Faculty

Research Summary

Mechanisms of human neurodegenerative diseases My group is using transgenic mouse models to study the mechanisms of human neurodegenerative diseases, particularly AD and PD. There are three broad areas of active interest. Understanding the pathogenesis/progression of PD using alpha-synuclein and LRRK2 transgenic mouse models. Mechanisms of amyloid-dependent neurodegeneration using transgenic mouse models of AD. Pathologic interactions between genetic and environmental factors.  While most cases of AD and PD are "sporadic", the key assumption is that genetic lesions that cause classic forms of the relevant neurodegenerative diseases will cause neural abnormalities that are common between the genetic and sporadic forms of the disease. When used in conjunction with careful analysis of human subjects, invertebrate models, and cell culture models, we will be able to define mechanisms that are directly relevant to the pathogenesis and identify possible targets for therapeutic intervention. The models generated are also essential for cross-platform screening and validation of novel therapeutic approaches. My group has identified several robust biochemical, pathological and behavioral outcome measures in transgenic mouse models of AD and PD. These measures will be essential for in vivo preclinical evaluation of therapeutics. 

Bio

Julia Lemos is an Assistant Professor of Neuroscience and member of the University's Medical Discovery Team on Addiction. Her laboratory investigates how stress is processed and encoded in the brain. In particular, they interested in understanding how stress-associated neuropeptides regulate the function of neural circuits important for motivation and emotion in individuals with different life histories. Her laboratory also works to understand how chronic or traumatic stress renders the brain vulnerable to disease states such as depression, anxiety, and addiction.

Research Summary

Intuitively we know that stress can influence our decision-making process; this is part of our daily lives. While responding to acute stressors appropriately allows us to make good decisions, chronic or severe stress can lead to bad decision-making. These processes can be observed across many species, from rodents to humans. In humans, this switch in how we make choices following chronic stress can make an individual vulnerable to diseases like addiction or depression. Despite compelling motivations to study the influence of stress on decision-making, the neurobiology of how acute or chronic stress alters decision-making remains largely unexplored. To answer these questions, my laboratory uses a multi-disciplinary approach in which we pair conventional physiological and behavioral techniques with novel transgenic and optogenetic technology in mice. We use the information obtained from our ex vivo experiments to make predictions about the impact of stress and stress-associated on exploration, reward learning and decision-making behavior. Moreover, we can put our ex vivo observations to task by testing the causal relationship between our cellular and circuit findings and behavioral output. We often see how a life history of chronic or severe stress impacts normal functioning to shift behavioral outputs. Using this paradigm, we can then test whether different therapeutic interventions can reverse the impact of chronic stress on exploration and decision-making behaviors. 

Research Summary

Abnormally aggregating proteins in cerebral brain tissues during the course of neurodegenerative disorders Despite evidence for a pathogenic role of amyloid plaques and associated neuronal dystrophy, it has become apparent in recent years that soluble, non-fibrillar Amyloid-Beta assemblies, also called Abeta oligomers, are more critical than plaque load in the pathogenesis of Alzheimer's disease-related neuronal dysfunction and memory impairment. However, the exact mechanism by which these multimeric forms are able to alter brain and neuronal function remains to be identified. Due to their size and presence in the extracellular space, our laboratory is examining whether and how Abeta oligomers can interact at neuronal plasma membranes with specific receptors involved in the cellular form of memory called long-term potentiation by combining biochemical and functional assays. In addition, since Abeta has been suggested in 2001 to influence the formation of neurofibrillary tangles, composed of hyperphosphorylated tau proteins, our group also focuses on examining whether soluble Abeta oligomers represent the missing link between tau and amyloid pathologies in Alzheimer's disease, using novel bigenic mice expressing the full human tau gene and APP, the precursor protein of Abeta. We investigate the effect of short- and long-term exposures of soluble Abeta oligomers on tau biochemistry, cellular localization and tau interaction with other microtubule-associated proteins by integrating in vitro and in vivo approaches using newly generated fluorescent protein-tagged knock-in transgenic mice crossed with transgenic mouse models of AD.

Research Summary

Molecular and Cellular Mechanisms of Synaptic Plasticity Activity-dependent modulation of glutamatergic synapses has been suggested to play important roles in learning and memory in adult brains, and the formation of synaptic connections in developmental brains. This modulation is at least partially mediated through the activation of "silent synapses," synapses that contain NMDA receptors but not AMPA receptors. Such synapses are silent at a normal resting potential due to voltage-dependent magnesium blockade of NMDA receptors. Our laboratory mainly uses electrophysiological, morphological and molecular biological techniques to investigate molecular and cellular mechanisms of activity-dependent synaptic plasticity. Particularly, we are interested in the cellular mechanisms responsible for the activation of silent synapses. It has been recently reported that silent synapses can be rapidly awakened through a rapid acquisition of AMPA receptors. Our goal is to understand the intracellular signaling pathways for the rapid synaptic targeting of AMPA receptors.

Research Summary

Unfolded Protein Response in Neurological Diseases The research in my laboratory is focused on understanding the effects of the unfolded protein response on neurological diseases and their underlying mechanisms.Endoplasmic reticulum stress, initiated by the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum lumen, activates an adaptive program known as the unfolded protein response, which coordinates endoplasmic reticulum protein-folding demand with protein-folding capacity and is essential to preserve cell function and survival under stressful conditions. Nevertheless, the unfolded protein response also controls an apoptotic program to eliminate cells whose folding problems in the endoplasmic reticulum cannot be resolved by the adaptive response. In eukaryotic cells, three endoplasmic reticulum–resident transmembrane proteins involved in the unfolded protein response have been identified: pancreatic ER kinase (PERK), inositol requiring enzyme 1 (IRE1), and activating transcription factor 6 (ATF6). It has become increasingly clear that endoplasmic reticulum stress is an important feature of a number of neurological diseases, such as myelin disorders, neurodegenerative diseases, and brain tumors. Due to the double-edged sword nature of the unfolded protein response, the role that the unfolded protein response plays in these diseases remains ambiguous.Our work utilizes sophisticated mouse models to dissect the precise role of individual branch of the unfolded protein response in myelin disorders, neurodegenerative diseases, and brain tumors. These studies could provide mechanistic insight necessary for designing novel therapeutic strategies for patients with these diseases.

