Alicia Ann Walf

Rensselaer Polytechnic Institute | RPI · Department of Cognitive Science

Progestogens' (e.g., progesterone and its neuroactive metabolite, allopregnanolone), cognitive effects and mechanisms among males are not well-understood. We hypothesized if progestogen's effects on cognitive performance are through its metabolite allopregnanolone, and not actions via binding to traditional progestin receptors (PRs), then progester...

Purpose of Review Here, we summarize current knowledge of androgens’ action gained over the recent years. Recent Findings Neurosteroids are produced in the brain and peripheral nerves, independent of endocrine glands have been investigated for how they are regulated, and have actions via non-steroid receptor targets to mediate social, affective, a...

We posit that biologically informed cognitive behavioral interventions directed at nudging older people to begin programs that ameliorate salient risks of developing Alzheimer disease will reduce the prevalence of the disease. That is the case provided that the interventions are applied early in the progression of the disease when people still have...

Finasteride (FIN) is the prototypical inhibitor of steroid 5α-reductase (5αR), the enzyme that catalyzes the rate-limiting step of the conversion of progesterone and testosterone into their main neuroactive metabolites. FIN is clinically approved for the treatment of benign prostatic hyperplasia and male baldness; while often well-tolerated, FIN ha...

This paper posits that use common cold and sleep medicines might increase the risks of diseases of the lungs and brain.

Our research objective is to understand more, through subjective, self-reports on discussion boards/forums, persons' experiences associated with the use of drugs that alter androgen metabolism, such as finasteride. Finasteride is an orally active, specific inhibitor of 5α-reductase, which is localized to many androgen-dependent tissues. Finasteride...

One of the hallmarks of drug abuse is a reduction in the salience of, and motivation for, natural rewards, such as mating. The effects of psychostimulants on male sexual interest and performance are conflicting; use of psychostimulants can produce increases in risky sexual behaviors but have detrimental effects on sexual ability. We hypothesize tha...

Drug use influences sexual behavior, performance, and can be associated with increased sexual risk-taking. Our prior results using an animal model indicate that progestogens contribute to hormonally-mediated changes in sexual behavior of female rodents during acute cocaine exposure. Androgens, such as testosterone, and its metabolite 3ɑ-androstaned...

This review provides the rationale for implementing cognitive behavioral therapy (CBT) for the prevention of Alzheimer’s disease (AD). There are known risk factors associated with the development of AD, some of which may be ameliorated with CBT. We posit that treating the risk factors of inactivity, poor diet, hyposmia and anosmia, sleep disorders...

How can building technologies accommodate different and often conflicting user preferences without dissolving the social cohesiveness, intrinsic of every architectural intervention? Individual thermal comfort has often been considered a negligible sensorial experience by modern heating and cooling technologies, and is often influenced by large-grou...

Neuroactive steroids are endogenous neuromodulators synthesised in the brain that rapidly alter neuronal excitability by binding to membrane receptors, in addition to the regulation of gene expression via intracellular steroid receptors. Neuroactive steroids induce potent anxiolytic, antidepressant, anticonvulsant, sedative, analgesic and amnesic e...

This review explores the effects of female reproductive hormones, estrogens and progestogens, with a focus on progesterone and allopregnanolone, on object memory. Progesterone and its metabolites, in particular allopregnanolone, exert various effects on both cognitive and non-mnemonic functions in females. The well-known object recognition task is...

Purpose: Our primary objective was to assess associations between urine cortisol as a biomarker of psychological stress and in vitro fertilization (IVF) outcomes. A secondary objective was to assess associations between toxic metals and cortisol. Methods: Urine and blood specimens were collected from 52 women and 28 male partners completing a fi...

Given that the pregnane neurosteroid, 5α-pregnan-3α-ol-20-one (3α,5α-THP), is increased following behavioral challenges (e.g., mating), and that there is behavioral-induced biosynthesis of 3α,5α-THP in midbrain and mesocorticolimbic structures, 3α,5α-THP likely has a role in homeostasis and motivated reproduction and reproduction-related behaviors...

A novel factor of interest for growth/plasticity in the brain is pregnane xenobiotic receptor (PXR). PXR is a liver factor known for its role in xenobiotic clearance and cholesterol metabolism. It is expressed in the brain, suggesting a potential role for plasticity, particularly involving cholesterol-based steroids and neurosteroids. Mating induce...

