Research Projects

This new REU site, Research Experiences in Neuroscience for Undergraduates from Rural and Tribal Colleges, will provide hands-on research experience in neuroscience for up to 10 students from tribal and rural colleges, or for other interested students. All students, including those with scholarships provided through the North Dakota Association of Tribal Colleges, will be paired with faculty mentors and perform their research at the University of North Dakota. The primary objectives of this program are to (1) foster academic and social independence, (2) promote an interest in research and science careers, and (3) encourage professional development for the student participants. To begin the program, students will receive one week of training in cell, molecular and imaging techniques. The students will develop their own research projects with their faculty mentor (see list of faculty mentors and their research activities below). Students will attend weekly professional development sessions that will include instruction in oral and written presentations, data analysis and proper research conduct. Students will be expected to present their findings at an end of session symposium. This will prepare them for professional scientific presentations at a regional meeting. Salary, room and board and childcare will be provided for all students. By providing childcare assistance we are incorporating an innovative approach to offer research opportunities for a demographic that has been historically and grossly underrepresented. It is our hope that participating American Indian and rural students will choose to pursue graduate degrees in the sciences and return to their communities to help strengthen science education, research and literacy.

The research activities being conducted by REU faculty mentors at UND:

Diane C. Darland Laboratory Student Projects:

Project #1: Vascular endothelial growth factor function in neural development.

Neurovascular interactions can impact the development of the CNS as well as the plasticity of developing neurons.  Several factors have been identified that show overlapping function in the nervous and vascular systems.  Among these is vascular endothelial growth factor A (VEGF).  VEGF has been identified as a potent regulator of angiogenesis and has recently been shown to impact neural proliferation and neuronal survival in vivo.  The angiogenesis-inducing effects of VEGF are largely mediated via activation of the VEGFR2 homodimer; however, VEGF has also been shown to act via formation of a co-receptor complex of VEGFR2 and neuropilin 1.  This project is designed to test the hypothesis that VEGF regulates neuronal stem cell proliferation and differentiation via the VEGFR2-neuropilin pathway.  The first component of this project is to determine the expression pattern of VEGF and VEGFR2 during developmental neurogenesis in the CNS.  The second component of this project is to examine developmental neurogenesis in VEGF-expressing mice that lack VEGF-mediated signaling via the VEGFR2-neuropilin heterodimer.

Project #2:  Vascular endothelial growth factor (VEGF) isoform regulation of neuronal survival and differentiation.

Neurogenesis requires the coordinated regulation of neural stem cell proliferation, initiation of differentiation with exit from the cell cycle, and acquisition of differentiated properties associated with a given cellular function. Neurogenesis in the brain occurs in concert with development of the CNS vasculature. Therefore, the coordinated regulation of heterotypic cell-cell interactions may play a role in regulating neurogenesis and neural differentiation. One factor that may impact neural and vascular cell interactions is VEGF, a potent angiogenesis factor that has more recently been implicated in neuronal survival and axon pathfinding. The goal of this project is to test the hypothesis that perictye-derived VEGF promotes contact-dependent differentiation of neurons and that perturbation of this molecular pathway disrupts neuronal differentiation. The first component of this project will involve the development of a tri-culture Transwell™ system consisting of primary brain endothelial cells and myofibroblasts cultured together in capillary-like tubes on one side of a Transwell™ membrane with primary neurons cultured on the other side. The second component of this project involves disrupting VEGF signaling in the tri-cultures and assessing the impact on neuronal survival, proliferation and differentiation.


Van A. Doze Laboratory Student Projects:

Noradrenergic Regulation of Neurogenesis & Cognition

The long-term goal of my research is to advance our knowledge of the biological functions of the neurotransmitter, norepinephrine (NE), in the brain. The objective of this project is to determine the effects of NE on neurogenesis and cognition. NE modulates cognitive function. NE also plays a role in synaptic plasticity, which is thought to underlie learning and memory. However, our understanding of how NE regulates these processes is incomplete. Neurogenesis, the production of new cells in the brain, occurs throughout life in adult mammals. The most active areas of adult neurogenesis are the subventricular zone of the lateral ventricles and the subgranular zone of the dentate gyrus in the hippocampus. These regions contain neural stem cells (NSCs) whose progenitors migrate and differentiate into new functioning neural cells. Molecular cues regulating this process include a wide range of growth and survival factors, but a regulatory link between neurogenesis and NE activity has not been explored directly.

