Activity of brain stem glucagon neurons are modulated by energy state and encode sex and frequency-dependent negative valence and anxiety.

Lopez, C. B.; Duran, M.; Virkus, S. A.; Yadav, E.; McMichen, K.; Singh, J.; Ramsey, V.; Stocking, S.; Habegger, K. M.; Hardaway, J. A.

doi:10.1101/2023.05.11.540425

bioRxiv · 10.1101/2023.05.11.540425

Activity of brain stem glucagon neurons are modulated by energy state and encode sex and frequency-dependent negative valence and anxiety.

Lopez, C. B.·Duran, M.·Virkus, S. A.·Yadav, E.·McMichen, K.·Singh, J.·Ramsey, V.·Stocking, S.·Habegger, K. M.·Hardaway, J. A.

View original source ↗Export metadata ↓

Abstract

The glucagon-like peptide 1 (GLP-1) system has emerged as an important drug target for the treatment of obesity and diabetes. Preclinical and clinical studies demonstrate that the activation of GLP-1 receptors (GLP-1Rs) directly in the brain through overexpression of GLP-1 or GLP-1R agonists produces potent anorexigenic effects, yet the behavioral role and modulation of the endogenous GLP-1 producing system in the brain by energy status is unclear. In this study, we examined the anatomical, physiological, and behavioral properties of preproglucagon-expressing neurons in the nucleus of the solitary tract, GcgNTS neurons, which serve as the primary source of GLP-1 in the brain. Using transgenic laboratory mice, we observed no sex differences in the density and distribution of GcgNTS neurons in male and female mice. Fos immunolabeling experiments show that GcgNTS neurons are not significantly activated after intermittent access to palatable food, but the magnitude of Fos activation was linearly related to the amount of food intake in mice provided with ad libitum intermittent access to palatable food. Electrophysiological examination of GcgNTS neurons revealed that these neurons show energy-status and sex-dependent changes in neuronal firing and intrinsic excitability. Twenty-four hour food deprivation produced a significant reduction in excitability and firing in male, but not female mice. We then used optogenetics to investigate the causal behavioral role of GcgNTS neurons. High frequency optogenetic activation of GcgNTS neurons using the red light-gated opsin ChrimsonR produced female-specific anxiety-like behavior and real-time place aversion. For feeding, we observed that reversible optogenetic stimulation at high frequencies produced a significant reduction in homeostatic refeeding that did not differ by sex. Using operant conditioning, we found that reversible optogenetic activation of GcgNTS neurons at 20 Hz, but not 5, also reduces appetitive behavior. These data demonstrate that GcgNTS neurons exert control over motivation and food-seeking behavior in addition to consumption.

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Lopez, C. B., Duran, M., Virkus, S. A., Yadav, E., McMichen, K., Singh, J., Ramsey, V., Stocking, S., Habegger, K. M., Hardaway, J. A.. 2023-05-12. Activity of brain stem glucagon neurons are modulated by energy state and encode sex and frequency-dependent negative valence and anxiety.. https://doi.org/10.1101/2023.05.11.540425

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

The Unreasonable Effectiveness of Cell Types in Describing Neuronal Physiological Features

Single-cell RNA sequencing (scRNA-seq) captures detailed gene expression profiles at scale, while patch-clamp recordings measure intrinsic neuronal electrophysiological properties. Modeling the relations between these two modalities remains a challenge. Here, we compare how well electrophysiological features can be predicted by traditional transcriptomic cell type classification, representations derived from a foundational model (scGPT) pretrained on large-scale scRNA-seq datasets, ion channel-coding genes, and highly variable genes. Using paired transcriptomic and electrophysiological patch-sequencing data from 495 human neurons from neurosurgical tissue, we find that cluster-level cell type representations consistently outperform highly variable gene selection, ion channel gene selection, and context-enriched scGPT embeddings. Notably, performance varies across model architectures and initializations, and the best results are obtained by combining the outputs of separate cell type and scGPT-based models. Together, these findings suggest that traditional discrete cellular classification is highly effective in predicting physiological features. For maximum performance it can be complemented by pretrained transformer models.

neuroscience↗

bioRxiv2026

A nonlinear inhibition pathway underlying cortical responses to tuned holographic optogenetic perturbations

Optogenetics enables causal manipulation of cortical activity. Perturbation responses can be counterintuitive due to network interactions, making theory essential for predicting them. Existing approaches often rely on linear approximations, which fail for many biologically relevant perturbations. Here we develop a nonlinear theory of responses to holographic perturbations in cell-type-specific recurrent networks with structured connectivity. We fit a nonlinear model to mouse V1 data, which shows cotuned-ensemble suppression: perturbing spatially clustered neurons with similar preferred orientations yields markedly stronger short-range suppression than perturbing untuned ensembles. We show that cotuned-ensemble suppression arises from a feature-tuned, nonlinear inhibition pathway implicating somatostatin-positive (SST) interneurons. The theory predicts that cotuned ensembles suppress parvalbumin-positive (PV) neurons but facilitate SST neurons, and links the degree of cotuned-ensemble suppression or facilitation to the variance of the SST response. This framework identifies mechanisms by which nonlinear inhibition sculpts cortical dynamics and establishes a predictive basis for targeted optogenetic interventions.

neuroscience↗

bioRxiv2026

Proteomic signatures of APOE ε4 across human tissues and cell types in Alzheimers disease

The apolipoprotein E {varepsilon}4 (APOE {varepsilon}4) allele is the strongest genetic risk factor for late-onset Alzheimers disease (AD). However, the underlying molecular mechanisms remain unclear. This study included 1691 participants from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), 1226 participants from the Accelerating Medicines Partnership - Alzheimers Disease (AMP-AD) Diverse Cohorts Study, and 735 participants from the Alzheimers Disease Neuroimaging Initiative (ADNI). To characterise APOE {varepsilon}4 molecular effects, we analysed proteomic data from plasma, cerebrospinal fluid (CSF), and induced pluripotent stem cell (iPSC)-derived astrocytes and neurons, as well as transcriptomic and proteomic data from multiple brain regions. The association of APOE {varepsilon}4 with AD neuropathology was also examined. APOE {varepsilon}4 carriers shared a plasma proteomic signature enriched for immune processes, irrespective of AD diagnosis. A machine learning classifier trained on this signature discriminated APOE {varepsilon}4 carriers from non-carriers in an independent cohort using CSF proteomics. APOE {varepsilon}4 carriage was associated with higher Braak stages and Consortium to Establish a Registry for Alzheimers Disease (CERAD) score. However, only limited APOE {varepsilon}4-associated transcriptomic and proteomic changes were observed in bulk brain tissue, with poor cross-layer concordance. Proteomic analyses of iPSC-derived astrocytes and neurons further revealed cell-type-specific APOE {varepsilon}4-associated changes. APOE {varepsilon}4 is associated with a consistent proteomic signature across plasma and CSF. Its molecular effects in the brain differ across cell types, brain regions and molecular layers. These findings support the need for cell-type-resolved multi-omic studies to elucidate how APOE {varepsilon}4 confers AD risk.

neuroscience↗