Neurosteroids are cholesterol-based hormones that can be produced in the brain, independent of secretion from peripheral endocrine glands, such as the gonads and adrenals. A focus in our laboratory for over 25 years has been how production of the pregnane neurosteroid, allopregnanolone, is regulated and the novel (i.e., non steroid receptor) target...

Progesterone and its metabolite, 5α-pregnan-3α-ol-20-one (3α,5α-THP), have actions in the ventral tegmental area (VTA) that are required for lordosis, a characteristic mating posture of female rodents. 17β-estradiol (estradiol) co-varies with progestogens over natural cycles, enhances production of 3α,5α-THP, and is required for successful reproduc...

Progestogens have actions in the midbrain ventral tegmental area (VTA) to mediate motivated behaviours, such as those involved in reproductive processes, among female rodents. In the VTA, formation and actions of one progestogen, 5α-pregnan-3α-ol-20-one (3α,5α-THP; 3α,5α-THP), are necessary and sufficient to facilitate sexual responding (measured b...

Progesterone (P4) may influence cognition in part through actions of its 5α-reduced metabolite, allopregnanolone. Ovariectomized mice that were C57BL/6 wildtype (WT), or deficient in the 5α-reductase Type 1 enzyme (5α-reductase knockout; 5αRKO), were administered vehicle, P4, allopregnanolone, or medroxyprogesterone acetate (MPA, 4mg/kg SC) after t...

Progesterone (P4) and its metabolites, rapidly facilitate lordosis of rats partly through actions in the ventral tegmental area (VTA). The study of membrane progestin receptors (mPRs), of the Progestin and AdipoQ Receptor (PAQR) superfamily, has been limited to expression and regulation, instead of function. We hypothesized that if mPRs are require...

Progesterone (P4) and its product, 5α-pregnan-3α-ol-20-one (3α,5α-THP), act in the midbrain ventral tegmental area (VTA) to alter motivated behaviors, such as mating, and motor and anxiety behavior. Of interest is whether 3α,5α-THP formation requires the pregnane xenobiotic receptor (PXR), which is expressed in the midbrain of rats. The role of PXR...

Evidence is emerging of the role of membrane progestin receptors (referred to as mPRs herein: members of Progestin and AdipoQ Receptor (Paqr) family) as a novel brain target in mammals, such as rats. In the present study, the role of mPRs in mice was assessed to further elucidate the conservation of this mechanism across species. The brain target i...

Stressors, during early life or adulthood, can alter steroid-sensitive behaviors, such as exploration, anxiety, and/or cognitive processes. We investigated if exposure to acute stressors in adulthood may alter behavioral and neuroendocrine responses of male rats that were exposed to gestational stress or not. We hypothesized that rats exposed to ge...

There are estrous cycle differences in affective behaviors of rodents that are generally attributed to cyclic variations in estradiol, progesterone (P) and its metabolites. A question is the role of the steroid metabolism enzyme, 5α-reductase, for these estrous cycle differences. To address the requirement of 5α-reductase, estrous cycle variations...

Psychological, physical and/or immune stressors during pregnancy are associated with negative birth outcomes, such as preterm birth and developmental abnormalities. In rodents, prenatal stressors can alter the expression of 5α-reductase enzymes in the brain and may influence cognitive function and anxiety-type behaviour in the offspring. Progestero...

There are a plethora of whole animal models that are utilized to assess the neurobiological substrates involved in complex constructs affecting the human condition, such as anxiety. One such behavioral measure that utilizes a conditioned response that can be utilized to assess the neurobiological underpinnings of anxiety is the Vogel punished drink...

The nature of progesterone (P₄)'s neuroprotective effects is of interest. We investigated effects of P₄ when administered before, or after, kainic acid, which produces ictal activity and damage to the hippocampus, to mediate effects on spatial performance. The hypothesis was that P₄, compared with vehicle, would reduce decrements in Morris Water Ma...

Progestogens [progesterone (P(4)) and its products] play fundamental roles in the development and/or function of the central nervous system during pregnancy. We, and others, have investigated the role of pregnane neurosteroids for a plethora of functional effects beyond their pro-gestational processes. Emerging findings regarding the effects, mecha...

