Biology subjects

Prevot, T. D.

Publications and source records attributed to Prevot, T. D..

At least 19 recordsLinked to original sources

bioRxiv2026

The Aging Brain Matrix: Cross-Species Evidence Linking FREM3 to Brain and Cognitive Aging

The human extracellular-matrix-related FREM3 gene is strongly age-dependent, enriched in age-sensitive excitatory long-range-projecting neurons, and implicated in neurodegenerative diseases. To establish the first translationally relevant causal evidence for the role of FREM3 in brain structure and cognition, we developed an excitatory-neuron-specific Frem3 conditional knockout mouse model (Frem3-cKO) and computed genetically regulated expression of FREM3 (FREM3-GReX) in humans, enabling convergent neurostructural and cognitive characterizations. Frem3-cKO mice showed widespread lower global and regional brain volume in middle age vs young adulthood, consistent with drastic age-dependent volume loss absent in wildtype mice. These effects were strongest in cognitively relevant cortical regions and paralleled by lower cognitive performance. In humans, lower FREM3-GReX was associated with lower total surface area, which further mediated an indirect link to lower cognitive performance across multiple age-sensitive domains. We provide the first translationally relevant cross-species evidence supporting a key role for FREM3/Frem3 in maintaining brain and cognitive health across aging.

neuroscience↗

bioRxiv2026

Dual Roles of Interferon-γ Receptor in Somatostatin Interneurons at Baseline and During Inflammation

Background: Neuropsychiatric disorders such as major depressive disorder show converging evidence of gamma-aminobutyric acid (GABA) dysfunction, including consistent reductions in somatostatin (SST) interneuron markers. SST interneurons are selectively vulnerable to inflammation, yet the underlying mechanisms remain unclear. Interferon-gamma (IFN-{gamma}), a pro-inflammatory cytokine implicated in mood and anxiety disorders, signals through the IFN-{gamma} receptor (IFNGR), which is expressed in neurons. We tested whether IFNGR signaling in SST interneurons regulates anxiety-like and cognitive behavior and prevents inflammation-induced molecular deficits. Methods: We generated mice with conditional deletion of IFNGR from SST cells and assessed anxiety-like behavior using elevated plus maze and working memory using Y-maze at baseline and after lipopolysaccharide (LPS) induced inflammation. Expression of SST-related, neurotrophic, synaptic, and glial markers was quantified. Results: At baseline and after LPS-induced inflammation, IFNGR deletion in SST cells increased anxiety-like behavior without affecting working memory. In control mice, LPS reduced Sst (p=0.0006), neuropeptide Y (Npy) (p=0.0022), brain-derived neurotrophic factor (Bdnf) (p<0.0001), and synapsin 1 (Syn1) (p=0.0150); these reductions were not significant in mice lacking IFNGR in SST cells. Knockouts also showed lower baseline Bdnf, Syn1, Gephyrin (Gphn), and allograft inflammatory factor 1 (Aif1, encoding Iba1) than controls. Conclusions: IFNGR signaling in SST cells plays a dual role: supporting normal behavior and molecular homeostasis while mediating LPS-induced molecular deficits. These findings link immune signaling to the GABAergic dysfunction implicated in major depressive disorder and suggest IFNGR signaling in SST cells may regulate cortical microcircuit integrity at baseline and during inflammatory challenge.

neuroscience↗

bioRxiv2025

The fecal microbiota transplantation from drug-naive schizophrenia patients distinctively changes gut microbiome and metabolic profiles in male and female mice

