A randomized, controlled, split-face, double-blind comparison of a multimodality pigment-correcting serum containing lotus sprout extract versus hydroquinone for moderate to severe facial hyperpigmentation, including melasma, in a diverse population.

Background: Hyperpigmentation results in uneven skin tone, with darker skin types disproportionately affected. Objective: Assess efficacy and safety of a novel, hydroquinone (HQ)-free, multimodal pigment-correcting serum (Advanced Brightening Treatment [ABT]) versus 4% HQ in moderate to severe hyperpigmentation, including melasma. Methods: In this split-face study, ABT and 4% HQ were applied topically on randomly assigned facial sides twice daily for 12 weeks. Hyperpigmentation, skin tone evenness, modified Melasma Area and Severity Index (mMASI), Melasma Quality of Life Questionnaire (MelasQoL), self-assessment questionnaires, and tolerability were assessed. Results: Subjects (n = 113; melasma subgroup, n = 44) were Asian (22%), Black/African American (27%), Hispanic (22%), and White/Caucasian (28%). ABT achieved comparable results to 4% HQ. ABT was well tolerated and resulted in improvement versus baseline at all visits in mean overall hyperpigmentation (-11.7% at week 12; P ≤ .001), skin tone evenness (-8.8%, P ≤ .005), and, in the melasma subgroup, mMASI (-50.6%; P ≤ .011) and MelasQoL scores (33.0 vs 46.6 for week 12 vs baseline, respectively; P ≤ .011), with similar results across racial subgroups. ABT was preferred over 4% HQ, with high satisfaction rate (≥89%). Limitations: Quality of life improvements per treatment were not evaluated separately. Conclusion: Efficacy and safety of ABT is comparable to 4% HQ in individuals with facial hyperpigmentation, including melasma, across multiple racial/ethnic backgrounds.

12-Week, Single-Center Study of a Targeted Pigment-Correcting Dark Spot Treatment for Post-Inflammatory Hyperpigmentation and Solar Lentigines.

Purpose: Post-inflammatory hyperpigmentation (PIH) and solar lentigines are dark spots of skin from excessive melanin production due to injury or UV exposure. This 12-week single-center study assessed the efficacy and tolerability of a novel targeted pigment-correcting spot treatment gel suspension cream (Dark Spot Treatment) for improving mild-to-moderate PIH or solar lentigines. Patients and Methods: Female participants (N = 41) aged 25-65 with mild-to-moderate facial dark spots applied Dark Spot Treatment daily for 12 weeks. Investigators assessed overall hyperpigmentation, skin tone evenness, and dark spot intensity, contrast, and size at Weeks 2, 4, 8, and 12. Participant self-assessments occurred at Weeks 1, 2, 4, 8, and 12. Tolerability was assessed by clinical grading and participant reporting. Results: Dark Spot Treatment improved overall hyperpigmentation, skin tone evenness, and dark spot intensity and contrast at Weeks 2 through 12, and dark spot size at Weeks 4 through 12 (all p < 0.001 compared to baseline). Participant self-assessments showed high overall satisfaction. Dark Spot Treatment was well tolerated. Conclusion: The novel pigment-correcting Dark Spot Treatment significantly improved the appearance of PIH and solar lentigines, had high participant satisfaction, and was well tolerated.

Restoration of Aging Body Skin: Evidence-Based Development of a Topical Formulation for Improving Body Skin Quality.