17β-estradiol (E(2)) can enhance reproductive, cognitive, and affective functions; however, the mechanisms by which E(2) has these effects need to be better understood. Pleiotrophic effects of E(2) can occur via traditional and novel actions at various forms of estrogen receptors (ERs). In the central nervous system, trophic effects of E(2) may be...

At middle-age, the reproductive capacity of female rats begins to decline. Whether there are consequences for social and reproductive behaviors related to changes in estradiol (E(2)), progesterone (P(4)) and its 5α-reduced metabolites, dihydroprogesterone (DHP) and 5α-pregnan-3α-ol-20-one (3α,5α-THP), is of interest. In Experiment 1, 1-year-old fem...

Cognitive decline can occur with aging; however, some individuals experience less cognitive decline than do others. Secretion of ovarian hormones is reduced post-menopause and may contribute to cognitive function. The extent to which hormonal effects may be parsed out from other age-related factors to influence cognition is of interest. Middle-aged...

The mechanisms by which progestogens influence affective behaviors in females are poorly understood despite clear changes in mood/affect that are associated with their decline during menopause. Conjugated equine estrogens (CEE), with or without medroxyprogesterone acetate (MPA), are commonly prescribed hormone-replacement, but there is heterogeneit...

Ovarian hormones organize and activate neural circuits for reproduction and may also mediate cognition. Research has focused on estradiol's mnemonic effects, albeit progesterone covaries with estradiol and its mechanisms for cognition require attention. Studies tested the hypothesis that cognitive effects of progesterone occur subsequent to its met...

Controversy surrounds the efficacy and safety of 17beta-estradiol (E2)-mimetic therapies to women for treatment of menopausal symptoms. An important question is the nature of the trophic actions of E2-mimetics in the brain for behavioral processes versus in the periphery for beneficial effects related to osteoporosis, or unwanted proliferative effe...

Some hippocampally-influenced affective and/or cognitive processes decline with aging. The role of androgens in this process is of interest. Testosterone (T) is aromatized to estrogen, and reduced to dihydrotestosterone (DHT), which is converted to 5alpha-androstane, 3alpha, 17alpha-diol (3alpha-diol). To determine the extent to which some age-rela...

Progesterone can enhance cognitive performance among young and aged mice; however, the mechanisms underlying these effects of progesterone are not well-understood. Aged, mice which lack functional progestin receptors (PRKO), or wildtype mice were administered progesterone (10mg/kg, SC), or vehicle, and learning/memory was evaluated. Progesterone, c...

In the 50 years since the initial reports of a cognate estrogen receptor (ER), much has been learned about the diverse effects and mechanisms of estrogens, such as 17β-estradiol (E2). This expert narrative review briefly summarizes perspectives and/or recent work of the authors, who have been addressing different aspects of estrogen action, but tak...

Changes in levels of estradiol and progesterone that occur with the transition to reproductive senescence may influence nociception or affect. To ascertain whether nociceptive and affective processes change with reproductive senescence, this study examined pain and anxiety-like behaviors in middle-aged female rats that were reproductively competent...

The steroid, 17beta-oestradiol (E(2)) has pervasive psychological and physical effects throughout the lifespan. The question arises as to whether there are divergent oestrogen receptor (ER)-mediated mechanisms for these effects in the central nervous system (CNS) and periphery. This review focuses on results of studies using a whole animal model (i...

Although estradiol (E(2)) may have some beneficial effects as a treatment for menopause symptoms, E(2) also has trophic effects that can increase vulnerability to some cancers, such as breast cancer. In the present study, a model to investigate the concomitant behavioral and proliferative effects of E(2) was developed. First, the effects of differe...

Beneficial effects of the ovarian steroid, 17beta-estradiol (E(2)), for affective behavior have been reported in young individuals, but less is known about the effects of E(2) among older individuals, and the capacity of older individuals to respond to E(2) following its decline. In the present study, the effects of acute E(2) administration to age...

Women with estrogen receptor (ER) positive breast cancer, who are treated with the ER blocker, tamoxifen, have an increased risk of depression. Trilostane, a 3b-hydroxysteroid dehydrogenase inhibitor, is now being used to treat tamoxifen-insensitive breast cancer. In-vitro assays show that trilostane may have actions through ERb. Results of in-vivo...

