Publications by authors named "Karyn M Frick"

71 Publications

Long-term oral administration of a novel estrogen receptor beta agonist enhances memory and alleviates drug-induced vasodilation in young ovariectomized mice.

Horm Behav 2021 Apr 8;130:104948. Epub 2021 Mar 8.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States of America. Electronic address:

Development of estrogen therapies targeting the β (ERβ) but not α (ERα) estrogen receptor is critically needed for the treatment of negative menopausal symptoms, as ERα activation increases health risks like cancer. Here, we determined the effects of long-term oral treatment with EGX358, a novel highly selective ERβ agonist, on memory, vasodilation, and affect in young ovariectomized mice. Mice were orally gavaged daily for 9 weeks with vehicle, 17β-estradiol (E), the ERβ agonist diarylpropionitrile (DPN), or EGX358 at doses that enhance memory when delivered acutely. Tail skin temperature was recorded as a proxy for vasodilation following injection of vehicle or senktide, a tachykinin receptor 3 agonist used to model hot flashes. Anxiety-like behavior was assessed in the open field (OF) and elevated plus maze (EPM), and depression-like behavior was measured in the tail suspension (TST) and forced swim tests (FST). Finally, memory was assessed in object recognition (OR) and object placement (OP) tasks. E, DPN, and EGX358 reduced senktide-mediated increases in tail skin temperature compared to vehicle. All three treatments also enhanced memory in the OR and OP tasks, whereas vehicle did not. Although E increased time spent in the center of the OF, no other treatment effects were observed in the OF, EPM, TST, or FST. These data suggest that long-term ERβ activation can reduce hot flash-like symptoms and enhance spatial and object recognition memories in ovariectomized mice. Thus, the highly selective ERβ agonist EGX358 may be a promising avenue for reducing menopause-related hot flashes and memory dysfunction.
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http://dx.doi.org/10.1016/j.yhbeh.2021.104948DOI Listing
April 2021

17β-estradiol activation of dorsal hippocampal TrkB is independent of increased mature BDNF expression and is required for enhanced memory consolidation in female mice.

Psychoneuroendocrinology 2021 Mar 15;125:105110. Epub 2020 Dec 15.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211 USA. Electronic address:

The potent estrogen 17β-estradiol (E) is known to enhance hippocampal memory and plasticity, however the molecular mechanisms underlying these effects remain unclear. Brain derived neurotrophic factor (BDNF) and its receptor tropomyosin receptor kinase B (TrkB) are regulated by E, but the potential mechanistic roles of neurotrophic signaling in E-induced enhancement of memory are not well understood. Here, we examined the effects of hippocampal TrkB signaling on E-induced enhancement of memory consolidation in the object placement and recognition tasks. Bilateral infusion of the TrkB antagonist ANA-12 into the dorsal hippocampus of ovariectomized female mice blocked E-induced enhancement of memory consolidation, supporting a role for TrkB-mediated signaling in estrogenic regulation of memory. Although dorsal hippocampal E infusion increased levels of phospho-TrkB and mature BDNF (mBDNF) in the dorsal hippocampus within 4-6 h, E-induced increases in hippocampal mBDNF expression were not required for hippocampal TrkB activation and were not inhibited by TrkB antagonism. Thus, E regulates TrkB signaling to facilitate memory consolidation in a manner independent of mBDNF expression. Together these results provide the first direct evidence that E modulation of hippocampal TrkB signaling is required for its beneficial effects on memory consolidation and provide additional characterization of the ways in which TrkB/BDNF signaling is regulated by E in the hippocampus.
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http://dx.doi.org/10.1016/j.psyneuen.2020.105110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7904635PMC
March 2021

Oestradiol as a neuromodulator of learning and memory.

Nat Rev Neurosci 2020 10 2;21(10):535-550. Epub 2020 Sep 2.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.

Although hormones such as glucocorticoids have been broadly accepted in recent decades as general neuromodulators of memory processes, sex steroid hormones such as the potent oestrogen 17β-oestradiol have been less well recognized by the scientific community in this capacity. The predominance of females in studies of oestradiol and memory and the general (but erroneous) perception that oestrogens are 'female' hormones have probably prevented oestradiol from being more widely considered as a key memory modulator in both sexes. Indeed, although considerable evidence supports a crucial role for oestradiol in regulating learning and memory in females, a growing body of literature indicates a similar role in males. This Review discusses the mechanisms of oestradiol signalling and provides an overview of the effects of oestradiol on spatial, object recognition, social and fear memories. Although the primary focus is on data collected in females, effects of oestradiol on memory in males will be discussed, as will sex differences in the molecular mechanisms that regulate oestrogenic modulation of memory, which may have important implications for the development of future cognitive therapeutics.
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http://dx.doi.org/10.1038/s41583-020-0362-7DOI Listing
October 2020

It takes a neural village: Circuit-based approaches for estrogenic regulation of episodic memory.

Front Neuroendocrinol 2020 10 8;59:100860. Epub 2020 Aug 8.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States. Electronic address:

Cognitive behaviors, such as episodic memory formation, are complex processes involving coordinated activity in multiple brain regions. However, much of the research on hormonal regulation of cognition focuses on manipulation of one region at a time or provides a single snapshot of how a systemic treatment affects multiple brain regions without investigating how these regions might interact to mediate hormone effects. Here, we use estrogenic regulation of episodic memory as an example of how circuit-based approaches may be incorporated into future studies of hormones and cognition. We first review basic episodic memory circuitry, rapid mechanisms by which 17β-estradiol can alter circuit activity, and current knowledge about 17β-estradiol's effects on episodic memory. Next, we outline approaches that researchers can employ to consider circuit effects in their estrogen research and provide examples of how these methods have been used to examine hormonal regulation of memory and other behaviors.
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http://dx.doi.org/10.1016/j.yfrne.2020.100860DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7669700PMC
October 2020

Dorsal Hippocampal Actin Polymerization Is Necessary for Activation of G-Protein-Coupled Estrogen Receptor (GPER) to Increase CA1 Dendritic Spine Density and Enhance Memory Consolidation.