BACKGROUND: Age-related changes in body skin are emerging as important therapeutic targets. A novel topical firming and toning body lotion (FTB) has been developed to target multiple pathways involved in body skin rejuvenation. METHODS: FTB was evaluated in a randomized, double-blind, vehicle-controlled, 12-week study in women (N=54) with mild to moderate lack of firmness on the upper arms and mild to moderate cellulite on the thighs. Investigator clinical assessments, instrumentation evaluations, and patient questionnaires were performed. Histological assessment of ex vivo human skin treated with FTB and gene expression analysis in 3-dimensional human skin models following application of FTB or product comparators were conducted. RESULTS: At week 12, FTB treatment significantly improved (vs baseline) firmness, sagging, smoothness, texture, cellulite, and crepiness on investigator-, instrument-, and photographically assessed outcomes. Participants reported significant improvements in self-perceived efficacy and overall satisfaction with the appearance of their skin following FTB treatment vs vehicle control. Adverse events were mild or moderate in severity. FTB supported new collagen and elastic fiber formation in ex vivo skin. FTB increased skin rejuvenation–associated gene expression vs comparator products. CONCLUSIONS: FTB provided significant improvements in the upper arms and thighs compared with baseline and vehicle control across multiple investigator and instrumentation evaluations. Most participants reported greater efficacy and treatment satisfaction with FTB vs vehicle. FTB treatment stimulated dermal extracellular matrix renewal and induced expression of genes involved in skin rejuvenation pathways. This study provides clinical and preclinical evidence supporting the use of FTB to improve body skin quality. Citation: Makino ET, Jiang LI, Acevedo SF, et al. Restoration of aging body skin: evidence-based development of a topical formulation for improving body skin quality. J Drugs Dermatol. 2023;22(9):887-897. doi:10.36849/JDD.7292.

Evaluation of a retinol containing topical treatment to improve signs of neck aging.

BACKGROUND: The neck region is an area that can be indicative of signs of skin aging. A novel topical product that combines multiple active ingredients including retinol, tripeptide and glaucine was formulated to specifically target neck aging correction and complement post-procedure as part of an integrated skincare regimen. OBJECTIVES: To evaluate the efficacy of a topical neck treatment through clinical subject evaluation, in addition to ultrasound and biopsy assessment. METHODS: Evaluation for the efficacy of this novel topical product on improving the aging signs of neck skin was performed in multiple clinical trials. The first trial focused on clinical efficacy and included clinical assessment, subject questionnaires, ultrasound imaging and digital photographs. The second trial focused on biomarker analysis through skin biopsy. RESULTS: Data from the clinical trials showed that aging signs on the neck were significantly improved after 12 or 16 weeks of product usage. Changes were readily observed by clinical evaluators and participants. They were documented with digital photos, ultrasound images, and biomarker expression in the skin which clearly display the improvements. CONCLUSIONS: This novel topical product is effective in treating the aging signs on the neck skin and has been shown to provide statistically significant improvement on a myriad of neck aging attributes including fine lines/wrinkles, crepiness, laxity, and texture.

Accessing Olfactory Habituation in Drosophila melanogaster with a T-maze Paradigm.

Habituation is the process whereby perceptual changes alter the value of environmental stimuli, enabling salience filtering. This behavioral response decrement is a form of non-associative learning, where the subject learns about the stimulus and does not involve sensory adaptation, sensory or motor fatigue. The range of behavioral responses in D. melanogaster led to the development of a number of habituation paradigms addressing various sensory modalities. Habituation of osmotactic responses has previously been measured with the Y-maze test and required 30 min of odor exposure. Here, we describe an olfactory habituation assay utilizing the widely used in associative learning paradigms T-maze. Continuous or repetitive odor exposure for 4 min is adequate to attenuate osmotactic responses both to attractive and aversive odors. Importantly, the decreased response conforms to habitation parameters, presenting dishabituation and spontaneous recovery. This assay allows the study of habituation after brief odor exposure, but also discriminates between the two distinct phases of the response, an initial habituation latency period followed by habituation. In addition, the characterization of the neuronal circuits implicated in each phase facilitates further study of the molecular components underlying this process.

Temporally specific engagement of distinct neuronal circuits regulating olfactory habituation in Drosophila.

