Lydia L. DonCarlos

Neuroprotection by estradiol

This review highlights recent evidence from clinical and basic science studies supporting a role for estrogen in neuroprotection. Accumulated clinical evidence suggests that estrogen exposure decreases the risk and delays the onset and progression of Alzheimers disease and schizophrenia, and may also enhance recovery from traumatic neurological injury such as stroke. Recent basic science studies show that not only does exogenous estradiol decrease the response to various forms of insult, but the brain itself upregulates both estrogen synthesis and estrogen receptor expression at sites of injury. Thus, our view of the role of estrogen in neural function must be broadened to include not only its function in neuroendocrine regulation and reproductive behaviors, but also to include a direct protective role in response to degenerative disease or injury. Estrogen may play this protective role through several routes. Key among these are estrogen dependent alterations in cell survival, axonal sprouting, regenerative responses, enhanced synaptic transmission and enhanced neurogenesis. Some of the mechanisms underlying these effects are independent of the classically defined nuclear estrogen receptors and involve unidentified membrane receptors, direct modulation of neurotransmitter receptor function, or the known anti-oxidant activities of estrogen. Other neuroprotective effects of estrogen do depend on the classical nuclear estrogen receptor, through which estrogen alters expression of estrogen responsive genes that play a role in apoptosis, axonal regeneration, or general trophic support. Yet another possibility is that estrogen receptors in the membrane or cytoplasm alter phosphorylation cascades through direct interactions with protein kinases or that estrogen receptor signaling may converge with signaling by other trophic molecules to confer resistance to injury. Although there is clear evidence that estradiol exposure can be deleterious to some neuronal populations, the potential clinical benefits of estrogen treatment for enhancing cognitive function may outweigh the associated central and peripheral risks. Exciting and important avenues for future investigation into the protective effects of estrogen include the optimal ligand and doses that can be used clinically to confer benefit without undue risk, modulation of neurotrophin and neurotrophin receptor expression, interaction of estrogen with regulated cofactors and coactivators that couple estrogen receptors to basal transcriptional machinery, interactions of estrogen with other survival and regeneration promoting factors, potential estrogenic effects on neuronal replenishment, and modulation of phenotypic choices by neural stem cells.

National Sleep Foundation’s sleep time duration recommendations: methodology and results summary

OBJECTIVE The objective was to conduct a scientifically rigorous update to the National Sleep Foundations sleep duration recommendations. METHODS The National Sleep Foundation convened an 18-member multidisciplinary expert panel, representing 12 stakeholder organizations, to evaluate scientific literature concerning sleep duration recommendations. We determined expert recommendations for sufficient sleep durations across the lifespan using the RAND/UCLA Appropriateness Method. RESULTS The panel agreed that, for healthy individuals with normal sleep, the appropriate sleep duration for newborns is between 14 and 17 hours, infants between 12 and 15 hours, toddlers between 11 and 14 hours, preschoolers between 10 and 13 hours, and school-aged children between 9 and 11 hours. For teenagers, 8 to 10 hours was considered appropriate, 7 to 9 hours for young adults and adults, and 7 to 8 hours of sleep for older adults. CONCLUSIONS Sufficient sleep duration requirements vary across the lifespan and from person to person. The recommendations reported here represent guidelines for healthy individuals and those not suffering from a sleep disorder. Sleep durations outside the recommended range may be appropriate, but deviating far from the normal range is rare. Individuals who habitually sleep outside the normal range may be exhibiting signs or symptoms of serious health problems or, if done volitionally, may be compromising their health and well-being.

Pubertal hormones modulate the addition of new cells to sexually dimorphic brain regions.

New cells, including neurons, arise in several brain regions during puberty in rats. Sex differences in pubertal addition of cells coincide with adult sexual dimorphisms: for each region, the sex that gains more cells during puberty has a larger volume in adulthood. Removing gonadal hormones before puberty eliminates these sex differences, indicating that gonadal steroids direct the addition of new cells during puberty to maintain and accentuate sexual dimorphisms in the adult brain.

