Adrienne Mueller

All Publications

• Innovations in Undergraduate Research Training Through Multisite Collaborative Programming: American Heart Association Summer Undergraduate Research Experience Syndicate. Journal of the American Heart Association Ajayi, T. B., Mueller, A. L., Okwuosa, I. S., Barshilia, A., Wu, J. C., Benjamin, E. J., Barnett, J. V., Oliver, K. H. 2022: e022380

  Abstract

  Background To support diversity in biomedical science, the American Heart Association launched the Supporting Undergraduate Research Experiences for undergraduate students from underrepresented backgrounds to provide mentorship and high-level exposure at 5 leading medical institutions. Here we describe the initial formation of the partnership and the alteration made in response to the program to accommodate COVID-19 safety precautions. Methods and Results We outline how programming shifted from local, in-person programming in the summer of 2019 to a collaborative, mainly virtual curriculum in 2020 using students' self-reported before and after surveys from both 2019 (n=33) and 2020 (n=42). Students from both in-person (2019) and virtual programs (2020) self-reported significant gains in scientific proficiency. A qualitative-directed content analysis of student open-response questions was performed. Students reported extensive benefits from the 2020 virtual training, including Personal Gains, Research Skills, Thinking and Working Like a Scientist, and Attitudes and Behaviors. Notedly, we observed increases in the Attitudes and Behaviors category. We outline the pros and cons of in-person and virtual programming and make recommendations moving forward in a postpandemic world with hybrid work and learning systems. Conclusions Our effort informs the development of future undergraduate research training programs, significantly maximizing a hybrid training modality. The American Heart Association Supporting Undergraduate Research Experiences serves as a model for building multi-institutional partnerships and providing research experiences that overcome institutional barriers and support students' interests, commitment, and ability to persist in science, technology, engineering, and math fields.

  View details for DOI 10.1161/JAHA.121.022380

  View details for PubMedID 35388707

• Linking ADHD to the Neural Circuitry of Attention TRENDS IN COGNITIVE SCIENCES Mueller, A., Hong, D. S., Shepard, S., Moore, T. 2017; 21 (6): 474-488

  Abstract

  Attention deficit hyperactivity disorder (ADHD) is a complex condition with a heterogeneous presentation. Current diagnosis is primarily based on subjective experience and observer reports of behavioral symptoms - an approach that has significant limitations. Many studies show that individuals with ADHD exhibit poorer performance on cognitive tasks than neurotypical controls, and at least seven main functional domains appear to be implicated in ADHD. We discuss the underlying neural mechanisms of cognitive functions associated with ADHD, with emphasis on the neural basis of selective attention, demonstrating the feasibility of basic research approaches for further understanding cognitive behavioral processes as they relate to human psychopathology. The study of circuit-level mechanisms underlying executive functions in nonhuman primates holds promise for advancing our understanding, and ultimately the treatment, of ADHD.

  View details for DOI 10.1016/j.tics.2017.03.009

  View details for PubMedID 28483638

• Postdoctoral T32 training is correlated with obtaining an academic primarily research faculty position. PloS one Mueller, A. L., Schnirel, A., Kleppner, S., Tsao, P., Leeper, N. J. 2024; 19 (6): e0303792

  Abstract

  The mission of NIH-sponsored institutional training programs such as the T32 is to provide strong research and career training for early career scientists. One of the main avenues to pursuing health-related research is becoming research faculty at an academic institution. It is therefore important to know whether these programs are succeeding in this mission, or, if barriers exist that prevent trainees from pursuing these careers. Our institution currently trains ~ 2400 post-doctoral scholars per year, approximately 5% of whom are enrolled in one of our 33 T32 programs. In this study, we 1) compare the proximal professional career trajectories of T32 trainees with non-T32 trainees at our institution, 2) compare proximal career trajectories of trainees in a subset of cardiovascular T32 programs based on their previous training backgrounds, and 3) survey past and current T32 trainees in a subset of cardiovascular T32 programs about the barriers and enablers they experienced to pursuing research-oriented careers. We find that former T32 trainees are significantly more likely to attain appointments as primarily research faculty members, compared to other trainees. Trainees report a perceived lack of stability, the paucity of open positions, and the 'publish or perish' mentality of academia as the top barriers to pursuing careers in academia. However, they were still more likely to choose research over clinical careers after participating in a dedicated T32 program. Our results support the conclusion that structured training programs strengthen the pipeline of young scientists pursuing careers in academic research, including those from underrepresented backgrounds. However, T32 postdoctoral researchers are held back from pursuing academic careers by a perceived lack of stability and high competition for faculty positions.

