologue) decreases spatial memory and increases brain amyloid-beta levels in female rats. Horm Behav. 2008;54:143–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Barron AM, Verdile G, Taddei K, Bates KA, Martins RN. Effect of chronic hCG administration on Alzheimer’s-related cognition and A beta accumulation in PS1KI mice. Endocrinology. 2010;151:5380–8.

    Article  CAS  PubMed  Google Scholar 

  11. Atwood CS. Alzheimer’s disease: the impact of age-related changes in reproductive hormones. Cell Mol Life Sci. 2005;62:255–6.

    Article  CAS  PubMed  Google Scholar 

  12. Aubele T, Kaufman R, Montalmant F, Kritzer MF. Effects of gonadectomy and hormone replacement on a spontaneous novel object recognition task in adult male rats. Horm Behav. 2008;54:244–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Palm R, Chang J, Blair J, Garcia-Mesa Y, Lee HG, Castellani RJ, et al. Down-regulation of serum gonadotropins but not estrogen replacement improves cognition in aged-ovariectomized 3xTg AD female mice. J Neurochem. 2014;130:115–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Blair JA, Palm R, Chang J, McGee H, Zhu X, Wang X, et al. Luteinizing hormone downregulation but not estrogen replacement improves ovariectomy-associated cognition and spine density loss independently of treatment onset timing. Horm Behav. 2016;78:60–66.

    Article  CAS  PubMed  Google Scholar 

  15. Xiong J, Kang SS, Wang Z, Liu X, Kuo TC, Korkmaz F, et al. FSH blockade improves cognition in mice with Alzheimer’s disease. Nature. 2022;603:470–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ryu V, Gumerova A, Korkmaz F, Kang SS, Katsel P, Miyashita S, et al. Brain atlas for glycoprotein hormone receptors at single-transcript level. Elife. 2022;11:e79612.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Terasawa E, Kawakami M, Sawyer CH. Induction of ovulation by electrochemical stimulation in androgenized and spontaneously constant-estrous rats. Proc Soc Exp Biol Med. 1969;132:497–501.

    Article  CAS  PubMed  Google Scholar 

  18. Gallo RV, Johnson JH, Kalra SP, Whitmoyer DI, Sawyer CH. Effects of luteinizing hormone on multiple-unit activity in the rat hippocampus. Neuroendocrinology. 1972;9:149–57.

    Article  CAS  PubMed  Google Scholar 

  19. Lei ZM, Rao CV, Kornyei JL, Licht P, Hiatt ES. Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. Endocrinology. 1993;132:2262–70.

    Article  CAS  PubMed  Google Scholar 

  20. Knowles F. Ependyma of the third ventricle in relation to pituitary function. Prog Brain Res. 1972;38:255–70.

    Article  CAS  PubMed  Google Scholar 

  21. Lukacs H, Hiatt ES, Lei ZM, Rao CV. Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus-associated behaviors in cycling female rats. Horm Behav. 1995;29:42–58.

    Article  CAS  PubMed  Google Scholar 

  22. Fiddes JC, Talmadge K. Structure, expression, and evolution of the genes for the human glycoprotein hormones. Recent Prog Horm Res. 1984;40:43–78.

    CAS  PubMed  Google Scholar 

  23. Serchov T, van Calker D, Biber K. Light/dark transition test to assess anxiety-like behavior in mice. Bio-Protoc. 2016;6:e1957.

    Article  Google Scholar 

  24. Stover KR, Campbell MA, Van Winssen CM, Brown RE. Early detection of cognitive deficits in the 3xTg-AD mouse model of Alzheimer’s disease. Behav Brain Res. 2015;289:29–38.

    Article  CAS  PubMed  Google Scholar 

  25. Hsiao KK, Borchelt DR, Olson K, Johannsdottir R, Kitt C, Yunis W, et al. Age-related CNS disorder and early death in transgenic FVB/N mice overexpressing Alzheimer amyloid precursor proteins. Neuron. 1995;15:1203–18.

    Article  CAS  PubMed  Google Scholar 

  26. Holcomb LA, Gordon MN, Jantzen P, Hsiao K, Duff K, Morgan D. Behavioral changes in transgenic mice expressing both amyloid precursor protein and presenilin-1 mutations: lack of association with amyloid deposits. Behav Genet. 1999;29:177–85.

    Article  CAS  PubMed  Google Scholar 

  27. Rustay NR, Cronin EA, Curzon P, Markosyan S, Bitner RS, Ellis TA, et al. Mice expressing the Swedish APP mutation on a 129 genetic background demonstrate consistent behavioral deficits and pathological markers of Alzheimer’s disease. Brain Res. 2010;1311:136–47.

    Article  CAS  PubMed  Google Scholar 

  28. Leger M, Quiedeville A, Bouet V, Haelewyn B, Boulouard M, Schumann-Bard P, et al. Object recognition test in mice. Nat Protoc. 2013;8:2531–7.

    Article  CAS  PubMed  Google Scholar 

  29. Clark RE, Martin SJ. Interrogating rodents regarding their object and spatial memory. Curr Opin Neurobiol. 2005;15:593–8.

