HBI Postdoc Pioneers Grant Program

Evelyn Avilés
Lab of Lisa Goodrich, Harvard Medical School
DCC-mediated molecular mechanisms of axon guidance

Our abilities to move, think, and sense and respond to the environment rely on a functioning nervous system. Neurons form connections with other cells to generate circuits that transmit signals resulting in an organism’s behavior. During development, these connections form by the extension of neuronal processes, called axons, that grow toward specific target cells. Axons can travel very long distances without being derailed from their stereotypical tracks. For this guidance to happen precisely, axons respond to molecules that they encounter in the tissue. For example, the secreted protein Netrin1 can act over a long-distance to guide axons expressing the receptor DCC on their surfaces. Even though this system has been studied for many decades, how Netrin1-DCC interactions enable the variety of guidance decisions that axons and cells make during development is unknown. Draxin is another secreted molecule that can interact with DCC, possibly influencing how the same axon responds to Netrin1. We aim to investigate how the DCC receptor modulates the action of Netrin1 by collaborating with Draxin in vivo and whether discrete portions of the DCC molecule have differential roles in axon guidance.

Ava Carter
Lab of Michael Greenberg, Harvard Medical School
High-throughput study of human-specific aspects of neuronal activity-dependent transcriptional programs

The human brain displays remarkable cognitive capabilities, achieved largely through increased size and connectivity in the neocortex.  Sensory experience contributes to the refinement of connectivity, in part through the action of genes that are activated in response to stimulus within neurons. We have identified an evolutionarily young family of genes, the KRAB-domain containing Zinc Finger Transcription Factors (KRAB-ZNFs) whose expression increases in human neurons following the application of a stimulus. To understand how each of these KRAB-ZNFs contributes to the cellular programs activated by neuronal stimulus, we are employing a new CRISPR-based screening technology. With this technology we can disrupt the expression of hundreds of genes in human cortical neurons, and assess the effect of their loss on gene expression in single neurons. Development of this technology in our lab will allow us to identify those KRAB-ZNFs, and other genes, whose expression is critical for driving human-specific features of brain development and response to external stimuli.

Yasmin Escobedo Lozoya
Lab of Susan Dymecki, Harvard Medical School
Modulating the encoding of reward memory

As a postdoctoral fellow in Susan Dymecki’s Laboratory, I explore how neuromodulatory systems can exploit the intrinsic flexibility of brain circuit dynamics to allow neuromodulatory transmitters such as serotonin to nudge circuits into activity states or behaviors useful to the animal. I study neuromodulation in the context of emotional memory formation by neurons that signal through both serotonin and glutamate.

My work proposes that a class of serotonin neurons gates the transfer of information between brain regions responsible for reward memory formation that may contribute to problematic states such as drug relapse. If correct, this model would suggest some neuromodulatory neurons can exert circuit actions akin to the switches of an old-fashioned telephone switchboard: they can control which circuits should be connected and when by tuning their dynamics to allow or prevent communication, thereby turning inter-area communication on or off.

The Pioneer Award will allow us to extend our experimental reach to record brain oscillatory dynamics and select neuron activity via in vivo electrophysiology, calcium imaging, and electroencephalography and test these hypotheses.

Jonathan Green
Lab of Christopher Harvey, Harvard Medical School
Scalable methods for understanding the cognitive roles of brain cells in the cerebral cortex

To understand how we think, we need to understand the basic building blocks of our brain – its neuronal cell types. We are developing new tools to study cell types in a more precise and scalable manner and applying these tools to study spatial cognition in cortex. Using a novel viral tool that targets a subtype of somatostatin neurons, we found that in posterior parietal cortex this subtype selectively and synchronously activates as the mouse corrects for errors as it navigates toward a reward. Using cellular resolution optogenetics, we found that these cells tend to excite each other, helping to explain their synchronous activity during error corrections. Previous studies in the same area and the same task did not identify this signal because it is present in a rare neuronal subtype, highlighting the importance of precise cell type tools. The discovery of this error correction signal is exciting because error signals are fundamental both to executing and learning tasks. My goal for the future is to build on this work to understand the functions of this error correction signal, and the functions of other cortical cell types in cognition.

