Uncovering the mechanisms of estrogen effects on hippocampal function

Spencer, Joanna L.; Waters, Elizabeth M.; Romeo, Russell D.; Wood, Gwendolyn E.; Milner, Teresa A.; McEwen, Bruce S.

doi:10.1016/j.yfrne.2007.08.006

Cited by 352 publications

(310 citation statements)

References 178 publications

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“…Estrogen is known to affect cell proliferation as well as cell survival in the hippocampus in adult female animals (Galea et al, 2006;Pawluski et al, 2009). Hippocampal estrogen receptors have been proposed as one pathway of estrogen effects on neural plasticity (Spencer et al, 2008). These receptors are also present in the human hippocampi (Österlund and Hurd, 2001;Tohgi et al, 1995).…”

Section: Discussionmentioning

confidence: 99%

Hippocampal volume and functional connectivity changes during the female menstrual cycle

et al. 2015

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Hippocampal volume has been shown to be sensitive to variations in estrogen and progesterone levels across rodents' estrous cycle. However, little is known about the covariation of hormone levels and brain structure in the course of the human menstrual cycle. Here, we examine this covariation with a multi-method approach that includes several brain imaging methods and hormonal assessments. We acquired structural and functional scans from 21 naturally cycling women on four time points during their cycles (early follicular phase, late follicular phase, ovulation and luteal phase). Hormone blood concentrations and cognitive performance in different domains were assessed on each of the measurement occasions. Structural MRI images were processed by means of whole-brain voxel-based morphometry and FreeSurfer. With either method, bilateral increases in hippocampal volume were found in the late follicular phase relative to the early follicular phase. The gray matter probability in regions of hippocampal volume increase was associated with lower mean diffusivity in the same region. In addition, we observed higher functional connectivity between the hippocampi and the bilateral superior parietal lobe in the late follicular phase. We did not find any reliable cycle-related performance variations on the cognitive tasks. The present results show that hormonal fluctuations covary with hippocampal structure and function in the course of the human menstrual cycle.

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Section: Discussionmentioning

confidence: 99%

Hippocampal volume and functional connectivity changes during the female menstrual cycle

et al. 2015

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“…Estrogen receptors a and b are expressed in the medial prefrontal cortex, amygdala, and hippocampus (Shughrue et al 1997;Ostlund et al 2003), structures that mediate extinction learning and consolidation . E 2 stimulates intracellular signaling cascades, growth factor induction, synaptogenesis, and protein synthesis (Spencer et al 2008;Frick 2012). Importantly, there is a synergistic overlap between the effects of E 2 and synaptic plasticity associated with extinction learning.…”

Section: Discussionmentioning

confidence: 99%

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

et al. 2013

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Human and preclinical models of addiction demonstrate that gonadal hormones modulate acquisition of drug seeking. Little is known, however, about the effects of these hormones on extinction of drug-seeking behavior. Here, we investigated how 17b-estradiol (E 2 ) affects expression and extinction of cocaine seeking in female rats. Using a conditioned place preference (CPP) paradigm, ovariectomized rats were maintained throughout conditioning with 2 d of E 2 treatment followed by 2 d of vehicle treatment, or were injected with E 2 daily. Hormone injections were paired or explicitly unpaired with place conditioning sessions. Expression of a cocaine CPP was of equal magnitude regardless of conditioning protocol, suggesting that E 2 levels during conditioning did not affect subsequent CPP expression. During extinction, daily E 2 administration initially enhanced expression of the cocaine CPP, but resulted in significantly faster extinction compared to controls. Whereas E 2 -treated rats were extinguished within 8 d, vehicle-treated rats maintained CPP expression for more than a month, indicative of perseveration. To determine whether E 2 could rescue extinction in these rats, half were given daily E 2 treatment and half were given vehicle. E 2 -treated rats showed rapid extinction, whereas vehicle-treated rats continued to perseverate. These data demonstrate for the first time that E 2 is necessary for extinction of cocaine seeking in female rats, and that it promotes rapid extinction when administered daily. Clinically, these findings suggest that monitoring and maintaining optimal E 2 levels during exposure therapy would facilitate therapeutic interventions for female cocaine addicts.Gonadal hormones render women more susceptible than men to developing compulsive patterns of psychostimulant use. Natural fluctuations in levels of the primary ovarian hormones, estrogens and progesterone, account for this increased abuse liability. Higher levels of estrogens, and lower levels of progesterone, are associated with greater sensitivity to the euphorigenic properties of cocaine in women (Evans 2007). This increased sensitivity may contribute to why women, compared with men, start using cocaine regularly at a younger age (Chen and Kandel 2002), transition from use to abuse more quickly (McCance-Katz et al. 1999), experience greater craving in response to drug-associated cues (Robbins et al. 1999) and stress (Potenza et al. 2012;Waldrop et al. 2012), and exhibit more severe drug-seeking behavior upon relapse (Gallop et al. 2007). In contrast, more women than men remain abstinent after treatment (Weiss et al. 1997). Thus, women are both more susceptible to cocaine abuse and, paradoxically, more responsive to treatment.A substantial literature supports that estrogens mediate the enhancement of drug seeking observed in females (Febo et al. 2002;Larson et al. 2007;Segarra et al. 2010; Kerstetter and Kippin 2011), but little is known regarding the role of estrogens during treatment. Preclinically, treatment is modeled through ext...

