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Neuroactive steroids
Neuroactive steroids
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Research
Neuroactive steroids occupy an important place among the signals that affect brain development and function. In our laboratory, we investigate the mechanisms of action of neuroactive steroids in neurons and glia, focusing mainly on the effects of ovarian hormones on neuronal plasticity and neuroprotection.
Our group is interested in studying the effects of estrogens in the brain. Estrogens, in addition to being gonadal hormones, are neuroactive steroids that are synthesized in the brain.
Lines of research
We have approached the investigation from two perspectives:
1) Neuroprotection
Estrogens have been shown to be neuroprotective in animal models of nervous system diseases that present with neuroinflammation and that show sex differences in incidence, age of onset, symptomatology, and response to treatment.
The studies are aimed at characterizing the response of glial cells, astrocytes, and microglia in models of inflammation, the sexual differences in said response, and the effect of exogenous estrogens in both sexes.
2) Triggers of proneural signals during development under physiological conditions and focused on repair in case of injury
In this context, we have described a signaling pathway through which estradiol is capable of inhibiting the Notch receptor signaling pathway and modifying the dendritic tree and the synaptogenesis of cultured neurons. Under this paradigm we have identified and described the intervention of some proteins, Ngn3, Formin1 and Kinesin 21B. We are currently studying the role of the kinesin Kif21B, as a mediator of the increase in the expression of Ngn3 produced by estradiol.
The results obtained in both situations lead us to wonder if certain diseases of the nervous system should be treated differently in men and women.
Team
Franco Juan Cruz
Predoctoral researcher
Elisa Baides
Technician
eli@cajal.csic.es
Álvaro Bautista
Predoctoral researcher
bautistaalvaro@gmail.com
Pablo Duque
Master student
pduq.uni@gmail.com
Publications
Representative publications
- Garcia-Segura LM*, Méndez P, Arevalo MA*, Azcoitia I. Neuroestradiol and neuronal development: Not an exclusive male tale anymore. Front Neuroendocrinol. 71:101102 (2023). doi: 10.1016/j.yfrne.2023.101102
- Santos-Toscano R, Arevalo MA, Garcia-Segura LM, Grassi D, Lagunas N. Interaction of gonadal hormones, dopaminergic system, and epigenetic regulation in the generation of sex differences in substance use disorders: A systematic review. Front Neuroendocrinol. 71:101085 (2023). doi: 10.1016/j.yfrne.2023.101085
- Ganchala D, Pinto-Benito D, Baides E, Ruiz-Palmero I, Grassi D and Arevalo MA. Kif21B mediates the effect of estradiol on the morphological plasticity of mouse hippocampal neurons. Front. Mol. Neurosci. 16:1143024 (2023) doi: 10.3389/fnmol.2023.1143024
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Auzmendi-Iriarte J, Moreno-Cugnon L, Saenz-Antoñanzas A, Grassi D, de Pancorbo MM, Arevalo MA, Wood IC, Matheu A. High levels of HDAC expression correlate with microglial aging. Expert Opin Ther Targets. 2022 Oct;26(10):911-922. doi: 10.1080/14728222.2022.2158081. Epub 2022 Dec 15. PMID: 36503367.
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McGovern AJ, Arevalo MA, Ciordia S, Garcia-Segura LM, Barreto GE. Respirasome Proteins Are Regulated by Sex-Hormone Interactions in the Brain. Int J Mol Sci. 2022 Nov 25;23(23):14754. doi: 10.3390/ijms232314754. PMID: 36499081; PMCID: PMC9741126.
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Dolcetti FJC, Falomir-Lockhart E, Acuña F, Herrera ML, Cervellini S, Barbeito CG, Grassi D, Arevalo MA*, Bellini MJ*. IGF1 gene therapy in middle-aged female rats delays reproductive senescence through its effects on hypothalamic GnRH and kisspeptin neurons. Aging (Albany NY). 2022 Nov 1;14(21):8615-8632. doi: 10.18632/aging.204360. Epub 2022 Nov 1. PMID: 36326686; PMCID: PMC9699762.
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Cabrera Zapata LE, Garcia-Segura LM, Cambiasso MJ, Arevalo MA. Genetics and Epigenetics of the X and Y Chromosomes in the Sexual Differentiation of the Brain. Int J Mol Sci. 2022 Oct 14;23(20):12288. doi: 10.3390/ijms232012288. PMID: 36293143; PMCID: PMC9603441.
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Cabrera Zapata LE, Cambiasso MJ, Arevalo MA. Epigenetic modifier Kdm6a/Utx controls the specification of hypothalamic neuronal subtypes in a sex-dependent manner. Front Cell Dev Biol. 2022 Oct 4;10:937875. doi: 10.3389/fcell.2022.937875. PMID: 36268511; PMCID: PMC9577230.
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Freire-Regatillo A, Diaz-Pacheco S, Frago LM, Arévalo MÁ, Argente J, Garcia-Segura LM, de Ceballos ML, Chowen JA. Sex Differences in Hypothalamic Changes and the Metabolic Response of TgAPP Mice to a High Fat Diet. Front Neuroanat. 2022 Jul 26;16:910477. doi: 10.3389/fnana.2022.910477. PMID: 35958733; PMCID: PMC9361789.