Dilansu Guneykaya Cinar
Lab of Sandeep Robert Datta, Harvard Medical School
The cell type specific role of Ms4a6 genes in Alzheimer’s Disease

Alzheimer’s Disease (AD) is a complex, multifactorial neurodegenerative disorder that causes memory loss, difficulty completing tasks, withdrawal, mood changes and ultimately death. Unfortunately, current therapeutic strategies are significantly limited. Recently, genetics research drew many road maps for AD researchers revealing potential risk factors to understand the disease progression. Among the genes implicated in these studies, certain members of the Ms4a gene family are suggested to be associated with immune regulation of AD. In addition, we know that Ms4a genes are expressed widely by many immune cell populations, including brain resident immune cells, myeloid cells and lymphocytes. My current lab (Datta lab) previously identified expression of Ms4a gene family in olfactory sensory neurons and developed related mouse models. Recent studies suggested the strong connection between central nervous system (CNS) and immune system. My research project aimed to investigate the consequences of Ms4a gene manipulations in immune cells in a subset of AD mouse models. This will allow us to identify cross reactions between CNS and periphery, as well as their ability to influence the onset or progression of AD. We are planning to learn more about how the Ms4a gene family acts in different immune cells, and influence the risk of developing AD.

Ryan Maloney
Lab of Benjamin de Bivort, Harvard University
Using expansion microscopy to understand the basis of individuality

What makes an individual an individual? While genetics and environment play a significant role, even genetically identical flies raised in the same environment show a wide range of individual preferences on a number of tasks. This poses a key question: what in the nervous system (and therefore what in our behavior) is determined by genetics and observable changes in our environment, and what parts vary by chance?

Answering this question requires looking at the parts of the fly brain involved in these behaviors with extreme detail, across a large number of flies with different measured preferences. Few techniques combine the resolution and throughput required to do this, however we’ve embraced a novel technique called Expansion Microscopy that does. Expansion Microscopy allows us to embed the fly brain in a gel and literally enlarge it to get a closer look at the neurons underlying behavioral circuits. This technique allows us to look at different proteins across different neurons and see how they vary between individuals—and in doing so understand how individuality at the molecular level connects to individuality in behavior.

Souvik Mandal
Lab of Venkatesh N. Murthy, Harvard University
How do simple minds make complex decisions? Deciphering the “basic rules” of individual and collective decision-making in ants

I am broadly interested in how behaviors in social animals are influenced by their evolutionary history, lifetime experience (i.e., learning and memory), and recent experiences. Social insects are of special interest because with a simple brain in their repertoire, they accomplish complex tasks, involving both individual as well as collective decision-making; they do so using simple and elegant rules of thumb. My research focuses on finding these minimal rules by quantifying animal behavior using cutting-edge technologies like computer vision and artificial intelligence. Currently, I am working on understanding how ants integrate current and prior olfactory information for making decisions individually (while searching for food in their natural habitat and following pheromone trails), as well as collectively (while working together to achieve a certain common goal). While I am developing theoretical frameworks of decision-making from these behavioral strategies, these can further be translated into algorithms that could inspire the development of new solutions for computational problems in the field of artificial intelligence.

Jeongho Park
Lab of Talia Konkle, Harvard University
Full-field fMRI: a novel approach to study immersive vision

Traditional functional MRI setups are limited to presenting images in the central 10-15 degrees of visual field, whereas we experience a more than 180 degree view of the world every day. In this project, we have developed a new method for ultra-wide angle presentation in the scanner, enabling us to measure responses for the first time in cortex responding to the far-periphery, and to immersive first-person views of environments. This works by bouncing an image off two angled mirrors directly into the scanner bore onto a custom-built curved screen, which creates an unobstructed view of 175 degrees. Additionally, we present images with a compatible wide field-of-view, rendered from custom-built virtual environments—a critical step as using standard pictures leads to highly distorted perceptions. With this new setup, now we can stimulate parts of brain that were methodologically out of reach. Further, we can examine brain responses to visual environments in an immersive setting beyond postcard-like views of the world used in current methods. More broadly, this project will provide new empirical traction on current theories which argue that fovea-to-peripheral organization underlies the basic blueprint of the visual system and its interface to broader whole-brain architecture.