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“…While ERα levels AHP afterhyperpolarization, ACC anterior cingulate cortex, AP action potential, ChAT choline acetyl-transferase, CII Cognitive Impairment Index, CSST conceptual set-shifting task, dlPFC dorsolateral prefrontal cortex, DNMS delayed nonmatching-to-sample, DR delayed response, DRST delayed recognition span test, EPSC excitatory postsynaptic current, IFG inferior frontal gyrus, IPSC inhibitory postsynaptic current, PFC prefrontal cortex, R receptor, RL reversal learning, SFG superior frontal gyrus, vmPFC ventromedial prefrontal cortex Table 2 Anatomical, neuronal, synaptic, and molecular parameters in the monkey hippocampus and related cortical regions in the context of chronological and cognitive aging remain stable across age and hormone treatment groups, the abundance of ERα within the PSD correlates with DR delay performance exclusively in aged monkeys receiving cyclic estradiol (Wang et al 2010). Hence, the cognitive benefits observed in aged monkeys with estradiol may be mediated by the activation of ERα in a synaptic domain coupled to signaling cascades involved in spine/synapse formation and stabilization (Spencer et al 2008). …”

Section: Estrogenmentioning

confidence: 98%

Neuronal and morphological bases of cognitive decline in aged rhesus monkeys

Hara

Rapp

Morrison

2011

AGE

115

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Rhesus monkeys provide a valuable model for studying the basis of cognitive aging because they are vulnerable to age-related decline in executive function and memory in a manner similar to humans. Some of the behavioral tasks sensitive to the effects of aging are the delayed response working memory test, recognition memory tests including the delayed nonmatching-to-sample and the delayed recognition span task, and tests of executive function including reversal learning and conceptual set-shifting task. Much effort has been directed toward discovering the neurobiological parameters that are coupled to individual differences in age-related cognitive decline. Area 46 of the dorsolateral prefrontal cortex (dlPFC) has been extensively studied for its critical role in executive function while the hippocampus and related cortical regions have been a major target of research for memory function. Some of the key age-related changes in area 46 include decreases in volume, microcolumn strength, synapse density, and α1-and α2-adrenergic receptor binding densities. All of these measures significantly correlate with cognitive scores. Interestingly, the critical synaptic subtypes associated with cognitive function appear to be different between the dlPFC and the hippocampus. For example, the dendritic spine subtype most critical to task acquisition and vulnerable to aging in area 46 is the thin spine, whereas in the dentate gyrus, the density of AGE (2012) large mushroom spines with perforated synapses correlates with memory performance. This review summarizes age-related changes in anatomical, neuronal, and synaptic parameters within brain areas implicated in cognition and whether these changes are associated with cognitive decline.

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Uncovering the mechanisms of estrogen effects on hippocampal function

Cited by 352 publications

References 178 publications

Hippocampal volume and functional connectivity changes during the female menstrual cycle

Hippocampal volume and functional connectivity changes during the female menstrual cycle

17β-Estradiol is necessary for extinction of cocaine seeking in female rats

Neuronal and morphological bases of cognitive decline in aged rhesus monkeys

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