A Student-Centered, Entrepreneurship Development (ASCEND) Undergraduate Summer Research Program: Foundational Training for Health Research.

Increasing the participation of students of African descent and other minoritized populations in the scientific workforce is imperative in generating a more equitable biomedical research infrastructure and increasing national research creativity and productivity. Undergraduate research training programs have shown to be essential tools in retaining underrepresented minority (URM) students in the sciences and attracting them into STEM and biomedical careers. This paper describes an innovative approach to harness students' entrepreneurial desire for autonomy and creativity in a Summer Research Institute (SRI) that has served as an entry point into a multiyear, National Institutes of Health Building Infrastructure Leading to Diversity (NIH BUILD)-funded research training program. The SRI was designed as an 8-week, student-centered and course-based research model in which students select their own research topics. We test here the effects of SRI training on students' science self-efficacy and science identity, along with several other constructs often associated with academic outcomes in the sciences. The data shown here comprise analysis of four different training cohorts throughout four subsequent summers. We show significant gains in students' science self-efficacy and science identity at the conclusion of SRI training, as well as academic adjustment and sense of belonging. SRI participants also displayed substantially improved retention in their science majors and graduation rates.

Building a Diverse Workforce and Thinkforce to Reduce Health Disparities.

The Research Centers in Minority Institutions (RCMI) Program was congressionally mandated in 1985 to build research capacity at institutions that currently and historically recruit, train, and award doctorate degrees in the health professions and health-related sciences, primarily to individuals from underrepresented and minority populations. RCMI grantees share similar infrastructure needs and institutional goals. Of particular importance is the professional development of multidisciplinary teams of academic and community scholars (the "workforce") and the harnessing of the heterogeneity of thought (the "thinkforce") to reduce health disparities. The purpose of this report is to summarize the presentations and discussion at the RCMI Investigator Development Core (IDC) Workshop, held in conjunction with the RCMI Program National Conference in Bethesda, Maryland, in December 2019. The RCMI IDC Directors provided information about their professional development activities and Pilot Projects Programs and discussed barriers identified by new and early-stage investigators that limit effective career development, as well as potential solutions to overcome such obstacles. This report also proposes potential alignments of professional development activities, targeted goals and common metrics to track productivity and success.

Divergent immune responses in behaviorally-inhibited vs. non-inhibited male rats.

Stable behavioral traits (temperament, personality) often predict health outcomes. Temperament-specific differences in immune function could explain temperament-specific health outcomes, however, we have limited information on whether immune function varies by personality. In the present study, we examined the relationship between a basic behavioral trait (behavioral-inhibition vs. non-inhibition) and two immune responses (innate inflammation and delayed-type hypersensitivity, DTH) in a rodent model. In humans, behavioral inhibition (fearful temperament) is associated with altered stress physiology and allergies. In laboratory rats, the trait is associated with elevated glucocorticoid production. We hypothesized that behavioral inhibition is associated with glucocorticoid resistance and dampened T-helper 1 cell responses often associated with chronic stress and allergies. Further, this immune profile would predict poorly-regulated innate inflammation and dampened DTH. In male Sprague-Dawley rats, we quantified consistent behavioral phenotypes by measuring latency to contact two kinds of novelty (object vs. social), then measured lipopolysaccharide(LPS)-induced innate inflammation or keyhole limpet hemocyanin(KLH)-induced DTH. Behaviorally-inhibited rats had heightened glucocorticoid and interleukin-6 responses to a low/moderate dose of LPS and reduced DTH swelling to KLH re-exposure compared to non-inhibited rats. These results suggest that behavioral inhibition is associated with a glucocorticoid resistant state with poorly regulated innate inflammation and dampened cell-mediated immune responses. This immune profile may be associated with exaggerated T-helper 2 responses, which could set the stage for an allergic/asthmatic/atopic predisposition in inhibited individuals. Human and animal models of temperament-specific immune responses represent an area for further exploration of mechanisms involved in individual differences in health.

Student Learning Dispositions: Multidimensional Profiles Highlight Important Differences among Undergraduate STEM Honors Thesis Writers.