BackgroundEmerging evidence suggests a role for the gut microbiome in schizophrenia (SCZ) and antipsychotic-induced metabolic perturbations. Using human fecal microbiota transplantation (FMT) in mice, this study investigated the role of gut microbiome in metabolic changes related to SCZ and antipsychotic (olanzapine) treatment. Methods5-6 weeks old germ-free NIH Swiss mice of both sexes received microbiota from either SCZ patients (SCZ-FMT) or healthy controls (HC-FMT) followed by a diet with or without olanzapine for six-weeks. Food intake and body weight were monitored weekly, and an intraperitoneal glucose tolerance test and open field test were performed. Serum glucose, and insulin were measured. Gut microbiome characterization and short-chain fatty acids (SCFAs) quantification were performed in the cecal samples using 16S rRNA gene sequencing and gas chromatography-mass spectrometry, respectively. ResultsOlanzapine treatment decreased the locomotor activity in the open field test, irrespective of sex or microbiota. Female SCZ-FMT recipient mice exhibited insulin resistance compared to HC-FMT, irrespective of olanzapine treatment. Female SCZ-FMT mice showed significantly lower alpha-diversity compared to HC-FMT, whereas olanzapine treatment increased alpha-diversity. SCZ-FMT and olanzapine treatment differentially altered the microbial abundances, and metabolic pathways in male and female mice. Interestingly, cecal SCFAs, mainly acetate levels, were significantly decreased in female SCZ-FMT mice compared to HC-FMT, while olanzapine treatment increased acetate levels in male mice. Both male and female SCZ-FMT mice showed elevated levels of isovaleric acid compared to HC-FMT. ConclusionThese preliminary findings suggest that gut microbiome could be a predisposing factor contributing to the intrinsic risk of developing type 2 diabetes associated with SCZ in females. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=80 SRC="FIGDIR/small/675957v1_ufig1.gif" ALT="Figure 1"> View larger version (31K): org.highwire.dtl.DTLVardef@8cfd10org.highwire.dtl.DTLVardef@3a6031org.highwire.dtl.DTLVardef@813428org.highwire.dtl.DTLVardef@87609e_HPS_FORMAT_FIGEXP M_FIG Graphical abstract C_FIG

neuroscience↗

bioRxiv2025

Protective effects of central leptin on whole-body energy homeostasis upon acute olanzapine exposure

Second-generation antipsychotic use is associated with severe metabolic side effects such as obesity and type 2 diabetes. Leptin is a hormone that is secreted by adipose tissue, and it acts on the brain to decrease body weight by reducing food intake and stimulating energy expenditure. Leptin also improves glucose and lipid metabolism. We examined the short-term impact of olanzapine, a commonly used second-generation antipsychotic, on the central leptin-mediated regulation of energy balance, lipid metabolism, and hypothalamic kinase activity. Male Sprague Dawley rats were given an acute intracerebroventricular (ICV, 3rd ventricle) injection of either leptin or vehicle, combined with subcutaneous olanzapine or vehicle. As expected, ICV leptin decreased food intake and importantly, olanzapine did not block this effect. Administration of leptin, olanzapine, or their combination reduced the average respiratory exchange ratio (RER) during the light cycle, which indicates that fat oxidation was increased. In the dark cycle, leptin decreased the average RER regardless of olanzapine administration, and in the presence of leptin, olanzapine did not affect the average RER. Leptin did not alter the olanzapine-induced increase in serum triglyceride concentrations. Olanzapine and central leptin treatment differentially activated hypothalamic kinases. In conclusion, regulation of food intake and fuel preference by central leptin is intact following acute olanzapine administration.

neuroscience↗

bioRxiv2024

Positive Allosteric Modulation of the α5-GABAA receptors prevents neuronal atrophy and cognitive decline independently of tau tangle accumulation in the PS19 mouse model

BackgroundDysregulated Tau phosphorylation (p-Tau) is a hallmark of neurodegenerative disorders such as Alzheimers disease (AD) or frontotemporal dementia (FTD), resulting in neurofibrillary tangle accumulation, neuronal atrophy and cognitive impairment. Impaired somatostatin (SST) expression and reduced SST-expressing GABAergic neurons significantly contributes to AD-related pathophysiology and correlates with cognitive impairment. SST+ interneurons inhibit the dendrites of excitatory neurons in cortical layers and hippocampus, primarily through 5-GABA-A receptors, regulating cognitive function. Leveraging a newly developed small molecule that targets the 5-GABA-A receptors via positive allosteric modulation (5-PAM), we assessed its effects on p-Tau-related neuronal morphology, cognitive deficits and protein expression. MethodsIn the PS19 transgenic mouse model, we administered the 5-PAM, GL-II-73, either acutely or chronically at 3 and 6 months, corresponding to early and advanced stage of p-Tau accumulation. Golgi staining analyzed dendritic morphology and spine density in mice chronically exposed to 5-PAM. Western blotting was used to quantify p-tau and Tau expression. Spatial working memory was assessed using the Y-maze. ResultsChronic treatment at 3 and 6 months mitigated p-Tau-induced loss of spine density and reduced dendritic length. 5-PAM treatment did not affect p-tau levels. 5-PAM effectively reversed spatial working memory deficits induced by p-tau accumulation both acutely and chronically. Conclusions5-GABA-A receptor positive allosteric modulation displayed neurotrophic (spine and dendritic pathology) and procognitive (working memory) effects in the PS19 model, independently of p-Tau burden. This suggests a novel therapeutic strategy for p-Tau-related pathologies with both symptomatic and disease-modifying potential.

