Biological Underpinnings Research Articles

Identifying Clinical Research Priorities in Adult Pulmonary and Critical Care. NHLBI Working Group Report.

Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the NHLBI. Decades of clinical research in acute respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising preclinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data," causal inference using observational data, novel clinical trial designs, preclinical disease modeling, and understanding of recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state of, research priorities for, and future directions in adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including 1) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment response with the goal of developing targeted, personalized interventions; 2) optimizing preclinical models by incorporating comorbidities, cointerventions, and organ support; 3) developing and applying novel clinical trial designs; and 4) advancing mechanistic understanding of injury and recovery to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.

Abstract P461: Genome-wide Analysis in Sedentary Adults of Non-completion of a Controlled Exercise Intervention

A wide range of health benefits of exercise have been documented in clinical lifestyle medicine. However, many individuals fail to complete or maintain an exercise program. We hypothesized that this behavior has biological underpinnings. Thus, we conducted analyses of multi-omic data obtained from genomic, transcriptomic and metabolomic data specific to subjects (n=603) initiating a well-characterized exercise training trial (STRRIDE-Study of a Targeted Risk Reduction Intervention through Defined Exercise) to understand the biology of non-completion. GWAS detected the strongest evidence of association with non-completion was at SNP rs722069 (P = 2.2 х 10 -7 , OR=2.23, T/C, risk allele =C) on chromosome 16, with other 8 SNPs in a linkage disequilibrium block (pairwise R 2 > 0.74). These SNPs were eQTLs of the EARS2, COG7 and DCTN5 genes in skeletal muscle tissue in GTEx portal. In a subset of the STRRIDE sample, the C allele of rs722069 was associated with lower pre-exercise skeletal muscle expression of EARS2 (P < 0.016) using Affymetrix platform (n=37). This was further replicated (P=0.017) in another set of skeletal muscle expression data using the Illumina gene expression array (n=67). The C allele was associated with lower pre-exercise skeletal muscle concentrations of C2- and C3-acylcarnitines (P < 0.03) - the incomplete oxidation products of fatty acid and amino acid metabolism. Lower EARS2 skeletal muscle expression was also related to the lower C2- and C3-acylcarnitine concentrations in skeletal muscle ( P < 0.05) before exercise. Rs722069 variants were not related to maximal oxygen uptake and insulin sensitivity in the individuals completing the exercise intervention. The tests of glucose and lipids levels associated with the genetic variants in this LD block are ongoing. To further understand the systemic genetics and biology of non-completion, in silico functional analysis for the genes in this region such as UBFD1, NDUFAB1, PALB2 is also under way. Our results imply that non-completion is genetically moderated through differential gene expression and metabolic pathways in skeletal muscle. Impaired mitochondrial energetics in skeletal muscle may be partly responsible for non-completion. Individual genetic traits may allow development of a biomarker-approach to identify individuals that would benefit from more intensive counseling to maintain exercise programs.

Evidence for a Novel Endometrioid Carcinogenic Sequence in the Fallopian Tube With Unique Beta-Catenin Expression.

Epithelial proliferations in the fallopian tube have been characterized by some as stem cell outgrowths (SCOUTs) and divided into type I and type II. Type II SCOUTs exhibit diffuse cellular beta-catenin nuclear staining (β-catenin), implying a CTNNB1 mutation. SCOUTs are more common in perimenopausal and postmenopausal women and are associated with ovarian cancer but have not been linked directly to malignancy. We analyzed type II SCOUTs in various gynecologic conditions, and searched for endometrioid atypical hyperplasias (tubal endometrioid intraepithelial neoplasia) or adenocarcinomas in the tube. β-catenin SCOUT frequency in cases of neoplasia was 66.7% per case and 30.7% per nonfimbrial cross-section for uterine endometrioid carcinomas versus 25% and 13.3% for controls, respectively (P=0.02 and 0.09). Multiple (3 or more) β-catenin SCOUTs in a single section were uncommon; 6 of 9 were associated with a carcinoma or proliferative lesion in the endometrium. Tubal endometrioid intraepithelial neoplasia/atypical hyperplasia displayed complex growth, including focal cribriform growth patterns and squamous morules. Two cases of type II SCOUTs associated with tubal endometrioid intraepithelial neoplasia/atypical hyperplasia and/or adenocarcinomas in the fallopian tube were identified, both of which coexisted with a separate endometrioid adenocarcinoma, one with bilateral ovarian endometrioid adenocarcinomas. Both benign and neoplastic tubal lesions were β-catenin. This report is the first to link components of a unique β-catenin endometrioid carcinogenic sequence in the fallopian tube. It further emphasizes the multifocal nature of endometrioid neoplasia in the female genital tract and poses questions regarding the frequency and biologic underpinnings of β-catenin proliferations in the oviduct.

