- Faculty Mentors
- UBRP Research Conference
My research and academic interests focus on the study of brain-behavior relationships in the context of aging and age-related, neurodegenerative disease. I use neuroimaging techniques, including structural and functional magnetic resonance imaging (MRI) and positron emission tomography (PET), in combination with measures of cognition and behavior to address research questions on the effects of healthy aging and Alzheimer’s disease on the brain and on the mechanisms of human cognitive aging. A major focus of my research program includes the use of univariate and multivariate network analysis techniques with multiple neuroimaging methods and measures of neuropsychological function, health status, and genetic risk to understand how these factors interact to influence cognitive function as we age. My research also includes the application of these techniques to non-human animal models of aging and age-related disease. I direct the Brain Imaging, Behavior & Aging Lab in the Department of Psychology, have an appointment in the Evelyn F. McKnight Brain Institute, and direct the MRI Morphology Core of the Arizona Alzheimer’s Research Center.
My research involves using electroencephalographic and autonomic psychophysiological measures as endophenotypes in the quest to identify risk factors for depression. I am interested broadly in the etiology and treatment of mood and anxiety disorders. Specific approaches include the investigation of whether asymmetrical frontal brain activity may serve as a marker of risk for depression, the examination of whether alteration of cardiac vagal control may predict treatment response in depression, and the investigation of how neural systems underlying cognitive control may be altered in anxiety disorders.
Examining the factors that may influence word learning; word learning in typically developing bilingual children; treatment efficacy for children with SLI; and speech perception in children with SLI.
Research conducted in the Bailey Lab has as its focus the voluntary and respiratory-related neuromuscular control of upper airway muscles. In particular, our interest is in the control of tongue musculature as a function of sleep and wakefulness, in response to respiratory-related sensory stimuli and simple volitional movements.Our experiments are designed to provide insights into the nervous system (efferent and afferent components) control of these upper airway muscles in human and non-human mammals.Our work combines behavioral, neurophysiological and computational approaches to the study of upper airway muscle activities.Our objective in conducting this work is to gain insight into the nervous system control of upper airway musculature and to establish a foundation for subsequent work that examines tongue muscle and motor unit activities in the performance of highly automated movements i.e., swallowing and speech and in disorders such as obstructive sleep apnea.Current research in non-human mammals has as its focus the hypoglossal (XII) motoneuronal pool.Our interest is in characterizing frequency and duration of apneic episodes in neonatal pups exposed to nicotine in utero.This work will serve as an important step toward understanding the development of the control of breathing and specifically, whether developmental breathing abnormalities are central or peripheral (i.e. obstructive) in origin.
We study auditory perception, plasticity, development, aging, and related disorders.
Acquired impairments of language associated with neurological damage such as stroke, head injury, and neurological disease; research relates to cognitive processes that support language and the nature of acquired language impairment, including aphasia, acquired alexia, and agraphia.
Research interests involve sentence comprehension; cerebral asymmetries; constraints on learning in humans; spatial cognition in humans; reading; and aesthetics. Lab has access to eye movement recorders, brain imaging, and standard cognitive experimental equipment. Current projects try to answer the theoretical question of what is the source of linguistic universals? Independent study and honors students are always welcome.
We are studying the neural circuits of animal behaviors, with a focus on understanding how the neural circuits regulate feeding and emotional behaviors, including fear, anxiety, and depression.
My research focuses on understanding how the activities of ensembles of neurons drive our capacity to decide, remember, and navigate. Towards this end, I utilize high-density recording technologies in behaving animals to investigate the physiological basis of cost-benefit decision making, spatial navigation, and memory consolidation.