J Neurosci 2019 11 18;39(48):9598-9610. Epub 2019 Oct 18.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211

Activation of the membrane estrogen receptor G-protein-coupled estrogen receptor (GPER) in ovariectomized mice via the GPER agonist G-1 mimics the beneficial effects of 17β-estradiol (E) on hippocampal CA1 spine density and memory consolidation, yet the cell-signaling mechanisms mediating these effects remain unclear. The present study examined the role of actin polymerization and c-Jun N-terminal kinase (JNK) phosphorylation in mediating effects of dorsal hippocampally infused G-1 on CA1 dendritic spine density and consolidation of object recognition and spatial memories in ovariectomized mice. We first showed that object learning increased apical CA1 spine density in the dorsal hippocampus (DH) within 40 min. We then found that DH infusion of G-1 increased both CA1 spine density and phosphorylation of the actin polymerization regulator cofilin, suggesting that activation of GPER may increase spine morphogenesis through actin polymerization. As with memory consolidation in our previous work (Kim et al., 2016), effects of G-1 on CA1 spine density and cofilin phosphorylation depended on JNK phosphorylation in the DH. Also consistent with our previous findings, E-induced cofilin phosphorylation was not dependent on GPER activation. Finally, we found that infusion of the actin polymerization inhibitor, latrunculin A, into the DH prevented G-1 from increasing apical CA1 spine density and enhancing both object recognition and spatial memory consolidation. Collectively, these data demonstrate that GPER-mediated hippocampal spinogenesis and memory consolidation depend on JNK and cofilin signaling, supporting a critical role for actin polymerization in the GPER-induced regulation of hippocampal function in female mice. Emerging evidence suggests that G-protein-coupled estrogen receptor (GPER) activation mimics effects of 17β-estradiol on hippocampal memory consolidation. Unlike canonical estrogen receptors, GPER activation is associated with reduced cancer cell proliferation; thus, understanding the molecular mechanisms through which GPER regulates hippocampal function may provide new avenues for the development of drugs that provide the cognitive benefits of estrogens without harmful side effects. Here, we demonstrate that GPER increases CA1 dendritic spine density and hippocampal memory consolidation in a manner dependent on actin polymerization and c-Jun N-terminal kinase phosphorylation. These findings provide novel insights into the role of GPER in mediating hippocampal morphology and memory consolidation, and may suggest first steps toward new therapeutics that more safely and effectively reduce memory decline in menopausal women.
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http://dx.doi.org/10.1523/JNEUROSCI.2687-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880457PMC
November 2019

Infralimbic Estradiol Enhances Neuronal Excitability and Facilitates Extinction of Cocaine Seeking in Female Rats a BDNF/TrkB Mechanism.

Front Behav Neurosci 2019 31;13:168. Epub 2019 Jul 31.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI, United States.

Women are more susceptible to developing cocaine dependence than men, but paradoxically, are more responsive to treatment. The potent estrogen, 17β-estradiol (E), mediates these effects by augmenting cocaine seeking but also promoting extinction of cocaine seeking through E's memory-enhancing functions. Although we have previously shown that E facilitates extinction, the neuroanatomical locus of action and underlying mechanisms are unknown. Here we demonstrate that E infused directly into the infralimbic-medial prefrontal cortex (IL-mPFC), a region critical for extinction consolidation, enhances extinction of cocaine seeking in ovariectomized (OVX) female rats. Using patch-clamp electrophysiology, we show that E may facilitate extinction by potentiating intrinsic excitability of IL-mPFC neurons. Because the mnemonic effects of E are known to be regulated by brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin-related kinase B (TrkB), we examined whether BDNF/TrkB signaling was necessary for E-induced enhancement of excitability and extinction. We found that E-mediated increases in excitability of IL-mPFC neurons were abolished by Trk receptor blockade. Moreover, blockade of TrkB signaling impaired E-facilitated extinction of cocaine seeking in OVX female rats. Thus, E enhances IL-mPFC neuronal excitability in a TrkB-dependent manner to support extinction of cocaine seeking. Our findings suggest that pharmacological enhancement of E or BDNF/TrkB signaling during extinction-based therapies would improve therapeutic outcome in cocaine-addicted women.
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http://dx.doi.org/10.3389/fnbeh.2019.00168DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6684748PMC
July 2019

Dickkopf-1 blocks 17β-estradiol-enhanced object memory consolidation in ovariectomized female mice.

Horm Behav 2019 08 12;114:104545. Epub 2019 Aug 12.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States. Electronic address:

The memory-enhancing effects of 17β-estradiol (E) depend upon rapid activation of several cell-signaling cascades within the dorsal hippocampus (DH). Among the many cell-signaling pathways that mediate memory processes, Wnt/β-catenin signaling has emerged as a potential key player because of its importance to hippocampal development and synaptic plasticity. However, whether E interacts with Wnt/β-catenin signaling to promote memory consolidation is unknown. Therefore, the present study examined whether Wnt/β-catenin signaling within the DH is necessary for E-induced memory consolidation in ovariectomized mice tested in the object recognition and object placement tasks. Ovariectomized C57BL/6 mice received immediate post-training infusions of E or vehicle into the dorsal third ventricle plus the endogenous Wnt/β-catenin antagonist Dickkopf-1 (Dkk-1) or vehicle into the DH to assess whether the memory-enhancing effects of E depend on activation of Wnt/β-catenin signaling. Our results suggest that Dkk-1 blocks E-induced memory enhancement as hypothesized, but may do so by only moderately blunting Wnt/β-catenin signaling while concurrently activating Wnt/JNK signaling. The current study provides novel insights into the mechanisms through which E enhances memory consolidation in the DH, as well as critical information about the mechanistic actions of Dkk-1.
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http://dx.doi.org/10.1016/j.yhbeh.2019.06.009DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732224PMC
August 2019

Chemogenetic Suppression of Medial Prefrontal-Dorsal Hippocampal Interactions Prevents Estrogenic Enhancement of Memory Consolidation in Female Mice.

eNeuro 2019 Mar-Apr;6(2). Epub 2019 Apr 16.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211.