Glial expression of estrogen and androgen receptors after rat brain injury

Estrogens and androgens can protect neurons from death caused by injury to the central nervous system. Astrocytes and microglia are major players in events triggered by neural lesions. To determine whether glia are direct targets of estrogens or androgens after neural insults, steroid receptor expression in glial cells was assessed in two different lesion models. An excitotoxic injury to the hippocampus or a stab wound to the parietal cortex and hippocampus was performed in male rats, and the resultant expression of steroid receptors in glial cells was assessed using double‐label immunohistochemistry. Both lesions induced the expression of estrogen receptors (ERs) and androgen receptors (ARs) in glial cells. ERα was expressed in astrocytes immunoreactive (ERα‐ir) for glial fibrillary acidic protein or vimentin. AR immunoreactivity colocalized with microglial markers, such as Griffonia simplicifolia lectin‐1 or OX‐6. The time course of ER and AR expression in glia was studied in the stab wound model. ERα‐ir astrocytes and AR‐ir microglia were observed 3 days after lesion. The number of ERα‐ir and AR‐ir glial cells reached a maximum 7 days after lesion and returned to low levels by 28 days postinjury. The studies of ERβ expression in glia were inconclusive; different results were obtained with different antibodies. In sum, these results suggest that reactive astrocytes and reactive microglia are a direct target for estrogens and androgens, respectively. J. Comp. Neurol. 450:256–271, 2002.

National Sleep Foundation's updated sleep duration recommendations: final report ☆

OBJECTIVE To make scientifically sound and practical recommendations for daily sleep duration across the life span. METHODS The National Sleep Foundation convened a multidisciplinary expert panel (Panel) with broad representation from leading stakeholder organizations. The Panel evaluated the latest scientific evidence and participated in a formal consensus and voting process. Then, the RAND/UCLA Appropriateness Method was used to formulate sleep duration recommendations. RESULTS The Panel made sleep duration recommendations for 9 age groups. Sleep duration ranges, expressed as hours of sleep per day, were designated as recommended, may be appropriate, or not recommended. Recommended sleep durations are as follows: 14-17 hours for newborns, 12-15 hours for infants, 11-14 hours for toddlers, 10-13 hours for preschoolers, 9-11 hours for school-aged children, and 8-10 hours for teenagers. Seven to 9 hours is recommended for young adults and adults, and 7-8 hours of sleep is recommended for older adults. The self-designated basis for duration selection and critical discussions are also provided. CONCLUSIONS Consensus for sleep duration recommendations was reached for specific age groupings. Consensus using a multidisciplinary expert Panel lends robust credibility to the results. Finally, limitations and caveats of these recommendations are discussed.

Interactions of estrogens and insulin-like growth factor-I in the brain: implications for neuroprotection

