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An anatomical substrate of credit assignment in reinforcement learning
No full textLearning turns experience into better decisions. A key problem in learning is credit assignment—knowing how to change parameters, such as synaptic weights deep within a neural network, in order to improve behavioral performance. Artificial intelligence owes its recent bloom largely to the error-backpropagation algorithm1, which estimates the contribution of every synapse to output errors and allows rapid weight adjustment. Biological systems, however, lack an obvious mechanism to backpropagate errors. Here we show, by combining high-throughput volume electron microscopy2 and automated connectomic analysis3–5, that the synaptic architecture of songbird basal ganglia supports local credit assignment using a variant of the node perturbation algorithm proposed in a model of songbird reinforcement learning6, 7. We find that key predictions of the model hold true: first, cortical axons that encode exploratory motor variability terminate predominantly on dendritic shafts of striatal spiny neurons, while cortical axons that encode song timing terminate almost exclusively on spines. Second, synapse pairs that share a presynaptic cortical timing axon and a postsynaptic spiny dendrite are substantially more similar in size than expected, indicating Hebbian plasticity8, 9. Combined with numerical simulations, these findings provide strong evidence for a biologically plausible credit assignment mechanism6
FACT depletion demonstrates a role for nucleosome organization in TAD formation
No full textMammalian genomes are organized into distinct chromatin structures, which include small-scale nucleosome arrays and large-scale topologically associating domains (TADs). The mechanistic interplay between chromatin structures across scales is poorly understood. Here, we investigate how changes in nucleosome organization impact TAD structure by studying the role of the histone chaperone facilitates chromatin transcription (FACT) in 3D genome organization. We show that FACT depletion perturbs TADs, causing decreased insulation and weaker CTCF loops. These changes in TAD structure cannot be attributed to changes in chromatin occupancy of CTCF or cohesin and occur specifically in transcribed regions of the genome, where we observe perturbed nucleosome organization in the absence of FACT. FACT depletion therefore allows us to separate the role of nucleosome organization and CTCF binding and to demonstrate that the organization of nucleosomes at TAD boundaries contributes to TAD formation
Large Data Set Analysis Reveals Structural Origin of Peptide Collisional Cross Section Bimodal Behavior
No full textRecent advances in ion mobility spectrometry have enabled the measurement of rotationally averaged collisional cross-sectional area (CCS) for millions of peptides as part of routine proteomic mass spectrometry workflows. One of the most striking findings in recent large ion mobility data sets is that CCS exhibits two distinct modes, most notably for charge 3+ peptides, with peptides predominantly exhibiting CCS in either the high or low mode. Here, using classical machine learning approaches, we identify that basic site positioning is a key sequence feature determining a peptide’s CCS mode. Molecular dynamics simulations suggest that peptides in the high CCS mode tend to adopt more extended conformations and form charge-stabilized helical structures, whereas those in the low CCS mode adopt more compact, globular conformations. Further supporting this structural hypothesis, we provide evidence for preferential protonation near the C-terminus and uncover multiple position-dependent sequence determinants that all suggest the predominance of helix formation in the high CCS mode. Together, these findings will enable better integration of CCS measurements into protein identification and quantification pipelines, improving the performance of ion mobility-based proteomics
One pocket to activate them all (?): Efforts on understanding the modulator pocket in K2P channels
No full textThe modulator pocket is a cryptic site discovered in the TREK1 (K2P2.1) K2P channel. This pocket, located close to the selectivity filter, accommodates agonists that enhance the channel’s activity. Since its discovery, equivalent sites in other K2P channels have been shown to bind various ligands, both endogenous and exogenous. In this review, we attempt to elucidate how the modulator pocket contributes to K2P channel activation. To this end, we first describe the gating mechanisms reported in the literature and rationalize their modes of action. We then highlight previous experimental and computational evidence for agonists that bind to the modulator pocket, together with mutations at this site that affect gating. Finally, we elaborate how the activation signal arising from the modulator pocket is transduced to the gates in K2P channels. In doing so, we outline a potential common modulator pocket architecture across K2P channels: a largely amphipathic structure – consistent with the expected properties of a pocket exposed at the interface between a hydrophobic membrane and the aqueous solvent – but still with some important channel-sequence-variations. This architecture and its key differences can be leveraged for the design of new selective and potent modulators
