By treating curably blind children in India, “Project Prakash” brings sight to children of different ages, offering insights into how their brains adapt to enable them to see. The project's experience highlights the benefits of merging basic research with societal service.

Deep neural networks (DNNs) for object classification have been argued to provide the most promising model of the visual system, accompanied by claims that they have attained or even surpassed human-level performance. Here, we evaluated whether DNNs provide a viable model of human vision when tested with challenging noisy images of objects, sometimes presented at the very limits of visibility. We show that popular state-of-the-art DNNs perform in a qualitatively different manner than humans-they are unusually susceptible to spatially uncorrelated white noise and less impaired by spatially correlated noise. We implemented a noise training procedure to determine whether noise-trained DNNs exhibit more robust responses that better match human behavioral and neural performance. We found that noise-trained DNNs provide a better qualitative match to human performance; moreover, they reliably predict human recognition thresholds on an image-by-image basis. Functional neuroimaging revealed that noise-trained DNNs provide a better correspondence to the pattern-specific neural representations found in both early visual areas and high-level object areas. A layer-specific analysis of the DNNs indicated that noise training led to broad-ranging modifications throughout the network, with greater benefits of noise robustness accruing in progressively higher layers. Our findings demonstrate that noise-trained DNNs provide a viable model to account for human behavioral and neural responses to objects in challenging noisy viewing conditions. Further, they suggest that robustness to noise may be acquired through a process of visual learning.

Studies of neuronal oscillations have contributed substantial insight into the mechanisms of visual, auditory, and somatosensory perception. However, progress in such research in the human olfactory system has lagged behind. As a result, the electrophysiological properties of the human olfactory system are poorly understood, and, in particular, whether stimulus-driven high-frequency oscillations play a role in odor processing is unknown. Here, we used direct intracranial recordings from human piriform cortex during an odor identification task to show that 3 key oscillatory rhythms are an integral part of the human olfactory cortical response to smell: Odor induces theta, beta, and gamma rhythms in human piriform cortex. We further show that these rhythms have distinct relationships with perceptual behavior. Odor-elicited gamma oscillations occur only during trials in which the odor is accurately perceived, and features of gamma oscillations predict odor identification accuracy, suggesting that they are critical for odor identity perception in humans. We also found that the amplitude of high-frequency oscillations is organized by the phase of low-frequency signals shortly following sniff onset, only when odor is present. Our findings reinforce previous work on theta oscillations, suggest that gamma oscillations in human piriform cortex are important for perception of odor identity, and constitute a robust identification of the characteristic electrophysiological response to smell in the human brain. Future work will determine whether the distinct oscillations we identified reflect distinct perceptual features of odor stimuli.

Many species execute ballistic escape reactions to avoid imminent danger. Despite fast reaction times, responses are often highly regulated, reflecting a trade-off between costly motor actions and perceived threat level. However, how sensory cues are integrated within premotor escape circuits remains poorly understood. Here, we show that in zebrafish, less precipitous threats elicit a delayed escape, characterized by flexible trajectories, which are driven by a cluster of 38 prepontine neurons that are completely separate from the fast escape pathway. Whereas neurons that initiate rapid escapes receive direct auditory input and drive motor neurons, input and output pathways for delayed escapes are indirect, facilitating integration of cross-modal sensory information. These results show that rapid decision-making in the escape system is enabled by parallel pathways for ballistic responses and flexible delayed actions and defines a neuronal substrate for hierarchical choice in the vertebrate nervous system.

Anticipating an odor improves detection and perception, yet the underlying neural mechanisms of olfactory anticipation are not well understood. In this study, we used human intracranial electroencephalography (iEEG) to show that anticipation resets the phase of delta oscillations in piriform cortex prior to odor arrival. Anticipatory phase reset correlates with ensuing odor-evoked theta power and improvements in perceptual accuracy. These effects were consistently present in each individual subject and were not driven by potential confounds of pre-inhale motor preparation or power changes. Together, these findings suggest that states of anticipation enhance olfactory perception through phase resetting of delta oscillations in piriform cortex.

