Altering the gain of the infralimbic to accumbens shell circuit alters economically dissociable decision-making algorithms

Faculty Advisor: Mark ThomasThis research was supported by the Undergraduate Research Opportunities Program (UROP)

Diminishing benefits of urban living for children and adolescents’ growth and development

Optimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was <1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Diminishing benefits of urban living for children and adolescents’ growth and development

AbstractOptimal growth and development in childhood and adolescence is crucial for lifelong health and well-being1–6. Here we used data from 2,325 population-based studies, with measurements of height and weight from 71 million participants, to report the height and body-mass index (BMI) of children and adolescents aged 5–19 years on the basis of rural and urban place of residence in 200 countries and territories from 1990 to 2020. In 1990, children and adolescents residing in cities were taller than their rural counterparts in all but a few high-income countries. By 2020, the urban height advantage became smaller in most countries, and in many high-income western countries it reversed into a small urban-based disadvantage. The exception was for boys in most countries in sub-Saharan Africa and in some countries in Oceania, south Asia and the region of central Asia, Middle East and north Africa. In these countries, successive cohorts of boys from rural places either did not gain height or possibly became shorter, and hence fell further behind their urban peers. The difference between the age-standardized mean BMI of children in urban and rural areas was &lt;1.1 kg m–2 in the vast majority of countries. Within this small range, BMI increased slightly more in cities than in rural areas, except in south Asia, sub-Saharan Africa and some countries in central and eastern Europe. Our results show that in much of the world, the growth and developmental advantages of living in cities have diminished in the twenty-first century, whereas in much of sub-Saharan Africa they have amplified.</jats:p

Worldwide trends in underweight and obesity from 1990 to 2022: a pooled analysis of 3663 population-representative studies with 222 million children, adolescents, and adults

Background Underweight and obesity are associated with adverse health outcomes throughout the life course. We estimated the individual and combined prevalence of underweight or thinness and obesity, and their changes, from 1990 to 2022 for adults and school-aged children and adolescents in 200 countries and territories. Methods We used data from 3663 population-based studies with 222 million participants that measured height and weight in representative samples of the general population. We used a Bayesian hierarchical model to estimate trends in the prevalence of different BMI categories, separately for adults (age ≥20 years) and school-aged children and adolescents (age 5–19 years), from 1990 to 2022 for 200 countries and territories. For adults, we report the individual and combined prevalence of underweight (BMI 2 SD above the median). Findings From 1990 to 2022, the combined prevalence of underweight and obesity in adults decreased in 11 countries (6%) for women and 17 (9%) for men with a posterior probability of at least 0·80 that the observed changes were true decreases. The combined prevalence increased in 162 countries (81%) for women and 140 countries (70%) for men with a posterior probability of at least 0·80. In 2022, the combined prevalence of underweight and obesity was highest in island nations in the Caribbean and Polynesia and Micronesia, and countries in the Middle East and north Africa. Obesity prevalence was higher than underweight with posterior probability of at least 0·80 in 177 countries (89%) for women and 145 (73%) for men in 2022, whereas the converse was true in 16 countries (8%) for women, and 39 (20%) for men. From 1990 to 2022, the combined prevalence of thinness and obesity decreased among girls in five countries (3%) and among boys in 15 countries (8%) with a posterior probability of at least 0·80, and increased among girls in 140 countries (70%) and boys in 137 countries (69%) with a posterior probability of at least 0·80. The countries with highest combined prevalence of thinness and obesity in school-aged children and adolescents in 2022 were in Polynesia and Micronesia and the Caribbean for both sexes, and Chile and Qatar for boys. Combined prevalence was also high in some countries in south Asia, such as India and Pakistan, where thinness remained prevalent despite having declined. In 2022, obesity in school-aged children and adolescents was more prevalent than thinness with a posterior probability of at least 0·80 among girls in 133 countries (67%) and boys in 125 countries (63%), whereas the converse was true in 35 countries (18%) and 42 countries (21%), respectively. In almost all countries for both adults and school-aged children and adolescents, the increases in double burden were driven by increases in obesity, and decreases in double burden by declining https://researchonline.ljmu.ac.uk/images/research_banner_face_lab_290.jpgunderweight or thinness. Interpretation The combined burden of underweight and obesity has increased in most countries, driven by an increase in obesity, while underweight and thinness remain prevalent in south Asia and parts of Africa. A healthy nutrition transition that enhances access to nutritious foods is needed to address the remaining burden of underweight while curbing and reversing the increase in obesity

Beyond Simple Tests of Value: A neuroeconomic, translational, disease-relevant, and circuit-based approach to resolve the computational complexity of decision making

