REQUEST FOR PROPOSALS
The Harvard Brain Science Initiative (HBI) is pleased to announce our third call for proposals for the HBI Collaborative Seed Grants Program, intended to foster projects linking faculty at the Harvard Medical School (HMS) and the Harvard University Faculty of Arts and Sciences (FAS).
Spearheaded by a generous donation from the Alice and Rodman W. Moorhead III Collaborative Grants Fund, this program supports a broad range of fundamental neuroscience research, focusing on projects whose long-term aim is to provide basic insights into mechanisms underlying brain disorders. Basic science proposals are encouraged but should articulate a relevant disease connection.
Faculty members from basic science departments at Harvard Medical School (HMS Quad Faculty) and the Harvard University Faculty of Arts and Sciences (FAS) are eligible to apply. Each proposal must involve a new collaboration between an HMS professor and an FAS professor. Renewal proposals are not permitted.
We anticipate making up to 5 one-year awards of $100,000 each in direct costs
The division of funds between HMS and FAS may vary, but the division should be clearly specified in the budget
More information on previous awardees is available below
Letters of Intent due Monday, April 16, 2018
Full proposals due Friday May 11, 2018
Selections will be made in June/July
Awards will start July 1 or August 1
TO LEARN MORE OR APPLY
The 80 billion neurons of the adult human brain develop from rapidly dividing neuronal progenitors cells. Recently, the Alt lab found that the DNA of numerous genes that encode proteins critical for mouse brain circuitry is highly susceptible to breakage in the progenitor cells. To maintain chromosomal integrity as they proliferate, neuronal progenitors repair breaks in their genes by rejoining their ends or, sometimes, by joining together two breaks in the same gene and deleting DNA in between. Based on the distribution of breaks across this set of neural genes, we hypothesize that joining two breaks within them could functionally alter encoded proteins, potentially contributing to diversification of brain circuitry and function. Also, most frequently breaking neural genes also have been implicated in neuropsychiatric disorders and/or cancer. In this regard, we propose that improperly joining breaks in these genes could contribute to such diseases by inactivating the genes or adversely altering their function. The Alt and Xie labs will combine their complementary expertise to test these hypotheses by elucidating the genes that similarly break and join in human neuronal progenitors and determining whether diversity generated by this process is developmentally propagated to mature brain neurons.
When we fall asleep, our relationship with the world changes dramatically: we no longer respond to most external stimuli, unless they are particularly strong or salient. Our goal is to understand how the brain builds a gating system that prevents most of the sensory information from arousing us during sleep. Specifically, we will look for genes that control information flow. Because sleep is a conserved process, we will use flies and zebrafish in our approach. Flies are an excellent system for identifying new genes, and zebrafish are vertebrates whose brains are very similar to our own. We will do rapid screening for new gating genes in the fly, and test their function in the zebrafish. Our combined approach will reveal new and conserved principles of sleep regulation.
Visual experience is alive with motion, but little is known about how the brain transforms patterns on the retina into such richly structured object motion. We approach this problem by combining behavioral, computational and clinical techniques. Structured object motion should eases tracking multiple objects simultaneously, which we will first study in healthy subjects. At the same time, we will explore theoretically how neurons could represent and operate with such structure. Finally, we will investigate if and how structured object tracking breaks down in autism, a disorder that has been previously associated with object tracking deficits. This work will provide initial insights into the neural representation of visual motion structure and open the door towards understanding how the brain represents structure in general.
Probing Cell Fate in the Central Nervous System
Constance Cepko, Department of Genetics, HMS
Sharad Ramanathan, Department of Molecular and Cellular Biology and School of Engineering and Applied Sciences, FAS
Our goal is to understand how cells in the developing central nervous system acquire their identities. How exactly does a cell integrate information from a variety of sources to ultimately choose what type of cell to become, i.e. a motor neuron or a photoreceptor? We will use as a test case the choice of developing neurons in the retina to become a rod vs. a cone photoreceptor cell. This is a key choice for cells to make, as cones detect and process light during the day to give us our high acuity, color vision, and rods detect dim light to give us great sensitivity at night. Our collaboration will bring together the generation and computational analyses of genome wide data and high throughput functional experiments to understand these fate choices. These methods and the resulting findings will provide a road map for understanding other cell fate decisions within the CNS, as well as a protocol for the generation of photoreceptors from stem cells. In particular, given the importance of cones for daylight and color vision, and their loss in many forms of retinal degeneration, the ability to create cones vs. rods may enable new, potentially more robust treatment strategies for certain eye diseases.
