Whole organism snRNA-seq reveals systemic peripheral changes in Alzheimer's Disease fly models.

Peripheral tissues become disrupted in Alzheimer's Disease (AD). However, a comprehensive understanding of how the expression of AD-associated toxic proteins, Aß42 and Tau, in neurons impacts the periphery is lacking. Using Drosophila, a prime model organism for studying aging and neurodegeneration, we generated the Alzheimer's Disease Fly Cell Atlas (AD-FCA): whole-organism single-nucleus transcriptomes of 219 cell types from adult flies neuronally expressing human Aß42 or Tau. In-depth analyses and functional data reveal impacts on peripheral sensory neurons by Aß42 and on various non-neuronal peripheral tissues by Tau, including the gut, fat body, and reproductive system. This novel AD atlas provides valuable insights into potential biomarkers and the intricate interplay between the nervous system and peripheral tissues in response to AD-associated proteins.

Menthol facilitates dopamine-releasing effect of nicotine in rat nucleus accumbens.

Menthol is a significant flavoring additive in tobacco products. Accumulating clinical evidence suggests that menthol may promote tobacco smoking and nicotine dependence. Our previous studies demonstrated that menthol enhanced nicotine reinforcement in rats. However, it is unclear whether menthol interacts with nicotine at the neurochemical level. The present study used intracranial microdialysis to examine whether and the ways in which menthol affects nicotine-induced dopamine release in rats in the nucleus accumbens core (NAc), a terminal field of brain reward circuitry. To make comparisons with our previous work that showed an enhancing effect of menthol on nicotine self-administration behavior, male Sprague-Dawley rats were first trained in 20 daily 1-h sessions to press a lever for intravenous nicotine self-administration (15 µg/kg/infusion). Dopamine levels were then measured in the right NAc using intracranial microdialysis coupled with high-performance liquid chromatography. Five minutes before microdialysis, the rats received an intraperitoneal injection of menthol (0, 1, 2.5, and 5 mg/kg), a subcutaneous injection of nicotine (0.2 mg/kg or its vehicle), or both. Menthol alone did not affect dopamine levels in dialysates, whereas nicotine alone elevated dopamine levels. Combined nicotine and menthol administration significantly increased dopamine levels compared with nicotine alone. These data indicate a facilitating effect of menthol on nicotine-induced dopamine release in the NAc. These findings shed light on our understanding of the neurobiological mechanisms that underlie the menthol-induced enhancement of nicotine reinforcement.

Effects of menthol and its interaction with nicotine-conditioned cue on nicotine-seeking behavior in rats.

RATIONALE: Increasing clinical evidence suggests that menthol, a significant flavoring additive in tobacco products, may contribute to smoking and nicotine dependence. Relapse to smoking behavior presents a formidable challenge for the treatment of tobacco addiction. An unresolved issue is whether the mentholation of tobacco products precipitates relapse to tobacco use in abstinent smokers. OBJECTIVES: The present study examined the effects of menthol on the perseverance and relapse of nicotine-seeking behavior in rats. METHODS: Male Sprague-Dawley rats were trained to press a lever for intravenous nicotine self-administration (0.03 mg/kg/infusion) under a fixed-ratio five schedule of reinforcement. Each nicotine infusion was signaled by the presentation of a sensory stimulus that was established as a discrete nicotine-conditioned cue. Five minutes prior to the sessions, the rats received an intraperitoneal injection of menthol (0.1 mg/kg) or vehicle. In the subsequent extinction test sessions, nicotine was unavailable with or without menthol and/or the nicotine-conditioned cue. The reinstatement tests were performed the following day after the extinction criterion was met. Menthol was also tested on food-seeking responses. In a subset of nicotine-trained rats, a transient receptor potential melastatin 8 (TRPM8) antagonist RQ-00203078 was given prior to menthol administration. RESULTS: Continued administration of menthol sustained responses on the previously active and nicotine-reinforced lever in the extinction tests. The readministration of menthol after extinction reinstated active lever responses. In both the extinction and the reinstatement tests, a combination of pre-session menthol administration and cue representation during the session produced a more robust behavioral effect than either menthol or the cue alone. No such effects of menthol was observed in food trained rats. RQ-00203078 did not change menthol effect on nicotine seeking. CONCLUSION: These data demonstrated that menthol specifically sustained and reinstated nicotine-seeking behavior, and this effect was independent of TRPM8 activity. These findings suggest that menthol in most tobacco products, even not menthol labeled, may contribute to the perseverance of and relapse to tobacco-seeking behavior.

Enhancing effect of menthol on nicotine self-administration in rats.

RATIONALE: Tobacco smoking is a leading preventable cause of premature death in the USA. Menthol is a significant flavoring additive in tobacco products. Clinical evidence suggests that menthol may promote tobacco smoking and nicotine dependence. However, it is unclear whether menthol enhances the reinforcing actions of nicotine and thus facilitates nicotine consumption. This study employed a rat model of nicotine self-administration to examine the effects of menthol on nicotine-taking behavior. METHODS: Male Sprague-Dawley rats were trained in daily 1-h sessions to press a lever for intravenous nicotine self-administration under a fixed-ratio 5 schedule of reinforcement. In separate groups, rats self-administered nicotine at four different doses (0.0075, 0.015, 0.03, and 0.06 mg/kg/infusion). Five minutes prior to the two test sessions, menthol (5 mg/kg) or its vehicle was administered intraperitoneally in all rats in a counterbalanced design within each group. In separate rats that self-administered 0.015 mg/kg/infusion nicotine, menthol dose-response function was determined. Menthol was also tested on food self-administration. RESULTS: An inverted U-shaped nicotine dose-response curve was observed. Menthol pretreatment shifted the nicotine dose-response curve to the left. The facilitating effect of menthol on the self-administration of 0.015 mg/kg/infusion nicotine was dose-dependent, whereas it produced similar effects at doses above the threshold of 2.5 mg/kg. Menthol tended to suppress the self-administration of food pellets. CONCLUSIONS: These data demonstrate that menthol enhances the reinforcing effects of nicotine, and the effect of menthol was specific to nicotine. The findings suggest that menthol directly facilitates nicotine consumption, thereby contributing to tobacco smoking.