The importance of the dorsal hippocampus (DH) in mediating the memory-enhancing effects of the sex-steroid hormone 17β-estradiol (E) is well established. However, estrogen receptors (ERs) are highly expressed in other brain regions that support memory formation, including the medial prefrontal cortex (mPFC). The mPFC and DH interact to mediate the formation of several types of memory, and behavioral tasks that recruit the mPFC are enhanced by systemic E administration, making this region a prime candidate for investigating circuit-level questions regarding the estrogenic regulation of memory. Further, infusion of E directly into the DH increases dendritic spine density in both the DH and mPFC, and this effect depends upon rapid activation of cell-signaling pathways in the DH, demonstrating a previously unexplored interaction between the DH and mPFC that led us to question the role of the mPFC in object memory consolidation and the necessity of DH-mPFC interactions in the memory-enhancing effects of E. Here, we found that infusion of E directly into the mPFC of ovariectomized mice increased mPFC apical spine density and facilitated object recognition and spatial memory consolidation, demonstrating that E in the mPFC increases spinogenesis and enhances on memory consolidation. Next, chemogenetic suppression of the mPFC blocked the beneficial effects of DH-infused E on memory consolidation, indicating that systems-level DH-mPFC interactions are necessary for the memory-enhancing effects of E. Together, these studies provide evidence that E in the mPFC mediates memory formation, and reveal that the DH and mPFC act in concert to support the memory-enhancing effects of E in female mice.
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http://dx.doi.org/10.1523/ENEURO.0451-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6477593PMC
February 2020

Activation of androgen receptors protects intact male mice from memory impairments caused by aromatase inhibition.

Horm Behav 2019 05 17;111:96-104. Epub 2019 Jan 17.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States of America. Electronic address:

Although 17β-estradiol (E) is known to regulate hippocampal function, the specific contributions of hippocampally-synthesized E remain unclear. Infusion of the aromatase inhibitor letrozole into the dorsal hippocampus (DH) of ovariectomized mice disrupts object recognition and object placement memory consolidation, suggesting that DH-synthesized E is essential for memory. However, the role of DH-synthesized E in memory among male rodents is unknown. Here, we examined effects of aromatase inhibition on memory consolidation in male mice. Intact and gonadectomized mice were infused with vehicle or letrozole into the DH immediately post-training in object placement and object recognition tasks. Letrozole blocked memory in both tasks among gonadectomized males only, suggesting that circulating androgens, or a rise in hippocampal androgens due to aromatase inhibition, may support memory consolidation in intact males. To test this hypothesis, intact males were infused with the androgen receptor antagonist flutamide into the DH after object training. A dose-dependent impairment was observed in both tasks, indicating that blocking androgen signaling can impair memory consolidation. To test if hippocampal androgen receptor activation protected intact males from the impairing effects of letrozole, a non-impairing dose of flutamide was co-infused with letrozole. Co-administration of both drugs blocked object placement and object recognition memory consolidation, demonstrating that letrozole impairs memory in intact males only if androgen receptors are blocked. Together, these data suggest that DH-synthesized E and androgen receptor activation may work in concert to mediate memory consolidation in intact males, such that androgen receptor activation protects against memory impairments caused by aromatase inhibition.
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http://dx.doi.org/10.1016/j.yhbeh.2019.01.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6527464PMC
May 2019

Chemogenetic inactivation of the dorsal hippocampus and medial prefrontal cortex, individually and concurrently, impairs object recognition and spatial memory consolidation in female mice.

Neurobiol Learn Mem 2018 12 5;156:103-116. Epub 2018 Nov 5.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States. Electronic address:

The dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) are brain regions essential for processing and storing episodic memory. In rodents, the DH has a well-established role in supporting the consolidation of episodic-like memory in tasks such as object recognition and object placement. However, the role of the mPFC in the consolidation of episodic-like memory tasks remains controversial. Therefore, the present study examined involvement of the DH and mPFC, alone and in combination, in object and spatial recognition memory consolidation in ovariectomized female mice. To this end, we utilized two types of inhibitory Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) to inactivate the DH alone, the mPFC alone, or both brain regions concurrently immediately after object training to assess the role of each region in the consolidation of object recognition and spatial memories. Our results using single and multiplexed DREADDS suggest that excitatory activity in the DH and mPFC, alone or in combination, is required for the successful consolidation of object recognition and spatial memories. Together, these studies provide critical insight into how the DH and mPFC work in concert to facilitate memory consolidation in female mice.
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http://dx.doi.org/10.1016/j.nlm.2018.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7310386PMC
December 2018

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

eNeuro 2018 Sep-Oct;5(5). Epub 2018 Oct 30.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211.

Little is known about how 17β-estradiol (E) mediates memory formation in males. In ovariectomized (OVX) mice, bilateral dorsal hippocampal (DH) infusion of E enhances memory consolidation in object recognition (OR) and object placement (OP) tasks in a manner dependent on activation of extracellular signal-regulated kinase (ERK) and Akt signaling. Here, bilateral DH E infusion enhanced memory consolidation in both tasks among OVX female, gonadally-intact male, and castrated male mice, suggesting comparable facilitation of memory consolidation in both sexes, independent of testicular hormones in males. Contrary to previous reports in OVX mice, E did not increase DH ERK or Akt phosphorylation in males, nor did the ERK inhibitor U0126 [1,4-diamino-2,3-dicyano-1,4-bis (o-aminophenylmercapto) butadiene] prevent E from enhancing memory consolidation among intact and castrated males. These data suggest that ERK activation is not necessary for E to enhance memory consolidation in males, and compared with previous reports in females, reveal novel sex differences in the cell-signaling pathways through which E facilitates memory consolidation. To explore the mechanisms underlying E-induced memory enhancements in males, phosphorylation of the transcription factor cAMP response element binding protein (CREB) in the DH was assessed. E increased phospho-CREB levels in both sexes, yet U0126 did not block these increases in castrated or intact males, indicating that E regulates CREB phosphorylation in males via an ERK-independent mechanism. Collectively, these findings suggest that the beneficial effects of hippocampal E on memory consolidation in males and females are mediated by different molecular mechanisms, which has important implications for the development of treatments to reduce memory dysfunction in men and women.
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http://dx.doi.org/10.1523/ENEURO.0267-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6220582PMC
April 2019

Estradiol and hippocampal memory in female and male rodents.

