Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABA-ergic Parvalbuminpositive Interneurons Attenuates Chronic Stress Adaptions in Male Mice

Nawreen, N.; Morano, R.; Mahbod, P.; Cotella, E.; Dalal, K.; Fitzgerald, M.; Martelle, S.; Packard, B.; Moloney, R. D.; Herman, J.

doi:10.1101/792721

bioRxiv · 10.1101/792721

Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABA-ergic Parvalbuminpositive Interneurons Attenuates Chronic Stress Adaptions in Male Mice

Nawreen, N.·Morano, R.·Mahbod, P.·Cotella, E.·Dalal, K.·Fitzgerald, M.·Martelle, S.·Packard, B.·Moloney, R. D.·Herman, J.

View original source ↗Export metadata ↓

Abstract

Hypofunction of the prefrontal cortex (PFC) contributes to stress-related neuropsychiatric illnesses. Mechanisms leading to prefrontal hypoactivity remain to be determined. Prior evidence suggests that enhanced activity of parvalbumin (PV) expressing GABAergic interneurons (INs) play a role in chronic stress related pathologies. In this study, the role of PFC PV INs in stress related phenotypes were explored using Cre inducible inhibitory DREADDs (Designer Receptors Exclusively Activated by Designer Drugs). Mice were first tested in the tail suspension test (TST) to determine the effects of PV IN inhibition during acute stress. Following this, the long term impact of PV IN inhibition during chronic variable stress (CVS) was tested in the forced swim test (FST). Acute PV IN inhibition reduced active (struggling) and increased passive coping behaviors (immobility) in the TST. In contrast, inhibition of PV INs during CVS increased active and reduced passive coping behaviors in the FST. Moreover, chronic inhibition of PV INs attenuated CVS-induced changes in Fos expression in the prelimbic cortex, basolateral amygdala and ventrolateral periaqueductal gray and also prevented adrenal hypertrophy and body weight loss associated with chronic stress. Our results suggest differential roles of PV INs to acute vs chronic stress, indicative of distinct biological mechanisms underlying acute vs. chronic stress responses. Our results also indicate a role for PV INs in driving chronic stress adaptation and support literature evidence suggesting cortical GABAergic interneurons as a therapeutic target in stress related diseases.\n\nSIGNIFICANCEStress related diseases are associated with prefrontal hypoactivity, the mechanism of which is currently not known. In this study we showed that by inhibiting prefrontal GABA-ergic Parvalbumin interneurons (PV INs) using DREADDs, we can attenuate some of chronic stress related phenotypes. Additionally, we showed that modulation of PV IN activity during acute vs chronic stress had opposing effects on stress coping strategies, suggesting different underlying mechanisms behind acute vs chronic stress paradigms. Our findings indicate that GABA-ergic PV INs may be involved in driving stress related phenotypes and thereby an important target for treatment of stress-related illnesses. Our data suggest that reducing PV IN activity to promote prefrontal output may be an effective treatment strategy for stress related disorders.

Source connections

Published article ↗

Explore related subjects

neuroscience Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Nawreen, N., Morano, R., Mahbod, P., Cotella, E., Dalal, K., Fitzgerald, M., Martelle, S., Packard, B., Moloney, R. D., Herman, J.. 2019-10-03. Chemogenetic Inhibition of Infralimbic Prefrontal Cortex GABA-ergic Parvalbuminpositive Interneurons Attenuates Chronic Stress Adaptions in Male Mice. https://doi.org/10.1101/792721

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↗