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Natural odorant scenes are complex landscapes comprising mixtures of volatile compounds. It was previously proposed that the Antennal Lobe circuit recovers the odorant identity in a concentration-invariant manner via divisive normalization of Local Neurons. It remains unclear, however, how identities of odorant components in a mixture is represented or recovered in the fruit fly early olfactory pathway. In the current work, we take a different approach from the traditional steady-state analyses that classify odorant mixture encoding into configural vs. elemental schemes. Instead, we focus on the spatio-temporal responses of the early olfactory pathway at the levels of the Antennal Lobe and the Mushroom Body, and formulate the odorant demixing problem as a blind source separation problem - where the identities of each individual odorant component and their corresponding concentration waveforms are recovered from the spatio-temporal PSTH of Olfactory Sensory Neurons (OSNs), Projection Neurons (PNs), and Kenyon Cells (KCs) respectively. Building upon previous models of the Antenna and the Antennal Lobe, we advanced a feedback divisive normalization architecture of the Mushroom Body Calyx circuit comprised of PN, KC and the giant Anterior Paired Lateral (APL) neuron. We demonstrate that the PN-KC-APL circuit produces a high dimensional representation of odorant mixture with robust sparsity, and results in greater odorant demixing performance than the PN responses.

The early olfactory system of the fruit fly, while sensing a complex odorant landscape, encodes the odorant object identity (semantic information) and the odorant concentration waveform (syntactic information) into a combinatorial neural code. Single-channel physiology recordings at the output of the Antenna Lobe (AL) exhibit concentration-invariance and contrast-boosting properties, indicating a decoupling of the odorant object identity from the concentration waveform in steady-state while responding strongly to odorant concentration onset and offset in transient states.Through exhaustive computational explorations of the AL circuits, we show that the steady-state and transient response features of the AL are, respectively, due to presynaptic and postsynaptic Local Neurons (LNs). Theoretical analysis reveals that the LN pathways can be modeled as parallel differential Divisive Normalization Processors (DNPs). Differential DNPs robustly extract odorant identity (semantic information) and ON/OFF odorant event-timing (syntactic information), thereby providing for the AL the functional logic of ON-OFF odorant identity recovery.

Over the past two decades, substantial amount of work has been conducted to characterize different odorant receptors, neuroanatomy and odorant response properties of the early olfactory system of Drosophila melanogaster. Yet many odorant receptors remain only partially characterized, and the odorant transduction process and the axon hillock spiking mechanism of the olfactory sensory neurons (OSNs) have yet to be fully determined. Identity and concentration, two key characteristics of the space of odorants, are encoded by the odorant transduction process. Detailed molecular models of the odorant transduction process are, however, scarce for fruit flies. To address these challenges we advance a comprehensive model of fruit fly OSNs as a cascade consisting of an odorant transduction process (OTP) and a biophysical spike generator (BSG). We model odorant identity and concentration using an odorant-receptor binding rate tensor, modulated by the odorant concentration profile, and an odorant-receptor dissociation rate tensor, and quantitatively describe the mechanics of the molecular ligand binding/dissociation of the OTP. We model the BSG as a Connor-Stevens point neuron. The resulting spatio-temporal encoding model of the Drosophila antenna provides a theoretical foundation for understanding the neural code of both odorant identity and odorant concentration and advances the state-of-the-art in a number of ways. First, it quantifies on the molecular level the spatio-temporal level of complexity of the transformation taking place in the antennae. The concentration-dependent spatio-temporal code at the output of the antenna circuits determines the level of complexity of olfactory processing in the downstream neuropils, such as odorant recognition and olfactory associative learning. Second, the model is biologically validated using multiple electrophysiological recordings. Third, the model demonstrates that the currently available data for odorant-receptor responses only enable the estimation of the affinity of the odorant-receptor pairs. The odorant-dissociation rate is only available for a few odorant-receptor pairs. Finally, our model calls for new experiments for massively identifying the odorant-receptor dissociation rates of relevance to flies., Author summary Identity and concentration, intrinsically embedded in the odorant space, are two key characteristics of olfactory coding that define the level of complexity of neural processing throughout the olfactory system in the fruit fly. In this paper we advance a theoretical foundation for understanding these two characteristics by quantifying mathematically the odorant space and devising a biophysical model of the olfactory sensory neurons (OSNs). To validate our modeling approach, we propose and apply an algorithm to estimate the affinity value and the dissociation rate, the two characteristics that define odorant identity, of multiple odorant-receptor pairs. We then evaluate our 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. Furthermore, we evaluate the model at the OSN population level and quantify on the molecular level the spatio-temporal level of complexity of the transformation taking place between the odorant space and the OSNs. The resulting concentration-dependent spatio-temporal code determines the level of complexity of the input space driving olfactory processing in the downstream neuropils. Lastly, our model demonstrates that the currently available data for OSN responses only enables estimation of affinity value. This calls for new experiments for massively identifying the odorant-receptor dissociation rates of relevance to flies.