neuroscience↗

bioRxiv2024

Spine loss in depression impairs dendritic signal integration in human cortical microcircuit models

Major depressive disorder (depression) is associated with altered dendritic structure and function in excitatory cortical pyramidal neurons, due to decreased inhibition from somatostatin interneurons and loss of spines and associated synapses, as indicated in postmortem human studies. Dendrites play an important role in signal processing as they receive the majority of synaptic inputs and exhibit nonlinear properties including backpropagating action potentials and dendritic Na+ spikes that enhance the computational power of the neuron. However, it is currently unclear how depression-related dendritic changes impact the integration of signals. Here, we expanded our previous data-driven detailed computational models of human cortical microcircuits in health and depression to include active dendritic properties that enable backpropagating action potentials as measured in human neurons, and spine loss in depression in terms of synapse loss and altered intrinsic property. We show that spine loss dampens signal response and thus results in a larger impairment of cortical function such as signal detection than due to reduced somatostatin interneuron inhibition alone. We further show that the altered intrinsic properties due to spine loss abolish nonlinear dendritic integration of signals and impair recurrent microcircuit activity. Our study thus mechanistically links cellular changes in depression to impaired dendritic processing in human cortical microcircuits.

neuroscience↗

bioRxiv2024

Therapeutic dose prediction of α5-GABA receptor modulation from simulated EEG of depression severity

Treatment for major depressive disorder (depression) often has partial efficacy and a large portion of patients are treatment resistant. Recent studies implicate reduced somatostatin (SST) interneuron inhibition in depression, and new pharmacology boosting this inhibition via positive allosteric modulators of 5-GABAA receptors (5-PAM) offers a promising effective treatment. However, testing the effect of 5-PAM on human brain activity is limited, meriting the use of detailed simulations. We utilized our previous detailed computational models of human depression microcircuits with reduced SST interneuron inhibition and 5-PAM effects, to simulate EEG of virtual subjects across depression severity and 5-PAM doses. We developed machine learning models that predicted optimal dose from EEG with high accuracy and recovered microcircuit activity and EEG. This study provides dose prediction models for 5-PAM administration based on EEG biomarkers of depression severity. Given limitations in doing the above in the living human brain, the results and tools we developed will facilitate translation of 5-PAM treatment to clinical use.

neuroscience↗

bioRxiv2024

EEG biomarkers of GABA α5 positive allosteric modulators in rodents

Reduced cortical inhibition mediated by gamma-aminobutyric acid (GABA) is reported in depression, anxiety disorders, and aging. Novel positive allosteric modulator that specifically target 5-GABAA receptor subunit (5-PAM), ligand GL-II-73, shows anxiolytic, antidepressant, and pro-cognitive effects without the common side effects associated with non-specific modulation by benzodiazepines such as diazepam (DZP), thus suggesting novel therapeutic potential. However, it is unknown if 5-PAM has detectable signatures in clinically-relevant brain electroencephalography (EEG). We analyzed EEG in freely moving rats at baseline and following injections of 5-PAM and DZP. We showed that 5-PAM specifically decreased theta peak power whereas DZP shifted peak power from high to low theta, while increasing beta and gamma power. EEG decomposition showed that these effects were periodic and corresponded to changes in theta oscillation event duration. Our study thus shows that 5-PAM has robust and distinct EEG biomarkers in rodents, indicating that EEG could enable non-invasive monitoring of 5-PAM treatment efficacy.

neuroscience↗

bioRxiv2023

LPS-Induced Inflammation Reduces GABAergic Interneuron markers and Brain-derived Neurotrophic Factor in Mouse Prefrontal Cortex and Hippocampus

