Cory M. Root, Ph.D. - US grants

DESCRIPTION (provided by applicant): The purpose of this work is to elucidate the transformation of olfactory information in the first relay of the Drosophila brain, the antennal lobe. Elucidating how information propagates in a hierarchical system is an important step towards understanding sensory coding mechanisms. Olfactory coding is a useful model for revealing how sensory circuits generate, propagate and read a neural code to create sensory perception. The insect olfactory system is a tractable system for deciphering mechanisms of sensory processing because they achieve odor discrimination with simpler circuits than that of mammals. Furthermore, Drosophila offers a powerful set of molecular tools available to manipulate individual elements of the underlying circuit. In a preliminary set of experiments, we have found anatomical and physiological evidence for GABAB modulation of olfactory receptor neurons in Drosophila. We find the receptor provides a mechanism to extend the dynamic range of the system, and surprisingly we find that level of presynaptic inhibition is heterogeneous between input channels. We hypothesize that GABAB expression in select neurons provides a mechanism for behaviorally relevant feedback modulation of olfactory input. We propose a set of experiments to further investigate the mechanism of feedback inhibition on a molecular, physiological and behavioral level. We use molecular techniques to characterize the receptor expression, and two-photon imaging of calcium and synaptopHluorin to monitor presynaptic activity and synaptic transmission. We will test the hypothesis that feedback inhibition provides a mechanism for olfactory adaptation and dynamic range expansion. The results will provide new insight into modulation of sensory input in the olfactory system and the findings could provide new insight into the function of feedback inhibition in detection of behaviorally relevant cues. Relevance to public health. Elucidating mechanisms of sensory perception is pivotal to understanding how sensory systems function normally and in disease. We study modulation of the sensory input signal in the fly olfactory system because of its relative simplicity and the powerful set of molecular tools for cutting edge science that is more difficult in other animals. The work of this proposal is basic science that seeks to reveal basic principles about the sensory nervous system creating a knowledge base from which future medical and technical research can stem. Such work may reveal fundamental circuit properties applicable to larger more complex circuits and neural functions that are relevant to neurological disorders of sensory systems.

? DESCRIPTION (provided by applicant): The brain translates internal representations of the external world into appropriate innate and adaptive behaviors. Elucidation of how sensory information is propagated through hierarchical systems is an important step towards understanding how the brain instructs behavior. The sense of smell is a tractable model because the pathways from the nose to associational cortex and emotional structures in the amygdala are relatively shallow. Moreover, Learned olfactory behaviors are thought to modify innate responses, suggesting that the two pathways intersect. Thus, determined pathways may serve as a substrate upon which experience acts to shape how animals respond to an unpredictable world. We have developed genetic strategies that demonstrate that a stereotyped neural circuit that transmits information form the olfactory bulb to the cortical amygdala is necessary for innate aversive and appetitive behaviors. Moreover, we have employed the promoter of the activity-dependent gene, arc, to express the photosensitive ion channel, channelrhodopsin, in neurons of the cortical amygdala activated by odors that elicit innate behaviors. Optical activation of these neurons leads to appropriate behaviors that recapitulate the responses to innate odors. Thus, we have revealed that neurons in the cortical amygdala are both necessary and sufficient to elicit innate olfactory-driven behavioral responses. The goal of this proposal is to further define pathways for innate behaviors and identify the underlying mechanisms for modulation of behavior by experience. We have demonstrated that the cortical amygdala is a substrate for innate pathways. Moreover, piriform cortex, a structure implicated in olfactory learning, has a strong projection to cortical amgydala. We propose a model whereby the convergence of processed associational input from piriform cortex and direct bulbar input to cortical amygdala provides a circuit for experience-dependent olfactory behaviors. We will employ a combination of behavioral experiments, molecular genetics and endoscopic imaging of neuronal activity to ask three principal questions: 1) How is the cortical amygdala organized to elicit different behaviors? 2) Is the pathway from piriform cortex to the cortical amygdala required for experience-dependent modulation of innate behaviors? 3) Does the polysynaptic circuit from piriform cortex to cortical amygdala play a role in adaptive responses to novel odors? The training plan, under the primary mentorship of Dr. Richard Axel at Columbia University, provides a comprehensive strategy for acquiring the necessary experimental and professional skills within an exemplary and collaborative neuroscience environment. An experienced team of collaborators will provide training in skills critical for my short- and long-term success, including in vivo imaging of neural activity and mapping of neural circuits. Focused mentor guidance, alongside frequent data presentation, will provide the communication and leadership skills vital for my transition to independence. In the long-term, this support will equip me to lead a laboratory that merges molecular and systems approaches to explore how internal states and past experiences affect choice behaviors.

Project Summary The brain translates internal representations of the external world into appropriate behaviors. Elucidation of how sensory information is propagated through hierarchical systems is an important step towards understanding how the brain instructs behavior. The sense of smell is a tractable model because the pathways from the nose to associational cortex and emotional structures in the amygdala are relatively concise. Innate behaviors are stereotypical between animals and likely result from genetically determined and conserved circuits, making them a tractable model. Our past work has revealed circuits in the cortical amygdala (plCoA) that mediate innate attraction and aversion to odor. Understanding how the sense organ is wired to the brain to produce behaviors of different valence is an important biological problem and may provide insight into emotional responses to sensory stimulation. We have combined anatomical tracing with functional manipulations to reveal two outputs of the plCoA, the nucleus accumbens (NAc) and medial amygdala (MeA), that are capable of eliciting approach and avoidance responses, respectively. Further, we have evidence to suggest that there is a topographic organization to the plCoA circuitry. Thus, we hypothesize that the plCoA contains topographically organized labeled lines to impart valence on odor-evoked behaviors. The goal of this proposal is decipher the plCoA circuitry and its connections to the NAc and MeA. We have demonstrated that the cortical amygdala projections to NAc and MeA are able to generate approach and avoidance behaviors. Moreover, these projection neurons appear to be distinct from each other. We propose a model whereby the plCoA sends projections to the NAc to signal positive valence, and to medial amygdala to signal aversion. We will employ a combination of behavioral experiments, viral tracing, genetics and endoscopic imaging of neuronal activity to answer three fundamental questions: 1) Do the plCoA projections to NAc and MeA mediate odor-evoked behaviors? 2) How are the plCoA projection neurons anatomically organized? 3) Do these projection neurons and their downstream targets exhibit odor tuning for valence? The answers to these questions will fill a knowledge gab about the representation of odor in the innate pathway and extend this pathway deeper into the brain towards behavioral output.