Neuron最新文献

The activities of appetite-regulated neurons-ARC^AGRP neurons-are modulated by multi-level feedback signals during feeding. In this issue of Neuron, Aitken et al.¹ expand our understanding of the feedback control within feeding circuits, revealing that food taste signals can causally and precisely regulate meal patterns through ARC^AGRP neurons.

The rewarding taste of food is critical for motivating animals to eat, but whether taste has a parallel function in promoting meal termination is not well understood. Here, we show that hunger-promoting agouti-related peptide (AgRP) neurons are rapidly inhibited during each bout of ingestion by a signal linked to the taste of food. Blocking these transient dips in activity via closed-loop optogenetic stimulation increases food intake by selectively delaying the onset of satiety. We show that upstream leptin-receptor-expressing neurons in the dorsomedial hypothalamus (DMH^LepR) are tuned to respond to sweet or fatty tastes and exhibit time-locked activation during feeding that is the mirror image of downstream AgRP cells. These findings reveal an unexpected role for taste in the negative feedback control of ingestion. They also reveal a mechanism by which AgRP neurons, which are the primary cells that drive hunger, are able to influence the moment-by-moment dynamics of food consumption.

Autophagy is a conserved mechanism that degrades damaged or superfluous cellular contents and enables nutrient recycling under starvation conditions. Many neurodegeneration-associated proteins are autophagy substrates, and autophagy upregulation ameliorates disease in many animal models of neurodegeneration by enhancing the clearance of toxic proteins, proinflammatory molecules, and dysfunctional organelles. Autophagy inhibition also induces neuronal and glial senescence, a phenomenon that occurs with increasing age in non-diseased brains as well as in response to neurodegeneration-associated stresses. However, aging and many neurodegeneration-associated proteins and mutations impair autophagy. This creates a potentially detrimental feedback loop whereby the accumulation of these disease-associated proteins impairs their autophagic clearance, facilitating their further accumulation and aggregation. Thus, understanding how autophagy interacts with aging, senescence, and neurodegenerative diseases in a temporal, cellular, and genetic context is important for the future clinical application of autophagy-modulating therapies in aging and neurodegeneration.

Brain health is intimately connected to fluid flow dynamics that cleanse the brain of potentially harmful waste material. This system is regulated by vascular dynamics, the maintenance of perivascular spaces, neural activity during sleep, and lymphatic drainage in the meningeal layers. However, aging can impinge on each of these layers of regulation, leading to impaired brain cleansing and the emergence of various age-associated neurological disorders, including Alzheimer's and Parkinson's diseases. Understanding the intricacies of fluid flow regulation in the brain and how this becomes altered with age could reveal new targets and therapeutic strategies to tackle age-associated neurological decline.

Some individuals are susceptible to chronic stress, and others are more resilient. While many brain regions implicated in learning are dysregulated after stress, little is known about whether and how neural teaching signals during stress differ between susceptible and resilient individuals. Here, we seek to determine if activity in the lateral habenula (LHb), which encodes a negative teaching signal, differs between susceptible and resilient mice during stress to produce different outcomes. After (but not before) chronic social defeat stress, the LHb is active when susceptible mice are in proximity of the aggressor strain. During stress, activity is higher in susceptible mice during aggressor interactions, and activation biases mice toward susceptibility. This manipulation generates a persistent and widespread increase in the balance of subcortical vs. cortical activity in susceptible mice. Taken together, our results indicate that heightened activity in the LHb during stress produces lasting brainwide and behavioral substrates of susceptibility.

Successful integration into a hierarchical social group requires knowledge of the status of each individual and of the rules that govern social interactions within the group. In species that lack morphological indicators of status, social status can be inferred by observing the signals exchanged between individuals. We simulated social interactions between macaques by juxtaposing videos of aggressive and appeasing displays, where two individuals appeared in each other's line of sight and their displays were timed to suggest the reciprocation of dominant and subordinate signals. Viewers of these videos successfully inferred the social status of the interacting characters. Dominant individuals attracted more social attention from viewers even when they were not engaged in social displays. Neurons in the viewers' amygdala signaled the status of both the attended (fixated) and the unattended individuals, suggesting that in third-party observers of social interactions, the amygdala jointly signals the status of interacting parties.

Accumulating evidence has shown that various brain functions are associated with experience-activated neuronal ensembles. However, whether such neuronal ensembles are engaged in the pathogenesis of stress-induced depression remains elusive. Utilizing activity-dependent viral strategies in mice, we identified a small population of stress-responsive neurons, primarily located in the middle part of the lateral hypothalamus (mLH) and the medial part of the lateral habenula (LHbM). These neurons serve as "starter cells" to transmit stress-related information and mediate the development of depression-like behaviors during chronic stress. Starter cells in the mLH and LHbM form dominant connections, which are selectively potentiated by chronic stress. Silencing these connections during chronic stress prevents the development of depression-like behaviors, whereas activating these connections directly elicits depression-like behaviors without stress experience. Collectively, our findings dissect a core functional unit within the LH-LHb circuit that mediates the development of depression-like behaviors in mice.

Efficient musculoskeletal simulators and powerful learning algorithms provide computational tools to tackle the grand challenge of understanding biological motor control. Our winning solution for the inaugural NeurIPS MyoChallenge leverages an approach mirroring human skill learning. Using a novel curriculum learning approach, we trained a recurrent neural network to control a realistic model of the human hand with 39 muscles to rotate two Baoding balls in the palm of the hand. In agreement with data from human subjects, the policy uncovers a small number of kinematic synergies, even though it is not explicitly biased toward low-dimensional solutions. However, selectively inactivating parts of the control signal, we found that more dimensions contribute to the task performance than suggested by traditional synergy analysis. Overall, our work illustrates the emerging possibilities at the interface of musculoskeletal physics engines, reinforcement learning, and neuroscience to advance our understanding of biological motor control.

Latent-cause inference is the process of identifying features of the environment that have caused an outcome. This problem is especially important in social settings where individuals may not make equal contributions to the outcomes they achieve together. Here, we designed a novel task in which participants inferred which of two characters was more likely to have been responsible for outcomes achieved by working together. Using computational modeling, univariate and multivariate analysis of human fMRI, and continuous theta-burst stimulation, we identified two brain regions that solved the task. Notably, as each outcome occurred, it was possible to decode the inference of its cause (the responsible character) from hippocampal activity. Activity in dorsomedial prefrontal cortex (dmPFC) updated estimates of association between cause-responsible character-and the outcome. Disruption of dmPFC activity impaired participants' ability to update their estimate as a function of inferred responsibility but spared their ability to infer responsibility.