Indiana University-Purdue University Indianapolis (IUPUI) / Social processing is the reception, interpretation, and reciprocation of social information and is critical for mental health. The neural structures, circuits, and substrates regulating these complex mechanisms are not well understood. Social processing in the form of social safety learning, as measured by a rat model of social familiarity-induced anxiolysis (SoFiA), was impaired following mild blast traumatic brain injury (mbTBI). Initial findings indicated that mbTBI altered resting state network activity in the orbitofrontal cortex (OFC) and was associated with accumulation of neurotoxin marker, acrolein, in lateral prefrontal cortex (PFC) (including OFC), indicating OFC as a brain region of interest that may contribute to social processing. Measuring GABA and Glutamate-related gene expression in OFC of mbTBI or sham-exposed rat brain revealed specific elevations of metabotropic glutamate receptor type 1 and 5 (mGluR1/5) expression in mbTBI but not sham OFC. Exposure-naïve rats intracranially injected with mGluR1/5 agonist demonstrated attenuated SoFiA, and this coincided with an impairment of social recognition (SR) behavior. Additionally, inactivation of OFC by local intracranial injection of GABAA agonist, muscimol, impaired two different measures of SR in which two conspecifics, or members of the same species, one novel and one familiar, were presented and required discrimination. Novelty seeking, decision-making, memory, and gregariousness were tested in isolation to determine OFC contributions to these specific behavioral contributions to SR test performance. OFC inactivation did not impair novelty seeking, non-social decision-making, or non-social memory as measured by novel object recognition (NOR) test, or gregariousness or social decision-making as measure by social preference (SP) test. When measuring SR behavior via consecutive presentation of two different conspecifics, OFC inactivation did not impact SR. Therefore, OFC is not directly responsible for social recognition, but rather the discrimination or ability to act upon discrimination of two simultaneously present conspecifics. These data suggest a novel role for OFC in high order processing or execution of action based on social information. / 2 years (2021-05-24)

Cricetidae, which includes a wide range of mice and rats, is the second-most diverse and abundant family of mammals. Though presently distributed across the Americas and Eurasia and also known from many fossil sites in western North America, few records have been studied from the east prior to the Pleistocene. This study has identified seven species of cricetids from the Gray Fossil Site (GFS), an early Pliocene site located in the northeast corner of Tennessee well-known for preserving fossils of many large mammals. While a few studies had previously noted the occurrence of cricetids at GFS, this study provides a detailed description of the cricetid assemblage and helps expand our understanding of small mammals from this site. Specimens were examined under stereomicroscope and DinoLite digital microscope camera, allowing qualitative assessment of occlusal morphology and quantitative comparison to modern cricetids and published fossil records from across North America. The most common taxa at the site included the deer mouse Peromyscus, which is currently the most abundant and widely distributed mammal in North America, deer mouse-like Postcopemys, and the woodrat Neotoma, which is larger rat with high-crowned molars that still lives in the region today. Other less common ones, like Sigmodon, Repomys, and Neotomodon, are also present. While most of the GFS specimens can be categorized into known genera, distinctive morphological features suggest the presence of new species. This assemblage of cricetids differs from those found at contemporaneous sites, emphasizing the spatial and temporal uniqueness of GFS. The Pliocene cricetid taxa at GFS exhibit diverse body sizes and dietary preferences, providing insights into the paleoecology of the region. As a biodiversity hotspot in the Appalachian region today, GFS was likely an important habitat for cricetid evolution during the Pliocene.

No / Further evidence for the rodent bone marrow micronucleus assay acting as a sensitive predictor of the possible germ cell mutagenicity of chemicals

