Abstract
Brain structures and functions are increasingly recognized to be directly affected by gonadal hormones, which classically determine reproductive functions and sexual phenotypes. In this regard, we found recently that ovariectomy trimmed the dendritic spines of female rat primary somatosensory cortical neurons and estradiol supplement reversed it. Here, we investigated whether in the male androgen also has a cortical modulatory effect. The dendritic arbors and spines of rat somatosensory cortical pyramidal neurons were studied following intracellular dye injection and three-dimensional reconstruction. Dendritic spines, but not length, of the layers III and V pyramidal neurons were found reduced at 2 weeks and rebounded slightly at 4 weeks and further at 8 and 24 weeks following castration, which, however, remained significantly fewer than those of the intact animals. Two weeks of osmotic pump-delivered testosterone treatment to animals castrated for 4 weeks replenished serum testosterone and reversed the densities of dendritic spines on these neurons to control animal levels. Androgen receptor appears to mediate this effect as its antagonist flutamide reduced the dendritic spines of normal adult rats while causing a mild feedback surge of serum testosterone. On the other hand, blocking the conversion of testosterone to estrogen with the aromatase inhibitor anastrozole failed to alter the dendritic spine densities in male adult rats. In conclusion, these results support our hypothesis that testosterone acts directly on the androgen receptor in males to modulate the dendritic spines of somatosensory cortical output neurons.
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References
Almeida OP, Waterreus A, Spry N, Flicker L, Martins RN (2004) One year follow-up study of the association between chemical castration, sex hormones, beta-amyloid, memory and depression in men. Psychoneuroendocrinology 29(28):1071–1081
Alonso M, Medina JH, Pozzo-Miller L (2004) ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem 11(2):172–178
Andrews TJ, Cowen T (1994) In vivo infusion of NGF induces the organotypic regrowth of perivascular nerves following their atrophy in aged rats. J Neurosci 14(5 Pt 2):3048–3058
Baloyannis SJ (2009) Dendritic pathology in Alzheimer’s disease. J Neurol Sci 283(1–2):153–157
Barrett-Connor E, Goodman-Gruen D, Patay B (1999) Endogenous sex hormones and cognitive function in older men. J Clin Endocrinol Metab 84(10):3681–3685
Beeri R, Le Novere N, Mervis R, Huberman T, Grauer E, Changeux JP, Soreq H (1997) Enhanced hemicholinium binding and attenuated dendrite branching in cognitively impaired acetylcholinesterase-transgenic mice. J Neurochem 69(6):2441–2451
Bimonte-Nelson HA, Singleton RS, Nelson ME, Eckman CB, Barber J, Scott TY, Granholm AC (2003) Testosterone, but not nonaromatizable dihydrotestosterone, improves working memory and alters nerve growth factor levels in aged male rats. Exp Neurol 181(2):301–312
Blurton-Jones M, Tuszynski MH (2002) Estrogen receptor-beta colocalizes extensively with parvalbumin-labeled inhibitory neurons in the cortex, amygdala, basal forebrain, and hippocampal formation of intact and ovariectomized adult rats. J Comp Neurol 452(3):276–287
Chen JR, Wang YJ, Tseng GF (2003) The effect of epidural compression on cerebral cortex: a rat model. J Neurotrauma 20(8):767–780
Chen JR, Wang YJ, Tseng GF (2004) The effect of decompression and exogenous NGF on cerebral cortex subjected to compression. J Neurotrauma 21(11):1640–1651
Chen JR, Yan YT, Wang TJ, Chen LJ, Wang YJ, Tseng GF (2009a) Gonadal hormones modulate the dendritic spine densities of primary cortical pyramidal neurons in adult female rat. Cereb Cortex 19(11):2719–2727
Chen JR, Wang TJ, Huang HY, Chen LJ, Huang YS, Wang YJ, Tseng GF (2009b) Fatigue reversibly reduced cortical and hippocampal dendritic spines concurrent with compromise of motor endurance and spatial memory. Neuroscience 161(4):1104–1113
Chen JR, Wang TJ, Wang YJ, Tseng GF (2010) The immediate large-scale dendritic plasticity of cortical pyramidal neurons subjected to acute epidural compression. Neuroscience 167(2):414–427
Cherrier MM, Aubin S, Higano CS (2009) Cognitive and mood changes in men undergoing intermittent combined androgen blockade for non-metastatic prostate cancer. Psychooncology 18(3):237–247