    Article  CAS  PubMed  Google Scholar 

  30. Ennaceur A, Delacour J. A new one-trial test for neurobiological studies of memory in rats. 1: behavioral data. Behav Brain Res. 1988;31:47–59.

    Article  CAS  PubMed  Google Scholar 

  31. Bevins RA, Besheer J. Object recognition in rats and mice: a one-trial non-matching-to-sample learning task to study ‘recognition memory’. Nat Protoc. 2006;1:1306–11.

    Article  PubMed  Google Scholar 

  32. Taglialatela G, Hogan D, Zhang WR, Dineley KT. Intermediate- and long-term recognition memory deficits in Tg2576 mice are reversed with acute calcineurin inhibition. Behav Brain Res. 2009;200:95–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Neaves WB, Johnson L, Porter JC, Parker CR Jr, Petty CS. Leydig cell numbers, daily sperm production, and serum gonadotropin levels in aging men. J Clin Endocrinol Metab. 1984;59:756–63.

    Article  CAS  PubMed  Google Scholar 

  34. Chakravarti S, Collins WP, Forecast JD, Newton JR, Oram DH, Studd JW. Hormonal profiles after the menopause. Br Med J. 1976;2:784–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hyde Z, Flicker L, Almeida OP, McCaul KA, Jamrozik K, Hankey GJ, et al. Higher luteinizing hormone is associated with poor memory recall: the health in men study. J Alzheimers Dis. 2010;19:943–51.

    Article  CAS  PubMed  Google Scholar 

  36. Rodrigues MA, Verdile G, Foster JK, Hogervorst E, Joesbury K, Dhaliwal S, et al. Gonadotropins and cognition in older women. J Alzheimers Dis. 2008;13:267–74.

    Article  CAS  PubMed  Google Scholar 

  37. Bourin M, Hascoet M. The mouse light/dark box test. Eur J Pharm. 2003;463:55–65.

    Article  CAS  Google Scholar 

  38. Crawley J, Goodwin FK. Preliminary report of a simple animal behavior model for the anxiolytic effects of benzodiazepines. Pharm Biochem Behav. 1980;13:167–70.

    Article  CAS  Google Scholar 

  39. Deacon RM, Rawlins JN. T-maze alternation in the rodent. Nat Protoc. 2006;1:7–12.

    Article  PubMed  Google Scholar 

  40. Prieur EAK, Jadavji NM. Assessing spatial working memory using the spontaneous alternation Y-maze test in aged male mice. Bio Protoc. 2019;9:e3162.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Henderson ND. A genetic analysis of spontaneous alternation in mice. Behav Genet. 1970;1:125–32.

    Article  CAS  PubMed  Google Scholar 

  42. Antunes M, Biala G. The novel object recognition memory: neurobiology, test procedure, and its modifications. Cogn Process. 2012;13:93–110.

    Article  CAS  PubMed  Google Scholar 

  43. Lee JLC. Chapter 3 - Mechanisms and Functions of Hippocampal Memory Reconsolidation. In: Alberini CM, (ed). Memory Reconsolidation. San Diego: Academic Press; 2013. p. 43–68.

    Chapter  Google Scholar 

  44. Bebbington P, Hurry J, Tennant C, Sturt E, Wing JK. Epidemiology of mental disorders in Camberwell. Psychol Med. 1981;11:561–79.

    Article  CAS  PubMed  Google Scholar 

  45. Bloch M, Daly RC, Rubinow DR. Endocrine factors in the etiology of postpartum depression. Compr Psychiatry. 2003;44:234–46.

    Article  PubMed  Google Scholar 

  46. Jenkins R. Sex differences in depression. Br J Hosp Med. 1987;38:485–86.

    CAS  PubMed  Google Scholar 

  47. Rubinow DR, Schmidt PJ. The neuroendocrinology of menstrual cycle mood disorders. Ann N. Y Acad Sci. 1995;771:648–59.

    Article  CAS  PubMed  Google Scholar 

  48. Weissman MM, Klerman GL. Sex differences and the epidemiology of depression. Arch Gen Psychiatry. 1977;34:98–11.

    Article  CAS  PubMed  Google Scholar 

  49. Liu P, Ji Y, Yuen T, Rendina-Ruedy E, DeMambro VE, Dhawan S, et al. Blocking FSH induces thermogenic adipose tissue and reduces body fat. Nature. 2017;546:107–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Sun L, Peng Y, Sharrow AC, Iqbal J, Zhang Z, Papachristou DJ, et al. FSH directly regulates bone mass. Cell. 2006;125:247–60.

    Article  CAS  PubMed  Google Scholar 

  51. Zhu LL, Blair H, Cao J, Yuen T, Latif R, Guo L, et al. Blocking antibody to the beta-subunit of FSH prevents bone loss by inhibiting bone resorption and stimulating bone synthesis. Proc Natl Acad Sci USA. 2012;109:14574–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Ji Y, Liu P, Yuen T, Haider S, He J, Romero R, et al. Epitope-specific monoclonal antibodies to FSHbeta increase bone mass. Proc Natl Acad Sci USA. 2018;115:2192–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Han X, Guan Z, Xu M, Zhang Y, Yao H, Meng F, et al. A novel follicle-stimulating hormone vaccine for controlling fat accumulation. Theriogenology. 2020;148:103–11.

