2010 Seed Grant Recipient Research Topics

The Developmental Basis of Dopaminergic Neuron Diversity
Dr. Awatramani proposes that there is a developmental basis for dopamine neuron diversity. In other words, during embryonic development, the dopamine progenitor pool is parceled in a manner meaningful to later dopamine subtype identity. Elucidating the developmental basis for this diversity will be critical for understanding differential susceptibility of dopamine neurons in Parkinson’s disease (PD), as well as generating accurate Embryonic Stem cell or induced Pluripotent Stem cell derived models and therapies for PD. Indeed, this has been identified as a priority by stem cell scientists in the field of PD (3).

Role of TRIP8b in Epilepsy
This proposal is to support initial experiments aimed at identifying a novel therapeutic target for treating
epilepsy that may ultimately benefit patients, including those with refractory epilepsy. Epilepsy is a
disease of abnormal hyperexcitability. This proposal will test the possibility that mice lack a critical
regulatory subunit of an ion channel important for controlling brain excitability will have increased
susceptibility to seizures or spontaneous epilepsy. The proposal seeks to test this hypothesis as a first step in characterizing a new drug target that could lead to benefits for patients with epilepsy.

The Role of beta2* Nicotine Receptors in Natural Reward Mechanisms
Nicotinic receptors are widely expressed in the brain, modulating many neuronal processes and contributing to neuropathologies such as Alzheimer’s disease, Parkinson’s disease, and epilepsy. We have found that a mutation in one of the receptor subunits alters the response to natural reward stimuli. Because the same neural pathways are involved in natural rewards (such as food, sex and exercise), and addictive processes in response to drugs of abuse, it is possible that these receptors are central to the development of addictive processes. In this study we will use genetically altered mice to determine whether nicotinic receptors play a significant role in natural reward, and map the specific brain circuits where these receptors may exert their actions. These studies will give insight into the biological underpinnings of reward mechanisms in the brain and may provide new targets for the treatment of addictive behaviors.

Neuronal Circuit Mechanisms of Visual Feature Integration
Humans and other advanced animals have an impressive capacity to recognize the behavioral significance, or category membership, of a wide range of sensory stimuli. This ability, which is disrupted by a number of brain diseases and conditions such as Alzheimer’s disease, autism, schizophrenia, stroke, and attention deficit disorder, is critical because it allows us to respond appropriately to the continuous stream of stimuli and events that we encounter in our daily lives. Recently, we found evidence that the activity of neurons in the parietal cortex play a role in encoding the learned significance, or category membership, of both spatial stimuli (such as motion patterns and spatial locations) and non-spatial visual stimuli (such as visual shapes). The goal of the proposed project is to build on the foundation of our recent work to develop a more detailed and mechanistic understanding of the neuronal mechanisms underlying our ability to interpret the behavioral significance, or meaning, of visual stimuli.

While much is known about how the brain processes simple sensory features (such as color, orientation, and direction of motion), much less is known about how the brain learns and represents the meaning, or category, of real-world stimuli which are often composed of multiple and distinct visual features. A greater understanding of this process is critical for addressing a number of brain diseases and conditions (e.g. stroke, Alzheimer’s disease, attention deficit disorder, and schizophrenia) that leave patients impaired in everyday tasks that require visual learning, recognition and/or evaluating and responding appropriately to incoming sensory information. The long term goal of Dr. Freedman’s research is to help guide the next generation of treatments for these brain-based diseases and disorders by developing a detailed understanding of the brain mechanisms that underlie learning, memory and recognition.

CRZF1 in Te Migration and Differentiation of Cajal-Retzius Cells
The cortex of the brain has a specific arrangement of specific types of neurons that is essential for its advanced functions. The first cells of cortex produced in the embryo, the Cajal-Retzius cells, migrate on the surface of the brain and from there orchestrate the positioning of the rest of the cortical neurons. We have identified a gene expressed by Cajal-Retzius cells and hypothesize that it is essential for their migration and function, and hence for proper formation of the cortex. We have generated mice lacking this gene and will examine them to test these and other hypotheses.

The Regulation of Dynamin and Actin Polymerization in Endocytic Vesicle Biogenesis

The results of this work will provide new insights into the molecular mechanisms of vesicle fission during CME. I expect that my research will significantly contribute to our knowledge of brain function, as synaptic vesicle recycling is a fundamental event mediating higher functions of the brain such as learning and memory. This work will also make general contributions to cell biology, as CME is the main form of endocytosis in many types of cells. The results from this proposal will likely have broad implications for human health, as impaired vesicle recycling is also linked to many human diseases such as Type II Diabetes, Parkinson's disease, Alzheimer’s disease and Down syndrome.

Perceptual Coding of Natural Odors in the Human Brain

The majority of natural scents encountered in the environment are complex mixtures of dozens, or even hundreds, of different molecular constituents. Thus a key challenge for the olfactory system is to transform these complex blends of odor stimuli into unified perceptions of smells. However, olfactory neuroscience research has focused almost exclusively on the neural processing of pure (monomolecular) odorants or simple odorant mixtures, overlooking the highdimensional ecological complexity of olfactory space. Using a combination of analytical chemistry, neuroimaging, and psychological research techniques, we will characterize the foundations of human olfactory perception simultaneously across molecular, neural, and behavioral levels. Parallel investigation of natural, real-world odor “wholes,” as well as their component “parts,” will provide new insights regarding how the human brain extracts olfactory meaning from a complex odiferous environment.

