Karyn M Frick

Karyn M Frick
University of Wisconsin - Milwaukee | UWM · Department of Psychology

PhD

About

123
Publications
15,457
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7,470
Citations
Citations since 2017
45 Research Items
3386 Citations
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20172018201920202021202220230100200300400500600
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Introduction
Karyn M. Frick is a behavioral neuroscientist in the Department of Psychology at the University of Wisconsin - Milwaukee. Her research seeks to understand the molecular mechanisms through which sex steroid hormones regulate memory formation throughout the adult lifespan in female and male rodents. She is also a Co-founder and the Chief Scientific Officer of Estrigenix Therapeutics, Inc., a privately held pharmaceutical company whose drug development program focuses on selectively activating specific estrogen receptor proteins that promote memory formation, improve mood, and reduce anxiety.
Additional affiliations
August 2010 - present
University of Wisconsin - Milwaukee
July 2000 - June 2010
Yale University
April 1996 - July 2000
Wellesley College
Education
September 1991 - March 1996
Johns Hopkins University
Field of study
  • Psychology
September 1987 - May 1991
Franklin and Marshall College
Field of study
  • Psychology and Biology

Publications

Publications (123)
Article
Full-text available
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 g...
Article
Women carriers of APOE4, the greatest genetic risk factor for late-onset Alzheimer's disease (AD), are at greatest risk of developing AD, yet factors underlying interactions between APOE4 and sex are not well characterized. Here, we examined how sex and APOE3 or APOE4 genotypes modulate object and spatial memory, dendritic spine density and branchi...
Article
Full-text available
Sex steroid hormones such as 17β-estradiol (E 2 ) are critical neuromodulators of hippocampal synaptic plasticity and hippocampus-dependent memory in both males and females. However, the mechanisms through which E 2 regulates memory formation in both sexes remain unclear. Research to date suggests that E 2 regulates hippocampus-dependent memory by...
Article
Anxiety is a prominent and debilitating symptom in Alzheimer's disease (AD) patients. Carriers of APOE4, the greatest genetic risk factor for late-onset AD, may experience increased anxiety relative to carriers of other APOE genotypes. However, whether APOE4 genotype interacts with other AD risk factors to promote anxiety-like behaviors is less cle...
Article
Full-text available
Episodic memory is a complex process requiring input from several regions of the brain. Emerging evidence suggests that coordinated activity between the dorsal hippocampus (DH) and medial prefrontal cortex (mPFC) is required for episodic memory consolidation. However, the mechanisms through which the DH and mPFC interact to promote memory consolida...
Article
The sex steroid hormones (SSHs) such as testosterone, estradiol, progesterone, and their metabolites have important organizational and activational impacts on the brain during critical periods of brain development and in adulthood. A variety of slow and rapid mechanisms mediate both organizational and activational processes via intracellular or mem...
Article
The ubiquitin proteasome system (UPS) is a primary mechanism through which proteins are degraded in cells. UPS activity in the dorsal hippocampus (DH) is necessary for multiple types of memory, including object memory, in male rodents. However, sex differences in DH UPS activation after fear conditioning suggest that other forms of learning may als...
Article
Full-text available
Anxiety disorders are one of the most prevalent mood disorders that can lead to impaired quality of life. Current treatment of anxiety disorders has various adverse effects, safety concerns, or restricted efficacy; therefore, novel therapeutic targets need to be studied. Sex steroid hormones (SSHs) play a crucial role in the formation of brain stru...
Article
Female APOE4 carriers are at greatest risk of Alzheimer's disease (AD). The potent estrogen 17β-estradiol (E2) may mediate AD risk, as the onset of memory decline coincides with the menopausal transition. Whether APOE genotype mediates E2's effects on memory and neuronal morphology is poorly understood. We used the APOE+/+/5xFAD+/- (EFAD) mouse mod...
Article
Hippocampal plasticity and memory are modulated by the potent estrogen 17β-estradiol (E2). Research on the molecular mechanisms of hippocampal E2 signaling has uncovered multiple intracellular pathways that contribute to these effects, but few have questioned the role that extracellular signaling processes may play in E2 action. Modification of the...
Poster
Background: Loss of circulating estrogens at menopause may contribute to increased risk for Alzheimer's disease (AD) in females relative to males. APOE4, the greatest genetic risk factor for AD, acts synergistically with estrogens to increase risk in females. However, despite the relative contributions of APOE genotype and estrogen loss to sex dif...