Brief Report: Genetic Links Between Autism and Suicidal Behavior-A Preliminary Investigation.

Evidence suggests there may be increased risk for suicidal behavior among individuals with autism spectrum disorder (ASD). An emerging body of research explores social factors that may contribute to increased risk, however little is known about the potential role of biological factors. The current project addresses this knowledge gap through a preliminary study of genes associated with both ASD and suicidal behavior. Gene set enrichment tests of eight genes strongly associated with both ASD and suicidal behavior revealed overrepresentation of nine biological processes, including cognition and synapse function, and 14 cellular components, including the neuron, the synapse, and the synaptic and postsynaptic membrane. These results can be used to inform future investigations of the biological underpinnings of suicidal behavior and ASD.

Social brain activation during mentalizing in a large autism cohort: the Longitudinal European Autism Project

BackgroundAutism spectrum disorder (ASD) is a neurodevelopmental condition with key deficits in social functioning. It is widely assumed that the biological underpinnings of social impairment are neurofunctional alterations in the “social brain,” a neural circuitry involved in inferring the mental state of a social partner. However, previous evidence comes from small-scale studies and findings have been mixed. We therefore carried out the to-date largest study on neural correlates of mentalizing in ASD.MethodsAs part of the Longitudinal European Autism Project, we performed functional magnetic resonance imaging at six European sites in a large, well-powered, and deeply phenotyped sample of individuals with ASD (N = 205) and typically developing (TD) individuals (N = 189) aged 6 to 30 years. We presented an animated shapes task to assess and comprehensively characterize social brain activation during mentalizing. We tested for effects of age, diagnosis, and their association with symptom measures, including a continuous measure of autistic traits.ResultsWe observed robust effects of task. Within the ASD sample, autistic traits were moderately associated with functional activation in one of the key regions of the social brain, the dorsomedial prefrontal cortex. However, there were no significant effects of diagnosis on task performance and no effects of age and diagnosis on social brain responses. Besides a lack of mean group differences, our data provide no evidence for meaningful differences in the distribution of brain response measures. Extensive control analyses suggest that the lack of case-control differences was not due to a variety of potential confounders.ConclusionsContrary to prior reports, this large-scale study does not support the assumption that altered social brain activation during mentalizing forms a common neural marker of ASD, at least with the paradigm we employed. Yet, autistic individuals show socio-behavioral deficits. Our work therefore highlights the need to interrogate social brain function with other brain measures, such as connectivity and network-based approaches, using other paradigms, or applying complementary analysis approaches to assess individual differences in this heterogeneous condition.

DSM 5: Controversial Acceptance and Ongoing Challenges

Mental health disorders effect almost 25% of Americans in a given year and is the leading cause of disability. These disorders can cause substantial detrimental changes in society due to lack of proper screening principles and comprehensive care. Disparities in health, education, employment, wealth and socio-economic standings are quite apparent in the psychiatric population. The Diagnostic and Statistical Manual of the American Psychiatric Association has published a book, which organized mental health pathologies into distinct groups to further standardize the way these illnesses can be categorized. The latest version of this manual, the DSM 5, was published in 2013 and it includes specific changes compared to the DSM IV. There continues to be still criticism aimed at the DSM 5 due its focus on symptomology instead of biological underpinnings of mental illness. Ultimately, the DSM 5 is an effort to further standardize diagnosis of mental illness among all populations with further reduction in mental health disparities.

