Neural mechanisms to incorporate visual counterevidence in self-movement estimation.

In selecting appropriate behaviors, animals should weigh sensory evidence both for and against specific beliefs about the world. For instance, animals measure optic flow to estimate and control their own rotation. However, existing models of flow detection can be spuriously triggered by visual motion created by objects moving in the world. Here, we show that stationary patterns on the retina, which constitute evidence against observer rotation, suppress inappropriate stabilizing rotational behavior in the fruit fly Drosophila. In silico experiments show that artificial neural networks (ANNs) that are optimized to distinguish observer movement from external object motion similarly detect stationarity and incorporate negative evidence. Employing neural measurements and genetic manipulations, we identified components of the circuitry for stationary pattern detection, which runs parallel to the fly's local motion and optic-flow detectors. Our results show how the fly brain incorporates negative evidence to improve heading stability, exemplifying how a compact brain exploits geometrical constraints of the visual world.

Long-timescale anti-directional rotation in Drosophila optomotor behavior.

Locomotor movements cause visual images to be displaced across the eye, a retinal slip that is counteracted by stabilizing reflexes in many animals. In insects, optomotor turning causes the animal to turn in the direction of rotating visual stimuli, thereby reducing retinal slip and stabilizing trajectories through the world. This behavior has formed the basis for extensive dissections of motion vision. Here, we report that under certain stimulus conditions, two Drosophila species, including the widely studied Drosophila melanogaster, can suppress and even reverse the optomotor turning response over several seconds. Such 'anti-directional turning' is most strongly evoked by long-lasting, high-contrast, slow-moving visual stimuli that are distinct from those that promote syn-directional optomotor turning. Anti-directional turning, like the syn-directional optomotor response, requires the local motion detecting neurons T4 and T5. A subset of lobula plate tangential cells, CH cells, show involvement in these responses. Imaging from a variety of direction-selective cells in the lobula plate shows no evidence of dynamics that match the behavior, suggesting that the observed inversion in turning direction emerges downstream of the lobula plate. Further, anti-directional turning declines with age and exposure to light. These results show that Drosophila optomotor turning behaviors contain rich, stimulus-dependent dynamics that are inconsistent with simple reflexive stabilization responses.

Machine learning approaches to predict drug efficacy and toxicity in oncology.

In recent years, there has been a surge of interest in using machine learning algorithms (MLAs) in oncology, particularly for biomedical applications such as drug discovery, drug repurposing, diagnostics, clinical trial design, and pharmaceutical production. MLAs have the potential to provide valuable insights and predictions in these areas by representing both the disease state and the therapeutic agents used to treat it. To fully utilize the capabilities of MLAs in oncology, it is important to understand the fundamental concepts underlying these algorithms and how they can be applied to assess the efficacy and toxicity of therapeutics. In this perspective, we lay out approaches to represent both the disease state and the therapeutic agents used by MLAs to derive novel insights and make relevant predictions.

Long timescale anti-directional rotation in Drosophila optomotor behavior.

Locomotor movements cause visual images to be displaced across the eye, a retinal slip that is counteracted by stabilizing reflexes in many animals. In insects, optomotor turning causes the animal to turn in the direction of rotating visual stimuli, thereby reducing retinal slip and stabilizing trajectories through the world. This behavior has formed the basis for extensive dissections of motion vision. Here, we report that under certain stimulus conditions, two Drosophila species, including the widely studied D. melanogaster, can suppress and even reverse the optomotor turning response over several seconds. Such "anti-directional turning" is most strongly evoked by long-lasting, high-contrast, slow-moving visual stimuli that are distinct from those that promote syn-directional optomotor turning. Anti-directional turning, like the syn-directional optomotor response, requires the local motion detecting neurons T4 and T5. A subset of lobula plate tangential cells, CH cells, show involvement in these responses. Imaging from a variety of direction-selective cells in the lobula plate shows no evidence of dynamics that match the behavior, suggesting that the observed inversion in turning direction emerges downstream of the lobula plate. Further, anti-directional turning declines with age and exposure to light. These results show that Drosophila optomotor turning behaviors contain rich, stimulus-dependent dynamics that are inconsistent with simple reflexive stabilization responses.

Neural mechanisms to incorporate visual counterevidence in self motion estimation.

In selecting appropriate behaviors, animals should weigh sensory evidence both for and against specific beliefs about the world. For instance, animals measure optic flow to estimate and control their own rotation. However, existing models of flow detection can confuse the movement of external objects with genuine self motion. Here, we show that stationary patterns on the retina, which constitute negative evidence against self rotation, are used by the fruit fly Drosophila to suppress inappropriate stabilizing rotational behavior. In silico experiments show that artificial neural networks optimized to distinguish self and world motion similarly detect stationarity and incorporate negative evidence. Employing neural measurements and genetic manipulations, we identified components of the circuitry for stationary pattern detection, which runs parallel to the fly's motion- and optic flow-detectors. Our results exemplify how the compact brain of the fly incorporates negative evidence to improve heading stability, exploiting geometrical constraints of the visual world.

Excitatory and inhibitory neural dynamics jointly tune motion detection.

