Title: Mechanistic Models of Neural Computation in the Fruit Fly Brain
Description: Understanding the operating principles of the brain functions is the key to building novel computing architectures for mimicking human intelligence. Neural activities at different scales lead to different levels of brain functions. For example, cellular functions, such as sensory transduction, occur in the molecular reactions, and cognitive functions, such as recognition, emerge in neural systems across multiple brain regions. To bridge the gap between neuroscience and artificial computation, we need systematic development of mechanistic models for neural computation across multiple scales. Existing models of neural computation are often independently developed for a specific scale and hence not compatible with others. In this thesis, we investigate the neural computations in the fruit fly brain and devise mechanistic models at different scales in a systematic manner so that models at one scale constitute functional building blocks for the next scale. Our study spans from the molecular and circuit computations in the olfactory system to the system-level computation of the central complex in the fruit fly.

First, we study how the two key aspects of odorant, identity and concentration, are encoded by the odorant transduction process at the molecular scale. We mathematically quantify the odorant space and propose a biophysical model of the olfactory sensory neuron (OSN). To validate our modeling approaches, we examine the OSN model with a multitude of odorant waveforms and demonstrate that the model output reproduces the temporal responses of OSNs obtained from in vivo electrophysiology recordings. In addition, we evaluate the model at the OSN population level and quantify the combinatorial complexity of the transformation taking place between the odorant space and the OSNs. The resulting concentration-dependent combinatorial code determines the complexity of the input space driving olfactory processing in the downstream neuropil, the antennal lobe. Second, we investigate the neural information processing in the antennal lobe across the molecule scale and the circuit scale. The antennal lobe encodes the output of the OSN population from a concentration-dependent code into a concentration-independent combinatorial code.

To study the transformation of the combinatorial code, we construct a computational model of the antennal lobe that consists of two sub circuits, a predictive coding circuit and an on-off circuit, realized by two distinct local neuron networks, respectively. By examining the entire circuit model with both monomolecular odorant and odorant mixtures, we demonstrate that the predictive coding circuit encodes the odorant identity into concentration invariant code and the on-off circuit encodes the onset and the offset of a unique odorant identity. Third, we investigate the odorant representation inherent in the Kenyon cell activities in the mushroom body. The Kenyon cells encodes the output of the antennal lobe into a high-dimensional, sparse neural code that is immediately used for learning and memory formation. We model the Kenyon cell circuitry as a real-time feedback normalization circuit converting odorant information into a time-dependent hash codes. The resultant real-time hash code represents odorants, pure or mixture alike, in a way conducive to classifications, and suggests an intrinsic partition of the odorant space with similar hash codes.

Forth, we study at the system scale the neural coding of the central complex. The central complex is a set of neuropils in the center of the fly brain that integrates multiple sensory information and play an important role in locomotor control. We create an application that enables simultaneous graphical querying and construction of executable model of the central complex neural circuitry. By reconfiguring the circuitry and generating different executable models, we compare the model response of the wild type and mutant fly strains. Finally, we show that the multi-scale study of the fruit fly brain is made possible by the Fruit Fly Brain Observatory (FFBO), an open-source platform to support open, collaborative fruit fly neuroscience research. The software architecture of the FFBO and its key application are highlighted along with several examples.