In 2015, the Brain Research Foundation Seed Grant Program funded critical research in 11 areas of neuroscience. In addition to our annual seed grant program, the Foundation awarded 3 larger grants to distinguished investigators in 2015 for our Scientific Innovations Award. Please see below how they’ll contribute to the field of neuroscience.
2015 Seed Grant Award Winners
Albert Kim, M.D., Ph.D.
Title: Therapeutic epigenetic reprogramming of brain cancer stem cells using microRNAs
Glioblastoma is a devastating form of brain cancer with no known cure. The existence of different types of cancer cells with diverse biological properties in the same glioblastoma tumor significantly contributes to the treatment failures observed in patients. Within glioblastoma tumors, a therapy-resistant population of cancer cells called cancer stem cells (CSCs) are thought to be responsible for treatment failures and disease recurrence, necessitating the discovery of strategies to confront this challenging cell pool. The malignant cell state of CSCs is dynamic and defined by a unique epigenetic profile. Recently, specific microRNAs were demonstrated to instruct human fibroblasts to become neurons through an epigenetic process called direct reprogramming. These results raise the exciting possibility that microRNAdirected epigenetic reprogramming might be harnessed to convert the malignant cell state of CSCs into a non-tumorigenic, neuron-like state. In preliminary data, we have found that expression of specific microRNAs in patient tumor-derived glioblastoma CSCs causes cells to stop dividing and dramatically decreases overall cell number. The major goals of this proposal are to demonstrate proof-of-concept, preclinical evidence for this innovative strategy using an animal model of glioblastoma with high fidelity to the human clinical scenario and also to identify the key epigenetic changes triggered by these therapeutic microRNAs, which will provide the foundational knowledge for a desired chromatin state for CSCs. The long-term goal of this proposal is to development novel strategies against glioblastoma by utilizing therapeutic reprogramming. Finally, these experiments will reveal fundamental insights into the epigenetic mechanisms underlying direct reprogramming into neurons, with ramifications for our understanding of nervous system development.
Lee Bassett, Ph.D.
University of Pennsylvania
Title: Nanoscale Optical Neuronal Recording using Nontoxic Quantum Probes
We aim to develop a new class of multifunctional sensors that respond to chemical signals in the brain through quantum physics and that can be probed using light. The sensors are based on atom-scale defects in diamond nanoparticles, which are nontoxic, stable fluorophores harboring electron spins that respond to nanoscale magnetic fields. By attaching molecules to the nanoparticles’ surface that bind neurotransmitters, we aim to make the sensors chemically active, using the diamond spins to transduce dynamical changes in neurotransmitter concentrations into an optical signal. The resulting modular probes can be programmed to respond to specific neurotransmitters and targeted to specific cell
types and locations (e.g., within synapses between neurons) to report the real-time activity of large-scale neuronal networks in living animals and, potentially, in humans.
Anjon Audhya, Ph.D.
University of Wisconsin – Madison
Title: Endoplasmic reticulum structure and function in neuronal maintenance
Our overall goal is to define new mechanisms that sustain and enhance neuron viability and function during development and aging. The functional characterization of TFG, which has been implicated in
several axonopathies including hereditary spastic paraplegia, Charot-Marie-Tooth Disease, and proximal dominant hereditary motor and sensory neuropathy, will contribute both to our understanding of the pathomechanisms underlying these diseases and reveal general requirements for lifelong axonal maintenance. Collectively, our studies may uncover new, unifying mechanisms that underlie a variety of neurodegenerative disorders, and establish a stemcell based model system, which is both facile and tractable, and can ultimately gauge the value of therapeutic treatments that are currently under development.
Bing Ye, Ph.D.
University of Michigan
Title: Mechanisms underlying the brain disorder in Down syndrome
While Down Syndrome (DS) is the most common genetic form of intellectual disability caused by a birth defect, there is currently no effective treatment for it. Development of the cerebral cortex is defective in DS patients. Understanding the cause behind these cortical defects in DS will lead researchers to comprehend the root mechanisms of the disease. The ultimate goal of the proposed research is to design therapeutic strategies for treating the brain disorder in DS patients. Using the powerful genetic tools available in the fruit fly Drosophila, the Ye lab recently found the importance of proper levels of the Down Syndrome Cell Adhesion Molecule (DSCAM), which is increased in the brains of DS patients. Their studies suggest that when there is too much of DSCAM during brain development, neurons do not form properly. Furthermore, they have identified a key molecule that mediates this effect of DSCAM, which inspires the design of potential therapeutic strategies for treating this disorder.
Extending the molecular models that the Ye lab obtained from studies in Drosophila, the team, as a next logical step, is investigating the consequences of abnormally high levels of DSCAM in the brain development of mouse models. They propose to investigate how high DSCAM levels lead to defective cortical development with the intention of providing potential targets for treating the intellectual disability in DS. The Seed Grant from the Brain Research Foundation will provide the support that they need to advance their research from the fruit fly model to the
mouse disease models.