Manipulating dopamine and/or adenosine 3',5' monophosphate regulated phosphoprotein of 32 kDa (DARPP-32) can influence sexual behavior of rodents. The ventral tegmental area (VTA) is an important brain site for progestogens to facilitate sexual behavior of rodents. We hypothesized that, in the VTA, dopamine type 1-like receptor (D1)-mediated increa...

Progesterone has a ubiquitous role in reproduction and fitness and may influence cognitive performance. We examined the effects of administration of progesterone (a regimen that facilitates sexual behaviour) on consolidation of complex information in Long-Evans rats, Rattus norvegicus, that may be relevant for social engagement. We also examined th...

Estradiol (E(2)) and progesterone (P(4)) have classical, steroid receptor-mediated actions in the ventral medial hypothalamus to initiate lordosis of female rodents. P(4) and the P(4) metabolite and neurosteroid, 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 alpha-THP), have non-classical actions in the midbrain ventral tegmental area (VTA) to modul...

To assess a construct, such as anxiety, and to determine potential neurobiological underpinnings of this construct, it is often necessary to utilize an animal model. For example, the elevated plus maze is a widely used behavioral assay that has been validated to assess the anxiety-related behavior of rodents. There is great value in using a whole s...

Although anxiety and depression are not the core symptoms of Alzheimer's Disease (AD), there are changes observed in mood in those with AD, as well as in the aging population. Anxiety and depression may be influenced by progesterone P(4) and/or its neuroactive metabolites, dihydroprogesterone (DHP) and 5 alpha-pregnan-3 alpha-ol-20-one (3 alpha,5 a...

With aging and menopause, which are associated with decreases in ovarian steroids such as 17beta-estradiol (E(2)), women might experience negative psychological symptoms, including anxiety and depression. Some women use E(2)-based therapies to alleviate these symptoms, but E(2) has been associated with trophic effects that might increase vulnerabil...

Decline in the ovarian steroid, estradiol (E(2)), with the menopause transition may influence cognitive and affective processing of older women and there is evidence that hormone replacement therapies (HRTs) with E(2)-mimetics may provide benefit in some, but not all, women. The parameters that play a role in determining whether the response to HRT...

There may be a role of age-related decline in androgen production and/or its metabolism for late-onset depression disorders of men and women. Thus, the anti-depressant-like effects of testosterone (T) and its metabolites are of interest. Given that these androgens have disparate mechanisms of action, it is important to begin to characterize and com...

17β-Estradiol (E2) may influence cognitive and/or affective behavior in part via the β isoform of the estrogen receptor (ERβ). Endocrine status and behavior in cognitive (object recognition, T-maze), anxiety (open field, elevated plus maze, mirror maze, emergence), and motor/coordination (rotarod, activity chamber) tasks of proestrous and diestrous...

Clinical and basic studies demonstrate that estrogen (E-sub-2)-based therapies influence anxiety and mood, but the receptor targets (e.g., a or ss isoform of the estrogen receptor, ER) for these effects requires further investigation. To address the specificity of E2's anxiolytic-like effects through ERss, anxiety, motor, and nociceptive behavior o...

The steroid hormone, estradiol (E(2)), has numerous targets in the central nervous system, including the hippocampus, which plays a key role in cognition and affective behavior. This review focuses on our evidence from studies in rodents that E(2) has diverse mechanisms in the hippocampus for its functional effects. E(2) has rapid, membrane-mediate...

In the ventral tegmental area (VTA), progestins facilitate lordosis via rapid actions at membrane dopamine Type 1-like (D(1)) and/or GABA(A) receptors (GBRs), rather than via cognate, intracellular progestin receptors (PRs). Downstream signal transduction pathways involved in these effects were investigated using lordosis as a bioassay. If progesti...

Steroid hormones have pervasive functional effects. Although steroids are generally known to have actions via binding to their cognate steroid receptors, it is becoming clearer that steroids can have non-traditional actions that do not require activation of cognate steroid receptors. We have found that progestogen-facilitated lordosis of rodents is...

In the ventral tegmental area, progestogens facilitate sexual receptivity of rodents via actions at dopamine type 1-like and/or γ-aminobutyric acid type A receptors and activation of downstream signal transduction molecules. In the present study, we investigated whether effects of progesterone's metabolite, 3α,5α-THP, to enhance lordosis via action...