Various personal dimensions of students-particularly motivation, self-efficacy beliefs, and epistemic beliefs-can change in response to teaching, affect student learning, and be conceptualized as learning dispositions. We propose that these learning dispositions serve as learning outcomes in their own right; that patterns of interrelationships among these specific learning dispositions are likely; and that differing constellations (or learning disposition profiles) may have meaningful implications for instructional practices. In this observational study, we examine changes in these learning dispositions in the context of six courses at four institutions designed to scaffold undergraduate thesis writing and promote students' scientific reasoning in writing in science, technology, engineering, and mathematics. We explore the utility of cluster analysis for generating meaningful learning disposition profiles and building a more sophisticated understanding of students as complex, multidimensional learners. For example, while students' self-efficacy beliefs about writing and science increased across capstone writing courses on average, there was considerable variability at the level of individual students. When responses on all of the personal dimensions were analyzed jointly using cluster analysis, several distinct and meaningful learning disposition profiles emerged. We explore these profiles in this work and discuss the implications of this framework for describing developmental trajectories of students' scientific identities.

Student Affect During an HBCU Summer Research Program.

The popularity and effectiveness of intensive summer research programs to increase student self-efficacy is known. The Summer Research Institute (SRI) training experience, as part of undergraduate student training in Morgan State University's NIH BUILD program, uses an entrepreneurial approach to prepare students for careers in health-related research. Bandura's self-efficacy theory's (1977) four antecedents are represented in the SRI curriculum, which provides multiple opportunities for mastery experiences and for moments of roused feelings. These occurrences are accompanied by extensive multilayered mentoring, where the mentors provide verbal encouragement, and facilitate various modes of academic, psychosocial and institutional support. To our knowledge, student affect over time has not been tested to assess impact or program effectiveness in a summer research training program. This study is based on the qualitative assessment of bi-weekly journals of 28 students in the SRI. The practice of students consistently writing journals is aligned with the scaffolded knowledge integration framework proposed by Linn (1995). The journals were reviewed for their cumulative affective content and change over time. The students responded as expected with positive and negative affect throughout the program and ended with overwhelmingly positive affect with their concluding presentations. Using Linguistic Inquiry Word Count (LIWC), a text analysis program, we matched the fluctuations in affect to activities during the program and interpreted the changes for program assessment. This type of analysis opens a window into student affective responses to training components that, to our knowledge, have not been widely used for research training programs of this kind.

Early Life Stress Alters Adult Inflammatory Responses in a Mouse Model for Depression.

Increased levels of pro-inflammatory cytokines and hypothalamic pituitary axis (HPA) activity are strongly associated with depression. Childhood stress and trauma predispose individuals for increased inflammatory tone and major depression in later life, suggesting that early life reprogramming of the stress/immune axis may be involved in the pathogenesis of depression. In this study, we are using a short duration neonatal maternal separation stress (MS) paradigm in mice to test if early life stress can impact plasma and brain inflammatory tone into adulthood. We use ELISA assays to investigate levels of the pro-inflammatory cytokines IL-1beta, IL-2, IL-6 and TNF-alpha, in both plasma and brain tissue of mice exposed to MS (STR), their unseparated littermates (LMC) and unhandled age matched controls (AMC). Cytokine levels are assessed in male and female adult mice with and without a bacterial lipopolysaccharide (LPS) induced immune challenge. We present evidence that stress exposure, during the first week of life, predisposes both male and female mice for increased inflammatory cytokine secretion, peripherally and in brain tissue, upon adult exposure to lipopolysaccharide (LPS).

An entrepreneurial training model to enhance undergraduate training in biomedical research.

BACKGROUND: Undergraduate students who are interested in biomedical research typically work on a faculty member's research project, conduct one distinct task (e.g., running gels), and, step by step, enhance their skills. This "apprenticeship" model has been helpful in training many distinguished scientists over the years, but it has several potential drawbacks. For example, the students have limited autonomy, and may not understand the big picture, which may result in students giving up on their goals for a research career. Also, the model is costly and may greatly depend on a single mentor. KEY HIGHLIGHTS: The NIH Building Infrastructure Leading to Diversity (BUILD) Initiative has been established to fund innovative undergraduate research training programs and support institutional and faculty development of the recipient university. The training model at Morgan State University (MSU), namely "A Student-Centered Entrepreneurship Development training model" (ASCEND), is one of the 10 NIH BUILD-funded programs, and offers a novel, experimental "entrepreneurial" training approach. In the ASCEND training model, the students take the lead. They own the research, understand the big picture, and experience the entire scope of the research process, which we hypothesize will lead to a greater sense of self-efficacy and research competency, as well as an enhanced sense of science identity. They are also immersed in environments with substantial peer support, where they can exchange research ideas and share experiences. This is important for underrepresented minority students who might have fewer role models and less peer support in conducting research. IMPLICATIONS: In this article, we describe the MSU ASCEND entrepreneurial training model's components, rationale, and history, and how it may enhance undergraduate training in biomedical research that may be of benefit to other institutions. We also discuss evaluation methods, possible sustainability solutions, and programmatic challenges that can affect all types of science training interventions.