Brain Metastases in Lung Cancers with Emerging Targetable Fusion Drivers.

The management of non-small cell lung cancer (NSCLC) has transformed with the discovery of therapeutically tractable oncogenic drivers. In addition to activating driver mutations, gene fusions or rearrangements form a unique sub-class, with anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) targeted agents approved as the standard of care in the first-line setting for advanced disease. There are a number of emerging fusion drivers, however, including neurotrophin kinase (NTRK), rearrangement during transfection (RET), and neuregulin 1 (NRG1) for which there are evolving high-impact systemic treatment options. Brain metastases are highly prevalent in NSCLC patients, with molecularly selected populations such as epidermal growth factor receptor (EGFR) mutant and ALK-rearranged tumors particularly brain tropic. Accordingly, there exists a substantial body of research pertaining to the understanding of brain metastases in such populations. Little is known, however, on the molecular mechanisms of brain metastases in those with other targetable fusion drivers in NSCLC. This review encompasses key areas including the biological underpinnings of brain metastases in fusion-driven lung cancers, the intracranial efficacy of novel systemic therapies, and future directions required to optimize the control and prevention of brain metastases.

The morality of evolution and a return to subjectivity.

Today societies display, almost uniformly, an aggressive demeanor that can hardly be covered by diplomacy; they are always prepared for war. The prophecy is repeatedly fulfilled and today we are engaged in protracted wars while fearing universal destruction. This basic attitude irremediably corrupts our consciousness and blemishes our self. The biological underpinnings of how we got to this point, psychologically, and the historical sublimations involved are explored here. The result, today, is that we live using a minimum of our human capacity at the huge cost in crucial energetic waste, while nature has started to protest. The self-feeding destructive mechanism is inordinate objectification, at the expense of our unique subjective power. Evolutionarily designed for balanced self-regulation-the sublimation of a dual instinctual disposition backed up by a dimorphic body and brain-nature warns us we have detoured from the moral blueprint and, were we to continue it will be at our own risk. We need to review our moral theories and return to our critical pre-patriarchal subjectivity, which was resourceful, dually-fed, balanced, and discriminating. That subjectivity is now largely replaced by pre-emptive, ideological cognitive modules and stereotypes that block intelligent dialogue and appear to be already modeled on a false Utopia of artificial intelligences.

Prehistoric languages and human self-domestication

Abstract The comparative method has enabled us to trace distant phylogenetic relationships among languages and reconstruct extinct languages from the past. Nonetheless, it has limitations, mostly resulting from the circumstance that languages also change by contact with unrelated languages and in response to external factors, particularly, aspects of human cognition and features of our physical and cultural environments. In this paper, it is argued that the limitations of historical linguistics can be partially alleviated by the consideration of the links between language structure and the biological underpinnings of human language, human cognition, and human behaviour, and specifically, of human self-domestication (that is, the existence in humans of features of domesticated mammals). Overall, we can expect that the languages spoken in remote prehistory exhibited most of the features of the so-called esoteric languages, which are used by present-day, close-knit, small human communities that share a great deal of knowledge about their environment.