Ants, bees, crawly things: why would anyone want to study those? The first thing people ask me when I tell them I work on ants is: do you know how to kill them? In fact, I wouldn’t tell if I knew. Ants, and the other social insects, to me are one of the most fascinating things evolution has produced on earth. They represent a higher level of organization than most other animals, called “superorganisms” by some authors. What this means is essentially that they live in societies of their own with complex communication systems, division of labor, and built structures that can be thousands of times the size of the individual insects. How do social insects achieve this, when colonies are made up of individuals who have no template or overview of the whole society? The algorithms and methods used by ants and bees to achieve adapted collective behavior are the focus of my research. For example, working with Lars Chittka I’ve discovered a communication system in bumble bees which is not dependent on two individuals meeting in person: one bee places information about the existence and quality of a newly discovered resource on a blackboard (a honeypot in the nest), where other bees can pick it up as needed. I’ve also discovered that a recruitment system doesn’t necessarily involve communicating where food is located; in bumble bees, it seems just the information on whether it is worth looking for food is sufficient. Our model calculations have shown that which communication system is most efficient depends strongly on the spatial distribution of resources. This result is supported by one of my studies on honey bees: the well-known waggle dance, the honey bees’ way of communicating about food locations, is in fact only useful in some habitats, probably again depending on resource distribution. It is possible that most of the time, this elaborate dance makes no difference to foraging success at all. I’ve also studied collective decision-making in rock ants, similar to those you find on pavements around the world. These little ants employ a voting-like procedure when deciding collectively which of several potential new homes to move to. My research with Nigel Franks showed that in fact the ants first make a decision about the urgency of the situation: if they have little time, only few ants contribute to the decision-making; if time is of no concern, a large number take part and vote on their favorite nest. I therefore believe that social insects offer a wealth of methods, optimized by evolution, of solving organizational problems in complex systems that consist of (relatively) simple parts. This research is of great interest to computer scientists and engineers alike, who need such algorithms to design artificial distributed problem solving systems. However, I also think it shows that we should never underestimate an animal because it is small. My main interests today are organisation of groups, mechanisms of coordination and task allocation and the role of communication in achieving coherent collective behaviour. I have worked with various species of social insects as model systems, studying foraging behaviour as well as decision-making and division of labour.
The Doyle lab investigates the role of the immune system in causing dementia after stroke. Up to 30% of stroke patients develop dementia in the months and years after their stroke and we are testing the hypothesis that in some patients this is due to a chronic inflammatory response that persists at the site of the stroke lesion. We suspect that in the weeks, months and possibly years after stroke, neurotoxic inflammatory mediators, including T cells, cytokines and antibodies, leak out of the stroke lesion and cause bystander damage to surrounding tissue, which then both impairs recovery, and in some instances leads to cognitive decline. To test this hypothesis we use a mouse model of stroke and human post-mortem tissue.
Memory dysfunction in neurodevelopmental disorders, including Down syndrome and autism. EEG and sleep in development.
The broad goal of research in our laboratory is to understand how inhibitory inputs influence neuronal signaling and sensory signal processing in the healthy and diabetic retina. To study sensory inhibition we use the retina, a unique preparation which can be removed intact and can be activated physiologically, with light, in vitro. Thus using the retina as a model system, we can study how inhibitory synaptic physiology influences inhibition in visual processing. This intact system also allows us to determine the mechanisms of retinal damage in early diabetes.
Translational Neuroscience with focus on Neurodegenerative Diseases, especially Parkinson's disease. Cell-based, gene-based and pharmacological strategies for the treatment of Parkinson's disease. Use of cell culture and rodent in vivo models of Parkinson's disease to test novel therapy strategies/candidates.
We are interested in the role of sleep in memory consolidation, in the role of dopamine in diseases such as PTSD, in the neural substrates of empathy, and the brain mechanisms of optimal spatial navigation. We use rodent models and a multi-disciplinary approach with a set of techniques that include: computational neuroscience (simulating the brain in using a computer), behavioral neuroscience (training rats to perform in mazes), in vivo behaving electrophysiology (recording from individual neurons while the rats are doing a task) and pharmacology (studying the influence of drugs on behavior).
Learning systems in infancy and early childhood, brain development, memory formation, language acquisition, sleep and learning.