Inflammation, reduced gamma-aminobutyric acidergic (GABAergic) function and altered neuroplasticity are co-occurring pathophysiologies in major depressive disorder (MDD). However, the link between these biological changes remains unclear. We hypothesized that inflammation induces deficits in GABAergic interneuron markers and that this effect is mediated by brain-derived neurotrophic factor (BDNF). We report here that systemic inflammation induced by intraperitoneal injection of lipopolysaccharide (LPS) (0.125, 0.25, 0.5, 1, 2mg/kg) in the first cohort of C57BL/6 mice (n=72; 9-12 weeks; 50% female) resulted in increased interleukin 1-beta and interleukin-6 in prefrontal cortex (PFC) and hippocampus (HPC), as measured using enzyme-linked immunosorbent assay (ELISA). Quantitative real-time polymerase reaction (qPCR) was used to explore the effect of LPS on the expression of GABAergic interneuron markers. In the PFC of the second cohort (n=39; 9-12 weeks; 50% female), 2mg/kg of LPS decreased the expression of somatostatin (Sst) (p=0.0014), parvalbumin (Pv) (p=0.0257), cortistatin (Cort) (p=0.0003), neuropeptide Y (Npy) (p=0.0033) and cholecystokinin (Cck) (p=0.0041), and did not affect corticotropin-releasing hormone (Crh) and vasoactive intestinal peptide (Vip) expression. In the HPC, 2mg/kg of LPS decreased the expression of Sst (P=0.0543), Cort (p=0.0011), Npy (p=0.0001), and Cck (p<0.0001), and did not affect Crh, Pv, and Vip expression. LPS decreased the expression of Bdnf in the PFC (P<0.0001) and HPC (P=0.0003), which significantly correlated with affected markers (Sst, Pv, Cort, Cck, and Npy). Collectively, these results suggest that inflammation may causally contribute to cortical cell microcircuit GABAergic deficits observed in MDD.

neuroscience↗

bioRxiv2023

Extrasynaptic localization is essential for α5GABAA receptor modulation of dopamine system function

Dopamine system dysfunction, observed in animal models with psychosis-like symptomatology, can be restored by targeting Gamma-Aminobutyric Acid type A receptors (GABAAR) containing the 5, but not 1, subunit in the ventral hippocampus (vHipp). The reason for this discrepancy in efficacy remains elusive; however, one key difference is that 1GABAARs are primarily located in the synapse, whereas 5GABAARs are mostly extrasynaptic. To test whether receptor location is responsible for this difference in efficacy, we injected a small interfering ribonucleic acid (siRNA) into the vHipp to knock down radixin, a scaffolding protein that holds 5GABAARs in the extrasynaptic space. We then administered GL-II-73, a positive allosteric modulator of 5GABAARs (5-PAM) known to reverse shock-induced deficits in dopamine system function, to determine if shifting 5GABAARs from the extrasynaptic space to the synapse would prevent the effects of 5-PAM on dopamine system function. As expected, knockdown of radixin significantly decreased radixin-associated 5GABAARs and increased the proportion of synaptic 5GABAARs, without changing the overall expression of 5GABAARs. Importantly, GL-II-73 was no longer able to modulate dopamine neuron activity in radixin-knockdown rats, indicating that the extrasynaptic localization of 5GABAARs is critical for hippocampal modulation of the dopamine system. These results may have important implications for clinical use of GL-II-73, as periods of high hippocampal activity appear to favor synaptic 5GABAARs, thus efficacy may be diminished in conditions where aberrant hippocampal activity is present. Significance StatementDopamine activity is known to be altered in both psychosis patients and in animal models, with promising new antipsychotics restoring normal dopamine system function. One such drug is GL-II-73, a positive allosteric modulator of 5GABAARs (5-PAM). Interestingly, previous research has shown that a positive allosteric modulator of 1GABAARs (1-PAM) does not share this ability, even when directly given to the ventral hippocampus, a region known to modulate dopamine activity. One potential explanation for this difference we examined in this study is that 1GABAARs are primarily located in the synapse, whereas 5GABAARs are mostly extrasynaptic. Determining the mechanism of this differential efficacy could lead to the refinement of antipsychotic treatment and improve patient outcomes overall.

neuroscience↗

bioRxiv2023

Lifespan Changes in Brain Structure and Cognitive Performance Associated with Normal Aging in Mice

