Sex Differences in the Rapid Cell Signaling Mechanisms Underlying the Memory-Enhancing Effects of 17β-Estradiol

Koss, Wendy A.; Haertel, Jacqueline M.; Philippi, Sarah M.; Frick, Karyn M.

doi:10.1523/eneuro.0267-18.2018

Cited by 59 publications

(71 citation statements)

References 69 publications

(164 reference statements)

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“…In the hippocampus of females, 17β-estradiol (E2) is thought to mediate object recognition memory via phosphorylation of the cell signaling kinase extracellular signal-related kinase (ERK) (Fan et al 2010;Fernandez et al 2008;Kuroki et al 2000;Pereira et al 2014). In the hippocampus of males, E2 does not increase ERK phosphorylation and increases in phosphorylated ERK in the hippocampus are not necessary for memory enhancements following E2 treatment (Koss et al 2018). While there is a body of literature examining the role of estrogen in the hippocampus on object memory, the role of sex hormones in the perirhinal cortex is not as well defined.…”

Section: Discussionmentioning

confidence: 99%

Paternal morphine self-administration produces object recognition memory deficits in female, but not male offspring

et al. 2020

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Rationale: Parental drug use around or before conception can have adverse consequences for offspring. Historically, this research has focused on the effects of maternal substance use on future generations but less is known about the influence of the paternal lineage. This study focused on the impact of chronic paternal morphine exposure prior to conception on behavioral outcomes in male and female progeny. Objectives: This study sought to investigate the impact of paternal morphine self-administration on anxiety-like behavior, the stress response, and memory in male and female offspring. Methods: Adult, drug-naïve male and female progeny of morphine-treated sires and controls were evaluated for anxiety-like behavior using defensive probe burying and novelty-induced hypophagia paradigms. Hypothalamic-pituitary-adrenal (HPA) axis function was assessed by measuring plasma corticosterone levels following a restraint stressor in male and female progeny. Memory was probed using a battery of tests including object location memory, novel object recognition and contextual fear conditioning. Results: Paternal morphine exposure did not alter anxiety-like behavior or stress-induced HPA axis activation in male or female offspring. Morphine-sired male and female offspring showed intact hippocampus-dependent memory: they performed normally on the long-term fear conditioning and object location memory tests. In contrast, paternal morphine exposure selectively disrupted novel object recognition in female, but not male progeny. Conclusions: Our findings demonstrate that paternal morphine taking produces sex-specific and selective impairments in object recognition memory while leaving hippocampal function largely intact.

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Section: Discussionmentioning

confidence: 99%

Paternal morphine self-administration produces object recognition memory deficits in female, but not male offspring

et al. 2020

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“…Sex differences in the distribution of ERs (Bourque et al, 2011), together with a different role of ER subtypes in brain plasticity, neuroprotection and repair in male and female neurons (Bryant and Dorsa, 2010; may participate in the generation of sex differences in the neuroprotective actions of estradiol. In addition, there are differences in ER signaling in the brain of males and females (Tabatadze et al, 2015;Oberlander and Woolley, 2016;Koss et al, 2018;Jain et al, 2019;Meitzen et al, 2019;Zafer et al, 2019), which are in part mediated by epigenetic modifications in ER encoding genes (Schwarz et al, 2010;Giatti et al, 2018) and micro RNAs (Giatti et al, 2018) and are also dependent on sexually differentiated interactions with the signaling mechanisms of other neuroprotective factors, such as BDNF (Scharfman and MacLusky, 2014), IGF-1 (Munive et al, 2016) or the endocannabinoid system (Tabatadze et al, 2015), which in turn also present sex differences in the brain. All these sexually differentiated molecular mechanisms cause different responses to estradiol in the brain of male and female animals (Tabatadze et al, 2015;Munive et al, 2016;Koss et al, 2018) and may determine sex differences in the neuroprotective actions of the hormone.…”