Drug- and toxin-induced pulmonary arterial hypertension: Current state of the literature

Drug- and toxin-induced pulmonary arterial hypertension (PAH) is an increasingly important sub-group of group 1 pulmonary hypertension (PH). In the last 60 years, we have seen the rise and fall of numerous prescription and illicit agents that have caused severe and deadly outbreaks of PAH. Currently, drugs and toxins are classified into “possible” and “definite” risk factors for PAH. While the exact mechanisms and pathogenesis of drug- and toxin-induced PAH are currently unknown, novel clinical and basic science studies are beginning to unravel the biologic factors and genetic underpinnings responsible for disease development. The clinical management of affected patients can be challenging as it is often difficult to identify patients early and demonstrate causality between drugs and PAH. Given the recent trends in drug utilization and development, it is highly likely that we will continue to identify new agents capable of causing pulmonary vascular disease. We must keep a high index of suspicion in order to identify patients and new compounds deemed definite or likely risk factors for PAH. Practicing pharmacovigilance, raising awareness, and working in tandem with PH patient associations and drug regulatory agencies may ultimately be our most effective strategy in preventing the next deadly outbreak of drug- and toxin-induced PAH.

Taking the Next Steps in Regenerative Rehabilitation: Establishment of a New Interdisciplinary Field

The growing field of regenerative rehabilitation has great potential to improve clinical outcomes for individuals with disabilities. However, the science to elucidate the specific biological underpinnings of regenerative rehabilitation–based approaches is still in its infancy and critical questions regarding clinical translation and implementation still exist. In a recent roundtable discussion from International Consortium for Regenerative Rehabilitation stakeholders, key challenges to progress in the field were identified. The goal of this article is to summarize those discussions and to initiate a broader discussion among clinicians and scientists across the fields of regenerative medicine and rehabilitation science to ultimately progress regenerative rehabilitation from an emerging field to an established interdisciplinary one. Strategies and case studies from consortium institutions—including interdisciplinary research centers, formalized courses, degree programs, international symposia, and collaborative grants—are presented. We propose that these strategic directions have the potential to engage and train clinical practitioners and basic scientists, transform clinical practice, and, ultimately, optimize patient outcomes.

Oligometastatic Breast Cancer: Is This a Curable Entity? A Contemporary Review of the Literature.

Oligometastatic breast cancer (OMBC) remains a poorly understood entity for which no standard of care exists at this time. This review will focus on our biologic understanding of OMBC and provide an update on current treatment strategies. The introduction of micro RNA expression profiling has advanced our understanding of the biologic underpinnings of OMBC. Although most of the data regarding treatment have come from retrospective studies, there are now prospective randomized trials reporting progression-free survival and overall survival improvements with stereotactic ablative radiotherapy (SABR). Ongoing studies designed to evaluate addition of SABR as well as other novel agents will further develop this field and provide new treatment options. A "cure" for OMBC remains elusive. With further basic research coupled with novel prospective trials, patients will hopefully enjoy increased progression-free survival and overall survival, and ideally a delay to more toxic systemic therapy.

A roadmap to precision medicine for multiple sclerosis

Multiple sclerosis (MS) affects approximately 1 million persons in the United States, and is the leading cause of neurological disability in young adults. The concept of precision medicine is now being applied to MS and has the promise of improved care. MS patients experience a variety of neurological symptoms, and disease severity ranges from mild to severe, and the biological underpinnings of these phenotypes are now starting to be elucidated. Precision medicine involves the classification of disease subtypes based on the underlying biology, rather than clinical phenotypes alone, and may govern disease course and treatment response. Over 18 disease-modifying drugs have been approved for the treatment of MS, and several biomarkers of treatment response are emerging. This article provides an overview of the concepts of precision medicine and emerging biological markers and their evolving role in decision-making in MS management.

A Systematic Review of DNA Methylation and Gene Expression Studies in Posttraumatic Stress Disorder, Posttraumatic Growth, and Resilience.