Curr Opin Behav Sci 2018 Oct 5;23:65-74. Epub 2018 Apr 5.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211.

Estrogens influence nearly every aspect of hippocampal function, including memory formation. Although this research has traditionally focused on ovariectomized females, more recent work is providing insights into the ways in which estrogens regulate hippocampal function in both sexes. This review provides an overview of estrogenic regulation of hippocampal function in female and male rodents, with a particular emphasis on memory formation. Where applicable, we discuss the involvement of specific estrogen receptors and molecular mechanisms that mediate these effects. The review concludes by suggesting gaps in the literature that need to be filled to provide greater insights into potential sex differences in the effects of estrogens on hippocampal function.
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http://dx.doi.org/10.1016/j.cobeha.2018.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191066PMC
October 2018

A-C Estrogens as Potent and Selective Estrogen Receptor-Beta Agonists (SERBAs) to Enhance Memory Consolidation under Low-Estrogen Conditions.

J Med Chem 2018 06 4;61(11):4720-4738. Epub 2018 Jun 4.

Department of Pharmaceutical Sciences, Center for Structure-Based Drug Design and Development , Concordia University Wisconsin , Mequon , Wisconsin 53097 , United States.

Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in postmenopausal women. Herein is reported a series of potent and selective ERβ agonists (SERBAs) with in vivo efficacy that are A-C estrogens, lacking the B and D estrogen rings. The most potent and selective A-C estrogen is selective for activating ER relative to seven other nuclear hormone receptors, with a surprising 750-fold selectivity for the β over α isoform and with ECs of 20-30 nM in cell-based and direct binding assays. Comparison of potency in different assays suggests that the ER isoform selectivity is related to the compound's ability to drive the productive conformational change needed to activate transcription. The compound also shows in vivo efficacy after microinfusion into the dorsal hippocampus and after intraperitoneal injection (0.5 mg/kg) or oral gavage (0.5 mg/kg). This simple yet novel A-C estrogen is selective, brain penetrant, and facilitates memory consolidation.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7217030PMC
June 2018

Mechanisms underlying the rapid effects of estradiol and progesterone on hippocampal memory consolidation in female rodents.

Horm Behav 2018 08 9;104:100-110. Epub 2018 May 9.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States.

Contribution to Special Issue on Fast effects of steroids. Although rapid effects of 17β‑estradiol (E) and progesterone on cellular functions have been observed for several decades, a proliferation of data in recent years has demonstrated the importance of these actions to cognition. In particular, an emerging literature has demonstrated that these hormones promote the consolidation of spatial and object recognition memories in rodents via rapid activation of numerous cellular events including cell signaling, histone modifications, and local protein translation in the hippocampus. This article provides an overview of the evidence demonstrating that E and progesterone enhance hippocampal memory consolidation in female rodents, and then discusses numerous molecular mechanisms thus far shown to mediate the beneficial effects of these hormones on memory formation.
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http://dx.doi.org/10.1016/j.yhbeh.2018.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226372PMC
August 2018

Sex differences in the brain: Implications for behavioral and biomedical research.

Neurosci Biobehav Rev 2018 02;85:126-145

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States.

Biological differences between males and females are found at multiple levels. However, females have too often been under-represented in behavioral neuroscience research, which has stymied the study of potential sex differences in neurobiology and behavior. This review focuses on the study of sex differences in the neurobiology of social behavior, memory, emotions, and recovery from brain injury, with particular emphasis on the role of estrogens in regulating forebrain function. This work, presented by the authors at the 2016 meeting of the International Behavioral Neuroscience Society, emphasizes varying approaches from several mammalian species in which sex differences have not only been documented, but also become the focus of efforts to understand the mechanistic basis underlying them. This information may provide readers with useful experimental tools to successfully address recently introduced regulations by granting agencies that either require (e.g. the National Institutes of Health in the United States and the Canadian Institutes of Health Research in Canada) or recommend (e.g. Horizon 2020 in Europe) the inclusion of both sexes in biomedical research.
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http://dx.doi.org/10.1016/j.neubiorev.2017.07.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5751942PMC
February 2018

Distinct effects of estrogen receptor antagonism on object recognition and spatial memory consolidation in ovariectomized mice.

Psychoneuroendocrinology 2017 Nov 14;85:110-114. Epub 2017 Aug 14.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States. Electronic address:

Exogenous treatment with the potent estrogen 17β-estradiol (E) or selective estrogen receptor α/β (ERα/β) agonists enhances the consolidation of hippocampal-dependent object recognition (OR) and object placement (OP) memories in ovariectomized rodents. Although such data suggest that individual ERs are sufficient for memory consolidation, the necessity of a given ER for memory consolidation can only be demonstrated by blocking receptor function, for example with an ER antagonist. However, the effects on memory of antagonizing ERα or ERβ function are not well understood. Moreover, ER antagonism in ovariectomized subjects also provides indirect information about the role of individual ERs in the memory-enhancing effects of local hippocampal E synthesis. Therefore, this study used pharmacological inhibition of ERα and ERβ to elucidate the importance of each ER to memory consolidation. Specifically, we examined effects on OR and OP memory consolidation of immediate post-training dorsal hippocampal (DH) infusion of MPP and PHTPP, selective antagonists for ERα and ERβ, respectively. Each drug exhibited a distinct effect on OR and OP. DH infusion of MPP (0.28 or 2.78ng/hemisphere) impaired memory in OP, but not OR. However, DH infusion of PHTPP (0.21 or 2.12ng/hemisphere) impaired memory in both OR and OP. Neither drug affected the elapsed time to accumulate object exploration in either task, suggesting a specific effect on memory. These results indicate that activation of either classical ER within the dorsal hippocampus is important for hippocampal memory consolidation in ovariectomized mice, but suggest that specific ER involvement is memory- or task-specific. The findings also indirectly support a role for ERα and ERβ in mediating the memory-enhancing effects of hippocampally-synthesized E.
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http://dx.doi.org/10.1016/j.psyneuen.2017.08.013DOI Listing
November 2017

17β-Estradiol Potentiates the Reinstatement of Cocaine Seeking in Female Rats: Role of the Prelimbic Prefrontal Cortex and Cannabinoid Type-1 Receptors.