The Fruit Fly Brain Observatory (FFBO) is a collaborative effort between experimentalists, theorists and computational neuroscientists at Columbia University, National Tsing Hua University and Sheffield University with the goal to (i) create an open platform for the emulation and biological validation of fruit fly brain models in health and disease, (ii) standardize tools and methods for graphical rendering, representation and manipulation of brain circuits, (iii) standardize tools for representation of fruit fly brain data and its abstractions and support for natural language queries, (iv) create a focus for the neuroscience community with interests in the fruit fly brain and encourage the sharing of fruit fly brain structural data and executable code worldwide. NeuroNLP and NeuroGFX, two key FFBO applications, aim to address two major challenges, respectively: i) seamlessly integrate structural and genetic data from multiple sources that can be intuitively queried, effectively visualized and extensively manipulated, ii) devise executable brain circuit models anchored in structural data for understanding and developing novel hypotheses about brain function. NeuroNLP enables researchers to use plain English (or other languages) to probe biological data that are integrated into a novel database system, called NeuroArch, that we developed for integrating biological and abstract data models of the fruit fly brain. With powerful 3D graphical visualization, NeuroNLP presents a highly accessible portal for the fruit fly brain data. NeuroGFX provides users highly intuitive tools to execute neural circuit models with Neurokernel, an open-source platform for emulating the fruit fly brain, with full data support from the NeuroArch database and visualization support from an interactive graphical interface. Brain circuits can be configured with high flexibility and investigated on multiple levels, e.g., whole brain, neuropil, and local circuit levels. The FFBO is publicly available and accessible at http://fruitflybrain.org from any modern web browsers, including those running on smartphones.

In the past two decades, a substantial amount of work characterized the odorant receptors, neuroanatomy and odorant response properties of the early olfactory system of Drosophila melanogaster. Yet many odorant receptors remain only partially characterized and, the odorant transduction process and the axon hillock spiking mechanism of the olfactory sensory neurons (OSNs) have yet to be fully determined.Identity and concentration, two key aspects of olfactory coding, originate in the odorant transduction process. Detailed molecular models of the odorant transduction process are, however, scarce for fruit flies. To address these challenges we advance a comprehensive model of fruit fly OSNs as a cascade consisting of an odorant transduction process (OTP) and a biophysical spike generator (BSG). We model identity and concentration in OTP using an odorant-receptor binding rate tensor, modulated by the odorant concentration profile, and an odorant-receptor dissociation rate tensor, and quantitatively describe the ligand binding/dissociation process. We model the BSG as a Connor-Stevens point neuron.The resulting combinatorial encoding model of the Drosophila antenna provides a theoretical foundation for understanding the neural code of both odorant identity and odorant concentration and advances the state-of-the-art in a number of ways. First, it quantifies on the molecular level the combinatorial complexity of the transformation taking place in the antennae. The concentration-dependent combinatorial code determines the complexity of the input space driving olfactory processing in the downstream neuropils, such as odorant recognition and olfactory associative learning. Second, the model is biologically validated using multiple electrophysiology recordings. Third, the model demonstrates that the currently available data for odorant-receptor responses only enable the estimation of the affinity of the odorant-receptor pairs. The odorant-dissociation rate is only available for a few odorant-receptor pairs. Finally, our model calls for new experiments for massively identifying the odorant-receptor dissociation rates of relevance to flies.

