Acetylcholine Signaling in the Basolateral Amygdala During Reward Learning

Animal survival relies in part on the ability to learn the outcomes that environmental stimuli predict and recall those associations to make decisions later in life. Learning is not monolithic, but instead is mediated by different brain regions depending on the type of information processed. Learning can happen at happen at different speeds, and memories can vary in their longevity. Much is still unknown about the neurobiology underlying learning and memory, thus further research into these processes is necessary to build foundational understanding of these critical phenomenon, and also to develop novel treatments for patients suffering from learning and memory related disorders such as Alzheimer’s Disease, addiction, and post-traumatic stress disorder. Memories that have a positive or negative emotional association are powerful and long-lasting. The basolateral amygdala (BLA) is a brain area involved in emotional processing, including associating initially neutral cues with the appetitive or aversive stimuli they come to predict. Acetylcholine (ACh), a neuromodulator with abundant release in the BLA, is implicated in many processes throughout the brain and body, not least of which is learning and memory. The following chapters detail my exploration of the connection between BLA ACh signaling and cue-reward learning. After explaining the background behind and rationale for the approach (Chapter 1), I briefly describe the development of a cue-reward learning task used to study the role of cholinergic signaling in appetitive learning (Chapter 2). Then, I discuss experiments we performed to record (Chapter 3) and manipulate (Chapter 4) BLA cholinergic signaling during this cue-reward learning. I conclude by integrating the results from recording and manipulation studies and attempt to reconcile these results internally and with external findings to move toward a more comprehensive understanding of the effect of BLA ACh signaling during reward learning (Chapter 5). The primary behavioral paradigm used in the following chapters was a cue-reward learning task in which mice must learn to nose poke during presentation of an auditory tone to receive a food reward. In Chapter 3, we used a genetically-encoded fluorescent ACh sensor to record ACh dynamics in the BLA as animals learned the task contingency. We found that ACh was released in the BLA in response to salient events during the task and evolved with task performance. In order to isolate the source of the ACh, we also recorded calcium dynamics in the BLA-projecting cholinergic terminal fibers of nucleus basalis of Meynert (NBM), a basal forebrain nucleus that is a main contributor of ACh to the BLA. The pattern of activity in these terminal fibers was similar to that observed for ACh signaling, suggesting that the NBM is responsible, at least in part, for cue-reward ACh signaling. Importantly, these shifts in time-locking were tightly correlated to acquisition of the task contingency. We also recorded the activity of BLA output cells, which revealed they were excited following reward-retrieval initially, but their response shifted to the reward-predictive tone after acquisition. Next, in Chapter 4, we optogenetically and pharmacologically modulated cholinergic signaling in the BLA and systemically investigated the effect of manipulating cholinergic signaling on reward learning. We found that both behaviorally-contingent and non-contingent stimulation of BLA ACh release enhanced cue-reward learning. Systemic antagonism of muscarinic, but not nicotinic, ACh receptors impaired task acquisition. Interestingly, nicotine administration led to a modest improvement in performance of the cue-reward task. The studies described here advance the understanding of how ACh might be involved in cue-reward learning and challenge notions of the precise timing required for neuromodulatory input to affect the formation of associations between stimuli

Spring 1956

This year the newly organized Turf Management Club has undertaken the publication of a booklet featuring various aspects of turf work. Through this we are attempting to present material that will be of interest to those who are familiar with the Massachusetts Turf Schools. At the same time we hope that it may have some educational value by presenting the view of both of those of us on the job and others engaged in research and promotion and selling. The publication will include information about the current years winter school and turf conference, articles about some of the professors here at the University who are responsible for the course work, reports about activities and honors earned by the Stockbridge Turf Majors while on campus; and reports on research in fine turf conducted here at the University of Massachusetts. There will also be articles written by men connected with turf work such as yourselves and articles written by staff members at the University. The main objective of this publication is to form a bond of common interest and friendship between the alumni and other friends of our turf schools. Those of us who graduate this year are looking forward to getting the news from the university in years to come. We hope you feel the same

Indirect adjustment for multiple missing variables applicable to environmental epidemiology

AbstractObjectivesDevelop statistical methods for survival models to indirectly adjust hazard ratios of environmental exposures for missing risk factors.MethodsA partitioned regression approach for linear models is applied to time to event survival analyses of cohort study data. Information on the correlation between observed and missing risk factors is obtained from ancillary data sources such as national health surveys. The relationship between the missing risk factors and survival is obtained from previously published studies. We first evaluated the methodology using simulations, by considering the Weibull survival distribution for a proportional hazards regression model with varied baseline functions, correlations between an adjusted variable and an adjustment variable as well as selected censoring rates. Then we illustrate the method in a large, representative Canadian cohort of the association between concentrations of ambient fine particulate matter and mortality from ischemic heart disease.ResultsIndirect adjustment for cigarette smoking habits and obesity increased the fine particulate matter-ischemic heart disease association by 3%–123%, depending on the number of variables considered in the adjustment model due to the negative correlation between these two risk factors and ambient air pollution concentrations in Canada. The simulations suggested that the method yielded small relative bias (<40%) for most cohort designs encountered in environmental epidemiology.ConclusionsThis method can accommodate adjustment for multiple missing risk factors simultaneously while accounting for the associations between observed and missing risk factors and between missing risk factors and health endpoints