Chu LW, Tam S, Kung AW, Lo S, Fan S, Wong RL, Morley JE, Lam KS (2008) Serum total and bioavailable testosterone levels, central obesity, and muscle strength changes with aging in healthy Chinese men. J Am Geriatr Soc 56(7):1286–1291
Chu LW, Tam S, Wong RL, Yik PY, Song Y, Cheung BM, Morley JE, Lam KS (2010) Bioavailable testosterone predicts a lower risk of Alzheimer’s disease in older men. J Alzheimers Dis 21(4):1335–1345
Clancy AN, Bonsall RW, Michael RP (1992) Immunohistochemical labeling of androgen receptors in the brain of rat and monkey. Life Sci 50(6):409–417
Cooke BM, Woolley CS (2005) Gonadal hormone modulation of dendrites in the mammalian CNS. J Neurobiol 64(1):34–46
de Brabander JM, Kramers RJ, Uylings HB (1998) Layer-specific dendritic regression of pyramidal cells with ageing in the human prefrontal cortex. Eur J Neurosci 10(4):1261–1269
Ferrer I, Gullotta F (1990) Down’s syndrome and Alzheimer’s disease: dendritic spine counts in the hippocampus. Acta Neuropathol 79(6):680–685
Flood JF, Farr SA, Kaiser FE, La Regina M, Morley JE (1995) Age-related decrease of plasma testosterone in SAMP8 mice: replacement improves age-related impairment of learning and memory. Physiol Behav 57(4):669–673
Hajszan T, MacLusky NJ, Leranth C (2008) Role of androgens and the androgen receptor in remodeling of spine synapses in limbic brain areas. Horm Behav 53(5):638–646
Hatanaka Y, Mukai H, Mitsuhashi K, Hojo Y, Murakami G, Komatsuzaki Y, Sato R, Kawato S (2009) Androgen rapidly increases dendritic thorns of CA3 neurons in male rat hippocampus. Biochem Biophys Res Commun 381(4):728–732
Hill JJ, Kolluri N, Hashimoto T, Wu Q, Sampson AR, Monteggia LM, Lewis DA (2005) Analysis of pyramidal neuron morphology in an inducible knockout of brain-derived neurotrophic factor. Biol Psychiatry 57(8):932–934
Hirshman E, Merritt P, Wang CC, Wierman M, Budescu DV, Kohrt W, Templin JL, Bhasin S (2004) Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 45(2):144–155
Hojo Y, Hattori TA, Enami T, Furukawa A, Suzuki K, Ishii HT, Mukai H, Morrison JH, Janssen WG, Kominami S, Harada N, Kimoto T, Kawato S (2004) Adult male rat hippocampus synthesizes estradiol from pregnenolone by cytochromes P45017alpha and P450 aromatase localized in neurons. Proc Natl Acad Sci USA 101(3):865–870
Horner CH (1993) Plasticity of the dendritic spine. Prog Neurobiol 41(3):281–321
Isgor C, Sengelaub DR (2003) Effects of neonatal gonadal steroids on adult CA3 pyramidal neuron dendritic morphology and spatial memory in rats. J Neurobiol 55(2):179–190
Janowsky JS, Chavez B, Orwoll E (2000) Sex steroids modify working memory. J Cog Neurosci 12(3):407–414
Kritzer M (2004) The distribution of immunoreactivity for intracellular androgen receptors in the cerebral cortex of hormonally intact adult male and female rats: localization in pyramidal neurons making corticocortical connections. Cereb Cortex 14(3):268–280
Larkman AU (1991) Dendritic morphology of pyramidal neurones of the visual cortex of the rat: III. Spine distributions. J Comp Neurol 306(2):332–343
Leranth C, Shanabrough M, Horvath TL (2000) Hormonal regulation of hippocampal spine synapse density involves subcortical mediation. Neuroscience 101(2):349–356
Leranth C, Petnehazy O, MacLusky NJ (2003) Gonadal hormones affect spine synaptic density in the CA1 hippocampal subfield of male rats. J Neurosci 23(5):1588–1592
Ma CH, Taylor JS (2010) Trophic responsiveness of purified postnatal and adult rat retinal ganglion cells. Cell Tissue Res 339(2):297–310
MacLusky NJ, Clark AS, Naftolin F, Goldman-Rakic PS (1987) Estrogen formation in the mammalian brain: possible role of aromatase in sexual differentiation of the hippocampus and neocortex. Steroids 50(4–6):459–474
MacLusky NJ, Hajszan T, Johansen JA, Jordan CL, Leranth C (2006) Androgen effects on hippocampal CA1 spine synapse numbers are retained in Tfm male rats with defective androgen receptors. Endocrinology 147(5):2392–2398
Mavroudis IA, Fotiou DF, Manani MG, Njaou SN, Frangou D, Costa VG, Baloyannis SJ (2011) Dendritic pathology and spinal loss in the visual cortex in Alzheimer’s disease: a Golgi study in pathology. Int J Neurosci 121(7):347–354