- Lagunas N, Fernández-García JM, Blanco N, Ballesta A, Carrillo B, Arevalo MA, Collado P, Pinos H, Grassi D. Organizational Effects of Estrogens and Androgens on Estrogen and Androgen Receptor Expression in Pituitary and Adrenal Glands in Adult Male and Female Rats. Front Neuroanat. 2022 Jun 23;16:902218. doi: 10.3389/fnana.2022.902218. PMID: 35815333; PMCID: PMC9261283.
- Pinto-Benito D, Paradela-Leal C, Ganchala D, de Castro-Molina P, Arevalo MA. IGF-1 regulates astrocytic phagocytosis and inflammation through the p110α isoform of PI3K in a sex-specific manner. Glia. 2022 Jun;70(6):1153-1169. doi: 10.1002/glia.24163. Epub 2022 Feb 17. PMID: 35175663; PMCID: PMC9305764.
- Klionsky DJ, et all. (2021) Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) Autophagy. 17(1):1-382. doi: 10.1080/15548627.2020.1797280.
- Yanguas-Casás N, Torres C, Crespo-Castrillo A, Diaz-Pacheco S, Healy K, Stanton C, Chowen JA, Garcia-Segura LM, Arevalo MA, Cryan JF, de Ceballos ML (2021) High-fat diet alters stress behavior, inflammatory parameters and gut microbiota in Tg APP mice in a sex-specific manner. Neurobiol Dis. 159:105495. doi: 10.1016/j.nbd.2021.105495.
- Cabrera Zapata LE, Cisternas CD, Sosa C, Garcia-Segura LM, Arevalo MA*, Cambiasso MJ* (2021) X-linked histone H3K27 demethylase Kdm6a regulates sexually dimorphic differentiation of hypothalamic neurons. Cell Mol Life Sci. 78(21-22):7043-7060. doi: 10.1007/s00018-021-03945-0
- Ortiz-Rodriguez A, Arevalo MA (2020) The Contribution of Astrocyte Autophagy to Systemic Metabolism.Int J Mol Sci. 21(7):2479. doi: 10.3390/ijms21072479.
- Crespo-Castrillo A, Arevalo MA (2020) Microglial and Astrocytic Function in Physiological and Pathological Conditions: Estrogenic Modulation. Int J Mol Sci. 21(9):3219. doi: 10.3390/ijms21093219
- Yanguas-Casás N, Crespo-Castrillo A, Arevalo MA, Garcia-Segura LM (2020) Aging and sex: Impact on microglia phagocytosis. Aging Cell. 19(8): e13182. doi: 10.1111/acel.13182
- Cisternas CD, Cabrera Zapata LE, Mir FR, Scerbo MJ, Arevalo MA, Garcia-Segura LM, Cambiasso MJ (2020) Estradiol-dependent axogenesis and Ngn3 expression are determined by XY sex chromosome complement in hypothalamic neurons. Sci Rep. 10(1):8223. doi: 10.1038/s41598-020-65183-x.
- Crespo-Castrillo A, Garcia-Segura LM, Arevalo MA (2020) The synthetic steroid tibolone exerts sex-specific regulation of astrocyte phagocytosis under basal conditions and after an inflammatory challenge. J of Neuroinflammation. 17(1):37 doi: 10.1186/s12974-020-1719-6.
- Acaz-Fonseca E, Ortiz-Rodriguez A, Azcoitia I, Garcia-Segura LM, Arevalo MA (2019) Notch signaling in astrocytes mediates their morphological response to an inflammatory challenge. Cell Death Discov, 5:85. doi: 10.1038/s41420-019-0166-6.
- Ortiz-Rodriguez A, Acaz-Fonseca E, Boya P, Arevalo MA, Garcia-Segura LM (2019) Lipotoxic Effects of Palmitic Acid on Astrocytes Are Associated with Autophagy Impairment. Mol Neurobiol, 56(3):1665-1680. doi: 10.1007/s12035-018-1183-9.
- Crespo-Castrillo A, Yanguas-Casás N, Arevalo MA, Azcoitia I, Barreto GE, Garcia-Segura LM (2018) The Synthetic Steroid Tibolone Decreases Reactive Gliosis and Neuronal Death in the Cerebral Cortex of Female Mice After a Stab Wound Injury. Mol Neurobiol, 55(11):8651-8667. doi: 10.1007/s12035-018-1008-x.
- Yanguas-Casás N, Crespo-Castrillo A, de Ceballos ML, Chowen JA, Azcoitia I, Arevalo MA, Garcia-Segura LM (2018). Sex differences in the phagocytic and migratory activity of microglia and their impairment by palmitic acid. Glia, 66(3):522-537. doi: 10.1002/glia.23263.
- Ruiz-Palmero I, Ortiz-Rodriguez A, Melcangi RC, Caruso D, Garcia-Segura LM, Rune GM, Arevalo MA (2016). Oestradiol synthesized by female neurons generates sex differences in neuritogenesis. Sci Rep, 6:31891. doi: 10.1038/srep31891.