University of Minnesota Ph.D. dissertation.July 2018. Major: Neuroscience. Advisors: Mark Thomas, A Redish. 1 computer file (PDF); vi, 258 pages + 1 supplementary video file.How the brain processes information when making decisions depends on how that information is stored. Distinct neural circuits are capable of storing information in many different ways that are better suited for different situations. The decision-making processes that access those different bits of stored information are not singular and occupy separable neural circuits, each of which can operate in parallel with one another, and each of which can confer different information processing properties based on the neural constraints within which a given computation resides. Such is the framework of recent theories in neuroeconomics, which suggest that decisions are multi-faceted and action-selection processes can arise from fundamentally distinct circuit-specific neural computations. In this thesis, I present a body of work that takes a neuroeconomics approach through a series of experiments that reveal the complexities of multiple, parallel decision-making systems through complex behaviors by moving beyond simple tests of value. In the first half of this thesis, I demonstrate how complex behavioral computations can resolve fundamentally distinct valuation algorithms thought to reside in separable neural circuits. I then translate this approach between human and non-human rodent animal models in order to reveal how multiple, parallel decision-making systems are conserved across species over evolution. In the second half of this thesis, I demonstrate the utility of behavioral economics in disease-relevant and circuit-based studies. If multiple, parallel decision-making processes are thought to be intimately related to the heterogeneous ways in which information can be stored in separable neural circuits, I examine how addiction – a disease which is thought to be a disorder of the neurobiological mechanisms of learning and memory – might alter how stored information is processed in separable decision-making systems uniquely using a mouse model of two different forms of addiction. In doing so, I demonstrate how different forms of addiction give rise to unique, lasting vulnerabilities in fundamentally distinct decision-making computations. These discoveries can aid in resolving neuropsychiatric disease heterogeneity by moving beyond simple tests of value where complex behaviors that are measured can more accurately reflect the neurally distinct computations that underlie those behaviors. Finally, I take a neuromodulation approach and directly alter the strength of synaptic transmission in a circuit-specific manner using optogenetics in mice tested in this neuroeconomic framework. I demonstrate how plasticity alterations in projections between the infralimbic cortex and the nucleus accumbens are capable of giving rise to long-lasting disruptions of self-control related decision processes in a foraging valuation algorithm independent of and separate from a deliberative valuation algorithm measured within the same trial. Furthermore, I developed a novel plasticity measurement tool that is assayed at the neuronal population ensemble level and reveals individual differences in separable decision processes. The second half of the thesis demonstrates a potential biomarker to target as a circuit-computation-specific therapeutic intervention tailored to those types of decision-making dysfunctions. Taken together, I present a body of work in this thesis that demonstrates the utility of moving beyond simple tests of value in order to resolve the computational complexity of decision making

Pushing the boundaries of behavioral analysis could aid psychiatric drug discovery

Drug discovery for psychiatric conditions is stagnating. Behavioral changes could be used as a primary phenotypic screen for new drug candidates, if enough useful data can be generated from behavioral models. Could machine learning be the answer to extracting the data we need? Behavioral changes could be used as a primary phenotypic screen for new drug candidates for psychiatric conditions, if enough useful data can be generated from current behavioral models. In this Perspective, the authors advocate for using machine learning to extract the data we need

Mice learn to avoid regret

<div><p>Regret can be defined as the subjective experience of recognizing that one has made a mistake and that a better alternative could have been selected. The experience of regret is thought to carry negative utility. This typically takes two distinct forms: augmenting immediate postregret valuations to make up for losses, and augmenting long-term changes in decision-making strategies to avoid future instances of regret altogether. While the short-term changes in valuation have been studied in human psychology, economics, neuroscience, and even recently in nonhuman-primate and rodent neurophysiology, the latter long-term process has received far less attention, with no reports of regret avoidance in nonhuman decision-making paradigms. We trained 31 mice in a novel variant of the Restaurant Row economic decision-making task, in which mice make decisions of whether to spend time from a limited budget to achieve food rewards of varying costs (delays). Importantly, we tested mice longitudinally for 70 consecutive days, during which the task provided their only source of food. Thus, decision strategies were interdependent across both trials and days. We separated principal commitment decisions from secondary reevaluation decisions across space and time and found evidence for regret-like behaviors following change-of-mind decisions that corrected prior economically disadvantageous choices. Immediately following change-of-mind events, subsequent decisions appeared to make up for lost effort by altering willingness to wait, decision speed, and pellet consumption speed, consistent with past reports of regret in rodents. As mice were exposed to an increasingly reward-scarce environment, we found they adapted and refined distinct economic decision-making strategies over the course of weeks to maximize reinforcement rate. However, we also found that even without changes in reinforcement rate, mice transitioned from an early strategy rooted in foraging to a strategy rooted in deliberation and planning that prevented future regret-inducing change-of-mind episodes from occurring. These data suggest that mice are learning to avoid future regret, independent of and separate from reinforcement rate maximization.</p></div

Development of deliberative behaviors during principal OZ valuations.

<p>(A-B) Example <b>x</b> and <b>y</b> locations of a mouse’s path trajectory in the OZ (wait zone not depicted) over time during a single trial (from day 70). (A) Skip decision for a high-delay offer. The mouse initially oriented toward entering (right) but then ultimately reoriented to skip (left). WZ Th. minus offer captures the relative subjective “value” of the offer. Negative value denotes an economically unfavorable offer. (B) Enter decision for positively valued offer; rapid without reorientations. This OZ trajectory pattern is indistinguishable from enter-then-quit decisions for negatively valued offers. (C) Average OZ RT split by enter versus skip decisions across days of training. (D) Average OZ VTE behavior split by enter versus skip decisions across days of training. Data are presented as the cohort’s (<i>N</i> = 31) daily means (±1 SE) across the entire experiment. Color code on the x-axis in (C-D) reflects the stages of training (offer cost ranges denoted from 1 to the number on the top of panel C). Vertical dashed lines (except pink) represent block transitions. * indicates gradual significant changes within the 1–30 s block during the early 2 wk adaptation period. Data available as a supplemental file. OZ, offer zone; RT, reaction time; VTE, vicarious trial and error; WZ Th., wait zone threshold.</p