In the last decade it has become increasingly apparent that epigenetic mechanisms regulating gene expression play an important role in brain function and dysfunction. Disruption in neuroepigenetic developmental processes such as DNA methylation and histone acetylation result in mental retardation and cognitive impairments. More recently, neuroepigenetic processes have also been implicated in adult behaviors, such as addiction and memory. This opens the possibility that these mechanisms may be able to control the establishment and maintenance of behavioral states. However, the underlying mechanisms through which neuroepigenetic processes can mediate changes in circuit excitability to determine behavioral states remain mysterious. Moreover, because of the complexity and heterogeneity of the mammalian brain, we have no knowledge about the genetic loci of integration between the environment and behavior, and the identity of the neural pathways that control them in specific circuits. This presents a major roadblock towards unlocking the interface between brain and environment and their role in human health and disease. Here we propose a three-prong solution to this problem by using: a brain that shows conserved neurochemistry and neuroepigenetic mechanisms, but with orders of magnitude fewer neurons and homogenous circuits compared to mammalian brains, behaviors that are regulated by the environment (hunger and satiety), and an environment that is experimentally controllable (fasting vs. re-feeding; normal diet vs. high sugar diet). Changes in the excitability and plasticity of conserved circuits determine outputs feeding states like hunger and satiety. These changes occur slow, are persistent over hours, depend on the physiological state and are bidirectional. Thus, they could be encoded neuroepigenetically to alter the expression of key genes important to modulate circuit excitability. Furthermore, because a large number of metabolism intermediates functions as cofactors for chromatin modifying enzymes, physiological changes in metabolites and nutrients can directly alter gene expression. My lab has pioneered techniques and established unique collaborations to address the functional role of neuroepigenetic processes in regulating the activity of specific circuits in the context of feeding states. We propose to map how environmental inputs act on chromatin and gene expression to direct the changes in neuronal excitability that underlie output feeding behaviors. First, we will identify the specific chromatin pathways that act in a unique circuit important to switch the behavioral state of the fly between hungry and sated. We will then map the functional genetic loci of integration between physiological state and output behavioral states by examining the occupancy of these pathways on chromatin and their effect on behavior and neural activity. We will then dissect how changes in environmental input (energy scarcity in fasting, energy availability in re-feeding, and energy surplus in a high sugar diet) directly affect gene expression by altering the activity of these pathways and their genetic loci of integration. To this end, we will work with analytical chemists to develop new methods to measure changes in metabolites in the blood, brain and specific circuits and with computational biologists to harness machine learning analysis to integrate metabolism and gene expression datasets to identify the molecular pathways that act at the interface between input and effector mechanisms to regulate output behavioral states. Because the endocrine and physiological changes that underlie hunger and satiety are evolutionary conserved, our approach will provide a model of how the environment can functionally determine bidirectional, flip-flop behavioral states through neuroepigenetic mechanisms. More broadly, these studies will uncover how epigenetic mechanisms may function as gatekeepers of ?behavioral states? (normal and abnormal), to provide the molecular and physiological mechanisms underlying the ?conditioning? effect of environments (from nutrients to maternal care) on neural plasticity.
The proposed study will identify how nutrients in diet play a key role in regulating hunger and satiety states by changing neuronal activity and behavior. This will pave the way to understanding how the increased consumption of calories is linked to diseases such as depression, cancer, aging and neurodegeneration. More broadly, these experiments will identify in detail the molecular and physiological adaptations of a cellular system to a changing environment, develop new methodologies to study metabolism, and computational tool to integrate large orthogonal gene expression and metabolism datasets.