  View details for DOI 10.1371/journal.pone.0303792

  View details for PubMedID 38848385

  View details for PubMedCentralID PMC11161096

• Opportunities to Increase Science of Diversity and Inclusion in Clinical Trials: Equity and a Lack of a Control. Journal of the American Heart Association Igwe, J., Wangdak Yuthok, T. Y., Cruz, E., Mueller, A., Lan, R. H., Brown-Johnson, C., Idris, M., Rodriguez, F., Clark, K., Palaniappan, L., Echols, M., Wang, P., Onwuanyi, A., Pemu, P., Lewis, E. F. 2023: e030042

  Abstract

  The United States witnessed a nearly 4-fold increase in personal health care expenditures between 1980 and 2010. Despite innovations and obvious benefits to health, participants enrolled in clinical trials still do not accurately represent the racial and ethnic composition of patients nationally or globally. This lack of diversity in cohorts limits the generalizability and significance of results among all populations and has deep repercussions for patient equity. To advance diversity in clinical trials, robust evidence for the most effective strategies for recruitment of diverse participants is needed. A major limitation of previous literature on clinical trial diversity is the lack of control or comparator groups for different strategies. To date, interventions have focused primarily on (1) community-based interventions, (2) institutional practices, and (3) digital health systems. This review article outlines prior intervention strategies across these 3 categories and considers health policy and ethical incentives for substantiation before US Food and Drug Administration approval. There are no current studies that comprehensively compare these interventions against one another. The American Heart Association Strategically Focused Research Network on the Science of Diversity in Clinical Trials represents a multicenter, collaborative network between Stanford School of Medicine and Morehouse School of Medicine created to understand the barriers to diversity in clinical trials by contemporaneous head-to-head interventional strategies accessing digital, institutional, and community-based recruitment strategies to produce informed recruitment strategies targeted to improve underrepresented patient representation in clinical trials.

  View details for DOI 10.1161/JAHA.123.030042

  View details for PubMedID 38108253

• Dopamine Receptor Expression Among Local and Visual Cortex-Projecting Frontal Eye Field Neurons CEREBRAL CORTEX Mueller, A., Krock, R. M., Shepard, S., Moore, T. 2020; 30 (1): 148–64

  View details for DOI 10.1093/cercor/bhz078

  View details for Web of Science ID 000515101400012

• Differences in Noradrenaline Receptor Expression Across Different Neuronal Subtypes in Macaque Frontal Eye Field. Frontiers in neuroanatomy Lee, M., Mueller, A., Moore, T. 2020; 14: 574130

  Abstract

  Cognitive functions such as attention and working memory are modulated by noradrenaline receptors in the prefrontal cortex (PFC). The frontal eye field (FEF) has been shown to play an important role in visual spatial attention. However, little is known about the underlying circuitry. The aim of this study was to characterize the expression of noradrenaline receptors on different pyramidal neuron and inhibitory interneuron subtypes in macaque FEF. Using immunofluorescence, we found broad expression of noradrenaline receptors across all layers of the FEF. Differences in the expression of different noradrenaline receptors were observed across different inhibitory interneuron subtypes. No significant differences were observed in the expression of noradrenaline receptors across different pyramidal neuron subtypes. However, we found that putative long-range projecting pyramidal neurons expressed all noradrenaline receptor subtypes at a much higher proportion than any of the other neuronal subtypes. Nearly all long-range projecting pyramidal neurons expressed all types of noradrenaline receptor, suggesting that there is no receptor-specific machinery acting on these long-range projecting pyramidal neurons. This pattern of expression among long-range projecting pyramidal neurons suggests a mechanism by which noradrenergic modulation of FEF activity influences attention and working memory.

  View details for DOI 10.3389/fnana.2020.574130

  View details for PubMedID 33328901

• Prefrontal Contributions to Attention and Working Memory. Current topics in behavioral neurosciences Bahmani, Z., Clark, K., Merrikhi, Y., Mueller, A., Pettine, W., Isabel Vanegas, M., Moore, T., Noudoost, B. 2019