Neuropsychopharmacology 2018 03 21;43(4):781-790. Epub 2017 Aug 21.

Department of Biomedical Sciences, Marquette University, Milwaukee, WI, USA.

Clinical observations imply that female cocaine addicts experience enhanced relapse vulnerability compared with males, an effect tied to elevated estrogen phases of the ovarian hormone cycle. Although estrogens can enhance drug-seeking behavior, they do not directly induce reinstatement on their own. To model this phenomenon, we tested whether an estrogen could augment drug-seeking behavior in response to an ordinarily subthreshold reinstatement trigger. Following cocaine self-administration and extinction, female rats were ovariectomized to isolate estrogen effects on reinstatement. Although neither peak proestrus levels of the primary estrogen 17β-estradiol (E2; 10 μg/kg, i.p., 1-h pretreatment) nor a subthreshold cocaine dose (1.25 mg/kg, i.p.) alone were sufficient to reinstate drug-seeking behavior, pretreatment with E2 potentiated reinstatement to the ordinarily subthreshold cocaine dose. Furthermore, E2 microinfusions revealed that E2 (5 μg/0.3 μl, 15-min pretreatment) acts directly within the prelimbic prefrontal cortex (PrL-PFC) to potentiate reinstatement. As E2 has been implicated in endocannabinoid mobilization, which can disinhibit PrL-PFC projection neurons, we investigated whether cannabinoid type-1 receptor (CB1R) activation is necessary for E2 to potentiate reinstatement. The CB1R antagonist AM251 (1 or 3 mg/kg, i.p., 30-min pretreatment) administered prior to E2 and cocaine suppressed reinstatement in a dose-dependent manner. Finally, PrL-PFC AM251 microinfusions (300 ng/side, 15-min pretreatment) also suppressed E2-potentiated reinstatement. Together, these results suggest that E2 can augment reactivity to an ordinarily subthreshold relapse trigger in a PrL-PFC CB1R activation-dependent manner.
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http://dx.doi.org/10.1038/npp.2017.170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809785PMC
March 2018

Estrogenic regulation of memory consolidation: A look beyond the hippocampus, ovaries, and females.

Physiol Behav 2018 04 27;187:57-66. Epub 2017 Jul 27.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States.

The potent estrogen 17β-estradiol (E) has long been known to regulate the hippocampus and hippocampal-dependent memories in females, and research from the past decade has begun to shed light on the molecular mechanisms through which E mediates memory formation in females. Although E can also regulate hippocampal function in males, relatively little is known about how E influences memory formation in males, or whether sex differences in underlying mechanisms exist. This review, based on a talk given in April 2017 at the American University symposium entitled, "Sex Differences: From Neuroscience to the Clinic and Beyond", first provides an overview of the molecular mechanisms in the dorsal hippocampus through which E enhances memory consolidation in ovariectomized female mice. Next, newer research is described demonstrating key roles for the prefrontal cortex and de novo hippocampal E synthesis to the memory-enhancing effects of E in females. The review then discusses the effects of de novo and exogenous E on hippocampal memory consolidation in both sexes, and putative sex differences in the underlying molecular mechanisms through which E enhances memory formation. The review concludes by discussing the importance and implications of sex differences in the molecular mechanisms underlying E-induced memory consolidation for human health.
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http://dx.doi.org/10.1016/j.physbeh.2017.07.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5787049PMC
April 2018

Sex differences in hippocampal function.

J Neurosci Res 2017 01;95(1-2):539-562

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin.

Sex differences in the function of the hippocampus have been observed in numerous mammalian species. However, the magnitude, extent, and specificity of these differences are unclear because they can depend on factors including age, methodology, and environment. This Review will discuss seminal studies examining sex differences in hippocampal memory, neuronal morphology, synaptic plasticity, and cell signaling in humans and rodents. We also describe possible organizational and activational effects of sex steroid hormones during early development, puberty, and adulthood that may lead to sex differences observed in the hippocampus. We conclude by discussing the implications of sex differences in hippocampal function for mental health. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/jnr.23864DOI Listing
January 2017

Inhibition of local estrogen synthesis in the hippocampus impairs hippocampal memory consolidation in ovariectomized female mice.

Horm Behav 2016 07 10;83:60-67. Epub 2016 May 10.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States. Electronic address:

The potent estrogen 17β-Estradiol (E2) plays a critical role in mediating hippocampal function, yet the precise mechanisms through which E2 enhances hippocampal memory remain unclear. In young adult female rodents, the beneficial effects of E2 on memory are generally attributed to ovarian-synthesized E2. However, E2 is also synthesized in the adult brain in numerous species, where it regulates synaptic plasticity and is synthesized in response to experiences such as exposure to females or conspecific song. Although de novo E2 synthesis has been demonstrated in rodent hippocampal cultures, little is known about the functional role of local E2 synthesis in mediating hippocampal memory function. Therefore, the present study examined the role of hippocampal E2 synthesis in hippocampal memory consolidation. Using bilateral dorsal hippocampal infusions of the aromatase inhibitor letrozole, we first found that blockade of dorsal hippocampal E2 synthesis impaired hippocampal memory consolidation. We next found that elevated levels of E2 in the dorsal hippocampus observed 30min after object training were blocked by dorsal hippocampal infusion of letrozole, suggesting that behavioral experience increases acute and local E2 synthesis. Finally, aromatase inhibition did not prevent exogenous E2 from enhancing hippocampal memory consolidation, indicating that hippocampal E2 synthesis is not necessary for exogenous E2 to enhance hippocampal memory. Combined, these data are consistent with the hypothesis that hippocampally-synthesized E2 is necessary for hippocampus-dependent memory consolidation in rodents.
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http://dx.doi.org/10.1016/j.yhbeh.2016.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915975PMC
July 2016

Why estrogens matter for behavior and brain health.