NE mediates its effects through activation of adrenergic receptors (ARs). Recently, we discovered that mice genetically engineered to overexpress a1AARs have enhanced cognitive functions. These animals also appear to possess more neurons, particularly in the hippocampus, an area of the brain critical for learning and memory. Further studies indicated that the NSCs in these mice express a1AARs and are undergoing increased cell division. These findings may be extremely important and suggest that NE, through activation of a1AARs, stimulates the production of new neurons, leading to improved cognitive function. This project will test this hypothesis by addressing the following specific aims: 1) Characterize a1AAR influences on adult neurogenesis, cell differentiation and fate, and 2) Determine the effects of a1AAR activation on cognitive performance and neuronal plasticity. This research study will not only increase our understanding of the role of NE in the brain, but may significantly add to our knowledge about the development, regeneration, and aging of the central nervous system.

REU participants will work alongside Dr. Doze's undergraduate and graduate students. In addition to basic lab procedures, REU students will be trained how to handle rodents, dissect brains and prepare brain slices, and depending on which aim they choose to work on, learn to use a variety of lab equipment and techniques. Neuroscience methods that the REU participants will be exposed to include electrophysiological recordings, fluorescent microscopy, immunohistochemistry, stereology, transgenics, and a number of mazes for testing learning and memory (Barnes, Morris). Participants will learn how to perform experiments, analyze data, interpret findings, give short oral and poster presentations, and write a summary of their results. In addition to daily interactions with the PI and his lab personnel, the REU student will attend weekly lab meetings at which data will be presented and discussed, and future research directions determined.


Peter J. Meberg Laboratory Student Projects:

Actin Cytoskeleton in Neuronal Function

Dr. Meberg’s research is focused on the regulation and role of the actin cytoskeleton in neuronal development and synaptic plasticity.  Recent work has focused on the role of two closely related actin binding proteins in neurons, actin depolymerizing factor (ADF) and cofilin, that are primarily localized to growth cones and dendritic spines.  ADF and cofilin are inhibited by phosphorylation.  Active ADF and cofilin increase actin turnover through F-actin severing and increasing the rate of actin monomer loss from the minus end of actin filaments.  Students would have projects related to one of the following research areas:

Project #1:  ADF/cofilin activity and growth cone dynamic.  Overexpression of ADF/cofilin increases neurite outgrowth, and extracellular signals that affect growth cone navigation require signaling through ADF/cofilin.  Students would inhibit or overexpress active forms of ADF/cofilin and do live imaging of growth cones.

Project #2:  Regulation of ADF/cofilin activity by synaptic activity. Seizures induce the loss of dendritic spines (ref) and sprouting of mossy fiber axons in the hippocampus.  Dr. Meberg and his students discovered that seizure induction in rats results in the redistribution of actin filaments in the hippocampus and dephosphorylation/activation of ADF and cofilin (manuscript in preparation).  These results indicate that ADF/cofilin may contribute to axon sprouting by altering actin dynamics.  Student projects could include investigations into the signal pathways upstream of ADF/cofilin dephosphorylation and in vitro models to study seizures, such as hippocampal slices (in collaboration with Dr. Doze). 

Project #3: Proteomic screen to discover other cytoskeleton regulating proteins involved in seizure effects on cytoskeleton.  ADF and cofilin are not the only proteins likely involved in mossy fiber sprouting and spine loss after seizures.  Currently the Meberg lab is screening for other candidate regulators of the cytoskeleton by comparing levels of protein phosphorylation between control and seizure animals.  Several likely candidates have already been identified by 1d gel electrophoresis and mass spectroscopy, and it is anticipated that several more will be identified on 2d gels in the next few months.  For each candidate identified, the following will need to be done:  a) Verify that the protein is indeed changed in phosphorylation by using western blots; b) Examine the intracellular and tissue distribution of the protein in neurons; and c) determine how changes in phosphorylation/ activity of the protein influence synaptic and morphological properties of the neurons.   


Tristan Darland

Zebrafish are currently the only vertebrate model organism amenable to forward genetics, in which mutagenesis, extensive screening for various phenotypes and genetic analysis are used to identify novel genes, or novel functions for known genes in biological processes of interest. I have two main projects in my developing research program; both involve characterizing mutations generated in zebrafish. The first set of mutants has defects in the ability to generate new neurons in the peripheral retina. These defects may represent genes important in adult neurogenesis which is prevalent in fish, but only limited in mammals. The second set of mutants display deviant behavioral responsiveness to cocaine, in short the drug has abnormal addictive potential in these fish. I am currently trying to identify the defective genes in these two sets of mutants and trying to understand their cellular context. While genetic means have been used to map the mutations, I would like to employ proteomic and microarray methods to complement genetic approaches in identifying the defective genes. I am also interested in developing new addiction related behavioral tests to serve as screening tools for additional genetic studies. My long term goal is to find novel genes and molecular pathways linked to retinal neural stem cell regulation and response to cocaine.


Colin Combs

One of our research goals is to determine the mechanisms by which inflammatory activation of brain glial cells contributes to neurodegeneration. Currently, our main interest is the process by which a specific type of glia, microglia, contribute to the pathophysiology of Alzheimer's disease (AD). AD is a neurodegenerative disorder characterized by progressive dementia and an accumulation of extracellular senile plaques and intracellular neurofibrillary tangles in the brain. In addition, diseased brains exhibit a profoundly increased microglial and astrocyte activation phenotype. One prevailing theory is that this “gliosis” contributes to the neuron loss that is observed during disease.