Effects of brief stress exposure during early postnatal development in balb/CByJ mice: I. Behavioral characterization.

Early life stress has been linked to the etiology of mental health disorders. Rodent models of neonatal maternal separation stress frequently have been used to explore the long-term effects of early stress on changes in affective and cognitive behaviors. However, most current paradigms risk metabolic deprivation, due to prolonged periods of pup removal from the dam. We have developed a new paradigm in Balb/CByJ mice, that combines very brief periods of maternal separation with temperature stress to avoid the confound of nutritional deficiencies. We have also included a within-litter control group of pups that are not removed from the dam. The present experiments provide an initial behavioral characterization of this new model. We show that neonatally stressed mice display increased anxiety and aggression along with increased locomotion but decreased exploratory behavior. In contrast, littermate controls show increased exploration of novelty, compared to age-matched, colony-reared controls. Behavioral changes in our briefly stressed mice substantially concur with the existing literature, except that we were unable to observe any cognitive deficits in our paradigm. However, we show that within litter control pups also sustain behavioral changes suggesting complex and long-lasting interactions between different environmental factors in early postnatal life.

Methamphetamine treatment causes delayed decrease in novelty-induced locomotor activity in mice.

Methamphetamine (METH) is a psychostimulant that causes damage to dopamine (DA) axons and to non-monoaminergic neurons in the brain. The aim of the present study was to investigate short- and long-term effects of neurotoxic METH treatment on novelty-induced locomotor activity in mice. Male BALB/c mice, 12-14 weeks old, were injected with saline or METH (i.p., 7.5 mg/kg x 4 times, every 2 h). Behavior and neurotoxic effects were assessed at 10 days, 3 and 5 months following drug treatment. METH administration caused marked decreases in DA levels in the mouse striatum and cortex at 10 days post-drug. However, METH did not induce any changes in novelty-induced locomotor activity. At 3 and 5 months after treatment METH-exposed mice showed significant recovery of DA levels in the striatum and cortex. In contrast, these animals demonstrated significant decreases in locomotor activity at 5 months in comparison to aged-matched control mice. Further assessment of METH toxicity using TUNEL staining showed that the drug induced increased cell death in the striatum and cortex at 3 days after administration. Taken together, these data suggest that delayed deficits in novelty-induced locomotor activity observed in METH-exposed animals are not due to neurodegeneration of DA terminals but to combined effects of METH and age-dependent dysfunction of non-DA intrinsic striatal and/or corticostriatal neurons.

Neonatal dopamine depletion induces changes in morphogenesis and gene expression in the developing cortex.

The mesocorticolimbic dopamine (DA) system is implicated in mental health disorders affecting attention, impulse inhibition and other cognitive functions. It has also been involved in the regulation of cortical morphogenesis. The present study uses focal injections of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of BALB/c mice to examine morphological, behavioral and transcriptional responses to selective DA deficit in the fronto-parietal cortex. Mice that received injections of 6-OHDA on postnatal day 1 (PND1) showed reduction in DA levels in their cortices at PND7. Histological analysis at PND120 revealed increased fronto-cortical width, but decreased width of somatosensory parietal cortex. Open field object recognition suggested impaired response inhibition in adult mice after 6-OHDA treatment. Transcriptional analyses using 17K mouse microarrays showed that such lesions caused up-regulation of 100 genes in the cortex at PND7. Notably, among these genes are Sema3A which plays a repulsive role in axonal guidance, RhoD which inhibits dendritic growth and tubulin beta-5 microtubule subunit. In contrast, 127 genes were down-regulated, including CCT-epsilon and CCT-zeta that play roles in actin and tubulin folding. Thus, neonatal DA depletion affects transcripts involved in control of cytoskeletal formation and pathway finding, instrumental for normal differentiation and synaptogenesis. The observed gene expression changes are consistent with histological cortical and behavioral impairments in the adult mice treated with 6-OHDA on PND1. Our results point towards specific molecular targets that might be involved in disease process mediated by altered developmental DA regulation.

Neonatal serotonin depletion alters behavioral responses to spatial change and novelty.

