Thursday, September 26, 2019
Conference room doors open at 9:00 a.m. in the Gill Center. Light breakfast will be provided. All lectures to be held in the Multi-disciplinary Sciences Building II, Room 102. For questions or directions, please contact us.
9:30—10:00 a.m. | Lecture: "Control of Sugar and Amino Acid Feeding via Integration of Distinct Pharyngeal Taste Inputs."—Yu-Chieh David Chen, University of California, Riverside
Abstract: Gustatory input plays instrumental roles in feeding behaviors, including food choice and intake. In adult Drosophila, the gustatory system comprises multiple taste organs throughout the body, including the labellum, legs, wings and pharynx. Gustatory receptor neurons (GRNs) in each taste sensillum of taste organs express distinct repertoires of chemosensory receptors for detecting various chemicals. To understand the neuronal underpinnings of taste-mediated feeding control, it is critical to determine how distinct classes of GRNs contribute to feeding behaviors. Recent studies have reported distinct taste-evoked responses and chemoreceptor expression in GRNs of different taste sensilla, indicating functional heterogeneity of molecularly distinct GRNs. Nevertheless, poorly defined tools for precise genetic control of individual GRNs have precluded genetic dissection of their functional roles in feeding behaviors. Here, we employed a Pox-neuron (Poxn) mutant as a minimal taste system model in which all the external taste sensilla are transformed into mechanosensory sensilla, while all pharyngeal GRNs remain intact. Combined with the genetic toolkit derived from our recent mapping of pharyngeal taste neurons, we investigated the extent to which taste information is integrated at the cellular level to regulate consumption of sugars and amino acids.
We first genetically silenced all pharyngeal GRNs in Poxn mutants with Ir25a>Kir2.1 and found that feeding attraction to appetitive tastants (sugar, amino acids) and avoidance of aversive tastants (bitter, acid, high salt) were both abolished in binary choice assays. These results indicate that taste input is essential for food choice in short-term feeding assays. We then genetically protected single classes of pharyngeal GRNs via selective expression of the GAL80 suppressor in molecularly defined classes of pharyngeal GRNs in Poxn, Ir25a>Kir2.1 taste-blind flies, which allowed a unique opportunity to test principles of taste coding and behavior in animals that possess only one type of functional taste neuron. We found that pharyngeal Gr43a GRNs drive behavioral responses to both sugars and amino acids, and Ca2+ imaging results confirm their multimodal taste sensing property. Moreover, genetic dissection experiments uncovered functionally redundant pharyngeal Ir20a neurons for detecting amino acids. To further investigate the functions of distinct pharyngeal GRNs we have a suite of single-fly quantitative FLIC assays, which suggest coordination of pharyngeal GRNs in regulating micro-feeding responses to sugars and amino acids. We are also performing complementary optogenetic activation analyses, which has revealed functional specialization between external and internal taste neurons. Taken together, our work has identified previously unexplored appetitive taste coding principles in the pharynx and found evidence for functional overlap as well as functional subdivision among taste neurons.
10:00—10:30 a.m. | Lecture: "The Impact of Dysregulated FGF-FGFR Signaling in Post-mitotic Neuron During Cortical Development."—Jui-Yen Huang, Ph.D., Lu Lab of Indiana University Bloomington
Abstract: A functional brain is reliant on proper communication between neurons; thus, brain function is determined by precise cellular connectivity. Given the importance of accurate brain wiring, aberrant brain circuitry, either misconnections or disrupted connections, is the primary cause of neurological diseases. As the demand increases to repair brain circuitry, my primary research interest is to identify factors that are essential for circuitry assembling and are capable to re-wire brain circuitry. My current research focuses on the function of the fibroblast growth factor (FGF) family in cortical development. The FGF family is composed of 22 ligands and 5 receptors. In the brain, the FGF family was found to regulate neural development through neurogenesis and brain patterning. Subsequent observations implicated that the FGF family also monitors neurogenesis in adult animals. Nevertheless, the function of specific FGF-FGFR signaling in relation to brain circuitry remains unclear. FGFs/FGFRs dysregulation is related to several neurological diseases, such as anxiety, schizophrenia, depression, brain tumors, Alzheimer’s disease (AD), and Parkinson’s disease (PD). However, the causal relationship between dysregulated FGF-FGFR signaling and its contribution to neurological disease remains to be elaborated. To address this, I extensively employ genetic approach combined with in utero electroporation to manipulate the expression levels of FGFs and FGFRs and examine their roles in brain at anatomical and functional levels. I will share our recent progresses with you.
