Search

BACKGROUND: The loss of insulin-like growth factor 1 (IGF-1) expression in senescent dermal fibroblasts during aging is associated with an increased risk of nonmelanoma skin cancer (NMSC). We tested how IGF-1 signaling can influence photocarcinogenesis during chronic UVB exposure to determine if fractionated laser resurfacing (FLR) of aged skin, which upregulates dermal IGF-1 levels, can prevent the occurrence of actinic keratosis (AK) and NMSC. METHODS: A human skin/immunodeficient mouse xenografting model was used to test the effects of a small molecule inhibitor of the IGF-1 receptor on chronic UVB radiation. Subsequently, the durability of FLR treatment was tested on a cohort of human participants aged 65 years and older. Finally, 48 individuals aged 60 years and older with considerable actinic damage were enrolled in a prospective randomized clinical trial in which they underwent a single unilateral FLR treatment of one lower arm. Numbers of AKs/NMSCs were recorded on both extremities for up to 36 months in blinded fashion. RESULTS: Xenografting studies revealed that chronic UVB treatment with a topical IGF-1R inhibitor resulted in a procarcinogenic response. A single FLR treatment was durable in restoring appropriate UVB response in geriatric skin for at least 2 years. FLR resulted in sustained reduction in numbers of AKs and decreased numbers of NMSCs in the treated arm (2 NMSCs) versus the untreated arm (24 NMSCs). CONCLUSION: The elimination of senescent fibroblasts via FLR reduced the procarcinogenic UVB response of aged skin. Thus, wounding therapies are a potentially effective prophylaxis for managing high-risk populations. TRIAL REGISTRATION: ClinicalTrials.gov (NCT03906253). FUNDING: National Institutes of Health, Veterans Administration.

BACKGROUND AND OBJECTIVES Actinic keratoses (AK) are common pre-cancerous lesions, which are associated with ultraviolet light exposure and aging. Wounding therapies such as fractionated laser resurfacing (FLR) have been previously demonstrated to effectively treat facial AK. However, the effectiveness of FLR on other sites commonly afflicted with AK has not been studied in detail. Previously, our group has reported that treatment of aged skin with wounding therapies including dermabrasion and ablative fractionated resurfacing results in the removal of senescent fibroblasts and normalizing the pro-carcinogenic acute ultraviolet B radiation responses associated with aged skin. The current studies were designed to test the effectiveness of FLR of the forearm skin of subjects aged 60 and older to remove AKs. STUDY DESIGN/MATERIALS AND METHODS Between February 2018 and March 2019, 30 subjects were enrolled in a study, in which they underwent a single FLR treatment of one extremity including the dorsal forearm, wrist, and dorsal hand. The number of AKs was recorded on both extremities at baseline, 3 and 6 months in a blinded fashion. Side effects of the FLR were documented. RESULTS A single FLR treatment resulted in a 62% reduction in the absolute number of AK in the treated arm at 6 months post-treatment. The laser treatment was well-tolerated without major complications. CONCLUSIONS These studies demonstrate that FLR using settings, which have demonstrated to remove senescent fibroblasts and normalize the pro-carcinogenic UVB-response of aged skin is a potentially effective and safe field therapy treatment that should be studied for long-term efficacy for use in treating upper extremity AKs. Lasers Surg. Med. © 2019 Wiley Periodicals, Inc.

A fundamental property of extinction is that the behavior that is suppressed during extinction can be unmasked through a number of postextinction procedures. Of the commonly studied unmasking procedures (spontaneous recovery, reinstatement, contextual renewal, and rapid reacquisition), rapid reacquisition is the only approach that allows a direct comparison between the impact of a conditioning trial before or after extinction. Thus, it provides an opportunity to evaluate the ways in which extinction changes a subsequent learning experience. In five experiments, we investigate the behavioral and neurobiological mechanisms of postextinction reconditioning. We show that rapid reconditioning of unsignaled contextual fear after extinction in male Long–Evans rats is associative and not affected by the number or duration of extinction sessions that we examined. We then evaluate c-Fos expression and histone acetylation (H4K8) in the hippocampus, amygdala, prefrontal cortex, and bed nucleus of the stria terminalis. We find that in general, initial conditioning has a stronger impact on c-Fos expression and acetylation than does reconditioning after extinction. We discuss implications of these results for theories of extinction and the neurobiology of conditioning and extinction.

A complete carcinogen, ultraviolet B (UVB) radiation (290-320 nm), is the major cause of skin cancer. UVB-induced systemic immunosuppression that contributes to photocarcinogenesis is due to the glycerophosphocholine-derived lipid mediator platelet-activating factor (PAF). A major question in photobiology is how UVB radiation, which only absorbs appreciably in the epidermal layers of skin, can generate systemic effects. UVB exposure and PAF receptor (PAFR) activation in keratinocytes induce the release of large numbers of microvesicle particles (MVPs; extracellular vesicles ranging from 100 to 1000 nm in size). MVPs released from skin keratinocytes in vitro in response to UVB (UVB-MVPs) are dependent on the keratinocyte PAFR. Here, we used both pharmacologic and genetic approaches in cells and mice to show that both the PAFR and enzyme acid sphingomyelinase (aSMase) were necessary for UVB-MVP generation. Our discovery that the calcium-sensing receptor is a keratinocyte-selective MVP marker allowed us to determine that UVB-MVPs leaving the keratinocyte can be found systemically in mice and humans following UVB exposure. Moreover, we found that UVB-MVPs contained bioactive contents including PAFR agonists that allowed them to serve as effectors for UVB downstream effects, in particular UVB-mediated systemic immunosuppression.