Data from epidemiological studies suggest that the decline in estrogen following menopause could increase the risk of neurodegenerative diseases. Furthermore, experimental studies on different animal models have shown that estrogen is neuroprotective. The mechanisms involved in the neuroprotective effects of estrogen are still unclear. Anti-oxidant effects, activation of different membrane-associated intracellular signaling pathways, and activation of classical nuclear estrogen receptors (ERs) could contribute to neuroprotection. Interactions with neurotrophins and other growth factors may also be important for the neuroprotective effects of estradiol. In this review we focus on the interaction between insulin-like growth factor-I (IGF-I) and estrogen signaling in the brain and on the implications of this interaction for neuroprotection. During the development of the nervous system, IGF-I promotes the differentiation and survival of specific neuronal populations. In the adult brain, IGF-I is a neuromodulator, regulates synaptic plasticity, is involved in the response of neural tissue to injury and protects neurons against different neurodegenerative stimuli. As an endocrine signal, IGF-I represents a link between the growth and reproductive axes and the interaction between estradiol and IGF-I is of particular physiological relevance for the regulation of growth, sexual maturation and adult neuroendocrine function. There are several potential points of convergence between estradiol and IGF-I receptor (IGF-IR) signaling in the brain. Estrogen activates the mitogen-activated protein kinase (MAPK) pathway and has a synergistic effect with IGF-I on the activation of Akt, a kinase downstream of phosphoinositol-3 kinase. In addition, IGF-IR is necessary for the estradiol induced expression of the anti-apoptotic molecule Bcl-2 in hypothalamic neurons. The interaction of ERs and IGF-IR in the brain may depend on interactions between neural cells expressing ERs with neural cells expressing IGF-IR, or on direct interactions of the signaling pathways of alpha and beta ERs and IGF-IR in the same cell, since most neurons expressing IGF-IR also express at least one of the ER subtypes. In addition, studies on adult ovariectomized rats given intracerebroventricular (i.c.v.) infusions with antagonists for ERs or IGF-IR or with IGF-I have shown that there is a cross-regulation of the expression of ERs and IGF-IR in the brain. The interaction of estradiol and IGF-I and their receptors may be involved in different neural events. In the developing brain, ERs and IGF-IR are interdependent in the promotion of neuronal differentiation. In the adult, ERs and IGF-IR interact in the induction of synaptic plasticity. Furthermore, both in vitro and in vivo studies have shown that there is an interaction between ERs and IGF-IR in the promotion of neuronal survival and in the response of neural tissue to injury, suggesting that a parallel activation or co-activation of ERs and IGF-IR mediates neuroprotection.

Insulin-like growth factor I receptors and estrogen receptors colocalize in female rat brain

Several findings indicate that there is a close interaction between estrogen and insulin-like growth factor I in different brain regions. In adult brain, both estrogen and insulin-like growth factor I have co-ordinated effects in the regulation of neuroendocrine events, synaptic plasticity and neural response to injury. In this study we have qualitatively assessed whether estrogen receptors and insulin-like growth factor I receptor are colocalized in the same cells in the preoptic area, hypothalamus, hippocampus, cerebral cortex and cerebellum of female rat brain using confocal microscopy. Immunoreactivity for estrogen receptors alpha and beta was colocalized with immunoreactivity for insulin-like growth factor I receptor in many neurons from the preoptic area, hypothalamus, hippocampus and cerebral cortex. Furthermore, estrogen receptor beta and insulin-like growth factor I receptor immunoreactivities were colocalized in the Purkinje cells of the cerebellum. Colocalization of estrogen receptor beta and insulin-like growth factor I receptor was also detected in cells with the morphology of astrocytes in all regions assessed. The co-expression of estrogen receptors and insulin-like growth factor I receptor in the same neurons may allow a cross-coupling of their signaling pathways. Furthermore, the colocalization of immunoreactivity for estrogen receptor beta and insulin-like growth factor I receptor in glial cells suggests that glia may also play a role in the interactions of insulin-like growth factor I and estrogen in the rat brain. In conclusion, the co-expression of estrogen receptors and insulin-like growth factor I receptors in the same neural cells suggests that the co-ordinated actions of estrogen and insulin-like growth factor I in the brain may be integrated at the cellular level.

Interactions of estrogen and insulin-like growth factor-I in the brain: molecular mechanisms and functional implications ☆