  Abstract

  The processes of attention and working memory are conspicuously interlinked, suggesting that they may involve overlapping neural mechanisms. Working memory (WM) is the ability to maintain information in the absence of sensory input. Attention is the process by which a specific target is selected for further processing, and neural resources directed toward that target. The content of WM can be used to direct attention, and attention can in turn determine which information is encoded into WM. Here we discuss the similarities between attention and WM and the role prefrontal cortex (PFC) plays in each. First, at the theoretical level, we describe how attention and WM can both rely on models based on attractor states. Then we review the evidence for an overlap between the areas involved in both functions, especially the frontal eye field (FEF) portion of the prefrontal cortex. We also discuss similarities between the neural changes in visual areas observed during attention and WM. At the cellular level, we review the literature on the role of prefrontal DA in both attention and WM at the behavioral and neural levels. Finally, we summarize the anatomical evidence for an overlap between prefrontal mechanisms involved in attention and WM. Altogether, a summary of pharmacological, electrophysiological, behavioral, and anatomical evidence for a contribution of the FEF part of prefrontal cortex to attention and WM is provided.

  View details for PubMedID 30739308

• Differential Expression of Dopamine D5 Receptors across Neuronal Subtypes in Macaque Frontal Eye Field FRONTIERS IN NEURAL CIRCUITS Mueller, A., Shepard, S. B., Moore, T. 2018; 12: 12

  Abstract

  Dopamine signaling in the prefrontal cortex (PFC) is important for cognitive functions, yet very little is known about the expression of the D5 class of dopamine receptors (D5Rs) in this region. To address this, we co-stained for D5Rs, pyramidal neurons (neurogranin+), putative long-range projection pyramidal neurons (SMI-32+), and several classes of inhibitory interneuron (parvalbumin+, calbindin+, calretinin+, somatostatin+) within the frontal eye field (FEF): an area within the PFC involved in the control of visual spatial attention. We then quantified the co-expression of D5Rs with markers of different cell types across different layers of the FEF. We show that: (1) D5Rs are more prevalent on pyramidal neurons than on inhibitory interneurons. (2) D5Rs are disproportionately expressed on putative long-range projecting pyramidal neurons. The disproportionately high expression of D5Rs on long-range projecting pyramidals, compared to interneurons, was particularly pronounced in layers II-III. Together these results indicate that the engagement of D5R-dependent mechanisms in the FEF varies depending on cell type and cortical layer, and suggests that non-locally projecting neurons contribute disproportionately to functions involving the D5R subtype.

  View details for PubMedID 29483863

• Distribution of N-Acetylgalactosamine-Positive Perineuronal Nets in the Macaque Brain: Anatomy and Implications. Neural plasticity Mueller, A. L., Davis, A. n., Sovich, S. n., Carlson, S. S., Robinson, F. R. 2016; 2016: 6021428

  Abstract

  Perineuronal nets (PNNs) are extracellular molecules that form around neurons near the end of critical periods during development. They surround neuronal cell bodies and proximal dendrites. PNNs inhibit the formation of new connections and may concentrate around rapidly firing inhibitory interneurons. Previous work characterized the important role of perineuronal nets in plasticity in the visual system, amygdala, and spinal cord of rats. In this study, we use immunohistochemistry to survey the distribution of perineuronal nets in representative areas of the primate brain. We also document changes in PNN prevalence in these areas in animals of different ages. We found that PNNs are most prevalent in the cerebellar nuclei, surrounding >90% of the neurons there. They are much less prevalent in cerebral cortex, surrounding less than 10% of neurons in every area that we examined. The incidence of perineuronal nets around parvalbumin-positive neurons (putative fast-spiking interneurons) varies considerably between different areas in the brain. Our survey indicates that the presence of PNNs may not have a simple relationship with neural plasticity and may serve multiple functions in the central nervous system.

  View details for DOI 10.1155/2016/6021428

  View details for PubMedID 26881119

  View details for PubMedCentralID PMC4735937

• N-acetylgalactosamine positive perineuronal nets in the saccade-related-part of the cerebellar fastigial nucleus do not maintain saccade gain. PloS one Mueller, A. n., Davis, A. n., Carlson, S. S., Robinson, F. R. 2014; 9 (3): e86154

  Abstract

  Perineuronal nets (PNNs) accumulate around neurons near the end of developmental critical periods. PNNs are structures of the extracellular matrix which surround synaptic contacts and contain chondroitin sulfate proteoglycans. Previous studies suggest that the chondroitin sulfate chains of PNNs inhibit synaptic plasticity and thereby help end critical periods. PNNs surround a high proportion of neurons in the cerebellar nuclei. These PNNs form during approximately the same time that movements achieve normal accuracy. It is possible that PNNs in the cerebellar nuclei inhibit plasticity to maintain the synaptic organization that produces those accurate movements. We tested whether or not PNNs in a saccade-related part of the cerebellar nuclei maintain accurate saccade size by digesting a part of them in an adult monkey performing a task that changes saccade size (long term saccade adaptation). We use the enzyme Chondroitinase ABC to digest the glycosaminoglycan side chains of proteoglycans present in the majority of PNNs. We show that this manipulation does not result in faster, larger, or more persistent adaptation. Our result indicates that intact perineuronal nets around saccade-related neurons in the cerebellar nuclei are not important for maintaining long-term saccade gain.