We study how brains control complex behaviors, focusing on two groups of animals: bees, ants, and wasps, which show sophisticated behavior, including communication, navigation, learning and memory, yet have simpler brains than vertebrates and are easier to study. Another emphasis is on spiders and their kin, focusing on their senses and orientation. We concentrate on vision and the sense of smell and use behavioral, anatomical and physiological techniques to figure out how certain parts of the brains, and particular neurons, generate and control the behavior of different species.
The Higgins Laboratory has active projects in the study of normal human sleep, neurofeedback therapy for mental disorders, computational modeling of insect visual navigation systems, computational modeling of cognition, and dragonfly-robot interfacing.
The goal of the Koshy lab is to understand the molecular and cellular effects of the neurotropic parasite Toxoplasma gondii on the brain. To do this, we use different strains of Toxoplasma to infect mice and then use a variety of imaging and molecular techniques to understand the impact of these strains on the brain.
My research is in the area of hearing loss and treatment in adults, with a focus on aging and cognitive factors in auditory perception and improving speech understanding in competing sounds.
The Miller laboratory investigates brain circuits that support vocal behavior. These studies are conducted in an animal model, the zebra finch songbird, which enables comparison of brain-behavior relationships at the molecular, cellular and whole behavioral levels. One particular emphasis is on dopamine modulation of basal ganglia circuits and the consequences of dopamine loss on these circuits (as in Parkinson's Disease). The long-term goal is to provide mechanistic insight into neural control of speech.
Various sleep parameters have been associated with glucose dysregulation, hyperglycemia, and impaired neurobehavioral functioning across the lifespan. Recent research has demonstrated that increasing sleep in children by as little as 30 minutes has a benefit in the classroom and their performance on neuropsychological tests. However, research has not examined these relations extensively in youth with type 1 diabetes, a population that already experiences impaired glucose control, compromised neurobehavioral functioning, and insufficient sleep. Further, experimental manipulation of sleep would demonstrate whether modifying sleep improves these outcomes and should be part of diabetes care. Our study will determine if polysomnograpy-recorded (including 6 EEG channels and ECG) contributes to overnight and daytime glucose value and if extending sleep in natural settings over multiple days leads to improvement in glucose control and neurobehavioral functioning in youth with Type 1 diabetes using a randomized clinical control trial. To assess sleep parameters we use PSG, actigraphy, and self-report questionnaires; to assess glucose we use continuous glucose monitors; we obtain hair samples to determine biomarkers; and administer measures of memory, learning, achievement, attention, and intelligence.
I use behavioral, psychophysiological, and imaging methods in normal and brain-damaged individuals to examine the complex processes involved in visual perception of objects, faces, and scenes.
Dr. Plante's lab supports behavioral studies of language and learning, and neuroimaging studies that examine issues related to normal language processing or brain correlates of language disorders. Ongoing neuroimaging research involves analysis of structural MRI scans, diffusion tensor images (DTI), and fMRI studies of language in normal and impaired subjects.
Summer: assessment and treatment of children with language disorders
The influence of the carbohydrate moiety on glycopeptide and glycolipid structure and function is an area of interest to the "Polt Group." Using synthetic methods developed in our laboratory, the preferred conformations of various glycopeptide and glycolipid systems are being determined using state-of-the-art 2-D NMR techniques coupled with computer driven molecular modeling. This data will permit us to understand intracellular trafficking and intercellular transport of glycopeptides at the molecular level. Work done by the "Polt Group" in collaboration with pharmacologists has produced glycopeptide analogues of neurotransmitters which are capable of crossing the blood-brain barrier (BBB). These are the first peptide-based chemicals to function as drugs in the brain, and we have focused on neuroprotective peptides that are potentially useful in Parkinson’s, Alzheimer’s and other forms of dementia. Only Freshmen and Sophomores need apply. A serious commitment to the federally-funded projects within the Polt group is expected.