IntroductionAs the population skews toward older age, elucidating mechanisms underlying human brain aging becomes imperative. Structural MRI has facilitated non-invasive investigation of lifespan brain morphology changes, yet this domain remains uncharacterized in rodents despite increasing use as models of disordered human brain aging. MethodsYoung (2m, n=10), middle-age (10m, n=10) and old (22m, n=9) mice were utilized for maturational (young vs. middle-age) and aging-related (middle-age vs. old mice) comparisons. Regional brain volume was averaged across hemispheres and reduced to 32 brain regions. Pairwise group differences in regional volume, residualized for total brain volume, and associations between volume and cognitive performance on the Y-maze task were tested. General linear models with total brain volume as a covariate, and logistic regression for sample wide associations were employed respectively, correcting for multiple comparisons. Structural covariance networks were generated using the R package igraph. Group differences in network centrality (degree), integration (mean distance), and segregation (transitivity, modularity) were tested across network densities (5-40%), using 5,000 (1,000 for degree) permutations with significance criteria of p<0.05 at [≥]5 consecutive density thresholds. ResultsWidespread significant maturational changes in volume occurred in 18 brain regions, including considerable loss in isocortex regions and increases in brainstem regions and white matter tracts. The aging-related comparison yielded 6 significant changes in brain volume, including further loss in isocortex regions and increases in white matter tracts. No significant volume changes were observed across either comparison for subcortical regions. Additionally, smaller volume of the anterior cingulate area ({chi}2=2.325, pO_SCPLOWBHC_SCPLOW=0.044) and larger volume of the hippocampal formation ({chi}2=-2.180, pO_SCPLOWBHC_SCPLOW=0.044) were associated with poorer cognitive performance. Maturational network comparisons yielded significant degree changes in 9 regions, but no aging related changes, aligning with network stabilization trends in humans. Maturational decline in modularity occurred (24-29% density), mirroring human trends of decreased segregation in young adulthood, while mean distance and transitivity remained stable. Conclusions/ImplicationsThese findings offer a foundational account of age effects on brain volume, structural brain networks, and cognition in mice, informing future work in facilitating translation between rodent models and human brain aging.

neuroscience↗

bioRxiv2023

In-silico testing of new pharmacology for restoring inhibition and human cortical function in depression

Reduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of 5 subunit-containing GABAA receptor (5-PAM) that selectively target this lost inhibition exhibit antidepressant and pro-cognitive effects in rodent models of chronic stress. However, the functional effects of 5-PAM on the human brain in vivo are unknown, and currently cannot be assessed experimentally. We modeled the effects of 5-PAM on tonic inhibition as measured in human neurons, and tested in silico 5-PAM effects on detailed models of human cortical microcircuits in health and depression. We found that 5-PAM effectively recovered impaired cortical processing as quantified by stimulus detection metrics, and also recovered the power spectral density profile of the microcircuit EEG signals. We performed an 5-PAM dose response and identified simulated EEG biomarker candidates. Our results serve to de-risk and facilitate 5-PAM translation and provide biomarkers in non-invasive brain signals for monitoring target engagement and drug efficacy.

neuroscience↗

bioRxiv2022

Positive allosteric modulation of α5-GABA A Receptor in the 5XFAD mouse model has cognitive and neurotrophic benefits

INTRODUCTIONReduced somatostatin (SST) and SST-expressing GABAergic neurons are well-replicated findings in Alzheimers disease (AD) and are associated with cognitive deficits. SST cells inhibit pyramidal cell dendrites through 5-GABA-A receptors (5-GABAA-R). 5-GABAAR positive allosteric modulation (5-PAM) has procognitive and neurotrophic effects in stress and aging models. METHODSWe tested whether 5-PAM (GL-II-73) could reverse cognitive deficits and neuronal spine loss in early and late stages of {beta}-amyloid deposition in the 5xFAD model (N=48/study; 50% female). RESULTSAcute or chronic administration of GL-II-73 reversed spatial working memory in 5xFAD mice at 2 and 5 months of age. Chronic GL-II-73 treatment reversed 5xFAD-induced loss of spine density, spine count and dendritic length at both time points, despite {beta}-amyloid accumulation. DISCUSSIONThese results demonstrate procognitive and neurotrophic effects of GL-II-73 in early and late stages of Alzheimer-related {beta}-amyloid deposition. This suggests 5-PAM as a novel {beta}-amyloid-independent symptomatic therapeutic approach.

pharmacology and toxicology↗

bioRxiv2021

Dynamic behavioral and molecular changes induced by chronic stress exposure in mice