Neurosci Biobehav Rev 2017 05 31;76(Pt B):363-379. Epub 2016 Mar 31.

Department of Psychology and Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada.

The National Institutes of Health (NIH) has required the inclusion of women in clinical studies since 1993, which has enhanced our understanding of how biological sex affects certain medical conditions and allowed the development of sex-specific treatment protocols. However, NIH's policy did not previously apply to basic research, and the NIH recently introduced a new policy requiring all new grant applications to explicitly address sex as a biological variable. The policy itself is grounded in the results of numerous investigations in animals and humans illustrating the existence of sex differences in the brain and behavior, and the importance of sex hormones, particularly estrogens, in regulating physiology and behavior. Here, we review findings from our laboratories, and others, demonstrating how estrogens influence brain and behavior in adult females. Research from subjects throughout the adult lifespan on topics ranging from social behavior, learning and memory, to disease risk will be discussed to frame an understanding of why estrogens matter to behavioral neuroscience.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5045786PMC
http://dx.doi.org/10.1016/j.neubiorev.2016.03.024DOI Listing
May 2017

17β-Estradiol and Agonism of G-protein-Coupled Estrogen Receptor Enhance Hippocampal Memory via Different Cell-Signaling Mechanisms.

J Neurosci 2016 Mar;36(11):3309-21

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, and

Unlabelled: The ability of 17β-estradiol (E2) to enhance hippocampal object recognition and spatial memory depends on rapid activation of extracellular signal-regulated kinase (ERK) in the dorsal hippocampus (DH). Although this activation can be mediated by the intracellular estrogen receptors ERα and ERβ, little is known about the role that the membrane estrogen receptor GPER plays in regulating ERK or E2-mediated memory formation. In this study, post-training DH infusion of the GPER agonist G-1 enhanced object recognition and spatial memory in ovariectomized female mice, whereas the GPER antagonist G-15 impaired memory, suggesting that GPER activation, like E2, promotes hippocampal memory formation. However, unlike E2, G-1 did not increase ERK phosphorylation, but instead significantly increased phosphorylation of c-Jun N-terminal kinase (JNK) in the DH. Moreover, DH infusion of the JNK inhibitor SP600125 prevented G-1 from enhancing object recognition and spatial memory, but the ERK inhibitor U0126 did not. These data suggest that GPER enhances memory via different cell-signaling mechanisms than E2. This conclusion was supported by data showing that the ability of E2 to facilitate memory and activate ERK signaling was not blocked by G-15 or SP600125, which demonstrates that the memory-enhancing effects of E2 are not dependent on JNK or GPER activation in the DH. Together, these data indicate that GPER regulates memory independently from ERα and ERβ by activating JNK signaling, rather than ERK signaling. Thus, the findings suggest that GPER in the DH may not function as an estrogen receptor to regulate object recognition and spatial memory.

Significance Statement: Although 17β-estradiol has long been known to regulate memory function, the molecular mechanisms underlying estrogenic memory modulation remain largely unknown. Here, we examined whether the putative membrane estrogen receptor GPER acts like the classical estrogen receptors, ERα and ERβ, to facilitate hippocampal memory in female mice. Although GPER activation did enhance object recognition and spatial memory, it did so by activating different cell-signaling mechanisms from ERα, ERβ, or 17β-estradiol. These data indicate that 17β-estradiol and GPER independently regulate hippocampal memory, and suggest that hippocampal GPER may not function as an estrogen receptor in the dorsal hippocampus. These findings are significant because they provide novel insights about the molecular mechanisms through which 17β-estradiol modulates hippocampal memory.
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http://dx.doi.org/10.1523/JNEUROSCI.0257-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4792941PMC
March 2016

Estradiol-Mediated Spine Changes in the Dorsal Hippocampus and Medial Prefrontal Cortex of Ovariectomized Female Mice Depend on ERK and mTOR Activation in the Dorsal Hippocampus.

J Neurosci 2016 Feb;36(5):1483-9

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211,

Unlabelled: Dendritic spine plasticity underlies the formation and maintenance of memories. Both natural fluctuations and systemic administration of 17β-estradiol (E2) alter spine density in the dorsal hippocampus (DH) of rodents. DH E2 infusion enhances hippocampal-dependent memory by rapidly activating extracellular signal-regulated kinase (ERK)-dependent signaling of mammalian target of rapamycin (mTOR), a key protein synthesis pathway involved in spine remodeling. Here, we investigated whether infusion of E2 directly into the DH drives spine changes in the DH and other brain regions, and identified cell-signaling pathways that mediate these effects. E2 significantly increased basal and apical spine density on CA1 pyramidal neurons 30 min and 2 h after infusion. DH E2 infusion also significantly increased basal spine density on pyramidal neurons in the medial prefrontal cortex (mPFC) 2 h later, suggesting that E2-mediated activity in the DH drives mPFC spinogenesis. The increase in CA1 and mPFC spine density observed 2 h after intracerebroventricular infusion of E2 was blocked by DH infusion of an ERK or mTOR inhibitor. DH E2 infusion did not affect spine density in the dentate gyrus or ventromedial hypothalamus, suggesting specific effects of E2 on the DH and mPFC. Collectively, these data demonstrate that DH E2 treatment elicits ERK- and mTOR-dependent spinogenesis on CA1 and mPFC pyramidal neurons, effects that may support the memory-enhancing effects of E2.