SummaryRecently, multiple focused efforts have resulted in substantial increase in the availability of connectome data in the fruit fly brain. Elucidating neural circuit function from such structural data calls for a scalable computational modeling methodology. We propose such a methodology that includes i) a brain emulation engine, with an architecture that can tackle the complexity of whole brain modeling, ii) a database that supports tight integration of biological and modeling data along with support for domain specific queries and circuit transformations, and iii) a graphical interface that allows for total flexibility in configuring neural circuits and visualizing run-time results, both anchored on model abstractions closely reflecting biological structure. Towards the realization of such a methodology, we have developed NeuroGFX and integrated it into the architecture of the Fruit Fly Brain Observatory (http://fruitflybrain.org). The computational infrastructure in NeuroGFX is provided by Neurokernel, an open source platform for the emulation of the fruit fly brain, and NeuroArch, a database for querying and executing fruit fly brain circuits. The integration of the two enables the algorithmic construction/manipulation/revision of executable circuits on multiple levels of abstraction of the same model organism. The power of this computational infrastructure can be leveraged through an intuitive graphical interface that allows visualizing execution results in the context of biological structure. This provides an environment where computational researchers can present configurable, executable neural circuits, and experimental scientists can easily explore circuit structure and function ultimately leading to biological validation. With these capabilities, NeuroGFX enables the exploration of function from circuit structure at whole brain, neuropil, and local circuit level of abstraction. By allowing for independently developed models to be integrated at the architectural level, NeuroGFX provides an open plug and play, collaborative environment for whole brain computational modeling of the fruit fly.

SummaryNeuroNLP, is a key application on the Fruit Fly Brain Observatory platform (FFBO, http://fruitflybrain.org), that provides a modern web-based portal for navigating fruit fly brain circuit data. Increases in the availability and scale of fruit fly connectome data, demand new, scalable and accessible methods to facilitate investigation into the functions of the latest complex circuits being uncovered. NeuroNLP enables in-depth exploration and investigation of the structure of brain circuits, using intuitive natural language queries that are capable of revealing the latent structure and information, obscured due to expansive yet independent data sources. NeuroNLP is built on top of a database system call NeuroArch that codifies knowledge about the fruit fly brain circuits, spanning multiple sources. Users can probe biological circuits in the NeuroArch database with plain English queries, such as “show glutamatergic local neurons in the left antennal lobe” and “show neurons with dendrites in the left mushroom body and axons in the fan-shaped body”. This simple yet powerful interface replaces the usual, cumbersome checkboxes and dropdown menus prevalent in today’s neurobiological databases. Equipped with powerful 3D visualization, NeuroNLP standardizes tools and methods for graphical rendering, representation, and manipulation of brain circuits, while integrating with existing databases such as the FlyCircuit. The userfriendly graphical user interface complements the natural language queries with additional controls for exploring the connectivity of neurons and neural circuits. Designed with an open-source, modular structure, it is highly scalable/flexible/extensible to additional databases or to switch between databases and supports the creation of additional parsers for other languages. By supporting access through a web browser from any modern laptop or smartphone, NeuroNLP significantly increases the accessibility of fruit fly brain data and improves the impact of the data in both scientific and educational exploration.

SummaryThe Fruit Fly Brain Observatory (FFBO) is a collaborative effort between experimentalists, theorists and computational neuroscientists at Columbia University, National Tsing Hua University and Sheffield University with the goal to (i) create an open platform for the emulation and biological validation of fruit fly brain models in health and disease, (ii) standardize tools and methods for graphical rendering, representation and manipulation of brain circuits, (iii) standardize tools for representation of fruit fly brain data and its abstractions and support for natural language queries, (iv) create a focus for the neuroscience community with interests in the fruit fly brain and encourage the sharing of fruit fly brain structural data and executable code worldwide. NeuroNLP and NeuroGFX, two key FFBO applications, aim to address two major challenges, respectively: i) seamlessly integrate structural and genetic data from multiple sources that can be intuitively queried, effectively visualized and extensively manipulated, ii) devise executable brain circuit models anchored in structural data for understanding and developing novel hypotheses about brain function. NeuroNLP enables researchers to use plain English (or other languages) to probe biological data that are integrated into a novel database system, called NeuroArch, that we developed for integrating biological and abstract data models of the fruit fly brain. With powerful 3D graphical visualization, NeuroNLP presents a highly accessible portal for the fruit fly brain data. NeuroGFX provides users highly intuitive tools to execute neural circuit models with Neurokernel, an open-source platform for emulating the fruit fly brain, with full data support from the NeuroArch database and visualization support from an interactive graphical interface. Brain circuits can be configured with high flexibility and investigated on multiple levels, e.g., whole brain, neuropil, and local circuit levels. The FFBO is publicly available and accessible at http://fruitflybrain.org from any modern web browsers, including those running on smartphones.