Depression is a leading cause of disabilities around the world, and the underlying mechanisms involved in its pathophysiology are broad and complex. Exposure to chronic stress is a risk factor for developing depressive-symptoms and contributes to cellular and molecular changes precipitating the emergence of symptoms. In the brain, excitatory neurons, inhibitory interneurons and supporting astroglial cells are all sensitive to chronic stress exposure and are known to be impaired in depression. Using an animal model of chronic stress, we assessed the impact of variable durations of chronic stress on the emergence of behavioral deficits and associated molecular changes in the prefrontal cortex (PFC), brain region highly sensitive to stress and impaired in depression. Mice were exposed to up to 35 days of chronic restraint stress and were assessed weekly on behavioral tests measuring anxiety and anhedonia. PFC Protein and RNA levels of specific markers of excitatory, inhibitory synapses and astroglia were quantified using western blot and qPCR, respectively. Correlation and integrative network analyses were used to investigated the impact of chronic stress on the different compartments. Results showed that chronic stress induces anxiety-like behaviors within 7 days, while anhedonia-like behaviors were observed only after 35 days. At the molecular level, alterations of many markers were observed, in particular with longer exposure to chronic stress. Finally, correlation analyses and integrative network analyses revealed that male and female mice react differently to chronic stress exposure and that some markers seem to be more correlated to behaviors deficits in males than in females. Our study demonstrate that chronic induces a dynamic changes that can be observed at the behavioral and molecular levels, and that male and female mice, while exhibiting similar symptoms, have different underlying pathologies.

neuroscience↗

bioRxiv2021

Symptomatic and Disease-Modifying Effects of GABAA Receptor Positive Allosteric Modulation in a Mouse Model of Chronic Stress

Chronic stress is a risk factor for Major depressive disorder (MDD), and in rodents, it recapitulates human behavioral, cellular and molecular changes. In MDD and after chronic stress, neuronal dysfunctions and deficits in GABAergic signaling are observed and responsible for symptom severity. GABA signals predominantly through GABAA receptors (GABAA-R) composed of various subunit types that relate to downstream outcomes. Activity at 2-GABAA-Rs contributes to anxiolytic properties, 5-GABAA-Rs to cognitive functions, and 1-GABAA-Rs to sedation. Therefore, a therapy aiming at increasing 2- and 5-GABAA-Rs activity, but devoid of 1-GABAA-R activity, has potential to address several symptomologies of depression while avoiding side effects. This study investigated the activity profiles and behavioral efficacy of two molecules enantiomers of each other (GL-II-73 and GL-I-54), separately and as a racemic mixture (GL-RM), and potential disease-modifying effects on neuronal morphology. Results confirm GL-I-54 and GL-II-73 exert positive allosteric modulation at the 2-, 3-, 5-GABAA-Rs and 5-containing GABAA-Rs, respectively, and have anti-depressant and pro-cognitive effects independently. Using unpredictable chronic mild stress (UCMS) in male and female mice (n=12/group), we show that acute and chronic administration of GL-RM combined the anti-depressant and pro-cognitive effects of each enantiomer, although at lower doses avoiding sedation. Morphology studies showed reversal of spine density loss caused by UCMS after chronic GL-RM treatment at apical and basal dendrites of the PFC and CA1. Together, these results support using a racemic mixture with combined 2-, 3-, 5-GABAA-R profile to reverse chronic stress-induced mood symptoms, cognitive deficits, and with anti-stress neurotrophic effects.

neuroscience↗

bioRxiv2021

Chronic Stress Alters Astrocyte Morphology in Mouse Prefrontal Cortex

BackgroundNeuromorphological changes are consistently reported in the prefrontal cortex (PFC) of patients with stress-related disorders and in rodent stress models, but the effects of stress on astrocyte morphology and potential link to behavioral deficits are relatively unknown. MethodsTo answer these questions, transgenic mice expressing green fluorescent protein (GFP) under the glial fibrillary acid protein (GFAP) promotor were subjected to 7, 21 or 35 days of chronic restraint stress (CRS). CRS induced behavioral effects on anhedonia- and anxiety-like behaviors were measured using the sucrose intake and the PhenoTyper tests, respectively. PFC GFP+ or GFAP+ cells morphology was assessed using Sholl analysis and associations with behavior were determined using correlation analysis. ResultsCRS-exposed male and female mice displayed anxiety-like behavior at 7, 21 and 35 days and anhedonia-like behavior at 35 days. Analysis of GFAP+ cell morphology revealed significant atrophy of distal processes following 21 and 35 days of CRS. CRS induced similar decreases in intersections at distal radii for GFP+ cells, accompanied by increased proximal processes. In males, the number of intersections at the most distal radius step significantly correlated with anhedonia-like behavior (r=0.622, p<0.05) for GFP+ cells and with behavioral emotionality calculated by z-scoring all behavioral measured deficits (r=-0.667, p<0.05). Similar but not significant correlations were observed in females. No correlation between GFP+ cell atrophy with anxiety-like behavior was found. ConclusionChronic stress exposure induces a progressive atrophy of cortical astroglial cells, potentially contributing to maladaptive neuroplastic and behavioral changes associated with stress-related disorders.