Novel Approach to Gene Manipulation in a Cerebral Cortical Signaling Center

The mammalian cerebral cortex is responsible for higher functions of the brain, such as perception, cognition and memory.  My lab focuses on how the developing cortex is organized into different areas specialized for different functions.  We have found that cell groups, called signaling centers, at the edges of the embryonic cortex, release signaling proteins that form gradients across the cortical tissue.  These protein gradients provide positional information that directs the development of the cortical “area map”.  Interestingly, these signaling centers are close to regions of the cortex implicated in human mental health disorders such as schizophrenia and autism, suggesting that perturbations of the signaling centers in development could have serious consequences on mental health.  In this project, I propose to establish, in mice, a new way to perturb signaling in one of these signaling centers, termed the cortical hem.  This new approach should allow us to uncover the functions of this and other signaling centers with great precision, and to determine what goes wrong with cortical development when these centers do not function properly.

Embolus Extravasation: A Link Between Vascular and Alzheimer's Pathology

Occlusion of microvessels in various organs is likely to occur frequently throughout life. The cumulative effect of these occlusions may lead to organ damage. In the brain, this may be the basis for age related cognitive decline and dementia. We have discovered a physiological mechanism that efficiently eliminates virtually any type of material occluding these small blood vessels. Alterations in the efficiency of this mechanism could have critical implications in the progression of age related cognitive decline. In Alzheimer’s disease blood vessels are covered by a layer of an abnormal peptide called amyloid. This abnormality may affect the process of vessel clearance that we have discovered, making it slower and leading to more severe damage to the brain after occlusion. The goal of this proposal is to determine if Alzheimer’s pathology has an effect on the speed of this new clearance mechanism and on the damage associated with occlusion of small blood vessels in the Alzheimer’s brain.

Regulation of Neural Stem Cells by Amyloid Precursor Protein Metabolites in the Adult Brain

Dr. Lazarov proposes to investigate the role of a-secretase and of APP metabolites in neurogenesis in the adult brain. These experiments will unravel new signaling pathways regulating neurogenesis in the adult brain, processes that are not fully understood. Second, these experiments will determine a physiological role for a-secretase and of APP metabolites, roles that are currently not entirely elucidated. Third, we propose the search for novel molecules exhibiting a-secretase activity. These studies will identify molecular targets that would enable manipulation the number of NPC and their rate of proliferation.

Role VEGF in Spinocerebellar Ataxia Type 1

Dr. Opal is studying a genetic disease called Spinocerebellar Ataxia Type 1 that affects the cerebellar region of the brain. This is a relentless and uniformly fatal disease with no current cure. Our hypothesis is that the vascular growth factor VEGF is decreased in SCA1 cerebella and that some aspects of the disease could be reversed by replenishing VEGF. Interest in VEGF from other branches of medicine increases the likelihood that our promising studies could rapidly bring therapies from bench to bedside for SCA1. The BRF grant will be crucial in providing my lab with the funds to obtain preliminary data to compete for NIH R01 level funding.

Development of a Calcium-Sensitive MRI Probe for Neural Activity

Dr. Wang proposes a new collaboration between chemists, biomedical and electrical engineers and neuroscientists to develop a MRI contrast method that directly assesses neural activity in real time. This new method is made possible by the recent development of novel chemical compounds designed to be exquisitely sensitive to changes in Ca2+ levels that mimic those seen in living animals. These compounds will enable us to directly measure changes in Ca2+ levels in living mammalian brain. This proposal would fund the first studies in mammalian brain of an MRI contrast agent that is able to detect changes in Ca2+ levels in specific brain regions that occur when an injury disrupts the normal pattern of neuronal firing.

Pri- and Postsynaptic Effects of muscarinic Acetylecholine Receptors in Somatosensory

The way in which the brain interprets incoming information is constantly changing according to the relevance of the incoming stimuli at that moment in time. This ‘plasticity’ results in part, from changes in the strengths of synaptic signals between neurons. Acetylcholine is a brain chemical that modulates the strength of synapses, but the manner in which it performs this modulation is unclear. In this proposal we will use electrical recording and high-resolution microscopy techniques to measure synaptic function before, during and after release of acetylcholine with ‘optogenetic’ tools. In this way we will determine the sites of action of acetylcholine and the mechanisms by which it alters synaptic signaling between neurons.

Phosphodiesterase 10A as a Novel Therapeutic Target in the Treatment of Levodopa-Induced Dyskinesias

Parkinson's disease (PD) afflicts approximately 1.5 million Americans annually.  Although drugs such as levodopa (Sinemet) are available for the treatment of parkinsonian symptoms, they often produce disabling side effects called dyskinesias.  These side effects are thought to arise as a result of abnormal drug- and disease-induced neurotransmitter interactions in an area of the brain called the basal ganglia.  Our proposed studies will use an animal model of PD and examine the utility of combining a new drug (a cyclic nucleotide phosphodiesterase inhibitor called TP-10) with levodopa for treating disease symptoms and associated side effects.   We will also assess how this novel drug combination affects neuron activity in the basal ganglia.  We anticipate that our proposed studies will identify more efficacious treatment strategies for patients suffering from PD and levodopa-induced dyskinesias.