Most people will experience a traumatic event within their lifetime. One commonly recognized response to trauma exposure is posttraumatic stress disorder (PTSD). The biological underpinnings of PTSD, including epigenetic mechanisms of DNA methylation and gene expression, have been studied intensively. However, psychological posttrauma responses vary widely and can include positive outcomes, such as posttraumatic growth (PTG) and, more commonly, resilience. The aim of this systematic review was to summarize the current DNA methylation and gene expression data with respect to three potential posttrauma responses: PTSD, PTG, and resilience. A literature search identified 486 studies, 51 of which were deemed eligible for inclusion (total N = 10,633). All included studies examined PTSD and consistently implicated DNA methylation and gene expression changes in hypothalamic-pituitary-adrenal axis and inflammatory genes. Ten studies acknowledged resilience as a posttrauma response, but only two studies examined epigenetics and gene expression using a scale to measure resilience. Low resilience was associated with gene expression patterns in immune and dopamine genes, and high resilience was associated with a blunted inflammatory response. No studies examined epigenetic or gene expression changes associated with PTG. These findings highlight a focus on pathogenic research, which has failed to adequately acknowledge and measure positive posttrauma outcomes of PTG and resilience. Future research should examine DNA methylation and gene expression changes associated with PTG and resilience in addition to PTSD in order to gain a more comprehensive picture of an individual's well-being following exposure to trauma.

A temporal chronnectomic framework: Cigarette smoking preserved the prefrontal dysfunction in schizophrenia

The widespread cigarette smoking behavior in schizophrenia is generally attributed to its alleviation of patients' symptomatology by the self-medication hypothesis. The prefrontal cortex (PFC), which predominantly supports orchestrating thoughts and actions, might underlie the biological underpinnings of smoking behavior in schizophrenia. However, few studies have focused on the impact of smoking on the prefrontal function in schizophrenia. This study assumed that smoking-related alterations on the prefrontal dynamics of information integration (chronnectome) were different between healthy control (HC) and schizophrenia patient (SP). We recruited SP smokers (N = 22)/nonsmokers (N = 27) and HC smokers (N = 22)/nonsmokers (N = 21) who underwent resting-state functional magnetic resonance imaging (rsfMRI) with a total of 240 volumes (lasting for 480 s). We employed a chronnectomic density analysis on the rsfMRI signal by using a sliding-window method. We examined the interaction effect between smoking status and diagnosis utilizing two-way analysis of covariance under permutation test. Whereas disease-related reduced effects were found on the bilateral dorsolateral PFC chronnectomic density, no smoking effect was observed. As regards interaction effect, a smoking-related reduced effect was found on the right dorsolateral PFC chronnectomic density in HC, while a smoking-related increased effect was observed in SP. Nevertheless, post-hoc analysis revealed significant group difference between SP smokers and HC nonsmokers. Therefore, these results indicated a smoking-related preservation effect on disrupted prefrontal dynamics in schizophrenia that cannot restore it to normal levels. The novel findings yield a prefrontal-based chronnectome framework to elaborate upon the self-medication hypothesis in schizophrenia.

Targeted Biomedical Treatment for Autism Spectrum Disorders.

A diagnosis of autism spectrum disorders (ASD) represents presentations with impairment in communication and behaviour that vary considerably in their clinical manifestations and etiology as well as in their likely pathophysiology. A growing body of data indicates that the deleterious effect of oxidative stress, mitochondrial dysfunction, immune dysregulation and neuroinflammation, as well as their interconnections are important aspects of the pathophysiology of ASD. Glutathione deficiency decreases the mitochondrial protection against oxidants and tumor necrosis factor (TNF)-α; immune dysregulation and inflammation inhibit mitochondrial function through TNF-α; autoantibodies against the folate receptors underpin cerebral folate deficiency, resulting in disturbed methylation, and mitochondrial dysfunction. Such pathophysiological processes can arise from environmental and epigenetic factors as well as their combined interactions, such as environmental toxicant exposures in individuals with (epi)genetically impaired detoxification. The emerging evidence on biochemical alterations in ASD is forming the basis for treatments aimed to target its biological underpinnings, which is of some importance, given the uncertain and slow effects of the various educational interventions most commonly used. Literature-based review of the biomedical treatment options for ASD that are derived from established pathophysiological processes. Most proposed biomedical treatments show significant clinical utility only in ASD subgroups, with specified pre-treatment biomarkers that are ameliorated by the specified treatment. For example, folinic acid supplementation has positive effects in ASD patients with identified folate receptor autoantibodies, whilst the clinical utility of methylcobalamine is apparent in ASD patients with impaired methylation capacity. Mitochondrial modulating cofactors should be considered when mitochondrial dysfunction is evident, although further research is required to identify the most appropriate single or combined treatment. Multivitamins/multiminerals formulas, as well as biotin, seem appropriate following the identification of metabolic abnormalities, with doses tapered to individual requirements. A promising area, requiring further investigations, is the utilization of antipurinergic therapies, such as low dose suramin. The assessment and identification of relevant physiological alterations and targeted intervention are more likely to produce positive treatment outcomes. As such, current evidence indicates the utility of an approach based on personalized and evidence-based medicine, rather than treatment targeted to all that may not always be beneficial (primum non nocere).