Research Summary

Central pattern generators Most rhythmic motor patterns in animals, including breathing, chewing, limbed locomotion, and undulatory swimming are programmed in part by neural circuits called central pattern generators. These pattern generators often have, at their core, rhythmically active neurons or neural networks. The study of these pattern generators has yielded insight not only into the origins of rhythmic activity, but also into the functioning and modulation of neural networks in general. My primary interest is to understand how spinal circuits are structurally and functionally organized to generate different rhythmic motor patterns. In vertebrates, neural circuits are located in spinal cord and mediate rhythmic movements by the activation of spinal motor neurons via premotor interneurons. Therefore, different movements must, in part, be determined by the differences in activity of the spinal premotor interneurons. To understand how different motor behaviors are produced by spinal circuits, it is critical to determine:Which classes of interneuron are involved in specific behaviors. The synaptic connectivity pattern in spinal circuits. The patterns of activity in identified classes during different behaviors. The intrinsic and modulated membrane and channel properties of the neurons invovled in the pattern generating circuit. How perturbation of a circuit changes the behavior. Until recently these issues have been difficult to address in vertebrate preparations because of the complexity of the spinal cord, the inability to monitor activity in identified classes of interneuron during different behaviors, the lack of appropriate genetic tools, and the difficulty in performing perturbation experiments. However, the larval zebrafish model system is an outstanding candidate to begin to address these questions. First, investigation of identified neurons and thus neural circuits is a tenable endeavor since there are a limited number of neurons in the spinal cord. Second, genetic and molecular tools have matured so that the identification and labeling of particular classes of interneurons is routine. Third, the translucent nature of the preparation combined with conventional or genetically encoded indicators makes it particularly appropriate for optical methods of investigation. Thus, optical imaging can be used to monitor activity in particular classes of interneuron during behavior. Finally, perturbation experiments can be used to examine the functional role of a particular class of interneuron in behavior, which may provide insights into the functional organization of spinal circuits. Therefore, my intent is to exploit the convergence of these tools in studies which address the functional organization of spinal interneurons involved in generating different patterns of motor activity.

Bio

Robert Meisel is a professor in the Department of Neuroscience. A key question addressed by his lab is what makes some people more vulnerable than others to the addictive effects of drugs? One idea he has been testing in an animal model of addiction vulnerability is that the converging neural plasticity of behavioral experience and drug use renders the brain more susceptible to the addictive properties of drugs.

Research Summary

Natural Experiences and Addiction Vulnerability Behavioral disorders are often pathological extensions of normal behavioral processes. Just as depression may be an inappropriate expression of feelings of sadness, drug addiction can be thought of as a pathology of motivation. The goal of this laboratory's research is to use female sexual behavior in rodents as a model system to further our understanding of neural mechanisms of motivations, and by extension compare these mechanisms to those mediating abnormal behaviors, such as addiction. One approach that we take is based on the observation that repeated drug use produces changes in the structure and cellular properties of dopaminergic neurons. We have found that similar neural plasticity in dopamine pathways is seen following repeated sexual experience in female hamsters. By comparing neural changes to drugs versus engaging in natural behaviors, we can separate the neural properties of drug addiction that result from exposure to potent, artificial pharmacological agents from the endogenous neural plasticity that underlies activities in everyday life.

Bio

Paul Mermelstein is a professor in the Department of Neuroscience. His laboratory researches sex differences in the brain. Specifically, how sex hormones (estrogen in females, testosterone in males) alter the synaptic connections in the brain to influence motivated behaviors. He and his team have discovered that when estrogen concentrations rise in females, their vulnerability to abuse addictive drugs increases. They are seeking to determine the mechanisms by which estrogens impart vulnerability to drug addiction, and ways to circumvent these changes in brain plasticity, ultimately in hopes of improving therapeutic interventions.

Research Summary

Estrogen Potentiation of Female Drug Addiction Research in my laboratory focuses on the effects of steroid hormones (particularly estrogens) on motivated behaviors. Of particular interest has been our study of membrane estrogen receptor signaling across the nervous system. We were the first to describe that estrogen receptor alpha and beta can functionally interact with metabotropic glutamate receptors (mGluRs), leading to glutamate-independent mGluR signaling. Throughout the female nervous system, estrogen receptors (ER) couple to both group I (mGluR1a, mGluR5) and group II (mGluR2, mGluR3) mGluRs, leading to changes in second messenger signaling, cell excitability, neurotransmission and ultimately behavior. Current projects in the lab center on understanding the mechanism by which ERs are trafficked to the surface membrane of neurons, allowing functional coupling with mGluRs. Recent findings suggest that palmitoylation of both ERs and structural caveolin proteins are essential for ER activation of mGluR signaling. Additionally, ER/mGluR signaling in the female nucleus accumbens appears responsible for women exhibiting heightened vulnerability to drug abuse. Through inhibition of ER/mGluR signaling, we are able to eliminate estrogen-mediated potentiated responsiveness to psychostimulants in models of drug addiction.