10:30—11:00 a.m. | Lecture: "A Dynamic View of the Proteomic Landscape During Differentiation of ReNcell VM Cells, an Immortalized Human Neural Progenitor Line."—Yuyu Song, M.D./Ph.D., Mass General Hospital/Harvard Medical School
Abstract: The immortalized human ReNcell VM cell line represents a reproducible and easy-to-propagate cell culture system for studying the differentiation of neural progenitors. To better characterize the starting line and its differentiation, we assessed protein and phospho-protein levels and cell morphology over a two-week period during which ReNcell progenitors differentiated into neurons, astrocytes, and oligodendrocytes. Five of the datasets measured protein levels or states of phosphorylation based on tandem-mass-tag (TMT) mass spectrometry and four datasets characterized cellular phenotypes using high-content microscopy. Proteomic analysis revealed reproducible changes in pathways responsible for cytoskeletal rearrangement, cell phase transitions, neuronal migration, glial differentiation, neurotrophic signalling and extracellular matrix regulation. Proteomic and imaging data revealed accelerated differentiation in cells treated with the poly-selective CDK and GSK3 inhibitor kenpaullone or the HMG-CoA reductase inhibitor mevastatin, both of which have previously been reported to promote neural differentiation. These data provide in-depth information on the ReNcell progenitor state and on neural differentiation in the presence and absence of drugs, setting the stage for functional studies.
11:00—11:30 a.m. | Lecture: "Δ9THC, a Major Component of Cannabis and its Metabolites, Bind and Activate GPR 119 to Induce Weight Loss in Diet Induced Obese Mice."—Amey Dhopeshwarkar, Ph.D., Mackie Lab of Indiana University Bloomington
Abstract: User anecdotes and several pre-clinical/clinical studies suggest that cannabis intake promotes increase in consumption of calorie rich food (aka “munchies”). In regular cannabis users, this behavior, along with a sedentary lifestyle would be expected to promote weight gain, obesity, a worsening of metabolic parameter and an increased risk for type 2 diabetes. However, several epidemiological studies indicate otherwise: Chronic cannabis users are modestly protected from obesity and type II diabetes when compared with non-users. THC and cannabidiol are major components of cannabis and thus may play an important role in protecting cannabis users from obesity. In this study, we show that THC and its metabolites bind and activate a lipid-sensing receptor, GPR119, in vitro with distinctive functional selectivity. Furthermore, THC induces GLP1 secretion from murine enteroendocrine GLUTag cells. In vivo, oral and parenteral treatment with THC promotes weight loss in wildtype diet induced obese (DIO) mice. This effect is absent in GPR119 knock out mice. Cannabidiol failed to activate GPR119 in vitro and had no weight loss promoting effects in DIO mice. These results indicate a novel role of THC and its metabolites in promoting weight loss via GPR119.
11:30—12:00 p.m. | Lecture: "Identification of Novel Antidepressant Mechanism of Ketamine by Kinome Profiling."—LiLian Yuan, Ph.D., Des Moines University
Abstract: Ketamine at sub-anesthetic doses has shown promising results as a potent and fast-acting antidepressant. Evidence from animal model studies suggests that the functional restoration by ketamine is associated with activation of MAPK and mTOR signaling cascades in the prefrontal cortex (PFC) within a few hours of ketamine administration, followed by a second wave of synaptic protein upregulation. Together, these molecular events lead to rapid synaptogenesis and reversal of neural atrophy. Furthermore, (2R, 6R)-hydroxynorketamine (HNK) has recently been identified as the main active component of ketamine metabolism. HNK is believed to be responsible for the antidepressant actions of ketamine, but with minimal side effects, providing a distinct tool to examine mechanisms of ketamine’s action. Although some kinases and related pathways have been implicated in both depression pathophysiology and ketamine treatment, there has not been a systematic, proteomics analysis of the kinome or the molecular mechanisms of ketamine action, to provide insight into its mechanism of action as an antidepressant. To fulfill this critical need, we performed a comprehensive brain kinome profile (and characterization of related substrates) through a unique, unbiased proteomic screening method to uncover novel targets of ketamine antidepressant signaling. This high-throughput screening is expected to provide information on the effects of three major factors on the kinome activity profile of PFC: 1) stress; 2) sex; 3) antidepressant treatment (ketamine or HNK). A better understanding of the kinase landscape will provide mechanistic insight into how ketamine promotes its rapid antidepressant effects.
NIH grant MH108043