The Vehicle, 1962, Vol. 4

Vol. 4 Table of Contents The SearchLarry Pricepage 7 If We Should MeetPauline B. Smithpage 16 Sonnet No. 1Linda Campbellpage 17 SnowflakesPauline B. Smithpage 17 Encounter in the VoidEric Crookspage 18 symbolBen Polkpage 24 The Sound of SilenceJames Wilhelmpage 24 ColoursJean Ellen Danenbargerpage 26 vegetableBen Polkpage 27 The GiftJan Holstlawpage 29 The Tiled OvenRichard Glassonpage 30 This Lover Ever WeepsBen Polkpage 31 El DoradoPauline B. Smithpage 32 I\u27m SorryMary Jean Pitratpage 32 The WalkDavid Schwarzpage 33 The Twenty-Third ChannelBen Polkpage 34 After the PicnicLinda Campbellpage 35 SoliloquyJanice Brookspage 35 JulieMyra Edmanpage 36 Poems (1) (2)Gale Crousepage 40 Boardwalk at NightSheran Broadwaypage 41 SunsetPauline B. Smithpage 42 SummerC.E.M.page 42 It\u27s Spring AgainJanice Brookspage 43 Chinese SymbolsJean Ellen Danenbargerpage 43 Why Do You Wait?Gale Crousepage 44 seekerBen Polkpage 46 Poems (3) (4) (5)Gale Crousepage 47 Opposite AttractionsC.E.M.page 48 Illustrations for the winning short story and poemDouglas Koertgehttps://thekeep.eiu.edu/vehicle/1010/thumbnail.jp

Stabilized Polymer Micelles for the Development of IT-147, an Epothilone D Drug-Loaded Formulation

Epothilones have demonstrated promising potential for oncology applications but suffer from a narrow therapeutic window. Epothilone D stabilizes microtubules leading to apoptosis, is active against multidrug-resistant cells, and is efficacious in animal tumor models despite lack of stability in rodent plasma. Clinical development was terminated in phase II due to dose limiting toxicities near the efficacious dose. Taken together, this made epothilone D attractive for encapsulation in a stabilized polymer micelle for improved safety and efficacy. We have designed a library of triblock copolymers to develop IT-147, a lead formulation of epothilone D that extends plasma circulation for accumulation in the tumor environment, and potentially decrease systemic exposure to reduce dose limiting toxicities. The drug loading efficiency for IT-147 exceeds 90%, is 75 nm in diameter, and demonstrates pH-dependent release of epothilone D without chemical conjugation or enzymatic activation. Administration of IT-147 at 20 mg/kg increases exposure of epothilone D to the plasma compartment over 6-fold compared to free drug. At the same dose, 20 mg/kg epothilone D from IT-147 is considered the no observed adverse effect level (NOAEL) but is the maximum tolerated dose for free drug. Consequently, IT-147 is positioned to be a safer, more effective means to deliver epothilone D

A national study of the association between traffic-related air pollution and adverse pregnancy outcomes in Canada, 1999–2008

AbstractNumerous studies have examined the association of air pollution with preterm birth and birth weight outcomes. Traffic-related air pollution has also increasingly been identified as an important contributor to adverse health effects of air pollution. We employed a national nitrogen dioxide (NO2) exposure model to examine the association between NO2 and pregnancy outcomes in Canada between 1999 and 2008. National models for NO2 (and particulate matter of median aerodynamic diameter <2.5µm (PM2.5) as a covariate) were developed using ground-based monitoring data, estimates from remote-sensing, land use variables and, for NO2, deterministic gradients relative to road traffic sources. Generalized estimating equations were used to examine associations with preterm birth, term low birth weight (LBW), small for gestational age (SGA) and term birth weight, adjusting for covariates including infant sex, gestational age, maternal age and marital status, parity, urban/rural place of residence, maternal place of birth, season, year of birth and neighbourhood socioeconomic status and per cent visible minority. Associations were reduced considerably after adjustment for individual covariates and neighbourhood per cent visible minority, but remained significant for SGA (odds ratio 1.04, 95%CI 1.02–1.06 per 20ppb NO2) and term birth weight (16.2g reduction, 95% CI 13.6–18.8g per 20ppb NO2). Associations with NO2 were of greater magnitude in a sensitivity analysis using monthly monitoring data, and among births to mothers born in Canada, and in neighbourhoods with higher incomes and a lower proportion of visible minorities. In two pollutant models, associations with NO2 were less sensitive to adjustment for PM2.5 than vice versa, and there was consistent evidence of a dose-response relationship for NO2 but not PM2.5. In this study of approximately 2.5 million Canadian births between 1999 and 2008, we found significant associations of NO2 with SGA and term birth weight which remained significant after adjustment for PM2.5, suggesting that traffic may be a particularly important source with respect to the role of air pollution as a risk factor for adverse pregnancy outcomes

