Why estrogens matter for behavior and brain health

Galea, Liisa A.M.; Frick, Karyn M.; Hampson, Elizabeth; Sohrabji, Farida; Choleris, Elena

doi:10.1016/j.neubiorev.2016.03.024

Cited by 138 publications

(97 citation statements)

References 249 publications

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“…As 16 these results indicate, taking endocrine factors into account is critical for fully 17 understanding the intrinsic dynamics of the human brain. The brain is an endocrine organ whose day-to-day function is intimately tied to the action 20 of neuromodulatory hormones [1][2][3][4] . Yet, the study of brain-hormone interactions in human 21 neuroscience has often been woefully myopic in scope: the classical approach of 22 interrogating the brain involves collecting data at a single time point from multiple 23 subjects and averaging across individuals to provide evidence for a 24 hormone-brain-behavior relationship.…”

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confidence: 99%

Functional reorganization of brain networks across the human menstrual cycle

Pritschet

Santander

Layher

et al. 2019

Preprint

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1The brain is an endocrine organ, sensitive to the rhythmic changes in sex hormone 2 production that occurs in most mammalian species. In rodents and nonhuman primates, 3 estrogen and progesterone's impact on the brain is evident across a range of 4 spatiotemporal scales. Yet, the influence of sex hormones on the functional architecture of 5 the human brain is largely unknown. In this dense-sampling, deep phenotyping study, we 6 examine the extent to which endogenous fluctuations in sex hormones alter intrinsic brain 7 networks at rest in a woman who underwent brain imaging and venipuncture for 30 8 consecutive days. Standardized regression analyses illustrate estrogen and progesterone's 9 widespread influence on cortical dynamics. Time-lagged analyses examined the 10 directionality of these relationships and reveal estrogen's ability to drive connectivity 11 across major functional brain networks, including the Default Mode and Dorsal Attention 12 Networks, whose hubs are densely populated with estrogen receptors. These results 13 reveal the rhythmic nature in which brain networks reorganize across the human 14 menstrual cycle. Neuroimaging studies that densely sample the individual connectome 15 have begun to transform our understanding of the brain's functional organization. As 16 these results indicate, taking endocrine factors into account is critical for fully 17 understanding the intrinsic dynamics of the human brain. The brain is an endocrine organ whose day-to-day function is intimately tied to the action 20 of neuromodulatory hormones [1][2][3][4] . Yet, the study of brain-hormone interactions in human 21 neuroscience has often been woefully myopic in scope: the classical approach of 22 interrogating the brain involves collecting data at a single time point from multiple 23 subjects and averaging across individuals to provide evidence for a 24 hormone-brain-behavior relationship. This cross-sectional approach obscures the rich, 25 rhythmic nature of endogenous hormone production. A promising trend in network 26 neuroscience is to flip the cross-sectional model by tracking small samples of individuals 27 over timescales of weeks, months, or years to provide insight into how biological, 28 behavioral, and state-dependent factors influence intra-and inter-individual variability in 29 the brain's intrinsic network organization [5][6][7] . Neuroimaging studies that densely sample 30 the individual connectome are beginning to transform our understanding of the dynamics 31 of human brain organization. However, these studies commonly overlook sex steroid 32 hormones as a source of variability-a surprising omission given that sex hormones are 33 powerful neuromodulators that display stable circadian, infradian, and circannual 34 rhythms in nearly all mammalian species. In the present study, we illustrate robust, 35 time-dependent interactions between the sex steroid hormones 17β-estradiol and 36 progesterone and the functional network organization of the brain over a complete 37 menstrual cycle, offering compell...

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confidence: 99%

Functional reorganization of brain networks across the human menstrual cycle

Pritschet

Santander

Layher

et al. 2019

Preprint

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“…However, increasing evidence suggests that the beneficial effects of 17β-estradiol may also be in part conferred through the modulation of glutamatergic signaling 27,35,36 . This is supported by animal studies which show that 17β-estradiol enhances performance on a number of cognitive tasks, including attention and learning and memory tasks in healthy animals 27,28,54 as well as models of psychosis 30,[55][56][57] . Importantly, it is the ability of 17β-estradiol to modulate both glutamatergic and GABAergic systems that underlies these enhancing effects 45,48,[58][59][60][61] .…”

