Jing Wang - US grants

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to determine the molecular mechanisms by which sex-determining genes and reproductive hormones differentially regulate olfactory sensitivity in males and females. In humans, olfactory performance is highly dependent on age and sex; women generally outperform men in smell identification, and men are more prone to olfactory impairment as they age. Similarly, in other animal species, select groups of odorant receptor neurons (ORNs), such as those important for pheromone detection, exhibit sexually dimorphic characteristics as animals reach the age of sexual maturity. However, the mechanisms underlying sexually-dimorphic neurophysiology are poorly understood.The research outlined here takes advantage of the powerful genetic toolkit of the Drosophila olfactory system to address this complex question. In this proposal, the first aim is to determine the generality of age-dependent sensitization in courtship- promoting ORNs. The hypothesis that all courtship-promoting ORNs in males undergo age-dependent sensitization will be tested using genetic, pharmacological, and functional imaging approaches. The second aim proposes a genetic analysis of downstream effector molecules that enhance olfactory sensitivity in the courtship-promoting ORNs. Finally, the third aim will test the hypothesis that a reproductive hormone promotes age-dependent sensitization through its interaction with a male-specific transcription factor. Results from these studies are expected to yield critical mechanistic insights into how sex-determining genes and reproductive hormones jointly regulate sensory neurophysiology and olfactory processing. These insights may have implications in understanding sexually dimorphic neurophysiology and sex-specific proclivities for certain neurodegenerative diseases.

Epigenetic regulation of gene expression is associated with long-lasting behavioral changes in animal models and humans. In response to environmental cues, epigenetic programs regulate gene expression in matured neurons via chromatin modifications and DNA methylation resulting in enduring neurophysiological changes. There is mounting evidence to implicate the involvement of dysfunctional epigenetic programs in many cognitive and neuropsychiatric disorders. However, establishing a causal link between epigenetic mechanism and neuronal properties that underlie behavioral adaptation in complex nervous systems has been difficult, mainly due to the paucity of behaviorally relevant neural and genetic substrates that are targeted by epigenetic regulation. Our goal is to determine the epigenetic basis of sensory experience-dependent changes in neurophysiology and behavior. We take advantage of the anatomical simplicity and the powerful genetic toolkit of the Drosophila olfactory receptor neurons (ORNs) involved in courtship behaviors, and the well- established Drosophila male courtship behavior, a robust ritualistic behavior governed by a single gene, fruitlessM (fruM) expressed in approximately 2000 interconnected neurons. Our pilot experiments and recent studies show that olfactory experience enhances the response of the Or47b and Ir84a ORNs in males and male courtship behavior. We also have linked olfactory receptor (OR) signaling through calcium, and histone acetyl transferase p300 to the expression of the transcriptional factor fruM as a molecular mechanism by which olfactory experience regulates neurophysiology and behavior. We hypothesize that fly and food odors in the environment lead to chromatin dependent changes in fruM transcription in sensory neurons to modify neurophysiology and courtship behavior with olfactory experience. To test this, we will first determine the effect of chromatin modulation by p300 on reprogramming neurophysiology and behavior. Next, we will characterize the molecular mechanisms by which olfactory experience and chromatin modulates fruM expression. Finally, we will determine the transcriptional and chromatin changes in ORNs with olfactory experience. .

Metabolic state has a profound impact on cognitive function and our perception of the external world. However, the mechanisms underlying behavioral changes during the transition from mild to severe starvation are poorly understood. Here, we propose to take advantage of the anatomical simplicity and genetic tractability of Drosophila to study how shifts in metabolic state shape olfactory circuit function and thus impact appetitive olfactory behavior. There are remarkable similarities between Drosophila and mammals in the organization and molecular regulation of olfactory systems, suggesting shared principles in the neurobiology of hunger. Elucidating how changes in olfactory neural circuits impact the perception of food quality and dietary selections may lead to a better understanding of factors that contribute to obesity as well as anorexia in the infirm and elderly. The experiments outlined here investigate the hypotheses that the decline of insulin, a global satiety signal, triggers local neuropeptide signaling to recruit distinct neuronal populations at different stages of starvation. The goals of these experiments are: 1) investigating the temporal expression pattern of sNPF receptors in different neuronal populations; 2) investigating the role of local sNPF (a homolog of NPY in Drosophila) signaling in modulating neuronal excitability in a higher order olfactory center; 3) Investigate changes across the broader gamma lobe MBON network.

PROJECT SUMMARY/ABSTRACT The long-term goal of this project is to uncover how the gut-brain axis regulates appetite in a nutrient-specific manner. In mammals, enteroendocrine cells in the gastrointestinal tract release a repertoire neuropeptides to regulate food intake. However, it is not clear how nutrients are represented by gut neuropeptides. The research outlined here takes advantage of the anatomical simplicity and the powerful genetic toolkit of the Drosophila to address the questions of how macronutrients ? carbohydrates, amino acids and fatty acids ? are transformed into a neuropeptide code and how nutritional information is processed to regulate appetite. The proposed study focuses on gut neuropeptide ? what macronutrients they represent (Aim 1) and whether they are anorexigenic hormones (Aim 2). In Aim 3, we will test the hypothesis that the level of an anorexigenic hormone represents not only the quantity but also the quality of amino acids. Results from these studies are expected to establish a neuropeptide code for macronutrients providing mechanistic insights into how food intake is regulated in a nutrient-specific manner. These insights are highly relevant to human health as reducing food intake by designed diets could provide a new avenue to fight the obesity epidemic