Biology subjects

Letai, K. C.

Publications and source records attributed to Letai, K. C..

4 recordsLinked to original sources

bioRxiv2025

Epithelial and stromal remodeling in murine Crohn's disease-like ileitis

Background and AimsInflammatory bowel disease is characterized by progressive epithelial, immune, and stromal dysfunction. Human datasets yield important insights yet are inherently descriptive, requiring animal models for in vivo mechanistic interrogation. The SAMP1/YitFc (SAMP) mouse model develops spontaneous Crohns disease (CD)-like ileitis while allowing controlled manipulation of pathophysiologic pathways. To understand cell-specific disease-associated transcriptional changes, we defined the single-nucleus transcriptomes of inflamed SAMP ilea using single-nucleus RNA-sequencing (snRNA-seq). MethodsWe performed whole-ileum snRNA-seq on SAMP (n=4) and control AKR/J (n=3) mice using the gut-optimized CitraPrep protocol, generating 58,349 high-quality nuclei across epithelial, immune, and stromal lineages. We corroborated SAMP-associated changes with immunofluorescent staining, Western blotting, spatial transcriptomic, and human single-cell RNA-sequencing data. ResultsWe observed a primary type 2 immune phenotype in SAMP compared to AKR mice, but most transcriptional changes occurred in stromal and epithelial, not immune, cells. Stromal remodeling included increased fibroblast-derived Igf1. In SAMP epithelium, expansion of tuft cells and emergence of SAMP-specific Pcsk6+ crypt enterocytes were observed and confirmed in human CD patients. Finally, we identified cross-compartmental changes in cell-cell signaling, including enterocyte-to-type 3 innate lymphoid cell (ILC3) communication and enhanced global Igf1 signaling. These features recapitulate known, as well as novel, characteristics of CD and extend our understanding of disease-associated multicellular networks. ConclusionThis atlas of ileitis-prone SAMP mice provides a high-resolution resource for dissecting conserved and novel mechanisms of inflammation and tissue remodeling. Herein, we uncover disease-associated transcriptional changes conserved in human CD, presenting a translational platform for future mechanistic and therapeutic studies.

molecular biology↗

bioRxiv2023

Enteric glial hub cells coordinate intestinal motility

The enteric nervous system is a complex network of neurons and glia within the gut that coordinate gut motility. By optimizing single nucleus RNA-sequencing methods and spatial transcriptomics, we generated maps of the mouse duodenum and identified distinct molecular classes of enteric glia across the intestine with unique morphological and spatial identities. Here we show enteric glial functional specialization, with one myenteric subtype directly sensing force and expressing the mechanosensory ion channel PIEZO2. Genetic reduction of PIEZO2 in enteric glial populations enriched for this mechanosensory subtype led to defects in gastrointestinal motility. These results provide insight into the multifaceted functions of distinct enteric glial cell subtypes in maintaining gut health, and emphasize the importance of considering subtype-specific roles of enteric glia in a wide range of diseases and disorders.

neuroscience↗

bioRxiv2020

Learning to Control the Brain through Adaptive Closed-Loop Patterned Stimulation

Stimulation of neural activity is an important scientific and clinical tool, causally testing hypotheses and treating neurodegenerative and neuropsychiatric diseases. However, current stimulation approaches cannot flexibly control the pattern of activity in populations of neurons. To address this, we developed an adaptive, closed-loop stimulation (ACLS) system that uses patterned, multi-site electrical stimulation to control the pattern of activity in a population of neurons. Importantly, ACLS is a learning system; it monitors the response to stimulation and iteratively updates the stimulation pattern to produce a specific neural response. In silico and in vivo experiments showed ACLS quickly learns to produce specific patterns of neural activity ([~]15 minutes) and was robust to noise and drift in neural responses. In visual cortex of awake mice, ACLS learned electrical stimulation patterns that produced responses similar to the natural response evoked by visual stimuli. Similar to how repetition of a visual stimulus causes an adaptation in the neural response, the response to electrical stimulation was adapted when it was preceded by the associated visual stimulus. Altogether, our results show ACLS can learn, in real-time, to generate specific patterns of neural activity, providing a framework for using closed-loop learning to control neural activity.

neuroscience↗

bioRxiv2019

Firing rate homeostasis occurs in the absence of neuronal activity-regulated transcription

Despite dynamic inputs, neuronal circuits maintain relatively stable firing rates over long periods. This maintenance of firing rate, or firing rate homeostasis, is likely mediated by homeostatic mechanisms such as synaptic scaling and regulation of intrinsic excitability. Because some of these homeostatic mechanisms depend on transcription of activity-regulated genes, including Arc and Homer1a, we hypothesized that activity-regulated transcription would be required for firing rate homeostasis. Surprisingly, however, we found that cultured mouse cortical neurons grown on multi-electrode arrays homeostatically adapt their firing rates to persistent pharmacological stimulation even when activity-regulated transcription is disrupted. Specifically, we observed firing rate homeostasis Arc knock-out neurons, as well as knock-out neurons lacking activity-regulated transcription factors, AP1 and SRF. Firing rate homeostasis also occurred normally during acute pharmacological blockade of transcription. Thus, firing rate homeostasis in response to increased neuronal activity can occur in the absence of neuronal-activity-regulated transcription.\n\nSIGNIFICANCE STATEMENTNeuronal circuits maintain relatively stable firing rates even in the face of dynamic circuit inputs. Understanding the molecular mechanisms that enable this firing rate homeostasis could potentially provide insight into neuronal diseases that present with an imbalance of excitation and inhibition. However, the molecular mechanisms underlying firing rate homeostasis are largely unknown.\n\nIt has long been hypothesized that firing rate homeostasis relies upon neuronal activity-regulated transcription. For example, a 2012 review (PMID 22685679) proposed it, and a 2014 modeling approach established that transcription could theoretically both measure and control firing rate (PMID 24853940). Surprisingly, despite this prediction, we found that cortical neurons undergo firing rate homeostasis in the absence of activity-regulated transcription, indicating that firing rate homeostasis is controlled by non-transcriptional mechanisms.

neuroscience↗