Article
To examine the role of estradiol in hippocampal-dependent spatial memory in women, 86 female undergraduates were tested in a virtual Morris water task (VMWT), a virtual radial arm maze (VRAM), and a mental rotation task (MRT) within a single daily session. The VMWT and RAM were also administered 24hours later to examine the effects of estradiol on...
Article
Full-text available
The sex steroid hormones (SSHs) play roles in regulation of various processes in the cardiovascular, immune, muscular and neural systems. SSHs affect prenatal and postnatal development of various brain structures, including regions associated with important physiological, behavioral, cognitive, and emotional functions. This action can be mediated b...
Article
Full-text available
The potent estrogen 17β-estradiol (E2) 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 E2, but the potential mechanistic roles of neurotrophic signaling in E...
Article
Full-text available
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 chronic oral treatment with EGX358, a novel highly selective ERβ agonist, on memory, vasodilation,...
Article
Memory dysfunction is a hallmark of Alzheimer’s disease (AD) and other dementias, yet truly effective treatments for memory loss do not exist. Memory dysfunction stems in part from reduced gene expression that leads to decreased levels of proteins essential for neural plasticity. Gene expression is facilitated by histone acetylation, an epigenetic...
Poster
Women carriers of the APOE4 genotype, which is the leading genetic risk factor for late‐onset Alzheimer’s disease (AD), are more likely than women carriers of other APOE genotypes and men of any APOE genotype to develop AD. However, factors underlying the interaction between APOE genotype and sex are not well characterized. The goal of this study w...
Article
Full-text available
Women are at greater risk of Alzheimer’s Disease (AD) than men, and symptoms associated with the menopausal loss of circulating estrogens, including hot flashes, exacerbate cognitive decline and AD risk. Although estrogen‐based therapies reduce hot flashes and mitigate AD risk early in the menopausal transition, these treatments can increase risks...
Article
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 inv...
Poster
Behavioral changes accompanying the cognitive decline associated with Alzheimer’s disease (AD) are a growing concern. Symptoms of anxiety occur in 50‐75% of AD patients and increase throughout disease progression (Gustavson and Cummings, 2004; de Toledo et al., 2004). APOE4 genotype, the leading genetic risk factor for AD, may influence symptoms of...
Chapter
Part IV of this book briefly integrates lessons learned among the many chapters and discusses paths forward for future research in both animals and humans. Suggested future directions for animal research include continued efforts to uncover molecular, cell-specific, and circuit-level mechanisms through which estrogens regulate memory, increased att...
Chapter
The goal of this introductory chapter is to provide historical and organizational context for the book as a whole. The chapter begins by discussing findings from previous studies published in the late 1980’s and beyond that stimulated contemporary research into the effects of estrogens on memory. Next, an overview of the book’s organization is prov...
Chapter
Research from the past decade has begun to shed light on the neural mechanisms through which the potent estrogen 17β‎-estradiol (E2) regulates the formation of memories. Consolidation is a rapid process which appears to take advantage of the ability of estrogen receptors to quickly trigger cell signaling alterations that increase gene expression, l...
Article
Full-text available
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 (E2) on hippocampal CA1 spine density and memory consolidation, yet the cell-signaling mechanisms mediating these effects remain unclear. The present study examined th...
Article
Full-text available
Women are more susceptible to developing cocaine dependence than men, but paradoxically, are more responsive to treatment. The potent estrogen, 17β-estradiol (E2), mediates these effects by augmenting cocaine seeking but also promoting extinction of cocaine seeking through E2’s memory-enhancing functions. Although we have previously shown that E2 f...
Article
Full-text available
Although 17β-estradiol (E2) is known to regulate hippocampal function, the specific contributions of hippocampally-synthesized E2 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...
Article
Full-text available
The importance of the dorsal hippocampus (DH) in mediating the memory-enhancing effects of the sex-steroid hormone 17β-estradiol (E2) 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...
Article
Full-text available
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...
Article
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 hip...
Article
Full-text available
Little is known about how 17β-estradiol (E2) mediates memory formation in males. In ovariectomized (OVX) mice, bilateral dorsal hippocampal (DH) infusion of E2 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....
Article
Full-text available
Estrogen receptor-beta (ERβ) is a drug target for memory consolidation in post-menopausal 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...
Article
Although rapid effects of 17β‑estradiol (E2) 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...
Article
Full-text available
Increased attention has been paid in recent years to the ways in which estrogens and estrogen receptors rapidly affect learning and memory. These rapid effects occur within a timeframe too narrow for the classical genomic mode of estrogen action, thus suggesting non-classical effects as underlying mechanisms. The present review examines recent deve...
Article
Full-text available
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,...