Multiple brain disorders that show serotonergic imbalances have a developmental onset. Experimental models indicate a role for serotonin as a morphogen in brain development. To selectively study the effects of serotonin depletions on cortical structural development and subsequent behavior, we developed a mouse model in which a serotonin neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), is injected into the medial forebrain bundle (mfb) on the day of birth. Littermates with saline injections into the mfb and age matched mice served as controls. This study characterized the extent and duration of serotonergic denervation after the selective neonatal lesion and investigated effects on exploratory behavior, spatial learning and anxiety in mice of both sexes. We report significant decreases in the serotonergic (5-HT) innervation to cortex and hippocampus, but not to subcortical forebrain structures in 5,7-DHT-lesioned mice. The depletion of 5-HT fibers in cortical areas was long lasting in lesioned mice but autoradiographic binding to high affinity 5-HT transporters was only transiently reduced. Male but not female lesioned mice reduced their exploration significantly in response to spatial rearrangement and object novelty, suggesting increased anxiety in response to change but normal spatial cognition. Our data show that developmental disruptions in the serotonergic innervation of cortex and hippocampus are sufficient to induce permanent, sex specific, behavioral alterations. These results may have significant implications for understanding brain disorders presenting with cortical morphogenetic abnormalities and altered serotonin neurotransmission, such as autism, schizophrenia and affective disorders.

Modeling early cortical serotonergic deficits in autism.

Autism is a developmental brain disorder characterized by deficits in social interaction, language and behavior. Brain imaging studies demonstrate increased cerebral cortical volumes and micro- and macro-scopic neuroanatomic changes in children with this disorder. Alterations in forebrain serotonergic function may underlie the neuroanatomic and behavioral features of autism. Serotonin is involved in neuronal growth and plasticity and these actions are likely mediated via serotonergic and glutamatergic receptors. Few animal models of autism have been described that replicate both etiology and pathophysiology. We report here on a selective serotonin (5-HT) depletion model of this disorder in neonatal mice that mimics neurochemical and structural changes in cortex and, in addition, displays a behavioral phenotype consistent with autism. Newborn male and female mice were depleted of forebrain 5-HT with injections of the serotonergic neurotoxin, 5,7-dihydroxytryptamine (5,7-DHT), into the bilateral medial forebrain bundle (mfb). Behavioral testing of these animals as adults revealed alterations in social, sensory and stereotypic behaviors. Lesioned mice showed significantly increased cortical width. Serotonin immunocytochemistry showed a dramatic long-lasting depletion of 5-HT containing fibers in cerebral cortex until postnatal day (PND) 60. Autoradiographic binding to high affinity 5-HT transporters was significantly but transiently reduced in cerebral cortex of 5,7-DHT-depleted mice. AMPA glutamate receptor binding was decreased at PND 15. We hypothesize that increased cerebral cortical volume and sensorimotor, cognitive and social deficits observed in both 5-HT-depleted animals and in individuals with autism, may be the result of deficiencies in timely axonal pruning to key cerebral cortical areas.

Prenatal exposure to the acetylcholinesterase inhibitor methanesulfonyl fluoride alters forebrain morphology and gene expression.

Methanesulfonyl fluoride (MSF) is a CNS-selective acetylcholinesterase (AChE) inhibitor, currently being developed and tested for the treatment of symptoms of Alzheimer's disease. We have previously confirmed that a single in utero exposure to MSF at clinically appropriate doses inhibits AChE activity in fetal rat brain by 20%, and when administered throughout gestation, MSF achieves a 40% level of inhibition. Here, we show that rats chronically exposed in utero to MSF display marked sex-specific differences in morphological development of the cerebral cortical layers compared with controls at 7 days of age. Forebrain size and cortical thickness were increased in females and decreased in males. An analysis of gene expression in neonate brain on the day of birth revealed sex-specific differential expression of over 25 genes, including choline acetyltransferase (ChAT), which were affected by prenatal MSF exposure. Many of these genes are associated with sexual differentiation and brain development, while others are involved in more generalized cellular and metabolic processes. The changes observed in cortical morphology and gene expression suggest a critical developmental role for AChE in the fetal nervous system, most likely through its effect on cholinergic neurotransmission.

Sex-specific development of cortical monoamine levels in mouse.