Section: Discussionmentioning

confidence: 74%

Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders

Erli

Palmos

Raval

et al. 2018

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Loss of glutamatergic synapses is thought to be a key cellular pathology associated with neuropsychiatric disorders including schizophrenia (SCZ) and major depressive disorder (MDD). Genetic and cellular studies of SCZ and MDD using in vivo and in vitro systems have supported a key role for dysfunction of excitatory synapses in the pathophysiology of these disorders. Recent clinical studies have demonstrated that the estrogen, 17β-estradiol can ameliorate many of the symptoms experienced by patients. Yet, to date, our understanding of how 17β-estradiol exerted these beneficial effects is limited. In this study, we have tested the hypothesis that 17βestradiol can restore dendritic spine number in a cellular model that recapitulates the loss of synapses associated with SCZ and MDD. Ectopic expression of wildtype, mutant or shRNA-mediated knockdown of Disrupted in Schizophrenia (DISC1) reduced dendritic spine density in primary cortical neurons. Acute or chronic treatment with 17β-estradiol increased spine density to control levels in neurons with altered DISC1 levels. In addition, 17β-estradiol reduced the extent to which ectopic wildtype and mutant DISC1 aggregated. Furthermore, 17β-estradiol also caused the enrichment of synaptic proteins at synapses and increased the number of dendritic spines containing PSD-95 or that overlapped with the pre-synaptic marker bassoon.Taken together, our data indicates that estrogens can restore lost excitatory synapses caused by altered DISC1 expression, potentially through the trafficking of DISC1 and its interacting partners. These data highlight the possibility that estrogens exert their beneficial effects in SCZ and MDD in part by modulating dendritic spine number. S. performed all experiments and subsequent analysis. J.M., S.J.M. and P.P. produced or oversaw production of reagents; J.M., N.J.B., P.P. and D.P.S. wrote the manuscript.

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“…39 This method is particularly suited for examining 40 relationships between brain dynamics and physiologi-41 cal variables that vary over relatively short time scales, 42 such as sex hormone fluctuations over the human men-43 strual cycle. A typical cycle, occurring every 25-30 44 days, is characterized by significant rises in estradiol 45 (∼12-fold) and progesterone (∼ 800-fold), both of which 46 are powerful neuromodulators that have a widespread 47 influence on the central nervous system [3]. Converg- 48 ing evidence from animal studies has established sex 49 hormones' influence on regions supporting higher-order 50 cognition, including the prefrontal cortex (PFC) and 51 hippocampus [4,5].…”

Section: Introduction 19mentioning

confidence: 99%

Dynamic community detection reveals transient reorganization of functional brain networks across a female menstrual cycle

Mueller

Pritschet

Santander

et al. 2020

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AbstractSex steroid hormones have been shown to alter regional brain activity, but the extent to which they modulate connectivity within and between large-scale functional brain networks over time has yet to be characterized. Here, we applied dynamic community detection techniques to data from a highly sampled female with 30 consecutive days of brain imaging and venipuncture measurements to characterize changes in resting-state community structure across the menstrual cycle. Four stable functional communities were identified consisting of nodes from visual, default mode, frontal control, and somatomotor networks. Limbic, subcortical, and attention networks exhibited higher than expected levels of nodal flexibility, a hallmark of between-network integration and transient functional reorganization. The most striking reorganization occurred in a default mode subnetwork localized to regions of the prefrontal cortex, coincident with peaks in serum levels of estradiol, luteinizing hormone, and follicle stimulating hormone. Nodes from these regions exhibited strong intra-network increases in functional connectivity, leading to a split in the stable default mode core community and the transient formation of a new functional community. Probing the spatiotemporal basis of human brain–hormone interactions with dynamic community detection suggests that ovulation results in a temporary, localized patterns of brain network reorganization.Author SummarySex steroid hormones influence the central nervous system across multiple spatiotemporal scales. Estrogen and progesterone concentrations rise and fall throughout the menstrual cycle, but it remains poorly understood how day-to-day fluctuations in hormones shape human brain dynamics. Here, we assessed the structure and stability of resting-state brain network activity in concordance with serum hormone levels from a female who underwent fMRI and venipuncture for 30 consecutive days. Our results reveal that while network structure is largely stable over the menstrual cycle, there is temporary reorganization of several largescale functional brain networks during the ovulatory window. In particular, a default mode subnetwork exhibits increased connectivity with itself and with regions from temporoparietal and limbic networks, providing novel perspective into brain-hormone interactions.

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Why estrogens matter for behavior and brain health

Cited by 138 publications

References 249 publications

Functional reorganization of brain networks across the human menstrual cycle

Functional reorganization of brain networks across the human menstrual cycle

Estradiol reverses excitatory synapse loss in a cellular model of neuropsychiatric disorders

Dynamic community detection reveals transient reorganization of functional brain networks across a female menstrual cycle

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