Chapter
The use of object recognition and object placement tasks in behavioural neuroendocrinology research has increased in recent years because learning can be rapidly measured in both rats and mice, which readily allows for assessment of hormonal regulation of object learning and memory, as well as identification of the molecular mechanisms underlying t...
Article
Clinical observations imply that female cocaine addicts experience enhanced relapse vulnerability compared to 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 est...
Article
The potent estrogen 17β-estradiol (E2) 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 E2 mediates memory formation in females. Although E2 can also regulate hippocampal function in males, relatively lit...
Article
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...
Article
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...
Article
Full-text available
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 m...
Article
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)...
Article
Neurotransmitters and neuromodulators, such as hormones and growth factors, are the agents through which most neurons communicate. Therefore, manipulating these neurochemicals is a powerful way in which to influence behaviors such as learning and memory. The goal of this chapter is to provide the basic tools you will need to pharmacologically manip...
Article
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...
Article
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,...
Article
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 dysfunct...
Article
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 consolidatio...
Article
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...
Article
Our laboratory has demonstrated that 17β-estradiol (E2) enhances hippocampal memory consolidation via rapid activation of multiple intracellular signaling cascades, including the ERK/MAPK cascade (Fernandez et al., 2008; Fan et al., 2010). However, the receptor mechanisms responsible for these effects of E2 remain unclear. In vitro, estrogen recept...
Article
Epigenetic alterations of histone proteins and DNA are essential for hippocampal synaptic plasticity and cognitive function, and contribute to the etiology of psychiatric disorders and neurodegenerative diseases. Hippocampal memory formation depends on histone alterations and DNA methylation, and increasing evidence suggests that regulation of thes...
Article
Wnt signaling has emerged as a potent regulator of hippocampal synaptic function, although no evidence yet supports a critical role for Wnt signaling in hippocampal memory. Here, we sought to determine whether canonical β-catenin-dependent Wnt signaling is necessary for hippocampal memory consolidation. Immediately after training in a hippocampal-d...
Article
Full-text available
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 17β-estradiol (E2) affects expression and extinction of cocaine seeking in female rats. Using a conditioned...
Article
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 17β-estradiol (E2) affects expression and extinction of cocaine seeking in female rats. Using a conditioned...
Article
The mammalian target of rapamycin (mTOR) signaling pathway is an important regulator of protein synthesis and is essential for various forms of hippocampal memory. Here, we asked whether the enhancement of object recognition memory consolidation produced by dorsal hippocampal infusion of 17β-estradiol (E(2)) is dependent on mTOR signaling in the do...
Article
Histone acetylation has recently been implicated in learning and memory processes, yet necessity of histone acetylation for such processes has not been demonstrated using pharmacological inhibitors of histone acetyltransferases (HATs). As such, the present study tested whether garcinol, a potent HAT inhibitor in vitro, could impair hippocampal memo...
Article
The research of the past two decades has firmly established that hormones modulate numerous aspects of cognitive function, including memory, attention, decision-making, and sensory processing. That such a wide variety of hormones influence cognition mediated by multiple nonhypothalamic brain regions illustrates the critical importance of hormones t...
Article
A wealth of data collected in recent decades has demonstrated that ovarian sex-steroid hormones, particularly 17β-estradiol (E2), are important trophic factors that regulate the function of cognitive regions of the brain such as the hippocampus. The loss of hormone cycling at menopause is associated with cognitive decline and dementia in women, and...
Article
Although much recent work has elucidated the biochemical mechanisms underlying the modulation of memory by 17β-estradiol, little is known about the signaling events through which progesterone (P) regulates memory. We recently demonstrated that immediate post-training infusion of P into the dorsal hippocampus enhances object recognition memory conso...
Article
Epigenetic processes have been implicated in everything from cell proliferation to maternal behavior. Epigenetic alterations, including histone alterations and DNA methylation, have also been shown to play critical roles in the formation of some types of memory, and in the modulatory effects that factors, such as stress, drugs of abuse and environm...
Article
Full-text available
On average, women now live one-third of their lives after menopause. Because menopause has been associated with an elevated risk of dementia, an increasing body of research has studied the effects of reproductive senescence on cognitive function. Compelling evidence from humans, nonhuman primates, and rodents suggests that ovarian sex-steroid hormo...
Article
Full-text available
Environmental enrichment has become increasingly utilized in rodent models of aging and neurodegenerative disease in order to prevent or reverse cognitive decline and neuronal dysfunction. However, the potential application of this body of work to human cognitive aging has rarely been discussed. The present article provides an overview of the roden...
