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Review
. 2006 Oct 11;26(41):10332-48.
doi: 10.1523/JNEUROSCI.3369-06.2006.

Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women

John H Morrison  1 , Roberta D Brinton, Peter J Schmidt, Andrea C Gore
Affiliations
Review

Estrogen, menopause, and the aging brain: how basic neuroscience can inform hormone therapy in women

John H Morrison et al. J Neurosci. .
No abstract available

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Figures

Figure 1.
Figure 1.
Interactions between the brain and reproductive endocrine system. The hypothalamic–pituitary–gonadal axis of females is shown, with the three levels of regulation of reproductive function. GnRH neurons in the hypothalamus (shown in blue) release the decapeptide into the portal capillary vasculature, leading to the pituitary gland (shown in purple). Pituitary gonadotropes release the gonadotropins LH and FSH into the general circulation. LH and FSH act on their receptors on the ovary (shown in pink) to regulate sex steroid hormone production and release and folliculogenesis and ovulation. Sex steroids in turn are released into the circulation in which they exert effects on the body, and they also exert feedback actions on the hypothalamus and pituitary gland. In addition, steroids exert regulatory actions on receptors in nonreproductive brain regions, including (but not limited to) prefrontal cortex and hippocampus, thalamus, and brainstem. Additional communication between reproductive and nonreproductive brain regions occurs via neural circuitry linking the hypothalamus to other CNS systems (shown with light blue arrows). Some of this circuitry probably involves glutamate inputs to GnRH neurons, acting on NMDARs on GnRH neurons and their surrounding hypothalamic milieu. BS, Brainstem; CB, cerebellum; CC, corpus callosum; FC, frontal cortex; HIPPO, hippocampus; HYP, hypothalamus; PIT, pituitary; THAL, thalamus.
Figure 2.
Figure 2.
Behavioral and morphological effects of cyclical estradiol treatment in aged female rhesus monkeys. A, Neuropsychological performance in aged OVX plus vehicle (OVX + VEH) and OVX plus estradiol (OVX + E) monkeys in DR (for details, see text), showing the mean percentage correct across delays of 5–60 s. Note enhanced performance of OVX + E group at all delays (Rapp et al., 2003a). B, Histogram showing quantitative data on spine density (spine number per micrometer of dendritic length) in layer III pyramidal neurons from area 46. Note that the OVX + E group has significantly higher spine density in both apical and basal dendritic arbors and throughout all branch orders in the apical tree. C, High-resolution examples of apical and basal dendritic segments from a filled neuron from both OVX + E- and OVX + VEH-treated monkeys. Scale bar, 5 μm. **p < 0.01. Error bars indicate SEM.
Figure 3.
Figure 3.
Estrogen mechanisms of action that lead to neurotrophic and neuroprotective outcomes. Top, 17-β-Estradiol (E2) acting via a membrane-associated site (mER) activates a cascade required for multiple responses that lead to enhanced neural plasticity, morphogenesis, neurogenesis, and neural survival. The signaling sequence induced by E2 at the membrane site is as follows: (1) E2 binding to mER, (2) E2–mER complexes with p85 to activate PI3K, (3) activating calcium-independent PKC, (4) phosphorylating the L-type calcium channel, (5) inducing calcium influx, (6) activating calcium-dependent PKCs, (7) activating Src kinase, (8) activating the MEK/ERK1/2 pathway, (9) ERK translocates to the nucleus, (10) activating and phosphorylating CREB, (11) enhancing transcription of antiapoptotic genes Bcl-2 and Bcl-xl, which enhance mitochondrial vitality, and spinophilin, which encourages synaptic growth, (12) simultaneously, estrogen activation of PI3K leads to activation of Akt, which phosphorylates and inhibits the proapoptotic protein BAD. Middle, Estrogen-induced neuroprotective mechanisms converge on mitochondria. Estrogen-activated cellular signaling cascade promotes enhanced mitochondrial function, leading to increased calcium load tolerance, enhanced electron transport chain efficiency, and promotion of antioxidant defense mechanisms. These actions are mediated by the regulation of both nuclear and mitochondrial encoded genes initiated by the activation of second-messenger signaling cascades. Bottom, Conceptual schematic of NeuroSERM design and therapeutic use. Consistent with the healthy cell bias of estrogen benefit hypothesis, NeuroSERM or PhytoSERM molecules would be administered before neurodegenerative insult while neurons are still healthy. NeuroSERM exposure would lead to enhanced neural survival mechanisms, represented as mitochondria with Bcl-2 additions, that promote neural defense against neurodegenerative insults associated with age-associated diseases such as Alzheimer's and Parkinson's. Designer NeuroSERM molecules target the membrane site of estrogen action, whereas PhytoSERM molecules preferentially target estrogen receptor β. AMPAR, AMPA receptor; C, cytochrome oxidase; F0, F1, ATPase subunits; LTD, long-term depression; LTP, long-term potentiation; NAD, nicotinamide adenine dinucleotide; NADH, nicotinamide adenine dinucleotide; VDCC, voltage-dependent calcium channel.
See this image and copyright information in PMC

References

    1. Adams MM, Shah RA, Janssen WG, Morrison JH. Different modes of hippocampal plasticity in response to estrogen in young and aged female rats. Proc Natl Acad Sci USA. 2001a;98:8071–8076. - PMC - PubMed
    1. Adams MM, Oung T, Morrison JH, Gore AC. Length of postovariectomy interval and age, but not estrogen replacement, regulate N-methyl-d-aspartate receptor mRNA levels in the hippocampus of female rats. Exp Neurol. 2001b;170:345–356. - PubMed
    1. Adams MM, Fink SE, Shah RA, Janssen WG, Hayashi S, Milner TA, McEwen BS, Morrison JH. Estrogen and aging affect the subcellular distribution of estrogen receptor-alpha in the hippocampus of female rats. J Neurosci. 2002;22:3608–3614. - PMC - PubMed
    1. Adams MM, Fink SE, Janssen WG, Shah RA, Morrison JH. Estrogen modulates synaptic N-methyl-d-aspartate receptor subunit distribution in the aged hippocampus. J Comp Neurol. 2004;474:419–426. - PubMed
    1. Akama KT, McEwen BS. Estrogen stimulates postsynaptic density-95 rapid protein synthesis via the Akt/protein kinase B pathway. J Neurosci. 2003;23:2333–2339. - PMC - PubMed

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