Although a great deal is known about neurobiological mechanisms of initial conditioning and extinction, relatively little is known about mechanisms involved in the return of behavior following extinction. In this article, we examine the effects of temporarily inactivating the bed nucleus of the stria terminalis (BNST) on initial conditioning and postextinction reconditioning. We investigate effects in unsignaled contextual fear conditioning, in which animals initially receive strong contextual conditioning, followed by three sessions of nonreinforced context exposure (extinction), and then receive a single context-shock reconditioning trial. In 2 experiments with male Long Evans rats, we evaluated the effects of delivery of a muscimol/baclofen cocktail to the BNST prior to initial conditioning or reconditioning. In Experiment 1, we found that a single context-shock pairing results in more freezing following extinction than when it is the initial conditioning trial. This rapid reconditioning effect was impaired by BNST inactivation. In Experiment 2, we found that BNST inactivation also causes a deficit in freezing after strong initial conditioning. These findings suggest that the BNST is involved in both initial conditioning and postextinction reconditioning. We discuss implications of these findings for current thinking about BNST function in learning and memory processes. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

The bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress, and glutamate transmission within this region has been implicated in the neurobiology of alcoholism. Herein, we used a combination of immunoblotting, neuropharmacological and transgenic procedures to investigate the role for metabotropic glutamate receptor 5 (mGlu5) signaling within the BNST in excessive drinking. We discovered that mGlu5 signaling in the BNST is linked to excessive alcohol consumption in a manner distinct from behavioral or neuropharmacological endophenotypes that have been previously implicated as triggers for heavy drinking. Our studies demonstrate that, in male mice, a history of chronic binge alcohol-drinking elevates BNST levels of the mGlu5-scaffolding protein Homer2 and activated extracellular signal-regulated kinase (ERK) in an adaptive response to limit alcohol consumption. Male and female transgenic mice expressing a point mutation of mGlu5 that cannot be phosphorylated by ERK exhibit excessive alcohol-drinking, despite greater behavioral signs of alcohol intoxication and reduced anxiety, and are insensitive to local manipulations of signaling in the BNST. These transgenic mice also show selective insensitivity to alcohol-aversion and increased novelty-seeking, which may be relevant to excessive drinking. Further, the insensitivity to alcohol-aversion exhibited by male mice can be mimicked by the local inhibition of ERK signaling within the BNST. Our findings elucidate a novel mGluR5-linked signaling state within BNST that plays a central and unanticipated role in excessive alcohol consumption.SIGNIFICANCE STATEMENTThe bed nucleus of the stria terminalis (BNST) is part of the limbic-hypothalamic system important for behavioral responses to stress and alcohol, and glutamate transmission within BNST is implicated in the neurobiology of alcoholism. The present study provides evidence that a history of excessive alcohol drinking increases signaling through the metabotropic glutamate receptor 5 (mGlu5) receptor within the BNST in an adaptive response to limit alcohol consumption. In particular, disruption of mGlu5 phosphorylation by extracellular signal-regulated kinase within this brain region induces excessive alcohol-drinking, which reflects a selective insensitivity to the aversive properties of alcohol intoxication. These data indicate that a specific signaling state of mGlu5 within BNST plays a central and unanticipated role in excessive alcohol consumption.

Homer postsynaptic scaffolding proteins regulate forebrain glutamate transmission and thus, are likely molecular candidates mediating hypofrontality in addiction. Protracted withdrawal from cocaine experience increases the relative expression of Homer2 versus Homer1 isoforms within medial prefrontal cortex (mPFC). Thus, this study used virus-mediated gene transfer strategies to investigate the functional relevance of an imbalance in mPFC Homer1/2 expression as it relates to various measures of sensorimotor, cognitive, emotional and motivational processing, as well as accompanying alterations in extracellular glutamate in C57BL/6J mice. mPFC Homer2b overexpression elevated basal glutamate content and blunted cocaine-induced glutamate release within the mPFC, whereas Homer2b knockdown produced the opposite effects. Despite altering mPFC glutamate, Homer2b knockdown failed to influence cocaine-elicited conditioned place preferences, nor did it produce consistent effects on any other behavioral measures. In contrast, elevating the relative expression of Homer2b versus Homer1 within mPFC, by overexpressing Homer2b or knocking down Homer1c, shifted the dose-response function for cocaine-conditioned reward to the left, without affecting cocaine locomotion or sensitization. Intriguingly, both these transgenic manipulations produced glutamate anomalies within the nucleus accumbens (NAC) of cocaine-naive animals that are reminiscent of those observed in cocaine experienced animals, including reduced basal extracellular glutamate content, reduced Homer1/2 and glutamate receptor expression, and augmented cocaine-elicited glutamate release. Together, these data provide novel evidence in support of opposing roles for constitutively expressed Homer1 and Homer2 isoforms in regulating mPFC glutamate transmissionin vivoand support the hypothesis that cocaine-elicited increases in the relative amount of mPFC Homer2 versus Homer1 signaling produces abnormalities in NAC glutamate transmission that enhance vulnerability to cocaine reward.