The trade-off between effort and reward is one of the main determinants of behavior, and its alteration is at the heart of major disorders such as depression or Parkinson's disease. Monoaminergic neuromodulators are thought to play a key role in this trade-off, but their relative contribution remains unclear. Rhesus monkeys (Macaca mulatta) performed a choice task requiring a trade-off between the volume of fluid reward and the amount of force to be exerted on a grip. In line with a causal role of noradrenaline in effort, decreasing noradrenaline levels with systemic clonidine injections (0.01 mg/kg) decreased exerted force and enhanced the weight of upcoming force on choices, without any effect on reward sensitivity. Using computational modeling, we showed that a single variable ("effort") could capture the amount of resources necessary for action and control both choices (as a variable for decision) and force production (as a driving force). Critically, the multiple effects of noradrenaline manipulation on behavior could be captured by a specific modulation of this single variable. Thus, our data strongly support noradrenaline's implication in effort processing.

Characterizing cellular diversity at different levels of biological organization and across data modalities is a prerequisite to understanding the function of cell types in the brain. Classification of neurons is also essential to manipulate cell types in controlled ways and to understand their variation and vulnerability in brain disorders. The BRAIN Initiative Cell Census Network (BICCN) is an integrated network of data-generating centers, data archives, and data standards developers, with the goal of systematic multimodal brain cell type profiling and characterization. Emphasis of the BICCN is on the whole mouse brain with demonstration of prototype feasibility for human and nonhuman primate (NHP) brains. Here, we provide a guide to the cellular and spatial approaches employed by the BICCN, and to accessing and using these data and extensive resources, including the BRAIN Cell Data Center (BCDC), which serves to manage and integrate data across the ecosystem. We illustrate the power of the BICCN data ecosystem through vignettes highlighting several BICCN analysis and visualization tools. Finally, we present emerging standards that have been developed or adopted toward Findable, Accessible, Interoperable, and Reusable (FAIR) neuroscience. The combined BICCN ecosystem provides a comprehensive resource for the exploration and analysis of cell types in the brain.

Failures in mitophagy, a process by which damaged mitochondria are cleared, results in neurodegeneration, while enhancing mitophagy promotes the survival of dopaminergic neurons. Using an artificial intelligence platform, we employed a natural language processing approach to evaluate the semantic similarity of candidate molecules to a set of well-established mitophagy enhancers. Top candidates were screened in a cell-based mitochondrial clearance assay. Probucol, a lipid-lowering drug, was validated across several orthogonal mitophagy assays. In vivo, probucol improved survival, locomotor function, and dopaminergic neuron loss in zebrafish and fly models of mitochondrial damage. Probucol functioned independently of PINK1/Parkin, but its effects on mitophagy and in vivo depended on ABCA1, which negatively regulated mitophagy following mitochondrial damage. Autophagosome and lysosomal markers were elevated by probucol treatment in addition to increased contact between lipid droplets (LDs) and mitochondria. Conversely, LD expansion, which occurs following mitochondrial damage, was suppressed by probucol and probucol-mediated mitophagy enhancement required LDs. Probucol-mediated LD dynamics changes may prime the cell for a more efficient mitophagic response to mitochondrial damage.

The NKCC1 ion transporter contributes to the pathophysiology of common neurological disorders, but its function in microglia, the main inflammatory cells of the brain, has remained unclear to date. Therefore, we generated a novel transgenic mouse line in which microglial NKCC1 was deleted. We show that microglial NKCC1 shapes both baseline and reactive microglia morphology, process recruitment to the site of injury, and adaptation to changes in cellular volume in a cell-autonomous manner via regulating membrane conductance. In addition, microglial NKCC1 deficiency results in NLRP3 inflammasome priming and increased production of interleukin-1β (IL-1β), rendering microglia prone to exaggerated inflammatory responses. In line with this, central (intracortical) administration of the NKCC1 blocker, bumetanide, potentiated intracortical lipopolysaccharide (LPS)-induced cytokine levels. In contrast, systemic bumetanide application decreased inflammation in the brain. Microglial NKCC1 KO animals exposed to experimental stroke showed significantly increased brain injury, inflammation, cerebral edema and worse neurological outcome. Thus, NKCC1 emerges as an important player in controlling microglial ion homeostasis and inflammatory responses through which microglia modulate brain injury. The contribution of microglia to central NKCC1 actions is likely to be relevant for common neurological disorders.

