Increased prevalence of indoor Aspergillus and Penicillium species is associated with indoor flooding and coastal proximity: a case study of 28 moldy buildings.

Indoor flooding is a leading contributor to indoor dampness and the associated mold infestations in the coastal United States. Whether the prevalent mold genera that infest the coastal flood-prone buildings are different from those not flood-prone is unknown. In the current case study of 28 mold-infested buildings across the U.S. east coast, we surprisingly noted a trend of higher prevalence of indoor Aspergillus and Penicillium genera (denoted here as Asp-Pen) in buildings with previous flooding history. Hence, we sought to determine the possibility of a potential statistically significant association between indoor Asp-Pen prevalence and three building-related variables: (i) indoor flooding history, (ii) geographical location, and (iii) the building's use (residential versus non-residential). Culturable spores and hyphal fragments in indoor air were collected using the settle-plate method, and corresponding genera were confirmed using phylogenetic analysis of their ITS sequence (the fungal barcode). Analysis of variance (ANOVA) using Generalized linear model procedure (GLM) showed that Asp-Pen prevalence is significantly associated with indoor flooding as well as coastal proximity. To address the small sample size, a multivariate decision tree analysis was conducted, which ranked indoor flooding history as the strongest determinant of Asp-Pen prevalence, followed by geographical location and the building's use.

Glial cells as therapeutic targets for smoking cessation.

Smoking remains the leading cause of morbidity and mortality in the United States, with less than 5% of smokers attempting to quit succeeding. This low smoking cessation success rate is thought to be due to the long-term adaptations and alterations in synaptic plasticity that occur following chronic nicotine exposure and withdrawal. Glial cells have recently emerged as active players in the development of dependence phenotypes due to their roles in modulating neuronal functions and synaptic plasticity. Fundamental studies have demonstrated that microglia and astrocytes are crucial for synapse formation and elimination in the developing brain, likely contributing to why glial dysfunction is implicated in numerous neurological and psychiatric disorders. Recently, there is increasing evidence for the involvement of glial cells in drug dependence and its associated behavioral manifestations. This review summarizes the newly evaluated role of microglia and astrocytes as molecular drivers of nicotine dependence and withdrawal phenotypes. This article is part of the special issue on 'Contemporary Advances in Nicotine Neuropharmacology.

Microglia morphology and proinflammatory signaling in the nucleus accumbens during nicotine withdrawal.

Smoking is the largest preventable cause of death and disease in the United States. However, <5% of quit attempts are successful, underscoring the urgent need for novel therapeutics. Microglia are one untapped therapeutic target. While previous studies have shown that microglia mediate both inflammatory responses in the brain and brain plasticity, little is known regarding their role in nicotine dependence and withdrawal phenotypes. Here, we examined microglial changes in the striatum-a mesolimbic region implicated in the rewarding effects of drugs and the affective disruptions occurring during withdrawal. We show that both nicotine and withdrawal induce microglial morphological changes; however, proinflammatory effects and anxiogenic behaviors were observed only during nicotine withdrawal. Pharmacological microglial depletion during withdrawal prevented these effects. These results define differential effects of nicotine and withdrawal on inflammatory signaling in the brain, laying the groundwork for development of future smoking cessation therapeutics.

Altered gating of Kv1.4 in the nucleus accumbens suppresses motivation for reward.

Deficient motivation contributes to numerous psychiatric disorders, including withdrawal from drug use, depression, schizophrenia, and others. Nucleus accumbens (NAc) has been implicated in motivated behavior, but it remains unclear whether motivational drive is linked to discrete neurobiological mechanisms within the NAc. To examine this, we profiled cohorts of Sprague-Dawley rats in a test of motivation to consume sucrose. We found that substantial variability in willingness to exert effort for reward was not associated with operant responding under low-effort conditions or stress levels. Instead, effort-based motivation was mirrored by a divergent NAc shell transcriptome with differential regulation at potassium and dopamine signaling genes. Functionally, motivation was inversely related to excitability of NAc principal neurons. Furthermore, neuronal and behavioral outputs associated with low motivation were linked to faster inactivation of a voltage-gated potassium channel, Kv1.4. These results raise the prospect of targeting Kv1.4 gating in psychiatric conditions associated with motivational dysfunction.

Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes.

Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well established. We found that extracellular dopamine triggered rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation but instead relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. This was accompanied by reduced duration and increased frequency of astrocytic Ca2+ transients, but little effect on astrocytic voltage-gated potassium channel currents. To isolate possible mechanisms underlying these structural and functional changes, we used whole-genome RNA sequencing and found prominent dopamine-induced enrichment of genes containing the CCCTC-binding factor (CTCF) motif, suggesting involvement of chromatin restructuring in the nucleus. CTCF binding to promoter sites bidirectionally regulates gene transcription and depends on activation of poly-ADP-ribose polymerase 1 (PARP1). Accordingly, antagonism of PARP1 occluded dopamine-induced changes, whereas a PARP1 agonist facilitated dopamine-induced changes on its own. These results indicate that astrocyte response to elevated dopamine involves PARP1-mediated CTCF genomic restructuring and concerted expression of gene networks. Our findings propose epigenetic regulation of chromatin landscape as a critical factor in the rapid astrocyte response to dopamine.SIGNIFICANCE STATEMENT Although dopamine is widely recognized for its role in modulating neuronal responses both in healthy and disease states, little is known about dopamine effects at non-neuronal cells in the brain. To address this gap, we performed whole-genome sequencing of astrocytes exposed to elevated extracellular dopamine and combined it with evaluation of effects on astrocyte morphology and function. We demonstrate a temporally dynamic pattern of genomic plasticity that triggers pronounced changes in astrocyte morphology and function. We further show that this plasticity depends on activation of genes sensitive to DNA-binding protein CTCF. Our results propose that a broad pattern of astrocyte responses to dopamine specifically relies on CTCF-dependent gene networks.