Hao, J. et al. Estrogen alters spine number and morphology in prefrontal cortex of aged female rhesus monkeys. J. Neurosci. 26, 2571-2578

University of Toronto, Toronto, Ontario, Canada
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 04/2006; 26(9):2571-8. DOI: 10.1523/JNEUROSCI.3440-05.2006
Source: PubMed


Long-term cyclic treatment with 17beta-estradiol reverses age-related impairment in ovariectomized rhesus monkeys on a test of cognitive function mediated by the prefrontal cortex (PFC). Here, we examined potential neurobiological substrates of this effect using intracellular loading and morphometric analyses to test the possibility that the cognitive benefits of hormone treatment are associated with structural plasticity in layer III pyramidal cells in PFC area 46. 17beta-Estradiol did not affect several parameters such as total dendritic length and branching. In contrast, 17beta-estradiol administration increased apical and basal dendritic spine density, and induced a shift toward smaller spines, a response linked to increased spine motility, NMDA receptor-mediated activity, and learning. These results document that, although the aged primate PFC is vulnerable in the absence of factors such as circulating estrogens, it remains responsive to long-term cyclic 17beta-estradiol treatment, and that increased dendritic spine density and altered spine morphology may contribute to the cognitive benefits of such treatment.

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    • "For example, glucocorticoids can inhibit reproductive function (Nikolarakis et al., 1986; Wingfield and Sapolsky, 2003) and, reciprocally, HPG axis hormones can act at the level of the hypothalamus to control the release of adrenal stress hormones (Weiser and Handa, 2009). Preclinical evidence suggests that 17β- estradiol also acts 'upstream' of the hypothalamus to regulate the structure and function of a distributed set of brain regions within stress neural circuitry (Nabekura et al., 1986; Wooley, 1998; Hao et al., 2006; Walf and Frye, 2006; Weiser and Handa, 2009). "
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    ABSTRACT: Many regions within stress circuitry, including the anterior hypothalamus, amygdala, hippocampus and medial prefrontal cortex, are densely populated with sex steroid receptors. Substantial evidence from animal studies indicates that the gonadal hormone 17β- estradiol impacts the structure and function of these regions, but human studies are limited. Characterizing estradiol’s role in stress circuitry in vivo in humans may have important clinical implications given the comorbidity between major depressive disorder (MDD), stress circuitry dysfunction and endocrine dysregulation. In this study, we determined estradiol’s role in modulating activity within cortical and subcortical stress circuitry regions in healthy and MDD women. Subjects were part of a neuroimaging follow-up study of a population-based birth cohort, the New England Family Study. Capitalizing on the endogenous fluctuation in 17β-estradiol (E2) during the menstrual cycle, we conducted a within-person repeated-measures functional neuroimaging study in which 15 women with recurrent MDD, in remission, and 15 healthy control women underwent hormonal evaluations, behavioral testing and fMRI scanning on two occasions, under low and high E2 conditions. Subjects completed an fMRI scan while undergoing a mild visual stress challenge that reliably activated stress neural circuitry. Results demonstrate that E2 modulates activity aross key stress circuitry regions, including bilateral amygdala, hippocampus and hypothalamus. In healthy women, robust task-evoked BOLD signal changes observed under low E2 conditions were attenuated under high E2 conditions. This hormonal capacity to regulate activity in stress circuitry was not observed in MDD women, despite their remitted status, suggesting that dysregulation of gonadal hormone function may be a characteristic trait of the disease. These findings serve to deepen our understanding of estradiol’s actions in the healthy brain and the neurobiological mechanisms that may underlie the pronounced sex difference in MDD risk.
    Full-text · Article · Aug 2014 · Neuropsychopharmacology
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    • "increase in the group of 50 mg/kg·BW/day in comparison with the controls, but estradiol levels of 0.05, 0.5, 5 and 50 mg/kg·BW/day were significantly decreased when comparing with the control group. In addition, estrogen can increase dendritic spine density on hippocampus CA1 (Schwarz et al., 2008), and alter spine number and morphology (Hao et al., 2006). Thus, there may be a correlation between structural modification of synapses and decreased estradiol levels with maternal exposure to BPA. "
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    ABSTRACT: Bisphenol A (BPA), a component of polycarbonate and epoxy resins, has been reported to adversely impact the central nervous system, especially with respect to learning and memory. However, the precise effect and specific mechanisms have not been fully elucidated. In the present study, pregnant Sprague-Dawley rats were orally administered with BPA at 0.05, 0.5, 5 or 50mg/kg·body weight (BW) per day from embryonic day 9 (E 9) to E 20. We examined the effects of maternal BPA exposure on memory and synaptic structure in the hippocampus of male offspring at postnatal day (PND) 21. Maternal BPA exposure significantly affected locomotor activity, exploratory habits, and emotional behavior in open field test, and increased reference and especially working memory errors in the radial arm maze during the postnatal developing stage. Maternal BPA exposure had an adverse effect on synaptic structure, including a widened synaptic cleft, a thinned postsynaptic density (PSD), unclear synaptic surface and disappeared synaptic vesicles. Furthermore, maternal BPA exposure decreased the mRNA and protein expressions of synaptophysin, PSD-95, spinophilin, GluR1 and NMDAR1 in the hippocampus of male offspring on PND 21. These results showed that fetal growth and development was more sensitive to BPA exposure. The decreased learning and memory induced by maternal exposure to BPA in this study may be involved in synaptic plasticity alteration.
    Full-text · Article · May 2014 · Toxicology
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    • "Memory impairments correlating with the loss of synapses and spines occur during neurodegenerative diseases and aging (Hao et al., 2006; Dumitriu et al., 2010; Penzes et al., 2011). In Tg2576 mice, a decrease in spine density in basal dendrites of CA1 pyramidal neurons takes place as early as 4.5 months of age (Lanz et al., 2003). "
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    ABSTRACT: PI3K activation promotes the formation of synaptic contacts and dendritic spines, morphological features of glutamatergic synapses that are commonly known to be related to learning processes. In this report, we show that in vivo administration of a peptide that activates the PI3K signaling pathway increases spine density in the rat hippocampus and enhances the animals' cognitive abilities, while in vivo electrophysiological recordings show that PI3K activation results in synaptic enhancement of Schaffer and stratum lacunosum moleculare inputs. Morphological characterization of the spines reveals that subjecting the animals to contextual fear-conditioning training per se promotes the formation of large spines, while PI3K activation reverts this effect and favors a general change toward small head areas. Studies using hippocampal neuronal cultures show that the PI3K spinogenic process is NMDA-dependent and activity-independent. In culture, PI3K activation was followed by mRNA upregulation of glutamate receptor subunits and of the immediate-early gene Arc. Time-lapse studies confirmed the ability of PI3K to induce the formation of small spines. Finally, we demonstrate that the spinogenic effect of PI3K can be induced in the presence of neurodegeneration, such as in the Tg2576 Alzheimer's mouse model. These findings highlight that the PI3K pathway is an important regulator of neuronal connectivity and stress the relationship between spine size and learning processes.
    Full-text · Article · Jan 2014 · Frontiers in Molecular Neuroscience
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