- Acaz-Fonseca E, Duran JC, Carrero P, Garcia-Segura LM, Arevalo MA (2015). Sex differences in glia reactivity after cortical brain injury. Glia, 63(11):1966–1981. doi: 10.1002/glia.22867.
- Arevalo MA, Azcoitia I, Garcia-Segura LM (2015). The neuroprotective actions of oestradiol and oestrogen receptors. Nat Rev Neurosci, 16(1):17-29. doi: 10.1038/nrn3856.
Contact
Where to find us
Neuroactive Steroids Laboratory
Instituto Cajal CSIC. Avda. Doctor Arce, 37. 28002. Madrid
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@DaniPB_9
@MAngelesArevalo
Others
Doctoral Thesis
- “Effect of the synthetic steroid Tibolone on reactive gliosis”. Andrea Crespo Castillo. Autonomous University of Madrid. School of Medicine. 2019. Qualification: Outstanding cum laude.
- “Regulation of autophagy before metabolic stimuli in astrocytes”. Ana Ortiz Rodriguez. Autonomous University of Madrid. School of Medicine. 2019. Qualification: Outstanding cum laude.
- “Role of Neurogenin 3 in the neuritogenic actions of estradiol in the hippocampus”. Isabel Ruiz Palmero. Autonomous University of Madrid. Faculty: Sciences. 2016. Qualification: Outstanding cum laude.
- “Sex differences and regulation of the Notch pathway during reactive gliosis”. Estefania Acaz Fonseca. Autonomous University of Madrid. Faculty: Sciences. 2015. Qualification: Outstanding cum laude.
- “Effects of Neurogenin 3 signaling and its intracellular localization on the development of hippocampal neurons”. Julia M. Simon Martin. Autonomous University of Madrid. Science Faculty. 2011. Qualification: Outstanding cum laude.
- “Neuroglobin: molecular, cellular and biomedical aspects”. Elisabetta DeMarinis. University of Roma Tre studies. Facoltà di Scienze Matematiche, Fisiche e Naturali. 2011.
Teaching
- Master in Neuroscience from the Autonomous University of Madrid (UAM-Cajal Institute, CSIC)
Subject: NEUROBIOLOGY OF BRAIN AGING AND NERVOUS SYSTEM DISEASES. From 2010 to present - Direction of Final Degree Projects (TFG) and Final Master’s Projects (TFM)
Complutense University of Madrid, Autonomous University of Madrid, University of Alcalá de Henares, University of Milan.
Colaborations
- Julie A. Chowen. Niño Jesús University Children’s Hospital. Madrid Spain).
- Paloma Collado. National University of Distance Education (UNED) (Spain).
- Giancarlo Panzica. Università di Torino (Italia).
- Roberto C. Melcangi. Università degli Studi di Milano (Italia).
- Maria Marino. Universitá degli studi Roma Tre (Italia).
- María Julia Cambiasso. Ferreyra Institute (INIMEC-CONICET-National University of Córdoba) (Argentina).
- Alejandro F. De Nicola. Institute of Biology and Experimental Medicine (IBYME-CONICET- National University of Buenos Aires) (Argentina).
- María José Bellini. Institute of Biochemical Research of La Plata (INIBIOLP-CONICET-National University of La Plata) (Argentina).
- George Barreto. University of Limerick (Irlanda).
- Flavia Marques Ribeiro. Universidade Federal do Rio Grande do Sul (UFRGS)(Brasil).
- Tamas L. Horvath. Yale University (EEUU).
Projects
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Project title: Impact of gender and age on glial function in the injured brain
Funding entity: Ministry of Science and Innovation, PID2020-115019RB-I00
Participating entities: Cajal Institute. CSIC
Duration, from: 9/2021 to: 8/2025 Subsidy amount: €266,200
Responsible researcher: Mª Angeles Arévalo
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Project title: Implications of brain synthesis of estradiol for neuroprotection: analysis of sex differences.
Funding entity: Ministry of Economy and Competitiveness, BFU2017-82754-R
Participating entities: Cajal Institute. CSIC
Duration, from: 2018 to: 2021 Subsidy amount: €296,087
Responsible investigator: Luis M. García Segura and Mª Angeles Arévalo
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Project title: The hypothalamus as a regulatory center of aging – anti-inflammatory gene therapy.
Funding entity: EMHE-CSIC, MHE-200028
Participating entities: Cajal Institute. CSIC & INIBIOLP-CONICET
Duration, from: 2017 to: 2019 Subsidy amount: €25,500
Responsible researcher: Mª Angeles Arévalo
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Project title: Diet-induced brain alterations: sexual differences and protective mechanisms of gonadal hormones and Tibolone.
Financing entity: Ministry of Economy and Competitiveness, BFU2014-51836-C2-1R
Participating entities: Cajal Institute. CSIC
Duration, from: 2015 to: 2017 Subsidy amount: €320,000
Responsible investigator: Luis M. García Segura and Mª Angeles Arévalo
Neuroscience Research Center dependent on the CSIC. Founded in 1920 and initially directed by Santiago Ramón y Cajal. World reference in the study of the brain. Custodian of the Cajal Legacy.
Activities