Genetics of brain development and neuronal plasticity; genetics of mental retardation My overarching interest is in the genetics of brain development, ranging from the control of large-scale morphogenetic movements to the remodeling of individual neurons. We use the fruit fly model system, Drosophila melanogaster, in part because of its phylogenetic similarities to mammals. In particular, we are using fruit flies to understand human developmental brain disorders, such as mental retardation and autism, and as a drug-discovery tool. Our methods include genetic manipulations, primary neuron cell culture, immunostaining and confocal microscopy, expression profiling (with Affymetrix microarrays), bioinformatics, and software development for neuron-image analysis. In order to study genetic pathways that control brain morphogenesis and neuronal plasticity, we focus on the metamorphosis portion of development because the nervous system undergoes dramatic changes, including neuronal remodeling. These changes are under the control of a steroid hormone, 20-hydroxyecdysone (20E), whose receptor subunits are members of the nuclear receptor superfamily. At the cellular level, steroid hormone-induced changes in neuronal structure and function are very similar in mammals and insects. Many of our studies deal with a fascinating brain region, the mushroom bodies, which are remodeled during metamorphosis and which mediate complex adult behaviors, including some forms of learning and memory. We used dissociated cell culture methods to demonstrate that 20E promotes neurite outgrowth of mushroom body neurons harvested early in the metamorphic interval. We also found a number of neuronal morphology phenotypes in vitro, which suggested that cell culture could provide a sensitive assay system for identifying neuronal defects (see below). We determined that Broad Complex transcription factors play a pivotal role in mediating 20E-regulated nervous system metamorphosis. This family of BTB-zinc-finger proteins (BRC-Z1 through -Z4) is generated by alternative splicing of transcripts from a large gene directly induced by 20E in the CNS and other tissues. Transgenic-rescue and spatial expression studies support a model of BRC function in coordinating cell-cell interactions that underlie central nervous system morphogenetic movements. Hundreds of human genes can mutate to a mental retardation (MR) phenotype, either in isolation or as part of a syndrome. We used bioinformatics methods to show that 75% of human MR genes have a candidate functional ortholog in Drosophila. To date, four of the Drosophila genes have been shown by others to have learning or memory phenotypes, and we predict that this will be true for many more of them. We showed that mutants of Drosophila fragile X mental retardation 1 (dfmr1) have defects in mushroom body development during metamorphosis. A major new initiative uses mushroom body cell culture methods to search for neuronal phenotypes of MR gene mutants in vitro. Our long-term goal is to use the Drosophila system as a stepping stone for discovery of drugs that will benefit human MR patients.
We study how specific aspects of voice production influence voice quality. Current research involves studying vocal fold vibration through high-speed endoscopy and computational modeling. We are assessing how several different components of vocal fold vibration change the acoustic signal and influence ratings of voice quaity. The long-term goals of our work are to improve evaluation and treatment of voice disorders caused by aging and by vocal fold paralysis.
Mechanisms of neuropathic pain Neuronal integration in pain pathways Neurochemical release during conditions of neuropathy Neuronal plasticity Opioid receptor pharmacology Novel targets for drug discovery
aphasia, neural basis of language
Neuroscience of learning and decision making
1. Translational control in glia-neural stem cell interactions We have recently discovered a novel role for the RNA binding protein, FMRP, in neural stem cells exit from quiescence, a universal mechanism utilized by stem and progenitor cells across phyla. Furthermore, using tissue specific RNAi we found that FMRP’s requirement switches from neural stem cells to glial cells during early larval brain development. While the genes that control stem cell quiescence remain largely unknown, recent findings indicate that the insulin signaling pathway is involved. Specifically, glial cells secrete insulin like peptides (dILPs) and this results in the activation of the PI3K/AKT pathway in both glia and neural stem cells. Based on these recent findings we hypothesize that FMRP may control exit from quiescence by regulating the insulin signaling pathway. We are currently testing this hypothesis using a combination of molecular and genetic approaches in Drosophila. 