Accurate and high throughput methods of measuring animal behavior are critical for many branches of neuroscience, allowing for mechanistic studies and preclinical drug testing. Methodological limitations contribute to narrow investigations, which may overlook the interplay between distinct but related behaviors, like affective behaviors and executive function (EF). To prevent such oversight, researchers can perform test batteries, or multiple assessments in one study. However, test batteries often exclude cognitive behaviors due to their lengthy testing period. This dissertation first reviews current evidence related to the investigation and relation of affective, pain-like, and operant behaviors in rodent models. Then, I demonstrate the use of traditional and novel test batteries to investigate these behavioral changes in multiple mouse models. First, I investigated affective and pain-like behavior in mice lacking Nape-pld, a key enzyme that synthesizes lipid mediators which activate receptors in the endocannabinoid system. I found that these mice displayed reduced sucrose preference, but otherwise normal anxiety- and depression-like behavior, and had baseline differences in thermal nociception and inflammation response. Then, I investigated the affective, pain-like, and operant effects of chronic vapor exposure (CVE) to vehicle or nicotine (NIC). Regardless of NIC content, acute abstinence from CVE increased mechanical sensitivity and self-grooming, while chronic abstinence from NIC CVE resulted in motor stimulation. Other traditional anxiety- and depression-like behaviors were unchanged by CVE. In an operant test battery, acute abstinence from NIC CVE impaired acquisition, decreased sucrose motivation, and impaired the response to aversive rewards. Finally, I developed a protocol for the high throughput analysis of six operant tests which can be completed in as few as nineteen sessions, significantly fewer sessions than traditional operant tests. This battery investigates multiple aspects of goal-directed behavior and EF including operant acquisition, cognitive flexibility, reward devaluation, motivation via response to increased instrumental effort, cue devaluation or the extinction of learned behavior, and reacquisition. I validated several of these tests by demonstrating that lesions to specific subregions of the orbitofrontal cortex impaired cognitive flexibility and altered response to instrumental effort as observed in traditional operant tests. I then used this battery to investigate the effects of the P129T mutation, which results in a mutated version of the Fatty Acid Amide Hydrolase (FAAH) enzyme that is associated with addiction, in male and female mice. Knock-in animals displayed reduced activity in response to increasing instrumental effort, and reduced activity on the first day of an extinction test. Then, to encourage others to use this new operant battery I outlined how to efficiently collect data, shared a database for customizable analysis, and described common issues and how to solve them. This protocol has potential implications for many aspects of neuroscience including the investigation of novel therapeutics and the neural circuitry underlying behaviors. Together, the information in this dissertation demonstrates the utility of multi-faceted behavioral assays and the combination of traditional and novel approaches to collect more comprehensive behavioral data, which will allow researchers to better investigate neural circuitry underlying behaviors or the behavioral changes associated with novel therapeutics. / Doctor of Philosophy / By measuring animal behavior researchers can gain insight into how specific brain regions interact to influence choice and action. Limitations in testing methods mean that researchers may fail to investigate the relationship between distinct aspects of behavior, like the influence of emotional state or pain on cognition. To prevent such oversight researchers can perform a test battery, a specific series of multiple tests that measures several different aspects of behavior. Traditional test batteries often overlook cognitive or operant (learning to perform an action for reward) behaviors due to time constraints, which limits their translational potential. This dissertation provides a brief overview of the ways that researchers investigate affective (emotional), pain-like (physical discomfort), and goal-directed behaviors. It further has a broad focus on mouse models related to addiction or the endocannabinoid system (ECS), which is shown to play a role in mood, pain (e.g., perception, relief, and inflammation), and cognition. Using a traditional test battery, we demonstrate that mice lacking a key enzyme in the ECS have altered responses to sugar, heat, and inflammation, but display otherwise normal performance in anxiety-, depression-, and pain-like tests. Next, we used a combined traditional and operant battery to investigate the effects of chronic vapor exposure (CVE) and nicotine in mice. We found that regardless of nicotine content, acute abstinence from CVE increased physical sensitivity and self-grooming but spared other anxiety- and depression-like behaviors. Acute abstinence from nicotine CVE resulted in motor stimulation, impaired operant learning, lower motivation for sucrose reward, and an impaired ability to withhold responding when presented with a bitter reward. Finally, I outline a novel operant test battery that addresses the limitations of current operant chamber- or place-based batteries. Using this battery, I first demonstrate that it captures similar behavioral changes to those seen in traditional operant chambers. Then, I demonstrate that mice containing an ECS mutation associated with problem drug use in humans display less motivation for food reward in response to increased effort, and more quickly inhibit a learned behavior when reward delivery is interrupted. I also found that in response to increased effort for reward or bitter rewards, male mice are more likely to alter their behavioral strategy. To encourage others to use this new operant battery I outlined how to efficiently collect data, shared a database for customizable analysis, and described common issues and how to solve them. This protocol has the potential to improve upon traditional tasks while opening cognitive research to more scientists. This has implications for many fields of neuroscience, especially the investigation of novel therapeutics and investigation of the neural circuitry underlying various disorders.