Neurons integrate excitatory and inhibitory signals to produce their outputs, but the role of input timing in this integration remains poorly understood. Motion detection is a paradigmatic example of this integration, since theories of motion detection rely on different delays in visual signals. These delays allow circuits to compare scenes at different times to calculate the direction and speed of motion. Different motion detection circuits have different velocity sensitivity, but it remains untested how the response dynamics of individual cell types drive this tuning. Here, we sped up or slowed down specific neuron types in Drosophila's motion detection circuit by manipulating ion channel expression. Altering the dynamics of individual neuron types upstream of motion detectors increased their sensitivity to fast or slow visual motion, exposing distinct roles for excitatory and inhibitory dynamics in tuning directional signals, including a role for the amacrine cell CT1. A circuit model constrained by functional data and anatomy qualitatively reproduced the observed tuning changes. Overall, these results reveal how excitatory and inhibitory dynamics together tune a canonical circuit computation.

Predicting individual neuron responses with anatomically constrained task optimization.

Artificial neural networks trained to solve sensory tasks can develop statistical representations that match those in biological circuits. However, it remains unclear whether they can reproduce properties of individual neurons. Here, we investigated how artificial networks predict individual neuron properties in the visual motion circuits of the fruit fly Drosophila. We trained anatomically constrained networks to predict movement in natural scenes, solving the same inference problem as fly motion detectors. Units in the artificial networks adopted many properties of analogous individual neurons, even though they were not explicitly trained to match these properties. Among these properties was the split into ON and OFF motion detectors, which is not predicted by classical motion detection models. The match between model and neurons was closest when models were trained to be robust to noise. These results demonstrate how anatomical, task, and noise constraints can explain properties of individual neurons in a small neural network.

Inhibiting LXRα phosphorylation in hematopoietic cells reduces inflammation and attenuates atherosclerosis and obesity in mice.

Atherosclerosis and obesity share pathological features including inflammation mediated by innate and adaptive immune cells. LXRα plays a central role in the transcription of inflammatory and metabolic genes. LXRα is modulated by phosphorylation at serine 196 (LXRα pS196), however, the consequences of LXRα pS196 in hematopoietic cell precursors in atherosclerosis and obesity have not been investigated. To assess the importance of LXRα phosphorylation, bone marrow from LXRα WT and S196A mice was transplanted into Ldlr-/- mice, which were fed a western diet prior to evaluation of atherosclerosis and obesity. Plaques from S196A mice showed reduced inflammatory monocyte recruitment, lipid accumulation, and macrophage proliferation. Expression profiling of CD68+ and T cells from S196A mouse plaques revealed downregulation of pro-inflammatory genes and in the case of CD68+ upregulation of mitochondrial genes characteristic of anti-inflammatory macrophages. Furthermore, S196A mice had lower body weight and less visceral adipose tissue; this was associated with transcriptional reprograming of the adipose tissue macrophages and T cells, and resolution of inflammation resulting in less fat accumulation within adipocytes. Thus, reducing LXRα pS196 in hematopoietic cells attenuates atherosclerosis and obesity by reprogramming the transcriptional activity of LXRα in macrophages and T cells to promote an anti-inflammatory phenotype.

A minimal synaptic model for direction selective neurons in Drosophila.

Visual motion estimation is a canonical neural computation. In Drosophila, recent advances have identified anatomic and functional circuitry underlying direction-selective computations. Models with varying levels of abstraction have been proposed to explain specific experimental results but have rarely been compared across experiments. Here we use the wealth of available anatomical and physiological data to construct a minimal, biophysically inspired synaptic model for Drosophila's first-order direction-selective T4 cells. We show how this model relates mathematically to classical models of motion detection, including the Hassenstein-Reichardt correlator model. We used numerical simulation to test how well this synaptic model could reproduce measurements of T4 cells across many datasets and stimulus modalities. These comparisons include responses to sinusoid gratings, to apparent motion stimuli, to stochastic stimuli, and to natural scenes. Without fine-tuning this model, it sufficed to reproduce many, but not all, response properties of T4 cells. Since this model is flexible and based on straightforward biophysical properties, it provides an extensible framework for developing a mechanistic understanding of T4 neural response properties. Moreover, it can be used to assess the sufficiency of simple biophysical mechanisms to describe features of the direction-selective computation and identify where our understanding must be improved.

Dynamic nonlinearities enable direction opponency in Drosophila elementary motion detectors.

Direction-selective neurons respond to visual motion in a preferred direction. They are direction-opponent if they are also inhibited by motion in the opposite direction. In flies and vertebrates, direction opponency has been observed in second-order direction-selective neurons, which achieve this opponency by subtracting signals from first-order direction-selective cells with opposite directional tunings. Here, we report direction opponency in Drosophila that emerges in first-order direction-selective neurons, the elementary motion detectors T4 and T5. This opponency persists when synaptic output from these cells is blocked, suggesting that it arises from feedforward, not feedback, computations. These observations exclude a broad class of linear-nonlinear models that have been proposed to describe direction-selective computations. However, they are consistent with models that include dynamic nonlinearities. Simulations of opponent models suggest that direction opponency in first-order motion detectors improves motion discriminability by suppressing noise generated by the local structure of natural scenes.