Habituation is the process that enables salience filtering, precipitating perceptual changes that alter the value of environmental stimuli. To discern the neuronal circuits underlying habituation to brief inconsequential stimuli, we developed a novel olfactory habituation paradigm, identifying two distinct phases of the response that engage distinct neuronal circuits. Responsiveness to the continuous odor stimulus is maintained initially, a phase we term habituation latency and requires Rutabaga Adenylyl-Cyclase-depended neurotransmission from GABAergic Antennal Lobe Interneurons and activation of excitatory Projection Neurons (PNs) and the Mushroom Bodies. In contrast, habituation depends on the inhibitory PNs of the middle Antenno-Cerebral Track, requires inner Antenno-Cerebral Track PN activation and defines a temporally distinct phase. Collectively, our data support the involvement of Lateral Horn excitatory and inhibitory stimulation in habituation. These results provide essential cellular substrates for future analyses of the molecular mechanisms that govern the duration and transition between these distinct temporal habituation phases. Editorial note: This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter).

Assessing health-related resiliency in HIV+ Latin women: Preliminary psychometric findings.

BACKGROUND: HIV-associated vulnerabilities-especially those linked to psychological issues-and limited mental health-treatment resources have the potential to adversely affect the health statuses of individuals. The concept of resilience has been introduced in the literature to shift the emphasis from vulnerability to protective factors. Resilience, however, is an evolving construct and is measured in various ways, though rarely among underserved, minority populations. Herein, we present the preliminary psychometric properties of a sample of HIV-seropositive Puerto Rican women, measured using a newly developed health-related resilience scale. METHODS AND DESIGN: The Resilience Scales for Children and Adolescents, an instrument with solid test construction properties, acted as a model in the development (in both English and Spanish) of the HRRS, providing the same dimensions and most of the same subscales. The present sample was nested within the Hispanic-Latino longitudinal cohort of women (HLLC), that is part of the NeuroAIDS Research Program at the University of Puerto Rico (UPR), Medical Sciences Campus (MSC). Forty-five consecutively recruited, HIV+ women from the HLLC completed a demographic survey, the HRRS, and the Beck Depression Inventory-I, Spanish version. RESULTS: The results demonstrate excellent overall internal consistency for the total HRRS score (α = 0.95). Each of the dimensional scores also evidenced acceptable internal consistency (α ≥ 0.88). All the dimensional and subscale content validity indices were above the 0.42 cut-off. Analysis revealed a significant negative correlation between the HRRS total score and BDI-I-S (r(45) = -0.453, p < 0.003). CONCLUSION: Albeit preliminary in nature, the present study provides support for the HRRS as a measure to assess resilience among individuals living with chronic medical conditions. Minority populations, especially non-English speaking ones, are understudied across the field of medicine, and when efforts are made to include these patient groups, measurement is rarely tailored to their unique cultural and linguistic experiences. The HRRS is a measure that addresses these notable voids in the medical literature.

CD44 Transmembrane Receptor and Hyaluronan Regulate Adult Hippocampal Neural Stem Cell Quiescence and Differentiation.

Adult neurogenesis in the hippocampal subgranular zone (SGZ) is involved in learning and memory throughout life but declines with aging. Mice lacking the CD44 transmembrane receptor for the glycosaminoglycan hyaluronan (HA) demonstrate a number of neurological disturbances including hippocampal memory deficits, implicating CD44 in the processes underlying hippocampal memory encoding, storage, or retrieval. Here, we found that HA and CD44 play important roles in regulating adult neurogenesis, and we provide evidence that HA contributes to age-related reductions in neural stem cell (NSC) expansion and differentiation in the hippocampus. CD44-expressing NSCs isolated from the mouse SGZ are self-renewing and capable of differentiating into neurons, astrocytes, and oligodendrocytes. Mice lacking CD44 demonstrate increases in NSC proliferation in the SGZ. This increased proliferation is also observed in NSCs grown in vitro, suggesting that CD44 functions to regulate NSC proliferation in a cell-autonomous manner. HA is synthesized by NSCs and increases in the SGZ with aging. Treating wild type but not CD44-null NSCs with HA inhibits NSC proliferation. HA digestion in wild type NSC cultures or in the SGZ induces increased NSC proliferation, and CD44-null as well as HA-disrupted wild type NSCs demonstrate delayed neuronal differentiation. HA therefore signals through CD44 to regulate NSC quiescence and differentiation, and HA accumulation in the SGZ may contribute to reductions in neurogenesis that are linked to age-related decline in spatial memory.