Article
The involvement of epigenetic alterations in mediating effects of estrogens on memory is unknown. The present study determined whether histone acetylation and DNA methylation are critical for the potent estrogen 17beta-estradiol (E(2)) to enhance object recognition memory. We show that dorsal hippocampal E(2) infusion increases acetylation of dorsa...
Article
We previously demonstrated that dorsal hippocampal extracellular signal-regulated kinase (ERK) activation is necessary for 17beta-estradiol (E(2)) to enhance novel object recognition in young ovariectomized mice (Fernandez et al., 2008). Here, we asked whether E(2) has similar memory-enhancing effects in middle-aged and aged ovariectomized mice, an...
Article
Traditional approaches to the study of hormones and cognition have been primarily observational or correlational in nature. Because this work does not permit causal relationships to be identified, very little is known about the specific molecules and cellular events through which hormones affect cognitive function. In this review, we propose a new...
Article
The effects of progesterone on memory are not nearly as well studied as the effects of estrogens. Although progesterone can reportedly enhance spatial and/or object recognition in female rodents when given immediately after training, previous studies have injected progesterone systemically, and therefore, the brain regions mediating this enhancemen...
Article
Previous work from our laboratory has shown that the ability of estradiol to enhance object memory consolidation in young ovariectomized mice is dependent on dorsal hippocampal activation of the extracellular signal-regulated kinase/mitogen-activated protein kinase (ERK/MAPK) signaling pathway [Fernandez SM, Lewis MC, Pechenino AS, Harburger LL, Or...
Article
Although sex differences have been reported in hippocampal-dependent learning and memory, including contextual fear memories, the underlying molecular mechanisms contributing to such differences are not well understood. The present study examined the extent to which sex differences in contextual fear conditioning are related to differential activat...
Article
The aim of this study was to determine if progesterone modulates object and spatial memory consolidation in young ovariectomized C57BL/6 mice. Object memory was tested in an object recognition task using 24- and 48-h delays. Spatial memory was tested in a 2-day version of the Morris water maze in which retention was tested 24 or 48 h after training...
Article
The question of whether ovarian hormone therapy can prevent or reduce age-related memory decline in menopausal women has been the subject of much recent debate. Although numerous studies have demonstrated a beneficial effect of estrogen and/or progestin therapy for certain types of memory in menopausal women, recent clinical trials suggest that suc...
Article
Previous studies have demonstrated that treatment with 17beta-estradiol (E(2)) improves both spatial and nonspatial memory in young female mice. Still unclear, however, are the molecular mechanisms underlying the beneficial effects of E(2) on memory. We have previously demonstrated that a single post-training intraperitoneal (i.p.) injection of 0.2...
Article
The extracellular signal-regulated kinase (ERK) pathway is critical for various forms of learning and memory, and is activated by the potent estrogen 17beta-estradiol (E(2)). Here, we asked whether E(2) modulates memory via ERK activation and putative membrane-bound estrogen receptors (ERs). Using ovariectomized mice, we first demonstrate that intr...
Article
This study examined the role of dorsal hippocampal NMDA receptors and PKA activation in 17 beta-estradiol (E2)-induced enhancement of object memory consolidation. Mice explored two identical objects during training, after which they immediately received intraperitoneal injections of 0.2 mg/kg E2, and bilateral dorsal hippocampal infusions of Vehicl...
Article
The present study examined the effects of acute progesterone administration on hippocampal-dependent memory consolidation in ovariectomized middle-aged (16 months old) and aged (22 months old) female mice. Spatial memory was tested in a 2-day Morris water-maze task and object memory was tested using an object recognition task with 24- and 48-h dela...
Article
Although environmental enrichment has been shown to improve various types of memory in young and aging mice, no study has directly compared the degree to which enrichment improves memory at different ages throughout the lifespan in male mice. Therefore, the present study investigated the effects of long-term continuous enrichment in young (3 months...
Article
The present study was designed to examine whether life-long exposure to standard or enriched housing affects the ability of estrogen to improve spatial and object memory throughout the lifespan. Three-week-old female mice were maintained in standard or enriched housing up to and through ovariectomy and behavioral testing at 5, 17, or 22 months of a...
Article
The authors sought to determine how different elements of enrichment, for example, cognitive stimulation and voluntary exercise, differ in their ability to improve memory throughout the lifespan. Young, middle-aged, and aged female C57BL/6 mice received 24-hr exposure in their home cages to toys alone (cognitive stimulation), running wheels alone (...
Article
The present study was designed to examine if 4 weeks of exposure to an enriched housing environment affects the ability of estrogen to facilitate object recognition in young and aged female mice. Object recognition was tested using a novel object recognition task. Ovariectomized young a