Microglia are the resident immune effector cells of the brain and their activation state can likely contribute to both degeneration and regeneration. This dichotomy provides the opportunity to modulate their phenotype to promote their regenerative function while limiting their degenerative behavior. For example, it is now becoming clearer that many of the neurodegenerative diseases that afflict our brains result, in part, from aberrant microglial responses. In addition to AD, Parkinson’s disease, amyotropic lateral sclerosis, and multiple sclerosis are other examples of chronic nervous system diseases in which microglial hyper-reactivity likely contributes to the cell death that occurs. We are working to understand specifically what goes wrong with the microglia in these conditions. Once we identify the nature of the pathologic response, we work to stop or reverse it in an effort to promote cell survival in the brain. This approach allows us to identify and propose novel therapeutic agents for treating these diseases. We routinely use in vitro primary cell culture models of disease to first define our molecular targets for therapeutic intervention. Next, we verify the efficacy of our approach through in vivo whole animal rodent models of disease. Currently we are pursuing ongoing projects related to Alzheimer’s disease, Parkinson’s disease, cerebrovascular disease, and multiple sclerosis.

Combs CK. J Neuroimmune Pharmacol. 2009 Dec;4(4):380-8. Epub 2009 Aug 11.


Dane Crossley

Neural Pharmacology of fetal vascular function.

Neural regulation of vascular function is surprisingly understudied in most fetal vertebrates. This is amazing given the major selective pressures that occur during critical developmental periods of the vertebrate life cycle. The focus of my research is to understand how neural and neuropharmacological control of cardiovascular function develops in vertebrates and the impact the developmental environment can have on that maturation process. This project will focus on the neuropharmacology of a unique fetal vascular bed, the chorio-allantois, in fetal chickens at two points of development. This vascular bed contains the majority of the fetal blood volume for long periods of time and thus must be tightly regulated to maintain normal cardiovascular function. While the potential contribution of the chorio-allantois (CA) vascular bed to fetal cardiovascular function is clear, the neuropharmacology is unknown. An assessment of cholinergic and adrenergic control is therefore critical. This project will utilize a perfused isolated CA vascular technique to investigate the change in sensitivity to adrenergic and cholinergic stimulation, two key components of autonomic nervous control. These studies will be carried out on fetal day 15 and 19, which represent the transition in gas exchange methods in the animal. Collectively the study will provide important information needed to expand our understanding of the regulatory overlap between the nervous system and the cardiovascular system during early vertebrate development.


Keith Henry

Dr. Henry uses modern molecular pharmacology and structural-computational biology to explore the function of the serotonin (SERT) and dopamine (DAT) neurotransmitter transporters. These transporters are major clinical targets for drugs that treat depression, anxiety, obsessive compulsive disorder, post-traumatic stress disorder and attention-deficit hyperactivity disorder. The SERT and DAT are also the target of many drugs of abuse such as cocaine, amphetamines and ecstasy. The Henry lab use mutations and species differences to identify and characterize important regions of the transporters involved in the interaction with these drugs. Another important aspect of these transporters is how they are driven energetically. We study mutations that alter the biophysical properties of the transporter and by understanding these changes we can glean insight into the mechanistic underpinnings of the transport process. Techniques used in the lab include PCR, affinity binding studies, biomolecular labaling, DNA and protein electrophoresis, protein purification, and in silico computational modeling.


Thad A. Rosenberger

Inflammation induced tissue injury is a major and primary contributing factor to the pathogenesis of a variety of human brain diseases including; cerebral ischemia, spinal cord injury, multiple sclerosis, AIDS-related dementia, and Alzheimers disease. Inflammation induces the production, by activated microglia and astrocytes, of the pro-inflammatory cytokines (e.g. IL-1, TNFa, etc.). These cytokines bind to receptors that, among other things, couple to "effector" enzymes such as phospholipases A2 and phospholipases C, provoking pathological lipid-mediated signaling cascades. Induction of these cascades is known to disrupt membrane phospholipid metabolism, increase the expression of enzymes found in the inflammatory cascades, and ultimately result in altered cellular homeostasis and cell death.

Our long-term goal is to understand the extent by which alterations in lipid-mediated signal transduction contribute to the progression of injury associated with neuroinflammation and to use this knowledge to develop therapeutic strategies to treat these diseases. Studies in our laboratory include: identifying lipid-mediated signaling pathways that contribute to the progression of inflammatory events in the central nervous system, identifying the specific roles phospholipases A2 and C play in the progression of disease, and to distinguish the role that ether phospholipid metabolism has in normal and injured brain.