What You Do Not Know Could Hurt You: What Women Wish Their Doctors Had Told Them About Chemotherapy Side Effects on Memory and Response to Alcohol.

For many patients, a cancer diagnosis is followed by chemotherapy treatment, which works by attacking cells that are growing and dividing throughout the body. Although cancer cells grow and divide more quickly than healthy cells, both are targets. The loss of healthy cells is associated with side effects, such as memory loss and altered response to a variety of food and drugs. In this pilot study, we use the "Survey of female cancer treatments, effects on memory and alcohol awareness" to explore trends in female experience and awareness of side effects associated with chemotherapy. We examined 79 female cancer patients, 46 Spanish-speaking women in Puerto Rico and 33 English-speaking women in the continental United States, and compared the rates of a reported memory loss or an altered ethanol response following chemotherapy, whether or not potential side effects were discussed with a medical professional, and whether they experienced changes in alcohol consumption after treatment. A majority of participants reported having experienced short-term memory loss postchemotherapy. Changes in response to alcohol and an altered sensitivity to alcohol were also reported by 25%-47% of the respondents. Additionally, more than half of all female cancer patients reported that they wished they would have received information on the side effects of chemotherapy and secondary medications prior to treatment. The survey results suggest that medical professionals are not adequately informing women of common, potentially harmful side effects of chemotherapy. Women do wish to be more educated about potential side effects related to memory and alcohol and be given the opportunity to discuss potential outcomes with a medical professional prior to treatment to reduce the negative impact of treatment-related side effects on posttreatment quality of life.

S6 Kinase Reflects and Regulates Ethanol-Induced Sedation.

Alcohol use disorders (AUDs) affect people at great individual and societal cost. Individuals at risk for AUDs are sensitive to alcohol's rewarding effects and/or resistant to its aversive and sedating effects. The molecular basis for these traits is poorly understood. Here, we show that p70 S6 kinase (S6k), acting downstream of the insulin receptor (InR) and the small GTPase Arf6, is a key mediator of ethanol-induced sedation in Drosophila. S6k signaling in the adult nervous system determines flies' sensitivity to sedation. Furthermore, S6k activity, measured via levels of phosphorylation (P-S6k), is a molecular marker for sedation and overall neuronal activity: P-S6k levels are decreased when neurons are silenced, as well as after acute ethanol sedation. Conversely, P-S6k levels rebound upon recovery from sedation and are increased when neuronal activity is enhanced. Reducing neural activity increases sensitivity to ethanol-induced sedation, whereas neuronal activation decreases ethanol sensitivity. These data suggest that ethanol has acute silencing effects on adult neuronal activity, which suppresses InR/Arf6/S6k signaling and results in behavioral sedation. In addition, we show that activity of InR/Arf6/S6k signaling determines flies' behavioral sensitivity to ethanol-induced sedation, highlighting this pathway in acute responses to ethanol. SIGNIFICANCE STATEMENT: Genetic factors play a major role in the development of addiction. Identifying these genes and understanding their molecular mechanisms is a necessary first step in the development of targeted therapeutic intervention. Here, we show that signaling from the insulin receptor in Drosophila neurons determines flies' sensitivity to ethanol-induced sedation. We show that this signaling cascade includes the small GTPase Arf6 and S6 kinase (S6k). In addition, activity of S6k is regulated by acute ethanol exposure and by neuronal activity. S6k activity is therefore both an acute target of ethanol exposure and a regulator of ethanol's effects on behavior.

RhoGAP18B Isoforms Act on Distinct Rho-Family GTPases and Regulate Behavioral Responses to Alcohol via Cofilin.