Significance Statement: Although systemically injected 17β-estradiol (E2) increases CA1 dendritic spine density, the molecular mechanisms regulating E2-induced spinogenesis in vivo are largely unknown. We found that E2 infused directly into the dorsal hippocampus (DH) increased CA1 spine density 30 min and 2 h later. Surprisingly, DH E2 infusion also increased spine density in the medial prefrontal cortex (mPFC), suggesting that estrogenic regulation of the DH influences mPFC spinogenesis. Moreover, inhibition of ERK and mTOR activation in the DH prevented E2 from increasing DH and mPFC spines, demonstrating that DH ERK and mTOR activation is necessary for E2-induced spinogenesis in the DH and mPFC. These findings provide novel insights into the molecular mechanisms through which E2 mediates dendritic spine density in CA1 and mPFC.
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http://dx.doi.org/10.1523/JNEUROSCI.3135-15.2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4737764PMC
February 2016

Sex steroid hormones matter for learning and memory: estrogenic regulation of hippocampal function in male and female rodents.

Learn Mem 2015 Sep 18;22(9):472-93. Epub 2015 Aug 18.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA.

Ample evidence has demonstrated that sex steroid hormones, such as the potent estrogen 17β-estradiol (E2), affect hippocampal morphology, plasticity, and memory in male and female rodents. Yet relatively few investigators who work with male subjects consider the effects of these hormones on learning and memory. This review describes the effects of E2 on hippocampal spinogenesis, neurogenesis, physiology, and memory, with particular attention paid to the effects of E2 in male rodents. The estrogen receptors, cell-signaling pathways, and epigenetic processes necessary for E2 to enhance memory in female rodents are also discussed in detail. Finally, practical considerations for working with female rodents are described for those investigators thinking of adding females to their experimental designs.
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http://dx.doi.org/10.1101/lm.037267.114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4561402PMC
September 2015

Molecular mechanisms underlying the memory-enhancing effects of estradiol.

Authors:
Karyn M Frick

Horm Behav 2015 Aug 8;74:4-18. Epub 2015 May 8.

Department of Psychology, University of Wisconsin-Milwaukee, 2441 E. Hartford Ave., Milwaukee, WI 53211, USA. Electronic address:

This article is part of a Special Issue "Estradiol and cognition". Since the publication of the 1998 special issue of Hormones and Behavior on estrogens and cognition, substantial progress has been made towards understanding the molecular mechanisms through which 17β-estradiol (E2) regulates hippocampal plasticity and memory. Recent research has demonstrated that rapid effects of E2 on hippocampal cell signaling, epigenetic processes, and local protein synthesis are necessary for E2 to facilitate the consolidation of object recognition and spatial memories in ovariectomized female rodents. These effects appear to be mediated by non-classical actions of the intracellular estrogen receptors ERα and ERβ, and possibly by membrane-bound ERs such as the G-protein-coupled estrogen receptor (GPER). New findings also suggest a key role of hippocampally-synthesized E2 in regulating hippocampal memory formation. The present review discusses these findings in detail and suggests avenues for future study.
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http://dx.doi.org/10.1016/j.yhbeh.2015.05.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4573242PMC
August 2015

Hippocampal Wnt Signaling: Memory Regulation and Hormone Interactions.

Neuroscientist 2016 06 25;22(3):278-94. Epub 2015 Feb 25.

Department of Psychology, University of Wisconsin-Milwaukee, WI, USA

Wnt signaling has emerged in recent years as a major player in both nervous system development and adult synaptic plasticity. Of particular relevance to researchers studying learning and memory, Wnt signaling is critical for normal functioning of the hippocampus, a brain region that is essential for many types of memory formation and whose dysfunction is implicated in numerous neurodegenerative and psychiatric conditions. Impaired hippocampal Wnt signaling is implicated in several of these conditions, however, little is known about how Wnt signaling mediates hippocampal memory formation. This review will provide a general overview of Wnt signaling and discuss evidence demonstrating a key role for Wnt signaling in hippocampal memory formation in both normal and disease states. The regulation of Wnt signaling by ovarian sex steroid hormones will also be highlighted, given that the neuroprotection afforded by Wnt-hormone interactions may have significant implications for cognitive function in aging, neurodegenerative disease, and ischemic injury.
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http://dx.doi.org/10.1177/1073858415574728DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7053425PMC
June 2016

Prenatal stress induces spatial memory deficits and epigenetic changes in the hippocampus indicative of heterochromatin formation and reduced gene expression.

Behav Brain Res 2015 Mar 8;281:1-8. Epub 2014 Dec 8.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States. Electronic address:

Stress during pregnancy has a wide variety of negative effects in both human [1] and animal offspring [2]. These effects are especially apparent in various forms of learning and memory such as object recognition [3] and spatial memory [4]. The cognitive effects of prenatal stress (PNS) may be mediated through epigenetic changes such as histone acetylation and DNA methylation [5]. As such, the present study investigated the effects of chronic unpredictable PNS on memory and epigenetic measures in adult offspring. Mice that underwent PNS exhibited impaired spatial memory in the Morris water maze, as well as sex-specific changes in levels of DNA methyltransferase (DNMT) 1 protein, and acetylated histone H3 (AcH3) in the hippocampus, and serum corticosterone. Male mice exposed to PNS exhibited decreased hippocampal AcH3, whereas female PNS mice displayed a further reduction in AcH3, as well as heightened hippocampal DNMT1 protein levels and corticosterone levels. These data suggest that PNS may epigenetically reduce transcription in the hippocampus, particularly in females in whom this effect may be related to increased baseline stress hormone levels, and which may underlie the sexual dimorphism in rates of mental illness in humans.
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http://dx.doi.org/10.1016/j.bbr.2014.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4305490PMC
March 2015

The mTOR and canonical Wnt signaling pathways mediate the mnemonic effects of progesterone in the dorsal hippocampus.

Hippocampus 2015 May 26;25(5):616-29. Epub 2014 Dec 26.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin.