Michael Hoppa, Ph.D.
Title: Ion Channel Trafficking at the Axon Initial Segment and Neural Excitability
Over 65 million people worldwide have epilepsy and suffer from debilitating seizures.
Seizures result from clusters of neurons in a circuit to fire synchronously as the result of a lowered excitability threshold. Although the susceptibility for becoming epileptic increases with age, we have little understanding about why this threshold for electrical activity weakens to a pathological state. The axon initial segment is a master integrator switch in the neuron that initiates firing and harbors many unique proteins associated with epilepsy making it a prime area for research. We have devised several quantitative optogenetic approaches to specifically measure initial segment function in the context of neuronal plasticity and epileptogenesis. Under this experimental regime we will gain an understanding of a critical piece of novel cellular physiology that could uncover new targets for therapeutic approaches to combat and prevent epilepsy.
Michael Higley, M.D., PhD.
Title: Determining the cell-autonomous role of GABAergic inhibition in visual processing
The activity of neurons in the brain is determined by the interplay of excitatory and inhibitory synaptic
inputs to each cell. Alterations in neuronal inhibition are thought to play key roles in several neuropsychiatric disorders. However, it has been difficult to study the normal function of inhibition in the intact animal, because large-scale changes in inhibitory signaling lead to gross perturbation of brain activity. Here, we use a recently developed approach to disrupt inhibition in only a few neurons of the mouse brain and monitor the activity of these cells using a powerful form of microscopy. Thus, we will investigate how disruption of inhibition leads to changes in cell function without the confounding changes in overall brain activity. These experiments will give us important new insights into how neuronal activity in the healthy brain is generated and how it may be altered in disease.
Stephan Lammel, Ph.D.
University of California, Berkeley
Title: Identifying input-specific mechanisms underlying drug-evoked plasticity in the dopamine system
Drug addiction is a major public issue worldwide because it strongly affects a person’s
health and places a costly burden upon society. A consistent finding in addiction research is that drugs of abuse elicit long-lasting synaptic changes in the brain’s “reward system”, a neural circuit important for 5 responding to natural rewards such as food and sex. Such pathologic synaptic plasticity represents a form of maladaptive learning that is thought to contribute to the development of the addicted state. A critical step in addiction research is to identify specific synapses in the reward system that are susceptible to drug-evoked synaptic plasticity. To identify these synapses we will combine cutting-edge technologies that allow unprecedented insights into brain structure and function. Our findings will accelerate the development of brain stimulation interventions that selectively target drug-induced changes in the synapses of the brain’s reward system, which may be efficacious in reducing drug use and relapse.
Matthew Kennedy, Ph.D.
University of Colorado
Title: Controlling synaptic function with light
Synaptic plasticity is thought to be essential for normal cognition and is impaired in numerous neuropsychiatric disorders and diseases, including schizophrenia, autism, and Alzheimer’s. While plasticity defects likely underlie many symptoms of these disorders, little is known about why plasticity is impaired. On a molecular level, plasticity dependent synaptic changes are governed by molecular signaling and trafficking events that occur at synapses. A major difficulty in studying these molecular events is the lack of suitable tools to study processes on fast time scales in localized regions of neurons. Furthermore, there remains an unmet need for tools to acutely, reversibly and locally control these events in vivo. Such tools would help resolve longstanding questions concerning where, when and whether intensely investigated forms of synaptic plasticity, mostly studied in brain slices or dissociated neurons, are relevant for behavior in normal and disease models.
Chia-Yi Kuan, M.D., Ph.D.
Title: Neuropathology and Experimental Therapy of Creatine Transporter (CrT) Deficiency
Creatine transporter deficiency is a common cause of mental retardation and autism-related disorder that has no effective therapy to date. We have generated a mouse model that recapitulates clinical symptoms of this disease, and will use a multitude of anatomical, biochemical, behavioral, and imaging methods to unravel the biological functions of creatine transporter in the brain. Positive outcomes of this project will expand our knowledge and change clinical management of this grave neurodevelopmental disorder.
Beata Chertok, Ph.D.
University of Michigan
Title: Microplatform for minimally-invasive spatio-temporal modulation of immune dynamics in the brain
The goal of this project is to develop tiny devices the size of blood cells that can be injected into the blood stream and non-invasively activated in specific locations of the brain to release molecules and genes with pre-programmed timing. These devices will be used to modulate responses of the immune system in the brain. When the immune system fights infections in the normal brain, the specific location and the timing of activation of the immune system components is tightly regulated. This regulation becomes abnormal in many brain disorders including neurodegenerative diseases, traumatic brain injury and brain tumors. The abnormal immune response acts to stimulate the disease instead of fighting it. By delivering molecules and genes that can modulate immune system activities in specific locations and with a pre-designed timing of presentation in the brain, we hope to re-program the immune system to fight the disease. During the time-frame of the proposed project, we will explore the ability of our
devices to modulate the immune system components in brain tumors in mice. If successful, we will work on further development of this technology for therapy of brain tumors and other disorders of the human brain.