Responses to the effects of ethanol are highly conserved across organisms, with reduced responses to the sedating effects of ethanol being predictive of increased risk for human alcohol dependence. Previously, we described that regulators of actin dynamics, such as the Rho-family GTPases Rac1, Rho1, and Cdc42, alter Drosophila's sensitivity to ethanol-induced sedation. The GTPase activating protein RhoGAP18B also affects sensitivity to ethanol. To better understand how different RhoGAP18B isoforms affect ethanol sedation, we examined them for their effects on cell shape, GTP-loading of Rho-family GTPase, activation of the actin-severing cofilin, and actin filamentation. Our results suggest that the RhoGAP18B-PA isoform acts on Cdc42, while PC and PD act via Rac1 and Rho1 to activate cofilin. In vivo, a loss-of-function mutation in the cofilin-encoding gene twinstar leads to reduced ethanol-sensitivity and acts in concert with RhoGAP18B. Different RhoGAP18B isoforms, therefore, act on distinct subsets of Rho-family GTPases to modulate cofilin activity, actin dynamics, and ethanol-induced behaviors.

Severity of eating disorder symptoms related to oxytocin receptor polymorphisms in anorexia nervosa.

Oxytocin is a peptide hormone important for social behavior and differences in psychological traits have been associated with variants of the oxytocin receptor gene in healthy people. We examined whether single nucleotide polymorphisms (SNPs) of the oxytocin receptor gene (OXTR) correlated with clinical symptoms in women with anorexia nervosa, bulimia nervosa, and healthy comparison (HC) women. Subjects completed clinical assessments and provided DNA for analysis. Subjects were divided into four groups: HC, subjects currently with anorexia nervosa (AN-C), subjects with a history of anorexia nervosa but in long-term weight recovery (AN-WR), and subjects with bulimia nervosa (BN). Five SNPs of the oxytocin receptor were examined. Minor allele carriers showed greater severity in most of the psychiatric symptoms. Importantly, the combination of having had anorexia and carrying either of the A alleles for two SNPS in the OXTR gene (rs53576, rs2254298) was associated with increased severity specifically for ED symptoms including cognitions and behaviors associated both with eating and appearance. A review of psychosocial data related to the OXTR polymorphisms examined is included in the discussion. OXTR polymorphisms may be a useful intermediate endophenotype to consider in the treatment of patients with anorexia nervosa.

CD44 is required for spatial memory retention and sensorimotor functions.

CD44 is a transmembrane receptor for the glycosaminoglycan hyaluronan, a component of the extracellular matrix. CD44 is expressed by neural stem/progenitor cells, astrocytes, and some neurons but its function in the central nervous system is unknown. To determine the role of CD44 in brain function, we behaviorally analyzed CD44-null (KO) and wild-type (WT) mice. KO mice showed increased activity levels in the light-dark test and a trend toward increased activity in the open field. In addition, KO mice showed impaired hippocampus-dependent spatial memory retention in the probe trial following the first hidden-platform training day in the Morris water maze: WT mice showed spatial memory retention and spent more time in the target quadrant than any other quadrant, while KO mice did not. Although there were no genotype differences in swim speeds during the water maze training sessions with the visible or hidden platform, sensorimotor impairments were seen in other behavioral tests. In the inclined screen and balance beam tests, KO mice moved less than WT mice. In the wire hang test, KO mice also fell off of the wire faster than WT mice. In contrast, there was no genotype difference when emotional learning and memory were assessed in the passive avoidance test. These data support an important role for CD44 in locomotor and sensorimotor functions, and in spatial memory retention.

Long-lasting, experience-dependent alcohol preference in Drosophila.

To understand the molecular and neural mechanisms underlying alcohol addiction, many models ranging from vertebrates to invertebrates have been developed. In Drosophila melanogaster, behavioral paradigms from assaying acute responses to alcohol and to behaviors more closely modeling addiction have emerged in recent years. However, both the CAFÉ assay, similar to a two-bottle choice consumption assay, as well as conditioned odor preference, where ethanol is used as the reinforcer, are labor intensive and have low throughput. To address this limitation, we have established a novel ethanol consumption preference assay, called FRAPPÉ, which allows for fast, high throughput measurement of consumption in individual flies, using a fluorescence plate reader. We show that naïve flies do not prefer to consume ethanol, but various pre-exposures, such as ethanol vapor or voluntary ethanol consumption, induce ethanol preference. This ethanol-primed preference is long lasting and is not driven by calories contained in ethanol during the consumption choice. Our novel experience-dependent model of ethanol preference in Drosophila-a highly genetically tractable organism-therefore recapitulates salient features of human alcohol abuse and will facilitate the molecular understanding of the development of alcohol preference.