Monovalent pseudo-natural products supercharge degradation of IDO1 by its native E3 KLHDC3
No full textAffine Hecke and Schur algebras of type A without a square root of q
No full textWe provide an affine cellular structure on the extended affine Hecke algebra and affine -Schur algebra of type that is defined over , that is, without an adjoined . This is with an eye to applications in the representation theory of for a -adic field over coefficient rings in which is invertible but does not have a square root, which have been a topic of recent interest. This is achieved via a renormalisation of the known affine cellular structure over at each left and right cell, which is chosen to ensure that the diagonal intersections remain subalgebras and that the left and right cells remain isomorphic. We furthermore show that the affine cellular structure on the Schur algebra has idempotence properties which imply finite global dimension, an important ingredient for the applications to representations of -adic groups
DNA methylation patterns and epigenetic aging associated with suicide attempts in bipolar disorder
No full textBackground: Suicidal thoughts and behaviors (STBs) are a public health issue highly prevalent in bipolar disorder (BD). Multiple factors contribute to STBs, and new evidence highlights the significant role of epigenetics, specifically DNA methylation (DNAm). Additionally, recent studies found accelerated epigenetic aging (EA) in both BD and STBs. This study aimed to detect epigenetic risk factors for STBs, particularly for suicide attempts (SAs), comparing DNAm patterns and EA between BD patients with (BD/SA) and without (BD/non-SA) a history of SAs. Moreover, EA was calculated to explore age acceleration (AgeAccel) in the BD/SA group. Methods: Genome-wide DNAm patterns of blood samples from 46 BD/SA and 32 BD/non-SA were assessed using Infinium HumanMethylationEPIC v1.0 BeadChip (Illumina). Differentially methylated positions (DMPs) and regions (DMRs) were compared between groups. Gene network analysis was performed using genes mapped to DMPs and DMRs. Lastly, EA from different epigenetic clocks was estimated and compared between groups. Results: We identified 18 DMPs and 2 DMRs (adjusted p-value 0.05) were found in BD/ SA. Limitations: Relatively small sample size, cross-sectional design, and use of peripheral blood.Conclusions: Our findings highlight the importance of considering epigenetic markers when studying SAs in mental disorders. These results may contribute to a better understanding of the biological basis of SAs in BD, which could ultimately help identify at-risk individuals for SAs
Long-term deep phenotyping of behavioral traits in mice using homecage monitoring
No full textNeuropsychiatric disorders represent a significant global health challenge, and a deeper understanding of their underlying neurobiology is urgently needed. Rodent models are indispensable in this pursuit, yet traditional behavioral phenotyping often relies on short-duration tests in artificial settings, raising concerns about ecological validity, stress confounds, and limited translational relevance. This paper begins by reviewing these limitations and highlighting the growing shift towards long-term, continuous monitoring of animals within their seminaturalistic environment. Building on this context and the critical need for robust methodologies, this paper outlines a comprehensive workflow for studying behavior of rodent cohorts in their home cages using AIsupported video tracking. Key steps include the design of experimental setups, video preprocessing, animal tracking, pose estimation, supervised or unsupervised interpretation of behavior, statistical analysis and visualization. The protocol encompasses an affordable and versatile pipeline for data acquisition and statistical interpretation. Ultimately, this work aims to provide researchers with both a critical overview of the field and a practical guide to implementing these powerful techniques, thereby fostering the generation of reproducible, high-quality data to enhance the depth and translational potential of neuroscience and behavioral research