Lowered insulin/insulin-like growth factor (IGF) signaling (IIS) can extend healthy lifespan in worms, flies, and mice, but it can also have adverse effects (the "insulin paradox"). Chronic, moderately lowered IIS rescues age-related decline in neurotransmission through the Drosophila giant fiber system (GFS), a simple escape response neuronal circuit, by increasing targeting of the gap junctional protein innexin shaking-B to gap junctions (GJs). Endosomal recycling of GJs was also stimulated in cultured human cells when IIS was reduced. Furthermore, increasing the activity of the recycling small guanosine triphosphatases (GTPases) Rab4 or Rab11 was sufficient to maintain GJs upon elevated IIS in cultured human cells and in flies, and to rescue age-related loss of GJs and of GFS function. Lowered IIS thus elevates endosomal recycling of GJs in neurons and other cell types, pointing to a cellular mechanism for therapeutic intervention into aging-related neuronal disorders.

Loners-individuals out of sync with a coordinated majority-occur frequently in nature. Are loners incidental byproducts of large-scale coordination attempts, or are they part of a mosaic of life-history strategies? Here, we provide empirical evidence of naturally occurring heritable variation in loner behavior in the model social amoeba Dictyostelium discoideum. We propose that Dictyostelium loners-cells that do not join the multicellular life stage-arise from a dynamic population-partitioning process, the result of each cell making a stochastic, signal-based decision. We find evidence that this imperfectly synchronized multicellular development is affected by both abiotic (environmental porosity) and biotic (signaling) factors. Finally, we predict theoretically that when a pair of strains differing in their partitioning behavior coaggregate, cross-signaling impacts slime-mold diversity across spatiotemporal scales. Our findings suggest that loners could be critical to understanding collective and social behaviors, multicellular development, and ecological dynamics in D. discoideum. More broadly, across taxa, imperfect coordination of collective behaviors might be adaptive by enabling diversification of life-history strategies.

During cortical development, human basal radial glial cells (bRGCs) are highly capable of sustained self-renewal and neurogenesis. Selective pressures on this cell type may have contributed to the evolution of the human neocortex, leading to an increase in cortical size. bRGCs have enriched expression for Forkhead Box P1 (FOXP1), a transcription factor implicated in neurodevelopmental disorders (NDDs) such as autism spectrum disorder. However, the cell type-specific roles of FOXP1 in bRGCs during cortical development remain unexplored. Here, we examine the requirement for FOXP1 gene expression regulation underlying the production of bRGCs using human brain organoids. We examine a developmental time point when FOXP1 expression is highest in the cortical progenitors, and the bRGCs, in particular, begin to actively produce neurons. With the loss of FOXP1, we show a reduction in the number of bRGCs, as well as reduced proliferation and differentiation of the remaining bRGCs, all of which lead to reduced numbers of excitatory cortical neurons over time. Using single-nuclei RNA sequencing and cell trajectory analysis, we uncover a role for FOXP1 in directing cortical progenitor proliferation and differentiation by regulating key signaling pathways related to neurogenesis and NDDs. Together, these results demonstrate that FOXP1 regulates human-specific features in early cortical development.

Neuron specification and maturation are essential for proper central nervous system development. However, the precise mechanisms that govern neuronal maturation, essential to shape and maintain neuronal circuitry, remain poorly understood. Here, we analyse early-born secondary neurons in the Drosophila larval brain, revealing that the early maturation of secondary neurons goes through 3 consecutive phases: (1) Immediately after birth, neurons express pan-neuronal markers but do not transcribe terminal differentiation genes; (2) Transcription of terminal differentiation genes, such as neurotransmitter-related genes VGlut, ChAT, or Gad1, starts shortly after neuron birth, but these transcripts are, however, not translated; (3) Translation of neurotransmitter-related genes only begins several hours later in mid-pupa stages in a coordinated manner with animal developmental stage, albeit in an ecdysone-independent manner. These results support a model where temporal regulation of transcription and translation of neurotransmitter-related genes is an important mechanism to coordinate neuron maturation with brain development.