The role of the actin cytoskeleton in regulating Drosophila behavior.

Over the past decade, the function of the cytoskeleton has been studied extensively in developing and mature neurons. Actin, a major cytoskeletal protein, is indispensable for the structural integrity and plasticity of neurons and their synapses. Disruption of actin dynamics has significant consequence for neurons, neuronal circuits, and the functions they govern. In particular, cell adhesion molecules, members of the Rho family of GTPases, and actin-binding proteins are important modulators of actin dynamics and neuronal as well as behavioral plasticity. In this review, we discuss recent advances in Drosophila that highlight the importance of actin regulatory proteins in mediating fly behaviors such as circadian rhythm, courtship behavior, learning and memory, and the development of drug addiction.

YWHAE/14-3-3ε: a potential novel genetic risk factor and CSF biomarker for HIV neurocognitive impairment.

YWHAE (14-3-3ε) protein levels are considered to be a reliable biomarker for neurodegeneration. The YWHAE protein interacts both directly and indirectly with human immunodeficiency virus (HIV) accessory proteins, leading to cell death. The purpose of this study was to examine the relationship between YWHAE polymorphisms and HIV-associated neurocognitive disorder (HAND) and the relationship between YWHAE protein levels and HAND. A cross-sectional study using random samples of HIV-seropositive (n = 20) and HIV-seronegative (controls) (n = 16) women from the Hispanic-Latino Longitudinal Cohort of Women was conducted. Individuals who are HIV-seropositive and heterozygous at the rs4790084/rs1204828 loci in the YWHAE gene were 3× more likely to display reduced cognitive functioning, to have received a HAND diagnosis, and to have less YHWAE protein expressed than homozygotes. Western blots from cerebral spinal fluid indicate that the HIV-seropositive women with HAND expressed 4.5× less YWHAE compared to HIV-seropositive cognitively normal women (94 % sensitivity, 84 % specificity; HIV-seropositive vs. controls). Therefore, polymorphism in YWHAE may be a genetic risk factor for HAND and levels of YWHAE protein are a likely biomarker for neurocognitive status in HIV-seropositive women.

Developmental methamphetamine exposure results in short- and long-term alterations in hypothalamic-pituitary-adrenal-axis-associated proteins.

Developmental exposure to methamphetamine (MA) causes long-term behavioral and cognitive deficits. One pathway through which MA might induce these deficits is by elevating glucocorticoid levels. Glucocorticoid overexposure during brain development can lead to long-term disruptions in the hypothalamic-pituitary-adrenal (HPA) axis. These disruptions affect the regulation of stress responses and may contribute to behavioral and cognitive deficits reported following developmental MA exposure. Furthermore, alterations in proteins associated with the HPA axis, including vasopressin, oxytocin, and glucocorticoid receptors (GR), are correlated with disruptions in mood and cognition. We therefore hypothesized that early MA exposure will result in short- and long-term alterations in the expression of HPA axis-associated proteins. Male mice were treated with MA (5 mg/kg daily) or saline from postnatal day (P) 11 to P20. At P20 and P90, mice were perfused and their brains processed for vasopressin, oxytocin, and GR immunoreactivity within HPA axis-associated regions. At P20, there was a significant decrease in the number of vasopressin-immunoreactive cells and the area occupied by vasopressin immunoreactivity in the paraventricular nucleus (PVN) of MA-treated mice, but no difference in oxytocin immunoreactivity in the PVN, or GR immunoreactivity in the hippocampus or PVN. In the central nucleus of the amygdala, the area occupied by GR immunoreactivity was decreased by MA. At P90, the number of vasopressin-immunoreactive cells was still decreased, but the area occupied by vasopressin immunoreactivity no longer differed from saline controls. No effects of MA were found on oxytocin or GR immunoreactivity at P90. Thus developmental MA exposure has short- and long-term effects on vasopressin immunoreactivity and short-term effects on GR immunoreactivity.