Pelvic Limb Amputation for the Treatment of a Soft-tissue Sarcoma of the Tibiotarso-tarsometatarsal Joint in a Blue-and-gold Macaw (Ara ararauna).

An unsexed, 16-year-old blue-and-gold macaw (Ara ararauna) was presented for evaluation of rapidly growing subcutaneous masses at the left tibiotarso-tarsometatarsal joint. Results of incisional biopsy were diagnostic for an intermediate-grade soft-tissue sarcoma. A distal-femoral amputation was performed and the leg was submitted for histopathology. Histopathologic examination confirmed the biopsy diagnosis and revealed neoplastic spread into the bone marrow cavity of the tibiotarsus. Excisional margins were complete. The macaw recovered and did well until it died suddenly 32 months after surgery. At necropsy, death was attributed to acute hepatic hemorrhage. No recurrence or metastasis of the sarcoma was identified.

Monitoring unmet needs: using 2-1-1 during natural disasters.

BACKGROUND: Hurricanes Katrina and Rita struck the Gulf Coast forcing unprecedented mass evacuation and devastation. Texas 2-1-1 is a disaster communication hub between callers with unmet needs and community services at disaster sites and evacuation destinations. PURPOSE: To describe the location and timing of unmet disaster needs collected in real-time through Katrina-Rita disaster phases. METHODS: In 2008-2010, a total of 25 data sets of Texas 2-1-1 calls from August-December 2005 were recoded and merged. In 2011-2012, analysis was performed of unmet need types, with comparisons over time and location; mapping was adjusted by population size. RESULTS: Of 635,983 total 2-1-1 calls during the study period, 65% included primary disaster unmet needs: housing/shelter (28%); health/safety (18%); food/water (15%); transportation/fuel (4%). Caller demand spiked on Mondays, decreasing to a precipitous drop on weekends and holidays. Unmet needs surged during evacuation and immediate disaster response, remaining at higher threshold through recovery. Unmet need volume was concentrated in metropolitan areas. After adjusting for population size, "hot-spots" showed in smaller evacuation destinations and along evacuation routes. CONCLUSIONS: New disaster management strategies and policies are needed for evacuation destinations to support extended evacuation and temporary or permanent relocation. Planning and monitoring disaster resources for unmet needs over time and location could be targeted effectively using real-time 2-1-1 call patterns. Smaller evacuation communities were more vulnerable, exhausting their limited resources more quickly. Emergency managers should devise systems to more quickly authorize vouchers and reimbursements. As 2-1-1s expand and coordinate disaster roles nationwide, opportunities exist for analysis of unmet disaster needs to improve disaster management and enhance community resiliency.

Genes associated with alcohol abuse and tobacco smoking in the human nucleus accumbens and ventral tegmental area.

BACKGROUND: The incidence of alcohol and tobacco co-abuse is as high as 80%. The molecular mechanism underlying this comorbidity is virtually unknown, but interactions between these drugs have important implications for the development of and recovery from drug dependence. METHODS: We investigated the effects of chronic tobacco and alcohol abuse and the interaction of the 2 behaviors on global gene expression in the human nucleus accumbens using cDNA microarrays and 20 alcoholic and control cases, with and without smoking comorbidity. Changes in gene expression were established by factorial ANOVA. Unsupervised hierarchical clustering was utilized to probe the strength of the data sets. Applying real-time PCR differential expression of candidate genes was confirmed in the nucleus accumbens and explored further in a second core region of the mesolimbic system, the ventral tegmental area. RESULTS: Subjecting the data sets derived from microarray gene expression screening to unsupervised hierarchical clustering tied the cases into distinct groups. When considering all alcohol-responsive genes, alcoholics were separated from nonalcoholics with the exception of 1 control case. All smokers were distinguished from nonsmokers based on similarity in expression of smoking-sensitive genes. In the nucleus accumbens, alcohol-responsive genes were associated with transcription, lipid metabolism, and signaling. Smoking-sensitive genes were predominantly assigned to functional groups concerned with RNA processing and the endoplasmic reticulum. Both drugs influenced the expression of genes involved in matrix remodeling, proliferation, and cell morphogenesis. Additionally, a gene set encoding proteins involved in the canonical pathway "regulation of the actin cytoskeleton" was induced in response to alcohol and tobacco co-abuse and included. Alcohol abuse elevated the expression of candidate genes in this pathway in the nucleus accumbens and ventral tegmental area, while smoking comorbidity blunted this induction in the ventral tegmental area. CONCLUSIONS: The region-specific modulation of alcohol-sensitive gene expression by smoking may have important consequences for alcohol-induced aberrations within the mesolimbic dopaminergic system.