Several mental health disorders exhibit sex differences in monoamine levels associated with dimorphic cortical ontogeny. Studies in rodents support the notion that monoamines can profoundly modulate morphogenesis. Here, we show significant sex and hemisphere differences in BALB/cByJ mice on postnatal day 3 for dopamine (DA) and serotonin (5-TH), supporting the notion that sex differences in early monoaminergic ontogeny may result in dimorphic cortical development. Such sex differences may also influence differential behavioral and/or clinical outcomes.

A morphogenetic role for acetylcholine in mouse cerebral neocortex.

Recently, cholinergic afferents to cerebral cortex have met renewed attention regarding the regulation of plasticity as well as cognitive processing. My laboratory has developed a mouse neonatal basal forebrain lesion paradigm that has contributed considerably to the understanding of cholinergic mechanisms in cortical development. We have shown that transient cholinergic deafferentation, beginning at birth, precipitates alterations in neuronal differentiation and synaptic connectivity that persist into maturity, and contribute to altered cognitive behavior. These data are in general agreement with studies in rats in which the cholinergic basal forebrain is lesioned very early in development but contrast with effects of later developmental lesions. Moreover, in mouse, both morphological and behavioral consequences of the lesion are sex dependent. Studies of receptors and secondary messengers that are instrumental in morphogenesis and plasticity suggest that sex dependent molecular alterations occur within days if not hours following cortical cholinergic deafferentation.

Early neonatal 192 IgG saporin induces learning impairments and disrupts cortical morphogenesis in rats.

We have shown previously that neonatal intraventricular injections of the selective cholinergic immunotoxin 192 IgG saporin on postnatal day 7 (pnd 7) induce marked cholinergic loss in hippocampus and neocortex and a learning impairment on pnd 15. In the present study, we analysed the behavioural, morphological and neurochemical effects of earlier intraventricular injection of the immunotoxin 192 IgG saporin (pnd 1 and 3). We hypothesised that these earlier lesions would interrupt a critical stage in neocortical maturation, and impair behavior more profoundly than the later lesions. Passive avoidance (PA) learning and locomotor activity during the PA test were assessed on pnd 15. Retention of the PA task was assessed on pnd 16. Reactivity to spatial and object novelty was assessed on pnd 180 in a spatial open field test with five objects. Choline acetyltransferase (ChAT) activity was measured in basal forebrain targets on pnd 20 and pnd 180. Neonatal administration of 192 IgG saporin resulted in a slower acquisition of the PA task in females; retention and locomotor activity were not affected. On pnd 180, reaction to spatial novelty was mildly impaired in lesioned rats of both sexes. There was a marked reduction of ChAT in the hippocampus and neocortex of lesioned rats of both sexes, at both ages. Morphological analysis of the somatosensory cortex of lesioned rats revealed alterations in cortical development with sex specific variations in total cortical thickness. These results suggest that interrupting cholinergic basal forebrain innervation of neocortex and hippocampus during the first postnatal days affects the development of cognitive behaviour, neurochemistry and cortical organisation in a sex specific manner. Furthermore, the alterations in cortical organization are more profound than those noted after a lesion later in postnatal development. These behavioural and morphological abnormalities could be considered a model for several neurodevelopmental disorders associated with mental retardation.

Neonatal electrolytic lesions of the basal forebrain stunt plasticity in mouse barrel field cortex.

Previous studies have shown that neonatal electrolytic lesions of basal forebrain cholinergic projections in mice lead to a transient cholinergic depletion of neocortex and to permanent alterations in cortical cytoarchitecture and in cognitive performance. The present study examines whether neonatal electrolytic lesions of the basal forebrain modify neocortical plasticity. Using cytochrome oxidase histochemistry, we compared cross-sectional areas of individual barrels in the barrel field of four groups of postnatal day 8 (P8) old mice that on P1 received either (1) right electrolytic lesions of the basal forebrain, (2) left C row 1-4 whisker follicle ablations, (3) combined lesion treatments or (4) ice anesthesia only. The size of barrels in basal forebrain lesioned animals was not significantly different from controls. However, the plastic response to whisker removal was compromised in basal forebrain lesioned animals. An index of plasticity, the ratio of row D/row C areas, was reduced significantly in the combined nBM lesioned/follicle ablation group. Compared to whisker-lesioned mice, the expansion in rows B and D and the shrinkage in the lesioned row C area were diminished in the combined treatment group. The present findings correspond to those from a study of rats injected with a cholinergic immunotoxin [Cereb. Cortex 8 (1998) 63]. These results suggest that cholinergic inputs play a role in regulating plasticity as well as in the morphogenesis of mouse sensory-motor cortex.