Moffat SD, Zonderman AB, Metter EJ, Kawas C, Blackman MR, Harman SM, Resnick SM (2004) Free testosterone and risk for Alzheimer disease in older men. Neurology 62(2):188–193
Nguyen TV, Yao M, Pike CJ (2009) Dihydrotestosterone activates CREB signaling in cultured hippocampal neurons. Brain Res 1298:1–12
Ottem EN, Beck LA, Jordan CL, Breedlove SM (2007) Androgen-dependent regulation of brain-derived neurotrophic factor and tyrosine kinase B in the sexually dimorphic spinal nucleus of the bulbocavernosus. Endocrinology 148(8):3655–3665
Pak TR, Chung WC, Lund TD, Hinds LR, Clay CM, Handa RJ (2005) The androgen metabolite, 5alpha-androstane-3beta, 17beta-diol, is a potent modulator of estrogen receptor-beta1-mediated gene transcription in neuronal cells. Endocrinology 146(1):147–155
Petanjek Z, Judas M, Kostovic I, Uylings HB (2008) Lifespan alterations of basal dendritic trees of pyramidal neurons in the human prefrontal cortex: a layer-specific pattern. Cereb Cortex 18(4):915–929
Rosario ER, Carroll J, Pike CJ (2010) Testosterone regulation of Alzheimer-like neuropathology in male 3xTg-AD mice involves both estrogen and androgen pathways. Brain Res 1359:281–290
Sarkey S, Azcoitia I, Garcia-Segura LM, Garcia-Ovejero D, DonCarlos LL (2008) Classical androgen receptors in non-classical sites in the brain. Horm Behav 53(5):753–764
Scimonelli T, Marucco M, Celis ME (1999) Age-related changes in grooming behavior and motor activity in female rats. Physiol Behav 66(3):481–484
Seidman SN (2003) Testosterone deficiency and mood in aging men: pathogenic and therapeutic interactions. World J Biol Psychiatry 4(1):14–20
Suravarapu S, Bergstralh EJ, Farmer SA, Knopman DS, Jacobsen SJ, Roberts RO (2006) Dementia and low testosterone and bioavailable testosterone levels in men: possible increased risk. Alzheimer Dis Assoc Disord 20(3):138–140
Tabori NE, Stewart LS, Znamensky V, Romeo RD, Alves SE, McEwen BS, Milner TA (2005) Ultrastructural evidence that androgen receptors are located at extranuclear sites in the rat hippocampal formation. Neuroscience 130(1):151–163
Tseng GF, Prince DA (1993) Heterogeneity of rat corticospinal neurons. J Comp Neurol 335(1):92–108
Tseng GF, Prince DA (1996) Structural and functional alterations in rat corticospinal neurons after axotomy. J Neurophysiol 75(1):248–267
Tyler WJ, Pozzo-Miller LD (2003) Miniature synaptic transmission and BDNF modulate dendritic spine growth and form in rat CA1 pyramidal neurones. J Physiol 553(Pt 2):497–509
Wang YJ, Chen JR, Tseng GF (2002) Fates of soma and dendrites of cord-projection central neurons following proximal and distal spinal axotomy: an intracellular dye injection study. J Neurotrauma 19(11):1487–1502
Wang TJ, Chen JR, Wang YJ, Tseng GF (2009) The cytoarchitecture and soma-dendritic arbors of the pyramidal neurons of aged rat sensorimotor cortex: an intracellular dye injection study. Neuroscience 158(2):776–785
Weickert CS, Hyde TM, Lipska BK, Herman MM, Weinberger DR, Kleinman JE (2003) Reduced brain-derived neurotrophic factor in prefrontal cortex of patients with schizophrenia. Mol Psychiatry 8(6):592–610
Woolley CS, McEwen BS (1992) Estradiol mediates fluctuation in hippocampal synapse density during the estrous cycle in the adult rat. J Neurosci 12(7):2549–2554
Zhang G, Shi G, Tan H, Kang Y, Cui H (2011) Intranasal administration of testosterone increased immobile-sniffing, exploratory behavior, motor behavior and grooming behavior in rats. Horm Behav 59:477–483
Acknowledgments
The work was supported by research grants from the National Science Council of Taiwan to Chen, JR (NSC99-2320-B-005-005-MY3) and Tseng, GF (NSC101-2320-B-320-001-MY3) and Wang, YJ (NSC100-2320-B-320-002) and the Tzu-Chi University grants to Tseng, GF and Wang, YJ (TCIRP-98006).
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The authors declare no conflict of interest with the organizations that sponsored the research.
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Chen, JR., Wang, TJ., Lim, SH. et al. Testosterone modulation of dendritic spines of somatosensory cortical pyramidal neurons. Brain Struct Funct 218, 1407–1417 (2013). https://doi.org/10.1007/s00429-012-0465-7
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DOI: https://doi.org/10.1007/s00429-012-0465-7