Why, After Chemotherapy, is it Necessary to Assess Memory Using Translational Testing?

As the number of cancer survivors rises, so does the importance of understanding what happens post-chemotherapy. The evidence is clear that chemotherapy affects not only cancer cells, but also healthy cells including neurons, leading to long-term cognitive dysfunction in a large portion of survivors. In order to understand the mechanism of action and in the hope of reducing the potential neurocognitive side effects of chemotherapy, pre-clinical testing should be used more effectively. However, the field is lacking translation from clinical studies to animal models. Spatial learning and memory paradigms based on the water maze, the most commonly used rodent model, are available for translational testing in humans and could overcome this weakness. There is an overwhelming need in the field to understand whether the water maze is an adequate model for post-chemotherapy impairments or whether other paradigms should be used. This is of great importance for the understanding of the mechanisms, side effects of new drugs, appropriate pharmacotherapy, and confounding factors related to chemotherapy treatment regiments. This review is very important to both basic scientists and clinicians determining how translational paradigms are critical to future cancer research, as well as what type of paradigms are appropriate in our technically advancing society.

Adult neuronal Arf6 controls ethanol-induced behavior with Arfaptin downstream of Rac1 and RhoGAP18B.

Alcohol use disorders affect millions of individuals. However, the genes and signaling pathways involved in behavioral ethanol responses and addiction are poorly understood. Here we identify a conserved biochemical pathway that underlies the sedating effects of ethanol in Drosophila. Mutations in the Arf6 small GTPase signaling pathway cause hypersensitivity to ethanol-induced sedation. We show that Arf6 functions in the adult nervous system to control ethanol-induced behavior. We also find that the Drosophila Arfaptin protein directly binds to the activated forms of Arf6 and Rac1 GTPases, and mutants in Arfaptin also display ethanol sensitivity. Arf6 acts downstream of Rac1 and Arfaptin to regulate ethanol-induced behaviors, and we thus demonstrate that this conserved Rac1/Arfaptin/Arf6 pathway is a major mediator of ethanol-induced behavioral responses.

Translational spatial task and its relationship to HIV-associated neurocognitive disorders and apolipoprotein E in HIV-seropositive women.

HIV-associated neurocognitive disorders (HAND) continue to be a neurological complication of HIV infection in the era of combined antiretroviral therapy. Hippocampal neurodegeneration and dysfunction occurs as a result of HIV infection, but few studies to date have assesses spatial learning and memory function in patients with HAND. We used the Memory Island (MI) test to study the effects of HIV infection, apolipoprotein E (ApoE) allele status, and cerebral spinal fluid (CSF) ApoE protein levels on spatial learning and memory in our cohort of Hispanic women. The MI test is a virtual reality-based computer program that tests spatial learning and memory and was designed to resemble the Morris Water Maze test of hippocampal function widely used in rodent studies. In the current study, HIV-seropositive women (n = 20) and controls (n = 16) were evaluated with neuropsychological (NP) tests, the MI test, ApoE, and CSF ApoE assays. On the MI, the HIV-seropositive group showed significant reduced learning and delayed memory performance compared with HIV-seronegative controls. When stratified by cognitive performance on NP tests, the HIV-seropositive, cognitively impaired group performed worse than HIV-seronegative controls in ability to learn and in the delayed memory trial. Interestingly, differences were observed in the results obtained by the NP tests and the MI test for ε4 carriers and noncarriers: NP tests showed effects of the ε4 allele in HIV-seronegative women but not HIV-seropositive ones, whereas the converse was true for the MI test. Our findings suggest that the MI test is sensitive in detecting spatial deficits in HIV-seropositive women and that these deficits may arise relatively early in the course of HAND.