No description available.

<p> We hypothesized that acute inhibition of the contraction-induced expansion of the muscle TCA cycle intermediate (TCAI) pool via would not adversely effect metabolism or contractile function. Forty rats were anaesthetized and the gastrocnemius muscle (GAS) from one leg was vascularly isolated and perfused with saline (CON) or a red cell media containing DL-cycloserine (CYCLO; Sigma C-7005; dose=0.05 mg/g), an inhibitor of alanine aminotransferase (AAT). After 1h of perfusion, the GAS muscle was either snap frozen (CON-Rest, n=11; CYCLO-Rest, n=9) or stimulated to contract for 10 min (1Hz, 0.3 ms, 2 V) with blood flow fixed at 30 ml min-1 100g-1 and then snap frozen (CON-Stim, n=10; CYCLO-Stim, n=10). The maximal activity of AAT was lower (P≤0.05) at both CYCLO-Rest (0.61±0.02 mmol·kg-1w.w./min; mean± SEM) and CYCLO-Stim (0.63±0.01 mmol·kg-1w.w./min) vs CON-Rest (3.56±0.16 mmol·kg-1w.w./min) and CON-Stim (3.92±0.29 mmol·kg-1w.w./min). Consistent with lower net flux through AAT, muscle [alanine] was lower (P≤0.05) after CYCLO-Stim (6.97±0.26 mmol·kg-1 dw) compared to CON-Stim (8.55±0.56 mmol·kg-1 dw) and not different vs CON-Rest (6.79±0.41 mmol·kg-1 dw). The sum of five measured TCAI (malate, fumarate, citrate, isocitrate, and 2-oxoglutarate) was higher (P≤0.05) at both CON-Rest (2.10± 0.09 mmol·kg-1 dw) and CON-Stim (2.48± 0.11 mmol·kg-1 dw) vs CYCLO-Rest (1.56± 0.11 mmol·kg-1 dw) and CYCLO-Stim (1.88± 0.15 mmol·kg-1 dw) respectively. Despite the reduction in [TCAI] following CYCLO treatment, there was no difference between conditions in muscle lactate accumulation or phosphocreatine degradation after 10 min of stimulation. Contractile function was not different (P≤0.05) between conditions at either rest or stimulation and the decline in force production over ten minutes of stimulation was identical (~60%) between CON-Stim and CYCLO-Stim respectively. We conclude that flux through AAT was reduced after cycloserine treatment, however the acute inhibition of TCAI expansion did not compromise aerobic energy provision. These data support the hypothesis that the contraction-induced increase in muscle [TCAI] is not causally linked to oxidative energy delivery.</p> / Thesis / Master of Science (MSc)

The second pandemic persisted for 500 years throughout Europe and some regions of Africa and Asia and far surpasses the first and third pandemics in terms of temporal and spatial breadth. It is still unclear what mechanisms facilitated the long-term maintenance and continued disease reintroductions experienced during the second pandemic. Many researchers believe it was the spread of plague infected Rattus spp. via trade routes, while others are beginning to support a model that reflects modern plague ecology such that plague was maintained in local rodent reservoirs in the Mediterranean region or Europe following its 14th century introduction. This study accumulated a list of rodent species known to host plague and analyzed host characteristics to determine what traits allow rodents to function as successful reservoir species. In addition, this study analyzed the ancient DNA within rodent remains in search of Yersinia pestis to add to the history of the pathogen. The results of this study demonstrate that there are 45 non-Rattus rodent species known to host plague within a modern context. Although ancient Y. pestis DNA was not identified from zooarchaeological remains within this study, it is clear that rodent reservoirs were key players in past plague pandemics. When viewed through the lens of a single model (i.e. trade routes or human-ectoparasites), several questions about past plague maintenance remain unanswered. This study shows that a more complex composite model is best fit to describe the 500-year reign of the second pandemic and the quiescent periods that extended between the cyclical disease reintroductions. This study presents the first comprehensive, interactive, and publicly available online database of rodent reservoirs to aid in future research and emphasizes the need to investigate a multi-mechanism model of plague maintenance and reintroduction in the past. With this research we facilitated a starting point for future studies, expanded the current knowledge on rodent reservoirs of plague, and contributed a valuable discussion to the field of plague studies on regions that have thus far gone underserved in plague studies, such as the Mediterranean littoral. / Thesis / Master of Arts (MA)