Alexandra Nelson, Ph.D.
University of California, San Francisco
Title: Optogenetic Dissection of Brain Circuits Causing Levodopa-Induced Dyskinesia
Patients with Parkinson's Disease eventually develop complications of the main medical therapy
available, levodopa, or L-dopa. These complications include disabling involuntary movements triggered by levodopa. We do not know why these complications develop, nor do we have good medications to manage them. We propose to study Parkinsonian mice treated with levodopa (who develop involuntary movements similar to those of humans) to identify the parts of the brain which cause the problem. By using new optical techniques that allow us to turn on or off specific classes of nerve cells within the brain, including those which we believe cause involuntary movements, we can determine which classes are responsible. We hope this will help find new targets for drug treatments for this disabling complication of Parkinson's Disease
Guoping Feng, Ph.D.
Massachusetts Institute of Technology
Title: Disruption of the Shank3 gene in a primate model for studying ASD
Brain disorders represent a great societal burden but are among the least understood of all diseases; for psychiatric disorders in particular, the underlying pathologies are largely unknown and treatment is mostly ineffective. Many brain disorders have a genetic component, and advances in genomic technologies have led to the identification of many risk genes. Understanding how risk genes may cause or contribute to the pathogenesis of psychiatric disorders requires studies of brain function in animal models with genetic alterations that mimic those of human patients. Current animal model studies are largely focused on mice, but mice are imperfect models for many aspects of human biology, particularly neuroscience, given the vast differences in brain and behavior between the two species. The difficulty of modeling complex brain functions and behaviors in mice is an important obstacle both to basic research and to the development of new treatments for human brain disorders. Thus, there is an urgent need to develop animal models that are more close humans in the brain structure and function. In this application, we propose to generate a marmoset (a small primate) model of autism by disrupting the Shank3 gene, which causes autism when mutated in humans. We will use this primate model to further our understanding of neurobiological basis of autism related behaviors. These studies may lead to the identification of novel disease mechanisms and neurobiological targets for drug development foe ASD. More generally, the proposed project, if successful, will establish the marmoset as a primate genetic model for the study of psychiatric disorders.
Kristen Harris, Ph.D.
University of Texas – Austin
Title: Synaptome of a Memory
A longstanding question in neuroscience concerns the cellular mechanisms of learning and memory. Since synapses were first discovered as the sites of communication between neurons, scientists have thought that changes in their number or structure would be a likely substrate of memory. Although evidence has accumulated, proof of this hypothesis has been elusive. Addressing this question requires substantial improvement in understanding how the brain is wired, namely, the “connectome”. Ultimately, the connectome will contain a map of the location and type of every synapse in the brain. The synaptome of a memory, sensation, or behavior is quite different from the co nectome of a brain region because these experiences likely involve a subset of synapses distributed across different brain regions. Hence, to understand mechanisms, it is necessary to know which specific synapses were involved. Detecting synapses and their subcellular components requires the nanoscale resolution of serial section electron microscopy, an approach that has been pioneered in my laboratory. We propose new strategies that will for the first time, provide specific identification of the progression and ultrastructural consequences of activity-dependent synapse remodeling in a cellular mechanism of learning and memory, a crucial first step in defining the synaptome of a memory. Nothing like this has ever been done before and the findings are crucial not only to understand the basic neuroscience and development of learning and memory, but also to illuminate synaptic dysfunction in prominent disease states, such as autism and Alzheimer’s disease.
Thomas Jessell, Ph.D.
Title: The Functional Logic of Inhibitory Microcircuits
Collectively, these studies will provide crucial insights into the construction and function of inhibitory microcircuits controlling movement. Importantly, they will provide an essential foundation for interpreting behavioral experiments assessing the contribution of V1 and other inhibitory interneurons to locomotor or skilled forelimb reaching tasks, where descending and sensory feedback systems are essential24. Because many of the transcription factors identified here (e.g. Sp8, Nr4a2, and Lmo3 among others) are also expressed in inhibitory interneurons in the brain25-27, characterizing spinal interneuron diversity may prove useful for dissecting inhibitory circuits in other systems. Finally, given the emerging view that neuropsychiatric and neurodevelopmental disorders result in part from dysfunction of inhibitory circuitry13, the studies outlined here should provide significant insight into the functional organization of inhibition in both development and disease.