Gaby Maimon - US grants

DESCRIPTION (Provided by the applicant) Abstract: Work in genetic model organisms has connected genes to behavior. Electrophysiology in awake, behaving animals has associated neuronal activity with cognition and action. This proposal lies at the interface of these two fields. We aim to reveal how genes, through their effects on cellular electrophysiology, influence higher brain function and behavior. We focus on a specific higher function, decision-making: the mental process that precedes and ultimately yields a behavioral choice. A healthy brain allows for choices that are adaptive and flexible. In drug addiction and mental illnesses such as depression, obsessive-compulsive disorder, and schizophrenia, behavioral choices are maladaptive, stereotypical, and repetitive. A deeper understanding of decision processes could improve the health of many. We propose to study decision-making in the fruit fly, Drosophila melanogaster, where there is a unique opportunity to form cross-disciplinary insights. We will use a new apparatus that allows us, for the first time, to record electrophysiological signals from genetically identified neurons in activly behaving fruit flies. Drosophila will perform simple choice tasks, like deciding to turn left or riht in response to visual stimuli. We will record and manipulate neuronal activity while the flies make up their mind or change their mind. After recordings, we will sequence RNA extracted from cells that govern decision-making to determine whether variability in their electrophysiological output, and variability in fly behavior, can be explained by the expression level of genes that regulate membrane and synaptic physiology. Drosophila offers a unique platform for this research program because behavioral paradigms, cell- type-specific genetic tools, and behavioral-physiology methods are mature. The work aims to reveal how genes, through their effect on cellular electrophysiology, influence decision-making, ultimately providing a foundation for more rational drug design for human mental illness. Public Health Relevance: A better understanding of how brains make choices could help modify risky behaviors that lead to HIV infection and drug addiction, which are major public health concerns. By providing a deeper understanding of decision-making circuits, the proposed work can ultimately yield insight into treatments for a variety of mental illnesses, such as depression, one of the leading causes of disability in the world.

Project Summary / Abstract Our brain provides us with a sense of where we are in space. The importance of this sense is clear when we become spatially disoriented, like when one is confused about one?s orientation after exiting a subway station. Central to the understanding of how brains give rise to spatial cognition has been the discovery of place cells in the 1970?s (i.e., neurons that are active when animals are in one specific location in space), head-direction cells in the 1980?s (i.e., neurons that are active when animals face one specific compass direction), and grid cells in the early 2000?s (i.e., neurons that are active when animals are in a grid of locations in space). A remarkable feature of these cells is that their patterns of firing persist even when animals navigate in complete darkness, wherein the animals must use an internal assessment of their own movements to update their sense of position or orientation. A fundamental next step in our understanding of spatial cognition would be to describe the circuit-level interactions that give rise to such physiological activity patterns and to understand how such cells ultimately influence navigational behavior. Our recent work has uncovered the first neural circuit to explain how heading-related cells update their activity levels when animals turn in the dark. This biological circuit in Drosophila is a realization of a circuit proposed to exist in the mammalian brain twenty years ago, based on computational modeling, but never proven to exist in any animal. Here we focus on three related questions that aim to provide a deeper understanding of how brains construct navigational signals and how these signals guide behavior. Our first aim is to identify a circuit path by which sensory information arrives to the central brain to update the head-direction or heading system when an animal turns in the dark. Our second aim is to determine the role of heading signals in guiding navigational behavior by perturbing the activity of heading-related cells in animals performing a heading task. Our third aim is to characterize new cell classes and circuitry to ultimately inform how brains might solve two-dimensional navigation tasks. The overarching goal of this work is to provide a detailed, circuit-level understanding of how brains compute spatial navigation- related variables. Such discoveries will inform our thinking on how our brains allow us to perform day-to-day navigation tasks, like driving home from work or finding our car in a parking lot, and how to approach psychiatric and neurological conditions in which these abilities are impaired, such as Alzheimer?s disease.

Project Summary / Abstract This grant focuses on how very recent experiences??over the past few seconds to minutes??allow brains to update expectations about the world and then use these expectations to guide behavior. The ability to flexibly adjust one's course of action in this manner is a hallmark of adaptive human behavior. At the neural level, relevant cellular-activity correlates have been described in non-human primates and other vertebrate model systems. For example, ramping neural activity has been observed in the few hundred milliseconds, or seconds, leading up to behavioral decisions and the rate of rise of these ramps tracks the gradual accumulation of information relevant for the decision being made. Ramping activity is thus a correlate of an increasing expectation that an important decision needs to be made and the moment at which the ramp reaches a threshold level typically signifies when a final decision is taken. Another salient correlate of internal expectations are reward-prediction error signals: bursts of dopamine-neuron activity when an animal receives an unexpected reward or a reward is surprisingly omitted. Reward-prediction error signals seem well poised to adjust animal and human behavior based on learned expectations. A clearer picture of how quantitative internal signals??like ramping and reward-prediction error activity??contribute to behavioral flexibility would be an important step forward for cognitive neuroscience. Here, we propose to develop two new behavioral tasks in tethered Drosophila, where we can perform simultaneous neurophysiology. Our first aim is to use one of these tasks to test the hypothesis that ramping neural signals are fundamental in forming behavioral decisions over tens-of-seconds to minutes timescales in ethologically relevant contexts, rather than just on much shorter timescales and in laboratory defined tasks (as has been shown to date). Such a discovery would argue that expectations built over minutes in real-world conditions are ultimately fed into slowly ramping neuronal signals so as to guide natural decision-making. Our second aim is to discover reward-prediction error signals in fruit flies actively performing a trial-by-trial conditioning task and to define a circuit mechanism through which such signals allow brains to form quantitatively precise expectations??updated on a trial-by-trial basis??on the likelihood of rewards arriving or not arriving in the near future. Such discoveries in a genetically tractable model will inform our thinking on how our brains generate expectations that allow for flexible, adaptive behaviors, ultimately informing new therapeutic approaches to neurological conditions in which flexibility is impaired, such as obsessive-compulsive disorder.