2. Lethal giant larvae (Lgl) in neural development. Using forward genetics in Drosophila we identified Lgl as a novel functional interactor of FMRP in neurons. This suggests that lgl may function in neuronal development, a role previously confounded by its requirement in neural stem cells. Preliminary data obtained in my laboratory indicate that loss of lgl results in abnormal neuromuscular junction synapses. Current experiments are aimed at determining whether Lgl is required pre- or post-synaptically at the neuromuscular synapse. The long-term goal of this project is to elucidate the role of the tumor suppressor Lgl in the developing nervous system. We are also testing candidate microRNAs (miRNAs) for their ability to mediate Lgl’s function in the nervous system. 3. Lgl – novel mechanisms for tumor suppression. Lgl is a tumor suppressor in flies and existing reports suggest that it may also be involved in cancer progression in humans. Using Drosophila as a model we are pursuing the potential connection between Lgl and RNA regulation during tumorigenesis. Through genetic interaction experiments we found that lgl may function in the miRNA pathway. In addition, using miRNA microarrays we identified a small number of miRNAs that are misexpressed in lgl mutant brains and the eye neuroepithelium. To determine if human Lgl1 (Hugl1) acts as a bona-fide tumor suppressor in mammals, we are collaborating with Dr. Joyce Schroeder (AZ Cancer Center) to test Hugl1’s role in breast cancer. We hypothesize that the miRNAs we discovered to be misexpressed in the fly model may act as effectors of Lgl in both the nervous system and/or during tumor growth. To test this possibility, we are using a combination of fly genetics, human cancer cells and mouse models to determine whether these candidate miRNAs mediate Lgl’s role in tumorigenesis. 4. Gene and drug discovery in a Drosophila model of Amyotrophic Lateral Sclerosis (ALS). The RNA binding protein TDP-43 has recently been implicated in ALS and FTLD both as a cause as well as a marker of pathology. We have developed a Drosophila model of ALS based on the RNA binding protein, TDP-43. Loss of function for TDP-43 in flies recapitulates the progressive loss of motor ability characteristic to ALS. The overexpression of wild-type and mutant TDP-43, which mimics the mutations found in patients, also recapitulate the neuronal loss and other aspects of ALS pathology, including motor neuron death, locomotor dysfunction and reduced survival. These tools will allow us to uncover the mechanisms leading to neuronal degeneration associated with ALS and other neurodegenerative disorders such as Alzheimer’s disease and Inclusion Body Myositis, where TDP-43 aggregates have been documented. We are currently performing a forward genetic screen and have already identified candidate chromosomal regions that modulate TDP-43’s neurotoxicity. We are also screening FDA approved drugs and small molecules to identify compounds that rescue the neurodegenerative phenotypes and locomotor defects in the fly model. 5. RNA regulation in heart development and disease In collaboration with Dr. Carol Gregorio (Cellular and Molecular Medicine) we have begun to investigate RNA based mechanisms in the heart by studying the function of Fragile X Related Protein 1 (FXR1). We hypothesize that FXR1, the muscle specific homolog of FMRP functions in cardiac muscle by controlling the localized translation of specific mRNAs during myogenesis and also in response to stress. Using a candidate gene approach as well as microarray experiments, we have identified the first mRNA targets that are translationally controlled by FXR1 in the heart. These include components of the costamere complex and intercalated disc, both structurally and functionally important in the developing heart. Notably, mutations in several candidate targets have been previously implicated in cardiomyopathies, which led us to investigate links between FXR1 and human heart disease. We are also working to develop a Drosophila model of heart disease based on FXR1, which we will use to complement the mouse model. The long-term goal of this project is to elucidate the mechanisms for RNA regulation in the heart, which remains an understudied area of muscle biology.
My laboratory has a long-standing interest in understanding molecular mechanisms that mediate and regulate synaptic structure & function, and more recently mitochondrial biology in axons. We investigate fundamental mechanisms by undertaking a multidisciplinary approach, exploiting the neuromuscular junction (NMJ) of genetically modified Drosophila as a model system. Currently, our research focuses on a) molecular mechanisms that control regulated neurotransmitter release and b) molecular mechanisms of mitochondrial transport and biology in axons. These projects use forward and reverse genetics to genetically dissect the role of key components that are conserved from invertebrates to mammals. Abnormal function is assayed by a variety of techniques including electrical recordings, electron microscopy, confocal microscopy, live imaging of intracellular calcium, endo- and exocytosis, and mitochondrial transport in axons of motor neurons.