Section: Participation Of Estrogen Signaling In the Generation Of Sexmentioning

confidence: 99%

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Azcoitia

Barreto

García‐Segura

2019

Frontiers in Neuroendocrinology

100

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Estradiol, either from peripheral or central origin, activates multiple molecular neuroprotective and neuroreparative responses that, being mediated by estrogen receptors or by estrogen receptor independent mechanisms, are initiated at the membrane, the cytoplasm or the cell nucleus of neural cells. Estrogen-dependent signaling regulates a variety of cellular events, such as intracellular Ca 2+ levels, mitochondrial respiratory capacity, ATP production, mitochondrial membrane potential, autophagy and apoptosis. In turn, these molecular and cellular actions of estradiol are integrated by neurons and non-neuronal cells to generate different tissue protective responses, decreasing blood-brain barrier permeability, oxidative stress, neuroinflammation and excitotoxicity and promoting synaptic plasticity, axonal growth, neurogenesis, remyelination and neuroregeneration. Recent findings indicate that the neuroprotective and neuroreparative actions of estradiol are different in males and females and further research is necessary to fully elucidate the causes for this sex difference.

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“…Several studies have reported that differences between male and female rats in evoked AMPAR/NMDAR signaling in hippocampal synapses, along with differences in the magnitude of evoked LTP, may underlie sex differences in spatial memory (Monfort et al, 2015;Qi et al, 2016). Estrous has been shown to modulate diffusion of AMPARs to the surface in female mice (Palomero-Gallagher et al, 2003;Tada et al, 2015;Bechard et al, 2018), which may underlie part of the reported importance of estrogenic mechanisms for memory in females (Cordeira et al, 2018;Frick et al, 2018;Koss et al, 2018;Wang et al, 2018;Koebele et al, 2019). However, the sex-specific role of AMPARs in memory may also be specific to the type of memory task being tested, as a study by Dachtler et al concluded that the GluA1 subunit was necessary only for male, not female, mice in fear conditioning memory, but that hippocampal GluA1 was necessary for spatial learning in both sexes (Dachtler et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Cornichon Homolog-3 (CNIH3) Modulates Spatial Memory in Female Mice

Frye

Williams

Trousdale

et al. 2019

Preprint

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Cornichon homolog-3 (CNIH3) is an AMPA receptor (AMPAR) auxiliary protein that traffics AMPARs to the postsynaptic membrane and potentiates AMPAR signaling. AMPARs are key components of hippocampal synaptic plasticity and memory formation, however the role of CNIH3 in memory has yet to be elucidated. To study the role of CNIH3 on mouse behavior, we bred and characterized a line of Cnih3 -/mice from C57BL/6 Cnih3 tm1a(KOMP)Wtsi mice obtained from the Knockout Mouse Project (KOMP). In agreement with previous studies of CNIH3 in the brain, we observed concentrated expression of Cnih3 in the dorsal hippocampus, a region associated with spatial learning and memory. Therefore, we tested Cnih3 +/+ , Cnih3 +/-, and Cnih3 -/mice in the Barnes maze paradigm to measure spatial memory. We observed no change in spatial memory in male Cnih3 +/and Cnih3 -/mice compared to male Cnih3 +/+ controls, however, Cnih3 -/female mice made significantly more primary errors, had a higher primary latency, and took less efficient routes to the target in the maze compared to Cnih3 +/+ female mice. Next, to investigate an enhancement of spatial memory by Cnih3 overexpression, specifically in the dorsal hippocampus, we developed an AAV5 viral construct to express wild-type Cnih3 in excitatory neurons. Female mice overexpressing Cnih3 made significantly fewer errors, had a lower primary latency to the target, and took more efficient routes to the maze target compared to YFP expressing control females. No change in spatial memory was observed in male Cnih3 overexpression mice. This study, the first to identify sex-specific effects of the AMPAR auxiliary protein CNIH3 on spatial memory, provides the groundwork for future studies investigating the role of CNIH3 on sexually dimorphic AMPAR-dependent behavior and hippocampal synaptic plasticity.

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Sex Differences in the Rapid Cell Signaling Mechanisms Underlying the Memory-Enhancing Effects of 17β-Estradiol

Abstract: Visual Abstract

Cited by 59 publications

References 69 publications

Paternal morphine self-administration produces object recognition memory deficits in female, but not male offspring

Paternal morphine self-administration produces object recognition memory deficits in female, but not male offspring

Molecular mechanisms and cellular events involved in the neuroprotective actions of estradiol. Analysis of sex differences

Cornichon Homolog-3 (CNIH3) Modulates Spatial Memory in Female Mice

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