animal behavior and cognition↗

bioRxiv2021

Reduced inhibition in depression impairs stimulus processing in human cortical microcircuits

Cortical processing depends on finely-tuned excitatory and inhibitory connections in neuronal microcircuits. Reduced inhibition by somatostatin-expressing interneurons is a key component of altered inhibition associated with treatment-resistant major depressive disorder (depression), which is implicated in cognitive deficits and rumination, but the link remains to be better established mechanistically in humans. Here, we tested the impact of reduced somatostatin interneuron mediated inhibition on cortical processing in human neuronal microcircuits using a data-driven computational approach. We integrated human cellular, circuit and gene-expression data to generate detailed models of human cortical microcircuits in health and depression. We simulated microcircuit baseline and response activity and found reduced signal-to-noise ratio and increased false/failed detection of stimuli due to a higher baseline activity in depression. Our results thus applied novel models of human cortical microcircuits to demonstrate mechanistically how reduced inhibition impairs cortical processing in depression, providing quantitative links between altered inhibition and cognitive deficits.

neuroscience↗

bioRxiv2020

Depressive-like behaviors induced by somatostatin-positive GABA neuron silencing are rescued by alpha 5 GABA-A receptor potentiation

IntroductionDeficits in somatostatin-positive gamma-aminobutyric acid interneurons ("SST+ cells") are associated with major depressive disorder (MDD) and a causal link between SST+ cell dysfunction and depressive-like deficits has been proposed, based on rodent studies showing that chronic stress induces a low SST+ GABA cellular phenotype across corticolimbic brain regions, that lowering Sst, SST+ cell, or GABA functions induces depressive-like behaviors, and that disinhibiting SST+ cell functions has antidepressant effects. Recent studies found that compounds preferentially potentiating receptors mediating SST+ cell functions with 5-GABA-A receptor positive allosteric modulators (5-PAMs) achieved antidepressant-like effects. Together, evidence suggests that SST+ cells regulate mood and cognitive functions that are disrupted in MDD and that rescuing SST+ cell function may represent a promising therapeutic strategy. MethodsWe developed a mouse model with chemogenetic silencing of brain-wide SST+ cells and employed behavioral characterization 30 min after acute or sub-chronic silencing to identify contributions to behaviors related to MDD. We then assessed whether an 5-PAM, GL-II-73, could rescue behavioral deficits induced by SST+ cell silencing. ResultsBrain-wide SST+ cell silencing induced features of stress-related illnesses, including elevated neuronal activity and plasma corticosterone levels, increased anxiety- and anhedonia-like behaviors, and impaired short-term memory. GL-II-73 led to antidepressant-like improvements among all behavioral deficits induced by brain-wide SST+ cell silencing. ConclusionOur data validate SST+ cells as regulators of mood and cognitive functions, support a role for SST+ cell deficits in depressive-like behaviors, and demonstrate that bypassing low SST+ cell function via 5-PAM represents a targeted antidepressant strategy. Significance StatementHuman and animal studies demonstrate somatostatin-positive GABAergic interneuron ("SST+ cell") deficits as contributing factors to the pathology of major depressive disorder (MDD). These changes involve reduced SST and GABAergic markers, occurring across corticolimbic brain regions. Studies have identified roles for SST+ cells in regulating mood and cognitive functions, but employed genetic or region-specific ablation that is not representative of disease-related processes. Here, we developed a chemogenetic mouse model of brain-wide low SST+ cell function. This model confirmed a role for SST+ cells in regulating anxiety- and anhedonia-like behaviors, overall behavioral emotionality, and impaired working memory. We next showed that a positive allosteric modulator at 5-GABA-A receptors (5-PAM, GL-II-73) rescued behavioral deficits induced by low SST+ cell function. These findings support a central role for brain-wide low SST+ cell function in MDD and validate targeting 5-GABA-A receptors as a therapeutic modality across MDD symptom dimensions.

pharmacology and toxicology↗