Gut-Amygdala Interactions in Autism Spectrum Disorders: Developmental Roles via regulating Mitochondria, Exosomes, Immunity and microRNAs.

Autism Spectrum Disorders (ASD) have long been conceived as developmental disorder. A growing body of data highlights a role for alterations in the gut in the pathoetiology and/or pathophysiology of ASD. Recent work shows alterations in the gut microbiome to have a significant impact on amygdala development in infancy, suggesting that the alterations in the gut microbiome may act to modulate not only amygdala development but how the amygdala modulates the development of the frontal cortex and other brain regions. This article reviews wide bodies of data pertaining to the developmental roles of the maternal and foetal gut and immune systems in the regulation of offspring brain development. A number of processes seem to be important in mediating how genetic, epigenetic and environmental factors interact in early development to regulate such gut-mediated changes in the amygdala, wider brain functioning and inter-area connectivity, including via regulation of microRNA (miR)-451, 14-3-3 proteins, cytochrome P450 (CYP)1B1 and the melatonergic pathways. As well as a decrease in the activity of monoamine oxidase, heightened levels of in miR-451 and CYP1B1, coupled to decreased 14-3-3 act to inhibit the synthesis of N-acetylserotonin and melatonin, contributing to the hyperserotonemia that is often evident in ASD, with consequences for mitochondria functioning and the content of released exosomes. These same factors are likely to play a role in regulating placental changes that underpin the association of ASD with preeclampsia and other perinatal risk factors, including exposure to heavy metals and air pollutants. Such alterations in placental and gut processes act to change the amygdala-driven biological underpinnings of affect-cognitive and affect-sensory interactions in the brain. Such a perspective readily incorporates previously disparate bodies of data in ASD, including the role of the mu-opioid receptor, dopamine signaling and dopamine receptors, as well as the changes occurring to oxytocin and taurine levels. This has a number of treatment implications, the most readily applicable being the utilization of sodium butyrate and melatonin.

Integrating Autism Spectrum Disorder Pathophysiology: Mitochondria, Vitamin A, CD38, Oxytocin, Serotonin and Melatonergic Alterations in the Placenta and Gut.

A diverse array of data has been associated with autism spectrum disorder (ASD), reflecting the complexity of its pathophysiology as well as its heterogeneity. Two important hubs have emerged, the placenta/prenatal period and the postnatal gut, with alterations in mitochondria functioning crucial in both. Factors acting to regulate mitochondria functioning in ASD across development are reviewed in this article. Decreased vitamin A, and its retinoic acid metabolites, lead to a decrease in CD38 and associated changes that underpin a wide array of data on the biological underpinnings of ASD, including decreased oxytocin, with relevance both prenatally and in the gut. Decreased sirtuins, poly-ADP ribose polymerase-driven decreases in nicotinamide adenine dinucleotide (NAD+), hyperserotonemia, decreased monoamine oxidase, alterations in 14-3-3 proteins, microRNA alterations, dysregulated aryl hydrocarbon receptor activity, suboptimal mitochondria functioning, and decreases in the melatonergic pathways are intimately linked to this. Many of the above processes may be modulating, or mediated by, alterations in mitochondria functioning. Other bodies of data associated with ASD may also be incorporated within these basic processes, including how ASD risk factors such as maternal obesity and preeclampsia, as well as more general prenatal stressors, modulate the likelihood of offspring ASD. Such a mitochondria-focussed integrated model of the pathophysiology of ASD has important preventative and treatment implications.