In the brain, as in other tissues, estradiol interacts with growth factors. One of the growth factors that is involved in the neural actions of estradiol is insulin-like growth factor-I (IGF-I). Estradiol and IGF-I cooperate in the central nervous system to regulate neuronal development, neural plasticity, neuroendocrine events and the response of neural tissue to injury. The precise molecular mechanisms involved in these interactions are still not well understood. In the central nervous system there is abundant co-expression of estrogen receptors (ERs) and IGF-I receptors (IGF-IRs) in the same cells. Furthermore, the expression of estrogen receptors and IGF-I receptors in the brain is cross-regulated. In addition, using specific antibodies for the phosphorylated forms of extracellular-signal regulated kinase (ERK) 1 and ERK2 and Akt/protein kinase B (Akt/PKB) it has been shown that estradiol affects IGF-I signaling pathways in the brain. Estradiol treatment results in a dose-dependent increase in the phosphorylation of ERK and Akt/PKB in the brain of adult ovariectomized rats. In addition, estradiol and IGF-I have a synergistic effects on the activation of Akt/PKB in the adult rat brain. These findings suggest that estrogen effects in the brain may be mediated in part by the activation of the signaling pathways of the IGF-I receptor.

DEVELOPMENTAL PROFILE OF ESTROGEN RECEPTOR MRNA IN THE PREOPTIC AREA OF MALE AND FEMALE NEONATAL RATS

Exposure to estrogen or estrogenic metabolites of testosterone during the early postnatal period has permanent effects on rodent brain development. Differential sensitivity to estrogen, as reflected by transcription of the estrogen receptor gene, might determine the period of maximal sensitivity to the masculinizing effects of estrogen. We used an 35S-labeled riboprobe and in situ hybridization to chart the development of estrogen receptor (ER) mRNA expression in the rat preoptic area, a brain region for which sexual dimorphisms and the effects of estrogen on development are particularly well documented. Neonatal male and female rats were sacrificed by perfusion fixation on postnatal days 0, 2, 4, 7 or 10 (PND; day of birth is PND 0). Many ER mRNA-containing cells were detected in the periventricular preoptic area and medical preoptic nucleus and the distribution of ER-synthesizing cells was similar in both sexes. Analysis of film autoradiograms showed that the relative steady state level of ER mRNA was significantly higher in females than in males at all ages except PND 0 and 10. The temporal profile of ER mRNA expression was different in males and females. ER mRNA did not change with age in males, whereas in females, ER mRNA was significantly higher on PND 2 compared with PND 0 and 10. These results demonstrate that the pattern of ER mRNA expression is quantitatively and qualitatively different between the sexes during the neonatal period. The pattern of ER mRNA expression contrasts markedly with previous reports of estrogen binding based on biochemical and autoradiographic steroid binding assays.(ABSTRACT TRUNCATED AT 250 WORDS)

Estrogen desensitizes 5-HT1A receptors and reduces levels of Gz, Gi1 and Gi3 proteins in the hypothalamus

The present study investigated whether estrogen would desensitize hypothalamic serotonin(1A) (5-HT(1A)) receptors by examining the neuroendocrine response to 8-OH-DPAT, a 5-HT(1A) agonist. Rats were ovariectomized, allowed to recover for 5 days, then given 2 daily injections of estradiol benzoate or vehicle (10 microg/day, s.c.). Twenty-four hours after the second injection, rats were challenged with a sub-maximal dose of 8-OH-DPAT (50 microg/kg, sc) or saline 15 min prior to sacrifice. 8-OH-DPAT produced a significant increase in plasma oxytocin, ACTH and corticosterone levels in ovariectomized rats. While estrogen treatment for 2 days did not alter basal hormone levels, it did significantly reduce the magnitude of oxytocin, ACTH and corticosterone responses to 8-OH-DPAT. The reduction in hormone responses was accompanied by a significant reduction in hypothalamic levels of G(z), G(i1) and G(i3) proteins (by 50%, 30% and 50%, respectively). These findings suggest that a reduction in these G proteins may contribute to the mechanisms underlying estrogen-induced desensitization of 5-HT(1A) receptors. The desensitization of 5-HT(1A) receptors has been suggested to underlie the therapeutic effects of antidepressant 5-HT uptake inhibitors (SSRIs). Thus, the present results suggest that estrogen or estrogen-like substances in combination with SSRIs may prove effective in developing novel therapeutic strategies for neuropsychiatric disorders in women.