Molecular Profiling of Neuronal Diversity in the Human Central and Peripheral Nervous Systems
Paola Arlotta, Department of Stem Cell and Regenerative Biology, FAS and HMS
Lisa Goodrich, Department of Neurobiology, HMS
Our long term goal is to understand how neurons differ at the level of their genetic material. This will point us towards specific drugs that might prevent neuronal loss, and provide us with the blueprints needed to engineer the exact type of neuron needed to repair the brain and restore function. We will devise and optimize a new method for purifying and characterizing defined types of neurons from the central and peripheral nervous systems. This method will enable researchers to access clinically relevant populations of neurons from any region of the nervous system, thereby laying a valuable foundation for the development of new drugs and therapies to prevent or treat diseases like Parkinson’s, ALS, and a wide range of other neurodevelopmental and neurodegenerative disorders.
Timing is central to many aspects of our behavior, such as associative learning and decision-making. We hypothesize that altering the effect of the neurotransmitter dopamine should affect the ability to keep track of time. We will test this hypothesis using mice that are trained to estimate short intervals of a few seconds. We will use a new technique, optogenetics, to use light to specifically alter the function of neurons in the brain that release dopamine, thus altering the critical balance between the direct and indirect pathways. These experiments will shed light on the normal function of cortical-basal ganglia brain circuits, which will in turn inform our understanding of the brain-circuit aberrations in psychiatric disorders such as schizophrenia.
Behavioral Neurogenetics: Deep Phenotyping of Genes Regulating Social Approach
Sandeep Robert Datta, Department of Neurobiology, HMS
Hopi Hoekstra, Departments of Organismic and Evolutionary Biology and Molecular and Cellular Biology, FAS
We have recently developed a new technology that gives us objective insight into the structure of mouse behavior, which we call “Deep Phenotyping”. We propose to apply this technique — coupled with modern advances in gene sequencing — to characterize complex patterns of social behavior in a variety of mouse strains and to identify individual genes responsible for a particular behavior called “social approach”. These experiments have the potential to fundamentally transform both the theory and practice of behavioral neurogenetics, and will significantly impact our understanding of the mechanisms that underlie social interactions.
Breathing not only supplies life-sustaining oxygen to the body, but also brings in smells (odorants) that modify critical behaviors such as feeding and mating. Yet, these demands for oxygen versus odor information are rarely in sync. How are these demands processed by our sensory system and brain so that the necessary, even life-sustaining, outcome is achieved? Results of this project are expected to inform not only basic neurophysiology but also disorders ranging from apnea syndromes (e.g. apneas of prematurity, the sudden infant death syndrome, and adult sleep apnea syndromes) to asthma to infant and adolescent eating and feeding disorders.
Investigating the Maturation of Connectivity within a Neural Circuit
Aravinthan Samuel, PhD, Professor of Physics, Department of Physics, FAS, and Center for Brain Science
Rachel Wilson, PhD, Professor of Neurobiology, HMS; Investigator, HHMI
A basic question in neuroscience is how a young brain develops into a mature brain. This problem is relevant to all developmental disorders of the nervous system. Previous studies have addressed this problem from many perspectives; however, no studies have ever examined how individual identifiable neurons and synaptic connections are altered during development. We aim to completely reconstruct the connectivity of a particular region of the fly brain (the antennal lobe). At the end of one year, we aim to have maps of the adult and juvenile circuits, as well as electrical activity patterns from both circuits. This one-year collaborative pilot project should serve as a template for efforts to understand brain development in larger and more complex organisms, as the technology in this field allows us to map ever larger volumes.