Neuron最新文献

Neuronal activity plays a critical role in the maturation of circuits that propagate sensory information into the brain. How widely does early activity regulate circuit maturation across the developing brain? Here, we used targeted recombination in active populations (TRAP) to perform a brain-wide survey for prenatally active neurons in mice and identified the piriform cortex as an abundantly TRAPed region. Whole-cell recordings in neonatal slices revealed preferential interconnectivity within embryonically TRAPed piriform neurons and their enhanced synaptic connectivity with other piriform neurons. In vivo Neuropixels recordings in neonates demonstrated that embryonically TRAPed piriform neurons exhibit broad functional connectivity within piriform and lead spontaneous synchronized population activity during a transient neonatal period, when recurrent connectivity is strengthening. Selectively activating or silencing these neurons in neonates enhanced or suppressed recurrent synaptic strength, respectively. Thus, embryonically TRAPed piriform neurons represent an interconnected hub-like population whose activity promotes recurrent connectivity in early development.

Mentoring the next generation of neuroscientists from historically excluded backgrounds brings several challenges. Successful mentor-mentee relationships are critical for addressing these challenges. Rodriguez-Romaguera and Quirk reflect on lessons learned from their cross-racial mentor-mentee relationship that could apply to many mentors.

Regulated neural-metabolic-inflammatory responses are essential for maintaining physiological homeostasis. However, the molecular machinery that coordinates neural, metabolic, and inflammatory responses is largely unknown. Here, we show that semaphorin 6D (SEMA6D) coordinates anxiogenic, metabolic, and inflammatory outputs from the amygdala by maintaining synaptic homeostasis. Using genome-wide approaches, we identify SEMA6D as a pleiotropic gene for both psychiatric and metabolic traits in human. Sema6d deficiency increases anxiety in mice. When fed a high-fat diet, Sema6d^-/- mice display attenuated obesity and enhanced myelopoiesis compared with control mice due to higher sympathetic activity via the β3-adrenergic receptor. Genetic manipulation and spatial and single-nucleus transcriptomics reveal that SEMA6D in amygdalar interneurons is responsible for regulating anxiogenic and autonomic responses. Mechanistically, SEMA6D is required for synaptic maturation and γ-aminobutyric acid transmission. These results demonstrate that SEMA6D is important for the normal functioning of the neural circuits in the amygdala, coupling emotional, metabolic, and inflammatory responses.

Microglia, the resident immune cells of the central nervous system, are intimately involved in the brain's most basic processes, from pruning neural synapses during development to preventing excessive neuronal activity throughout life. Studies have reported both helpful and harmful roles for microglia at the blood-brain barrier (BBB) in the context of disease. However, less is known about microglia-endothelial cell interactions in the healthy brain. To investigate the role of microglia at a healthy BBB, we used the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 to deplete microglia and analyzed the BBB ultrastructure, permeability, and transcriptome. Interestingly, we found that, despite their direct contact with endothelial cells, microglia are not necessary for the maintenance of BBB structure, function, or gene expression in the healthy brain. However, we found that PLX5622 treatment alters brain endothelial cholesterol metabolism. This effect was independent from microglial depletion, suggesting that PLX5622 has off-target effects on brain vasculature.

Transmembrane channel-like (TMC) proteins are expressed throughout the animal kingdom and are thought to encode components of ion channels. Mammals express eight TMCs (mTMC1-8), two of which (mTMC1 and mTMC2) are subunits of mechanotransduction channels. C. elegans expresses two TMCs (TMC-1 and TMC-2), which mediate mechanosensation, egg laying, and alkaline sensing. The mechanisms by which nematode TMCs contribute to such diverse physiological processes and their functional relationship to mammalian mTMCs is unclear. Here, we show that association with accessory proteins tunes nematode TMC-1 to divergent sensory functions. In addition, distinct TMC-1 domains enable touch and alkaline sensing. Strikingly, these domains are segregated in mammals between mTMC1 and mTMC3. Consistent with these findings, mammalian mTMC1 can mediate mechanosensation in nematodes, while mTMC3 can mediate alkaline sensation. We conclude that sequence diversification and association with accessory proteins has led to the emergence of TMC protein complexes with diverse properties and physiological functions.

By establishing semaphorin 6D expression in the amygdala as a central coordinator of brain, metabolic, and immunologic function, the Neuron publication by Nakanishi et al.¹ provides new insight to how primary brain deficiency impacts physiological systems beyond the brain.

In this issue of Neuron, Torres-Berrío et al.¹ show that stress-susceptible mice exhibit elevated H3K27me1 levels in nucleus accumbens neurons due to the action of the SUZ12 VEFS domain, strengthening the link between specific epigenetic changes and long-lasting stress-induced social, emotional, and cognitive alterations.

Cortical organization should constrain the study of how the brain performs behavior and cognition. A fundamental concept in cortical organization is that of arealization: that the cortex is parceled into discrete areas. In part one of this report, we review how non-human animal studies have illuminated principles of cortical arealization by revealing: (1) what defines a cortical area, (2) how cortical areas are formed, (3) how cortical areas interact with one another, and (4) what "computations" or "functions" areas perform. In part two, we discuss how these principles apply to neuroimaging research. In doing so, we highlight several examples where the commonly accepted interpretation of neuroimaging observations requires assumptions that violate the principles of arealization, including nonstationary areas that move on short time scales, large-scale gradients as organizing features, and cortical areas with singular functionality that perfectly map psychological constructs. Our belief is that principles of neurobiology should strongly guide the nature of computational explanations.

Logistic classification is a simple way to make choices based on a set of factors: give each factor a weight, sum the results, and use the sum to set the log odds of a random draw. This operation is known to describe human and animal choices based on value (economic decisions). There is increasing evidence that it also describes choices based on sensory inputs (perceptual decisions), presented across sensory modalities (multisensory integration) and combined with non-sensory factors such as prior probability, expected value, overall motivation, and recent actions. Logistic classification can also capture the effects of brain manipulations such as local inactivations. The brain may implement it by thresholding stochastic inputs (as in signal detection theory) acquired over time (as in the drift diffusion model). It is the optimal strategy under certain conditions, and the brain appears to use it as a heuristic in a wider set of conditions.

Histone post-translational modifications are critical for mediating persistent alterations in gene expression. By combining unbiased proteomics profiling and genome-wide approaches, we uncovered a role for mono-methylation of lysine 27 at histone H3 (H3K27me1) in the enduring effects of stress. Specifically, mice susceptible to early life stress (ELS) or chronic social defeat stress (CSDS) displayed increased H3K27me1 enrichment in the nucleus accumbens (NAc), a key brain-reward region. Stress-induced H3K27me1 accumulation occurred at genes that control neuronal excitability and was mediated by the VEFS domain of SUZ12, a core subunit of the polycomb repressive complex-2, which controls H3K27 methylation patterns. Viral VEFS expression changed the transcriptional profile of the NAc, led to social, emotional, and cognitive abnormalities, and altered excitability and synaptic transmission of NAc D1-medium spiny neurons. Together, we describe a novel function of H3K27me1 in the brain and demonstrate its role as a "chromatin scar" that mediates lifelong stress susceptibility.