Testosterone (T) and its metabolites may underlie some beneficial effects for anxiety and cognition, but the mechanisms for these effects are unclear. T is reduced to dihydrotestosterone (DHT), which can be converted to 5alpha-androstane,3alpha,17beta-diol (3alpha-diol) and/or 5alpha-androstane-3beta,17beta-diol (3beta-diol). Additionally, T can be...

Research on how steroid hormones mediate mnemonic processes have focused on effects of 17beta-estradiol (E(2)); yet, progesterone (P(4)) co-varies with E(2) across endogenous hormonal milieu, and itself may influence cognitive processes. We investigated the hypothesis that acute P(4) treatment enhances cognitive performance compared to vehicle. Ova...

Progesterone (P4) has actions in the ventral tegmental area (VTA) to regulate female sexual behavior in rodents. However, there are few intracellular progestin receptors (PRs) that have been identified in the VTA through which P4 may have its actions to facilitate lordosis. There are N-methyl-D: -aspartate receptors (NMDARs) in the VTA that may be...

Studies in people and animal models suggest that depression is influenced by natural fluctuations in the levels of 17beta-oestradiol (E(2)), as well as administration of E(2)-based therapies, such as selective oestrogen receptor modulators (SERMs). Elucidating the effects and mechanisms of E(2) is important to improve future E(2)-based therapeutics...

Ovarian steroids alter cognitive performance of young individuals. Whether progesterone enhances learning and memory in tasks involving the prefrontal cortex and/or hippocampus in aged mice was investigated. Aged mice received progesterone (10 mg/kg, s.c.) or vehicle and were tested for cortical and/or hippocampal learning and memory. Progesterone...

The ovarian hormone, 17beta-estradiol (E2), has numerous targets in the body and brain, and can influence cognitive, affective, and social behavior. However, functional effects of commonly prescribed E2-based hormone therapies are less known. The effects of conjugated equine estrogen (CEE) on middle-aged female rats for cognitive (object recognitio...

Cognitive processes mediated by the hippocampus and cortex are influenced by estradiol (E(2)); however, the mechanisms by which E(2) has these effects are not entirely clear. As such, studies were conducted to begin to address the role of actions at the beta form of the intracellular estrogen receptor (ERbeta) for E(2)'s cognitive effects in adult...

Progesterone (P(4)) and its metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP) have trophic effects and may improve cognitive function. We investigated the role of progestins in a murine model of Alzheimer's Disease (AD) in which transgenic mice co-overexpress a mutant form of amyloid precursor protein (APPswe) and a deletion in presen...

Evidence from clinical and basic research studies demonstrates that estradiol (E(2)) reduces anxiety and/or depressive behavior; however, this effect is not observed in all studies. One factor that may mitigate differential responses to E(2) may be previous E(2) experience, i.e. parity. To investigate this, performance in tasks that are utilized to...

Estradiol (E(2)) modulates affective and socio-sexual behavior of female rodents. E(2)'s functional effects may involve actions through alpha and beta isoforms of estrogen receptor (ERs). The importance of E(2)'s actions at these isoforms for anxiety (open field, elevated plus maze), depression (forced swim test), and sexual behavior (lordosis) was...

Progestin-facilitated lordosis of rodents is enhanced by activation of dopamine type 1 (D(1)) or GABA(A) receptors, their downstream G-proteins, and/or second messengers in the ventral tegmental area (VTA). We examined whether the ability of progestins to enhance lordosis via actions at D(1) and/or GABA(A) receptors is contingent upon activation of...

Steroid modulation of cognitive function has focused on estrogen (E2), but progestins naturally co-vary with E2 and may also influence cognitive performance. Spatial performance in the object placement task over endogenous hormonal states in which E2 and progestins vary, and when E2 and/or progestins were administered, was examined. Experiment 1: R...

Although there is evidence that estradiol has effects in women and in animal models to reduce anxiety and depressive behavior and enhance performance in some cognitive tasks, this is not seen among all individuals. Given the interaction between estradiol and hypothalamic-pituitary-adrenal function, we hypothesized that an individual's prior exposur...