An n-bit Gray code is a circular listing of all 2^nn-bit binary strings in which consecutive strings differ at exactly one bit. For n@?t@?2^n^-^1, an (n,t)-antipodal Gray code is a Gray code in which the complement of any string appears t steps away from the string, clockwise or counterclockwise. Killian and Savage proved that an (n,n)-antipodal Gray code exists when n is a power of 2 or n=3, and does not exist for n=6 or odd n>3. Motivated by these results, we prove that for odd n>=3, an (n,t)-antipodal Gray code exists if and only if t=2^n^-^1-1. For even n, we establish two recursive constructions for (n,t) codes from smaller (n^',t^'). Consequently, various (n,t)-antipodal Gray codes are found for even n's. Examples are for t=2^n^-^1-2^k with k odd and 1@?k@?n-3 when n>=4, for t=2^n^-^k when n>=2k with 1@?k@?3, for t=n when n=2^k>=2 (an alternative proof for Killian and Savage's result) ...etc.

A rich set of genetic tools and extensive anatomical data make the olfactory system of the fruit fly a neural circuit of choice for studying function in sensory systems. Though a substantial amount of work has been published on the neural coding of olfactory sensory neurons (OSNs) of the fruit fly, yet little is known how projection neurons (PNs) encode time-varying odor stimuli [1]. Here we address this question with in vivo experiments coupled with a phenomenological characterization of the spiking activity of PNs. Recently, a new class of identification algorithms called Channel Identification Machines (CIMs) [2] was proposed for identifying dendritic processing in simple neural circuits using conditional phase response curves (cPRCs) [3]. By combining cPRCs with the reduced project-integrated-andfire neuron (PIF) model [4], the CIM algorithms identify a complete phenomenological description of spike generation of a biological neuron for weak to moderately strong stimuli. Moreover, the identification method employed does not require white noise stimuli nor an infinitesimal pulse injection protocol as widely used in the past [5]. Here we identify the PNs both in silico and in vivo. Starting with simulations, we investigate the feasibility of the CIM method on PNs modeled as pseudo uni-polar neurons in silico, as shown in Figures 1.(B) and 1.(C). We then systematically convert the CIM method into a stepby-step experimental protocol, and carry it out in vivo by injecting currents into PNs using the patch clamping technique [6,7]. A snapshot of PN patching is depicted in Figure 1.(A).

This paper presents an ultra-low-power voice activity detector (VAD). It uses analog signal processing for acoustic feature extraction (AFE) directly on the microphone output, approximate event-driven analog-to-digital conversion (ED-ADC), and digital deep neural network (DNN) for speech/non-speech classification. New circuits, including the low-noise amplifier, bandpass filter, and full-wave rectifier contribute to the more than 9 $\times $ normalized power/channel reduction in the feature extraction front-end compared to the best prior art. The digital DNN is a three-hidden-layer binarized multilayer perceptron (MLP) with a 2-neuron output layer and a 48-neuron input layer that receives parallel event streams from the ED-ADCs. To obtain the DNN weights via off-line training, a customized front-end model written in python is constructed to accelerate feature generation in software emulation, and the model parameters are extracted from Spectre simulations. The chip, fabricated in 0.18- $\mu \text{m}$ CMOS, has a core area of 1.66 $\times $ 1.52 mm2 and consumes 1 $\mu \text{W}$ . The classification measurements using the 1-hour 10-dB signal-to-noise ratio audio with restaurant background noise show a mean speech/non-speech hit rate of 84.4%/85.4% with a 1.88%/4.65% 1- $\sigma $ variation across ten dies that are all loaded with the same weights.