Characterization of genetically complex Collaborative Cross mouse strains that model divergent locomotor activating and reinforcing properties of cocaine.

Few effective treatments exist for cocaine use disorders due to gaps in knowledge aboutits complex etiology. Genetically defined animal models provide a useful tool for advancing our understanding of the biological and genetic underpinnings of addiction-related behavior and evaluating potential treatments. However, many attempts at developing mouse models of behavioral disorders were based on overly simplified single gene perturbations, often leading to inconsistent and misleading results in pre-clinical pharmacology studies. A genetically complex mouse model may better reflect disease-related behaviors. Screening defined, yet genetically complex, intercrosses of the Collaborative Cross (CC) mice revealed two lines, RIX04/17 and RIX41/51, with extreme high and low behavioral responses to cocaine. We characterized these lines as well as their CC parents, CC004/TauUnc and CC041/TauUnc, to evaluate their utility as novel model systems for studying the biological and genetic mechanisms underlying behavioral responses to cocaine. Behavioral responses to acute (initial locomotor sensitivity) and repeated (behavioral sensitization, conditioned place preference, intravenous self-administration) exposures to cocaine were assessed. We also examined the monoaminergic system (striatal tissue content and in vivo fast scan cyclic voltammetry), HPA axis reactivity, and circadian rhythms as potential mechanisms for the divergent phenotypic behaviors observed in the two strains, as these systems have a previously known role in mediating addiction-related behaviors. RIX04/17 and 41/51 show strikingly divergent initial locomotor sensitivity to cocaine with RIX04/17 exhibiting very high and RIX41/51 almost no response. The lines also differ in the emergence of behavioral sensitization with RIX41/51 requiring more exposures to exhibit a sensitized response. Both lines show conditioned place preference for cocaine. We determined that the cocaine sensitivity phenotype in each RIX line was largely driven by the genetic influence of one CC parental strain, CC004/TauUnc and CC041/TauUnc. CC004 demonstrates active operant cocaine self-administration and CC041 is unable to acquire under the same testing conditions, a deficit which is specific to cocaine as both strains show operant response for a natural food reward. Examination of potential mechanisms driving differential responses to cocaine show strain differences in molecular and behavioral circadian rhythms. Additionally, while there is no difference in striatal dopamine tissue content or dynamics, there are selective differences in striatal norepinephrine and serotonergic tissue content. These CC strains offer a complex polygenic model system to study underlying mechanisms of cocaine response. We propose that CC041/TauUnc and CC004/TauUnc will be useful for studying genetic and biological mechanisms underlying resistance or vulnerability to the stimulatory and reinforcing effects of cocaine.

Chapter 20 - Learning abilities

Learning abilities are present in infancy, as they are critical for adaptation. From simple habituation and novelty responses to stimuli, learning capacities evolve throughout the lifespan. During development, learning abilities become more flexible and integrated across sensory modalities, allowing the encoding of more complex information, and in larger amounts. In turn, an increasing knowledge base leads to adaptive changes in behavior, making responses and actions more precise and effective. The objective of this chapter is to review the main behavioral manifestations of human learning abilities in early development and their biologic underpinnings, ranging from the cellular level to neurocognitive systems and mechanisms. We first focus on the ability to learn from repetitions of stimuli and how years of research in this field have recently contributed to theories of fundamental brain mechanisms whose implications for cognitive development are under study. The ability to memorize associations between different items and events is addressed next as we review the variety of contexts in which this associative memory and its neurologic bases come into play. Together, repetition-based learning and associative memory provide powerful means of understanding the surrounding environment, not only through the gathering and consolidation of specific types of information, but also by continually testing and adjusting stored information to better adapt to changing conditions.