Intrinsic rewarding effects of estradiol (E(2)) may underlie some of the sex differences that emerge postpuberty for the prevalence of drug use and behavioral responses to drugs, but the effects and mechanisms of E(2) for reward have not been well characterized. Conditioned place preference (CPP), as measured by the time spent on the nonpreferred/d...

Estradiol (E(2)) may influence some of the sex differences in neuropsychiatric disorders that emerge post-puberty. Studies in our laboratory, and others, have shown that actions at the beta isoform of estrogen receptor (ER) are important for E(2)'s effects for anxiety and/or depressive behavior. Whether ERbeta in the hippocampus is a target for the...

Androgens, such as testosterone (T), can have reinforcing effect, which may be due in part to actions of T's metabolite, 3alpha-androstanediol (3alpha-diol). To investigate rewarding effects of 3alpha-diol, gonadally intact adult male hamsters were given a two-bottle choice test to determine the amount of 3alpha-diol that would be self-administered...

The elevated plus maze is a widely used behavioral assay for rodents and it has been validated to assess the anti-anxiety effects of pharmacological agents and steroid hormones, and to define brain regions and mechanisms underlying anxiety-related behavior. Briefly, rats or mice are placed at the junction of the four arms of the maze, facing an ope...

In the ventral tegmental area (VTA), progestins have actions involving dopamine type 1-like receptors (D(1)) and gamma-aminobutyric acid (GABA)(A)/benzodiazepine receptor complexes (GBRs) for lordosis. Evidence suggests that D(1) and GBRs can have G-protein-mediated effects. We investigated if, in the VTA, inhibiting G-proteins prevents D(1)- and/o...

In the ventral tegmental area (VTA), progestins facilitate lordosis via actions at gamma-aminobutyric acid (GABA)(A)/benzodiazepine receptor complexes (GBRs) and dopamine type 1 receptors (D1). The relationship between progestins' actions at GBRs and D1 in the VTA for facilitating sexual behavior of hamsters and rats was examined. Ovariectomized (o...

Increasing cAMP, or activating dopamine type 1 (D(1)) or GABA(A)/benzodiazepine receptor complexes (GBRs), in the ventral tegmental area (VTA) enhances lordosis of rodents. Whether D(1)- and/or GBR-mediated increases in progestin-facilitated lordosis involve the cAMP-synthesizing enzyme, adenylyl cyclase, in the VTA, was investigated. In Experiment...

Learning and memory processes may be influenced by fluctuations in steroid hormones, such as estrogens and progestins. In this study, we have used an animal model to investigate the effects of endogenous fluctuations in ovarian steroids in intact female rats and effects of administration of ovarian steroids to ovariectomized rats for non-spatial, w...

Estrogen (E2) has many effects in the central nervous system, including effects on anxiety and depression behavior. This review will address effects of E2 on behaviors related to anxiety and depression in women and animal models and include recent findings from our laboratory related to this topic. E2's antianxiety and antidepressant-like effects m...

Greater incidence of anxiety and depressive disorders of women compared to men may be due in part to progesterone (P) and its neuroactive metabolite, 5alpha-pregnan-3alpha-ol-20-one (3alpha,5alpha-THP), acting in limbic regions, such as the amygdala. If P's metabolism via 5alpha-reduction to 3alpha,5alpha-THP in the amygdala is critical for antianx...

Progestin-facilitated lordosis of hamsters and rats is enhanced by activation of dopamine type 1 (D1) or GABAA/benzodiazepine receptor complexes (GBRs) in the ventral tegmental area (VTA) and these effects involve G-proteins and second messengers, such as adenosine 3',5'-monophosphate (cAMP). We examined whether D1- and/or GBR-mediated increases in...

Progestins mediate the onset and duration of lordosis, the mating posture of female rodents, through actions in the hypothalamus and ventral tegmental area. In the hypothalamus, progesterone has traditional, "genomic" actions via intracellular progestin receptors. In the ventral tegmental area, 3alpha-hydroxy-5alpha-pregnan-20-one has "non-genomic"...

17beta-Estradiol (E2) may influence anxiety behavior; however, its effects and mechanisms are not well understood. To determine whether E2's effects on anxiety behavior may involve actions at intracellular estrogen receptor (ER) alpha or beta isoforms, selective ER modulators (SERMs) were administered (10 microg; s.c.) to ovariectomized rats 48 h b...