Associations between ambient air pollution and daily mortality in a cohort of congestive heart failure: Case-crossover and nested case-control analyses using a distributed lag nonlinear model.

BACKGROUND: Persons with congestive heart failure may be at higher risk of the acute effects related to daily fluctuations in ambient air pollution. To meet some of the limitations of previous studies using grouped-analysis, we developed a cohort study of persons with congestive heart failure to estimate whether daily non-accidental mortality were associated with spatially-resolved, daily exposures to ambient nitrogen dioxide (NO2) and ozone (O3), and whether these associations were modified according to a series of indicators potentially reflecting complications or worsening of health. METHODS: We constructed the cohort from the linkage of administrative health databases. Daily exposure was assigned from different methods we developed previously to predict spatially-resolved, time-dependent concentrations of ambient NO2 (all year) and O3 (warm season) at participants' residences. We performed two distinct types of analyses: a case-crossover that contrasts the same person at different times, and a nested case-control that contrasts different persons at similar times. We modelled the effects of air pollution and weather (case-crossover only) on mortality using distributed lag nonlinear models over lags 0 to 3 days. We developed from administrative health data a series of indicators that may reflect the underlying construct of "declining health", and used interactions between these indicators and the cross-basis function for air pollutant to assess potential effect modification. RESULTS: The magnitude of the cumulative as well as the lag-specific estimates of association differed in many instances according to the metric of exposure. Using the back-extrapolation method, which is our preferred exposure model, we found for the case-crossover design a cumulative mean percentage changes (MPC) in daily mortality per interquartile increment in NO2 (8.8 ppb) of 3.0% (95% CI: -0.4, 6.6%) and for O3 (16.5 ppb) 3.5% (95% CI: -4.5, 12.1). For O3 there was strong confounding by weather (unadjusted MPC = 7.1%; 95% CI: 1.7, 12.7%). For the nested case-control approach the cumulative MPC for NO2 in daily mortality was 2.9% (95% CI: -0.9, 6.9%) and for O3 7.3% (95% CI: 3.0, 11.9%). We found evidence of effect modification between daily mortality and cumulative NO2 and O3 according to the prescribed dose of furosemide in the nested case-control analysis, but not in the case-crossover analysis. CONCLUSIONS: Mortality in congestive heart failure was associated with exposure to daily ambient NO2 and O3 predicted from a back-extrapolation method using a land use regression model from dense sampling surveys. The methods used to assess exposure can have considerable influence on the estimated acute health effects of the two air pollutants

Genetic Mapping of Multiple Metabolic Traits Identifies Novel Genes for Adiposity, Lipids and Insulin Secretory Capacity in Outbred Rats

Despite the successes of human genome-wide association studies, the causal genes underlying most metabolic traits remain unclear. We used outbred heterogeneous stock (HS) rats, coupled with expression data and mediation analysis, to identify quantitative trait loci (QTLs) and candidate gene mediators for adiposity, glucose tolerance, serum lipids, and other metabolic traits. Physiological traits were measured in 1519 male HS rats, with liver and adipose transcriptomes measured in over 410 rats. Genotypes were imputed from low coverage whole genome sequence. Linear mixed models were used to detect physiological and expression QTLs (pQTLs and eQTLs, respectively), employing both SNP- and haplotype-based models for pQTL mapping. Genes with cis-eQTLs that overlapped pQTLs were assessed as causal candidates through mediation analysis. We identified 14 SNP-based pQTLs and 19 haplotype-based pQTLs, of which 10 were in common. Using mediation, we identified the following genes as candidate mediators of pQTLs: Grk5 for a fat pad weight pQTL on Chr1, Krtcap3 for fat pad weight and serum lipids pQTLs on Chr6, Ilrun for a fat pad weight pQTL on Chr20 and Rfx6 for a whole pancreatic insulin content pQTL on Chr20. Furthermore, we verified Grk5 and Ktrcap3 using gene knock-down/out models, thereby shedding light on novel regulators of obesity