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Biology subjects

May, H.

Publications and source records attributed to May, H..

4 recordsLinked to original sources

Dopaminergic reward signals shape foraging decisions through learned value expectations

A fundamental function of the nervous system is to direct animals towards life-sustaining resources and enable adaptive strategies for acquiring them. Foraging, the challenge of securing these resources from the environment, requires making decisions that balance local gains against costs, opening a window on value-based decision making in ecological context. Yet despite the centrality of foraging in life, the algorithms and neural mechanisms underlying foraging decisions are not well understood. We studied mice making stay-or-leave patch foraging decisions for water across poor- and rich-resource environments with dynamic local reward outcomes. We found that mice integrate immediate rewards, local reward history, and reward (i.e. value) expectations to guide foraging decisions, favoring greater time investment in rich-environment patches. Computational models revealed influence of a time-varying bias which mirrored the shape of a learned value function. Consistent with a reinforcement learning mechanism, dopamine in the ventral striatum signaled a temporal-difference reward prediction error, which could be used as a teaching signal to construct value functions, and calibrated optogenetic manipulation of dopamine to create fictive reward signals recapitulated the value-related decision bias. Taken together, our results shed new light on the neurocomputational basis of foraging, revealing a novel role for value expectations in dynamic environments. Further, they establish generalized function of biological reinforcement learning in ecological context, demonstrating a specific role for the canonical dopamine reward circuit in shaping temporally resolved value expectations to guide behavior and cognition. The unification of this framework with foraging opens a new avenue to elucidate principles of how animals learn and dynamically adjust cognitive strategies for real-world ecological problems.

neuroscience↗

CRISPR gene and transcriptome engineering (CRISPRgate) improves loss-of-function genetic screening approaches

The CRISPR/Cas9 technology has revolutionized genotype-to-phenotype assignments through large-scale loss-of-function (LOF) screens. However, limitations like editing inefficiencies and unperturbed genes cause significant noise in data collection. To address this, we introduce CRISPR Gene and Transcriptome Engineering (CRISPRgate), which uses two specific sgRNAs to simultaneously repress and cleave the target gene within the same cell, increasing LOF efficiencies and reproducibility. CRISPRgate outperforms conventional CRISPRko, CRISPRi, or CRISPRoff systems in suppressing challenging targets and regulators of cell proliferation. Additionally, it efficiently suppresses modulators of EMT and impairs neuronal differentiation in a human iPSC model. In a multiplexed chromatin-focused phenotypic LOF screen, CRISPRgate exhibits improved depletion efficiency, reduced sgRNA performance variance, and accelerated gene depletion compared to individual CRISPRi or CRISPRko, ensuring consistency in phenotypic effects and identifying more significant gene hits. By combining CRISPRko and CRISPRi, CRISPRgate increases LOF rates without increasing genotoxic stress, facilitating library size reduction for advanced LOF screens. MotivationThe CRISPR technology (CRISPRko/CRISPRi) enables the specific depletion of target genes with fewer off-target effects, facilitating precise investigations of gene function. Despite its benefits, CRISPR applications have limitations. Residual active protein expression mediated by in-frame DNA repair or alternative splicing1-8 as well as strong epigenetic regulation and difficulties in sgRNA design to the transcription start site (TSS)9-12 hinder the full potential of loss-of-function studies using CRISPRko or CRISPRi. We aimed to achieve robust target gene reduction in order to improve the reproducibility of the CRISPR technology by integrating the widely used CRISPRko and CRISPRi approaches into a single application.

biochemistry↗

The hidden secrets of the dental calculus: Calibration of a mass spectrometry protocol for dental calculus protein analysis

Dental calculus is a solid deposit that forms and accumulates on the tooth surface, entrapping oral microorganisms, biomolecules, and other micro-debris found in the oral cavity. Mass spectrometry analysis of its protein content opens a vista into the subjects diet, oral flora, and even some aspects of health, thus providing new insight and expanding our knowledge of archaic cultures. Multiple experimental protocols have been proposed for the optimal extraction of proteins from dental calculus. Herein, we compared various experimental conditions in order to calibrate and validate a protocol for protein extraction. Our results show that a high concentration of acetic acid followed by mechanical crushing and sonication provided the highest protein yield, while acetone precipitation enabled the identification of more distinct proteins. We validated this protocol using archeological samples, identifying human and microbial proteins in specimens from the 8th and 17th centuries (approximately 250-1300 years ago). These findings demonstrate that the developed protocol is useful for studying excavated archaeological samples and that it might be utilized to explore the biohistory, dietary habits, and microbiome of archaic populations.

molecular biology↗

Late Pleistocene human genome suggests a local origin for the first farmers of central Anatolia

Anatolia was home to some of the earliest farming communities. It has been long debated whether a migration of farming groups introduced agriculture to central Anatolia. Here, we report the first genome-wide data from a 15,000-year-old Anatolian hunter-gatherer and from seven Anatolian and Levantine early farmers. We find high genetic continuity ([~]80-90%) between the hunter-gatherer and early farmers of Anatolia and detect two distinct incoming ancestries: an early Iranian/Caucasus related one and a later one linked to the ancient Levant. Finally, we observe a genetic link between southern Europe and the Near East predating 15,000 years ago that extends to central Europe during the post-last-glacial maximum period. Our results suggest a limited role of human migration in the emergence of agriculture in central Anatolia.

genetics↗