Doctor of Philosophy / Department of Biology / Brett K. Sandercock / Habitat heterogeneity is a key driver of biodiversity in many ecosystems. In native ecosystems, habitat heterogeneity can arise from multiple drivers including nutrients, topoedaphic conditions, and ecological disturbance. Historically, the prairies of North America existed as a heterogeneous mosaic of habitat conditions created by the interaction of fire and grazing by native ungulates. The focus of many grazing systems has been to minimize disturbance caused by grazing by promoting uniform distributions of grazing animals across management units. Patch-burn grazing is an alternative rangeland management practice that has been proposed to restore historical patch dynamics and biodiversity to rangelands by simulating historical disturbance processes. In my dissertation research, I tested the hypothesis that patch- burn grazing restores habitat heterogeneity to rangelands, and that the resulting habitat heterogeneity can promote biodiversity of native wildlife. I focus on responses of small mammals and coyotes to patch-burn grazing to gain a better understanding of wildlife responses to rangeland management, and because grassland mammals are an ecologically important group. My 3.5-year field study of habitat and small mammal responses to rangeland management showed that: 1) patch-burn grazing created greater heterogeneity in vegetative structure and composition of plant functional groups than in positive and negative controls; 2) habitat heterogeneity created by the interaction of fire and grazing increased small mammal richness and diversity compared to a negative control managed for uniform grazing distributions; 3) the interaction of fire and grazing structured small mammal communities in tallgrass prairie; and 4) population dynamic responses of small mammals to fire and grazing disturbance were species- specific. My 3-year study of coyote survival and resource selection revealed that: 1) rangeland management influences resource selection by coyotes in seasons when they depend on small mammal prey, but not during other seasons; and 2) anthropogenic sources of mortality are important for coyotes at a protected area, even in the absence of harvest. My field results show that restoring the drivers of historical patch dynamics to managed rangelands and publicly held grasslands that are not currently grazed could have profound effects on biodiversity conservation in North America, while continuing to provide ecosystem services to society.

No description available.

Demography of nocturnal desert rodents was monitored for nine years. Three dissimilar areas were sampled with three distinct trapping configurations and time regimes. All three areas contained similar rodent species. Increased plant growth and seed production resulting from variations in rainfall seemed to have the most profound effect on both rodent densities and species composition. Deviations from the bimodal rainfall pattern occurred in the latter parts of 1972, 1977, and 1978 and early 1973, 1978, and 1979. During these times there was a 2-4 fold increase in rainfall. This pattern produced "desert blooms" in the spring of 1973, 1978, and to some extent 1979. In addition, 1972 and 1978 were years of high rainfall. The reaction of the rodents to the increased plant production was rapid and dramatic. Heteromyid numbers increased approximately six fold with some species increasing twelve fold within a matter of five months. The smaller heteromyids, Perognathus amplus and P. penicillatus, were the first to increase substantially, while the larger rodents reached peak populations in the following year. The resulting population crash that followed the high densities was as dramatic as the increase. Neotoma albigula populations did not increase substantially after the first rainfall phenomenon but did so dramatically after the second period of aberrant rains. The densities of N. albigula remained high long after the heteromyid populations decreased to "normal" levels. The three areas were found to be dominated by different species while the overall rodent densities in the three areas were very similar within the same time frame.