  View details for DOI 10.1371/journal.pone.0086154

  View details for PubMedID 24603437

  View details for PubMedCentralID PMC3945643

• Sources of tonic firing properties of saccade-related cerebellar neurons Mueller, A., Robinson, R. ASSOC RESEARCH VISION OPHTHALMOLOGY INC. 2013

  View details for Web of Science ID 000436232704277

• When during horizontal saccades in monkey does cerebellar output affect movement? Brain research Buzunov, E. n., Mueller, A. n., Straube, A. n., Robinson, F. R. 2013; 1503: 33–42

  Abstract

  The caudal part of the cerebellar fastigial nucleus (CFN) influences the horizontal component of saccades. Previous reports show that activity in the CFN contralateral to saccade direction aids saccade acceleration and that activity in the ipsilateral CFN aids saccade deceleration. Here we refine this description by characterizing how blocking CFN activity changes the distance that the eye rotates during each of 4 phases of saccades, the increasing and decreasing saccade acceleration (phases 1 and 2) and deceleration (3 and 4). We found that unilateral CFN inactivation increases total eye rotation to ∼1.8× normal. This resulted from rotation increases in all four phases of ipsiversive saccades. Rotation during phases 1 and 2 increases slightly, more during phase 3, and most during phase 4, to ∼4.4× normal. Thus, the ipsilateral CFN normally reduces eye rotation throughout a saccade but reduces it the most near saccade end. After unilateral CFN inactivation, rotation during contraversive saccades was ∼0.8× normal. This resulted from decreased rotation during phases 1-3, to ∼0.7× normal, and then normal rotation during phase 4. Thus the CFN contraversive to saccade direction normally increases eye rotation during acceleration and the first phase of deceleration. These data indicate that the influences of the CFNs on saccades overlap extensively and that there is a smooth shift from predominance of the contralateral CFN early in a saccade to the ipsilateral CFN later. The pathway from the CFN to contralateral IBNs and then to the abducens nucleus can account for these effects.

  View details for DOI 10.1016/j.brainres.2013.02.001

  View details for PubMedID 23399683

  View details for PubMedCentralID PMC4556436

• Long-term size-increasing adaptation of saccades in macaques. Neuroscience Mueller, A. L., Davis, A. J., Robinson, F. R. 2012; 224: 38-47

  Abstract

  Motor learning adjusts movement size and direction to keep movements accurate. A useful model of motor learning, saccade adaptation, uses intra-saccade target movement to make saccades seem inaccurate and elicit adaptive changes in saccades. In the most studied saccade adaptation procedure, which we call short-term saccade adaptation (STSA), monkeys decrease or increase the size of their saccades by tracking 1000-2000 adapting target movements in a single saccade session. STSA elicits rapid changes of limited size and duration. Larger, more persistent reduction in saccade size results from adapting saccades daily for 19 days, a procedure that we call long-term saccade adaptation (LTSA). LTSA mimics the demands of rehabilitation more closely than does STSA and, unlike STSA, produces changes that could maintain long-term accuracy. Previous work describes LTSA that reduces saccade size in monkeys. Though convenient to study, size-decreasing LTSA is not a good model for rehabilitation because few injuries necessitate making movements smaller. Here we characterize size-increasing LTSA and compare it, in the same monkeys, to size-reducing LTSA. We found that size-increasing LTSA can double saccade gain in ∼21 days, and is slower than size-decreasing LTSA. In contrast to a single size-decreasing STSA, a single size-increasing STSA does not prevent additional saccade size increase at the normal rate when a monkey continues to track adapting target movements. We conclude that size-increasing LTSA is slower than size-decreasing LTSA but can make larger changes in saccade size. Size-increasing and size-decreasing LTSA use distinct mechanisms with different performance characteristics.

  View details for DOI 10.1016/j.neuroscience.2012.08.012

  View details for PubMedID 22902543

  View details for PubMedCentralID PMC3468708