    Article  CAS  PubMed  Google Scholar 

  54. Geng W, Yan X, Du H, Cui J, Li L, Chen F. Immunization with FSHbeta fusion protein antigen prevents bone loss in a rat ovariectomy-induced osteoporosis model. Biochem Biophys Res Commun. 2013;434:280–6.

    Article  CAS  PubMed  Google Scholar 

  55. Andersen K, Launer LJ, Dewey ME, Letenneur L, Ott A, Copeland JR, et al. Gender differences in the incidence of AD and vascular dementia: the EURODEM studies. EURODEM incidence research group. Neurology. 1999;53:1992–7.

    Article  CAS  PubMed  Google Scholar 

  56. Fisher DW, Bennett DA, Dong H. Sexual dimorphism in predisposition to Alzheimer’s disease. Neurobiol Aging. 2018;70:308–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Laws KR, Irvine K, Gale TM. Sex differences in cognitive impairment in Alzheimer’s disease. World J Psychiatry. 2016;6:54–65.

    Article  PubMed  PubMed Central  Google Scholar 

  58. Koran MEI, Wagener M, Hohman TJ, Alzheimer’s Neuroimaging I. Sex differences in the association between AD biomarkers and cognitive decline. Brain Imaging Behav. 2017;11:205–13.

    Article  PubMed  PubMed Central  Google Scholar 

  59. Pandaranandaka J, Poonyachoti S, Kalandakanond-Thongsong S. Differential effects of exogenous and endogenous estrogen on anxiety as measured by elevated T-maze in relation to the serotonergic system. Behav Brain Res. 2009;198:142–8.

    Article  CAS  PubMed  Google Scholar 

  60. Walf AA, Frye CA. A review and update of mechanisms of estrogen in the hippocampus and amygdala for anxiety and depression behavior. Neuropsychopharmacology. 2006;31:1097–11.

    Article  CAS  PubMed  Google Scholar 

  61. Walf AA, Frye CA. Antianxiety and antidepressive behavior produced by physiological estradiol regimen may be modulated by hypothalamic-pituitary-adrenal axis activity. Neuropsychopharmacology. 2005;30:1288–301.

    Article  CAS  PubMed  Google Scholar 

  62. Walf AA, Frye CA. Anti-nociception following exposure to trimethylthiazoline, peripheral or intra-amygdala estrogen and/or progesterone. Behav Brain Res. 2003;144:77–85.

    Article  CAS  PubMed  Google Scholar 

  63. Frye CA, Walf AA. Estrogen and/or progesterone administered systemically or to the amygdala can have anxiety-, fear-, and pain-reducing effects in ovariectomized rats. Behav Neurosci. 2004;118:306–13.

    Article  CAS  PubMed  Google Scholar 

  64. Prendergast BJ, Onishi KG, Zucker I. Female mice liberated for inclusion in neuroscience and biomedical research. Neurosci Biobehav Rev. 2014;40:1–5.

    Article  PubMed  Google Scholar 

  65. Gera S, Sant D, Haider S, Korkmaz F, Kuo TC, Mathew M, et al. First-in-class humanized FSH blocking antibody targets bone and fat. Proc Natl Acad Sci USA. 2020;117:28971–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Work at Icahn School of Medicine at Mount Sinai performed at the Center for Translational Medicine and Pharmacology was supported by fundings from the National Institute of Health (R01AG071870, R01AG074092 and U01AG073148 to M.Z. and T.Y.; and U19AG060917 and R01DK113627 to M.Z.).

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Authors and Affiliations

  1. Center for Translational Medicine and Pharmacology, Departments of Pharmacological Sciences and of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, 10029, USA

    Steven Sims, Orly Barak, Vitaly Ryu, Sari Miyashita, Hasni Kannangara, Funda Korkmaz, Soleil Wizman, Anne Macdonald, Anisa Gumerova, Ki Goosens, Mone Zaidi, Tony Yuen, Daria Lizneva & Tal Frolinger

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  1. Steven Sims
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Contributions

SS, VR, SM, HK, FK, SW and AG collected data. OB, AM, HK, TY and TF performed data analysis and statistical testing. KG, MZ, TY, DL and TF conceived and designed the study, authored manuscript, and supervised this work.

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Correspondence to Mone Zaidi, Daria Lizneva or Tal Frolinger.

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Competing interests

MZ is inventor on issued and pending patients on the use of FSH as a target for osteoporosis, obesity and Alzheimer’s disease. MZ, TY and DL are inventors on a submitted patent application relating to the role of LH in regulating body composition. The patents will be held by Icahn School of Medicine at Mount Sinai, and MZ, TY and/or DL would be recipient of royalties, per institutional policy. The other authors declare no competing financial interests.

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Sims, S., Barak, O., Ryu, V. et al. Absent LH signaling rescues the anxiety phenotype in aging female mice. Mol Psychiatry 28, 3324–3331 (2023). https://doi.org/10.1038/s41380-023-02209-6

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