Although much is known about the neural mechanisms responsible for the mnemonic effects of 17β-estradiol (E2 ), very little is understood about the mechanisms through which progesterone (P4 ) regulates memory. We previously showed that intrahippocampal infusion of P4 in ovariectomized female mice enhances object recognition (OR) memory consolidation in a manner dependent on activation of dorsal hippocampal ERK and mTOR signaling. However, the role of specific progesterone receptors (PRs) in mediating the effects of progesterone on memory consolidation and hippocampal cell signaling are unknown. Therefore, the goals of this study were to investigate the roles of membrane-associated and intracellular PRs in mediating hippocampal memory consolidation, and identify downstream cell signaling pathways activated by PRs. Membrane-associated PRs were targeted using bovine serum albumin-conjugated progesterone (BSA-P), and intracellular PRs (PR-A, PR-B) were targeted using the intracellular PR agonist R5020. Immediately after OR training, ovariectomized mice received bilateral dorsal hippocampal infusion of vehicle, P4 , BSA-P, or R5020. OR memory consolidation was enhanced by P4 , BSA-P, and R5020. However, only P4 and BSA-P activated ERK and mTOR signaling. Furthermore, dorsal hippocampal infusion of the ERK inhibitor U0126 blocked the memory-enhancing effects of BSA-P, but not R5020. The intracellular PR antagonist RU486 blocked the memory-enhancing effects of R5020, but not BSA-P. Interestingly, P4 robustly activated canonical Wnt signaling in the dorsal hippocampus, which is consistent with our recent findings that canonical Wnt signaling is necessary for OR memory consolidation. R5020, but not BSA-P, also elicited a modest increase in canonical Wnt signaling. Collectively, these data suggest that activation of ERK signaling is necessary for membrane-associated PRs to enhance OR, and indicate a role for canonical Wnt signaling in the memory-enhancing effects of intracellular PRs. This study provides the first evidence that membrane and intracellular PRs may employ different molecular mechanisms to enhance hippocampal memory.
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http://dx.doi.org/10.1002/hipo.22398DOI Listing
May 2015

Regulation of object recognition and object placement by ovarian sex steroid hormones.

Behav Brain Res 2015 May 15;285:140-57. Epub 2014 Aug 15.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, United States. Electronic address:

The ovarian hormones 17β-estradiol (E2) and progesterone (P4) are potent modulators of hippocampal memory formation. Both hormones have been demonstrated to enhance hippocampal memory by regulating the cellular and molecular mechanisms thought to underlie memory formation. Behavioral neuroendocrinologists have increasingly used the object recognition and object placement (object location) tasks to investigate the role of E2 and P4 in regulating hippocampal memory formation in rodents. These one-trial learning tasks are ideal for studying acute effects of hormone treatments on different phases of memory because they can be administered during acquisition (pre-training), consolidation (post-training), or retrieval (pre-testing). This review synthesizes the rodent literature testing the effects of E2 and P4 on object recognition (OR) and object placement (OP), and the molecular mechanisms in the hippocampus supporting memory formation in these tasks. Some general trends emerge from the data. Among gonadally intact females, object memory tends to be best when E2 and P4 levels are elevated during the estrous cycle, pregnancy, and in middle age. In ovariectomized females, E2 given before or immediately after testing generally enhances OR and OP in young and middle-aged rats and mice, although effects are mixed in aged rodents. Effects of E2 treatment on OR and OP memory consolidation can be mediated by both classical estrogen receptors (ERα and ERβ), and depend on glutamate receptors (NMDA, mGluR1) and activation of numerous cell signaling cascades (e.g., ERK, PI3K/Akt, mTOR) and epigenetic processes (e.g., histone acetylation, DNA methylation). Acute P4 treatment given immediately after training also enhances OR and OP in young and middle-aged ovariectomized females by activating similar cell signaling pathways as E2 (e.g., ERK, mTOR). The few studies that have administered both hormones in combination suggest that treatment can enhance OR and OP, but that effects are highly dependent on factors such as dose and timing of administration. In addition to providing more detail on these general conclusions, this review will discuss directions for future avenues of research into the hormonal regulation of object memory.
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http://dx.doi.org/10.1016/j.bbr.2014.08.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4329280PMC
May 2015

17β-Estradiol regulates histone alterations associated with memory consolidation and increases Bdnf promoter acetylation in middle-aged female mice.

Learn Mem 2014 Sep 15;21(9):457-67. Epub 2014 Aug 15.

Department of Psychology, University of Wisconsin-Milwaukee, Milwaukee, Wisconsin 53211, USA

Histone acetylation is essential for hippocampal memory formation in young adult rodents. Although dysfunctional histone acetylation has been associated with age-related memory decline in male rodents, little is known about whether histone acetylation is altered by aging in female rodents. In young female mice, the ability of 17β-estradiol (E2) to enhance object recognition memory consolidation requires histone H3 acetylation in the dorsal hippocampus. However, the extent to which histone acetylation is regulated by E2 in middle-aged females is unknown. The mnemonic benefits of E2 in aging females appear to be greatest in middle age, and so pinpointing the molecular mechanisms through which E2 enhances memory at this age could lead to the development of safer and more effective treatments for maintaining memory function without the side effects of current therapies. Here, we show that dorsal hippocampal infusion of E2 rapidly enhanced object recognition and spatial memory, and increased histone H3 acetylation in the dorsal hippocampus, while also significantly reducing levels of histone deacetylase (HDAC2 and HDAC3) proteins. E2 specifically increased histone H3 acetylation at Bdnf promoters pII and pIV in the dorsal hippocampus of both young and middle-aged mice, despite age-related decreases in pI and pIV acetylation. Furthermore, levels of mature BDNF and pro-BDNF proteins in the dorsal hippocampus were increased by E2 in middle-aged females. Together, these data suggest that the middle-aged female dorsal hippocampus remains epigenetically responsive to E2, and that E2 may enhance memory in middle-aged females via epigenetic regulation of Bdnf.
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http://dx.doi.org/10.1101/lm.034033.113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4138358PMC
September 2014