Biology subjects

Sabat, M.

Publications and source records attributed to Sabat, M..

4 recordsLinked to original sources

bioRxiv2025

Neurons in auditory cortex integrate information within constrained temporal windows that are invariant to the stimulus context and information rate

Much remains unknown about the computations that allow animals to flexibly integrate across multiple timescales in natural sounds. One key question is whether multiscale integration is accomplished by diverse populations of neurons, each of which integrates information within a constrained temporal window, or whether individual units effectively integrate across many different temporal scales depending on the information rate. Here, we show that responses from neurons throughout the ferret auditory cortex are nearly completely unaffected by sounds falling beyond a time-limited "integration window". This window varies substantially across cells within the auditory cortex ([~]15 to [~]150 ms), increasing substantially from primary to non-primary auditory cortex across all cortical layers, but is unaffected by the information rate of sound. These results indicate that multiscale computation is predominantly accomplished by diverse and hierarchically organized neural populations, each of which integrates information within a highly constrained temporal window.

neuroscience↗

bioRxiv2024

Different varieties of arousal converge on a shared cortical network

The term arousal is very often used, but classical textbooks from different domains of neuroscience and psychology offer surprisingly different views on what arousal is. The huge number of scientific articles with the term arousal ([~]50.000) highlights the importance of the concept but also explains why such a vast literature has never been systematically reviewed so far. Here, we leverage the tools of natural language processing to probe the nature of arousal in a data-driven, comprehensive manner. We show that arousal comes in seven varieties: cognitive, emotional, physiological, sexual, related to stress disorders, to sleep, or to sleep disorders. We then ask whether domain-general arousal exists, and run meta-analyses of the brain imaging literature to reveal that all varieties of arousal, except arousal in sleep disorders for lack of data, converge onto a cortical arousal network composed of the pre-supplementary motor area and the left and right dorsal anterior insula. More precisely, we find that activity in dysgranular insular area 7, the region with the highest convergence across varieties of arousal is also specific to arousal. Our results show that arousal corresponds to a construct at least partially shared across different domains of neuroscience and identify the domain-general cortical arousal network. Novel taxonomies of arousal reconciling seemingly opposing views on what arousal is should thus include domain-general arousal as a central component. Significance statementThe term arousal has been used in almost 50.000 scientific papers, but it is only loosely defined. The few attempts at defining arousal in neuroscience and psychology resulted in divergent views: arousal as a multi-dimensional construct or arousal as a global state. Is arousal an abstraction of the scientists mind reflecting a myriad of distinct processes, or is there some common neuronal feature? We used large-scale semi-automatic text mining methods and neuroimaging meta-analyses to review this vast and heterogeneous literature. Our results reveal the existence of domain-general arousal, a process shared by situations as different as a cognitive task, an emotional context, and the transition to wakefulness or sexual behavior. Domain-general arousal reconciles the concepts of general and multi-dimensional arousal.

neuroscience↗

bioRxiv2023

Tuft cell-derived acetylcholine regulates epithelial fluid secretion

Tuft cells are solitary chemosensory epithelial cells that can sense lumenal stimuli at mucosal barriers and secrete effector molecules to regulate the physiology and immune state of their surrounding tissue. In the small intestine, tuft cells detect parasitic worms (helminths) and microbe-derived succinate, and signal to immune cells to trigger a Type 2 immune response that leads to extensive epithelial remodeling spanning several days. Acetylcholine (ACh) from airway tuft cells has been shown to stimulate acute changes in breathing and mucocilliary clearance, but its function in the intestine is unknown. Here we show that tuft cell chemosensing in the intestine leads to release of ACh, but that this does not contribute to immune cell activation or associated tissue remodeling. Instead, tuft cell-derived ACh triggers immediate fluid secretion from neighboring epithelial cells into the intestinal lumen. This tuft cell-regulated fluid secretion is amplified during Type 2 inflammation, and helminth clearance is delayed in mice lacking tuft cell ACh. The coupling of the chemosensory function of tuft cells with fluid secretion creates an epithelium-intrinsic response unit that effects a physiological change within seconds of activation. This response mechanism is shared by tuft cells across tissues, and serves to regulate the epithelial secretion that is both a hallmark of Type 2 immunity and an essential component of homeostatic maintenance at mucosal barriers.

immunology↗

bioRxiv2021

Structures of TRPM5 channel elucidate mechanism of activation and inhibition

The Ca2+-activated TRPM5 channel plays an essential role in the perception of sweet, bitter, and umami stimuli in type II taste cells and in insulin secretion by pancreatic beta cells1-3. Interestingly, the voltage dependence of TRPM5 in taste bud cells depends on the intracellular Ca2+ concentration4, yet the mechanism remains elusive. Here we report cryo-electron microscopy structures of the zebrafish TRPM5 in an apo closed state, a Ca2+-bound open state, and an antagonist-bound inhibited state, at resolutions up to 2.3 [A]. We defined two novel ligand binding sites: a Ca2+ binding site (CaICD) in the intracellular domain (ICD), and an antagonist binding site in the transmembrane domain (TMD) for a drug (NDNA) that regulates insulin and GLP-1 release5. The CaICD site is unique to TRPM5 and has two roles: shifting the voltage dependence toward negative membrane potential, and promoting Ca2+ binding to the CaTMD site that is conserved throughout Ca2+-sensitive TRPM channels6. Replacing glutamate 337 in the CaICD site with an alanine not only abolished Ca2+ binding to CaICD but also reduced Ca2+ binding affinity to CaTMD, suggesting a cooperativity between the two sites. We have defined mechanisms underlying channel activation and inhibition. Conformational changes initialized from both Ca2+ sites, 70 [A] apart, are propagated to the ICD-TMD interface and cooperatively open the ion-conducting pore. The antagonist NDNA wedges into the space between the S1-S4 domain and pore domain, stabilizing the TMD in an apo-like closed state. Our results lay the foundation for understanding the voltage-dependent TRPM channels and developing new therapeutic agents to treat metabolic disorders.

biophysics↗