Biology subjects

Sibille, E.

Publications and source records attributed to Sibille, E..

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↗

bioRxiv2026

Selective depletion of upper-layer somatostatin interneuron subtypes in schizophrenia

Schizophrenia (SCZ) is associated with cortical GABAergic dysfunction, but whether inhibitory interneurons are lost or persist in an altered molecular state remains unresolved. Here, we harmonized seven prefrontal post-mortem single-nucleus RNA-seq datasets onto a fine-grained taxonomy of cortical cell types and meta-analyzed their gene expression and abundance changes in SCZ (298 controls, 171 SCZ). First, we find a subclass-wide reduction of SST mRNA within somatostatin (Sst) neurons. Second, we find reduced abundance (depletion) of a subset of upper-layer Sst interneurons and increased abundance of L6b excitatory neurons, with both changes confirmed in spatial transcriptomics (12 controls, 12 SCZ). Notably, SCZ genetic risk is enriched in the most depleted Sst cells. Depleted Sst subtypes highly express HCN1, partially correspond to primate-specialized CALB1-expressing double-bouquet cells, and are among the cells lost earliest in Alzheimer's disease. These upper-layer Sst interneurons constitute an intrinsically vulnerable population and a promising target for neuroprotective and compensatory therapies.

bioinformatics↗

bioRxiv2026

Molecular Characterization of the Progressive Landscape of Depression

Major Depressive Disorder (MDD) frequently follows a recurrent trajectory of episodes and remissions, often culminating in treatment-resistance. Molecular differences defining state-specific changes during episode and remission have been explored. However, progressive differences--defined here as cross-sectional linear trends across clinical stages from first to recurrent episodes or remissions, reflecting increasing illness burden over time--remain poorly understood, limiting sustained therapeutic outcomes. Here, we analyzed RNA-seq data from postmortem sgACC to identify progressive differences across MDD episodes or remission relative to state-specific differences, using an integrative assessment of molecular and cellular specificity, genetic-risk, disease-comorbidity and potential therapeutic targets. Differential expression analysis showed greater overlap between progressive and state-specific differences during remission than episode. Pathway enrichment highlighted disruptions in extracellular-matrix pathways shared by state-specific and progressive episodes, while metabolic and catalytic pathways were restored during remission. Cell-type-specific analyses showed that progressive changes were linked to superficial-layer intra-telencephalic neurons, whereas state-specific changes were enriched in pyramidal neuron subtypes and deeper layer SST-positive interneurons. Genome-wide association-informed enrichment analysis further linked these transcriptomic changes to genetic risk factors and symptom dimensions. Anhedonia was associated with both state-specific episode and progressive-remission signatures, suggesting that it is a persistent trait-like feature of MDD. Finally, an integrative pharmacological analysis revealed shared molecular mechanisms between pro-disease and therapeutic targets, highlighting pleiotropic effects of key pathways depending on disease state and dosage. Together, these findings provide a novel perspective on biological underpinnings of MDD progression over episodes or remissions and identify pharmacological targets that account for pathological and/or compensatory/therapeutic processes.

neuroscience↗

bioRxiv2025

Neuronal and Astrocytic Activity Changes Induced by Acute and Chronic Stress

Exposure to acute, repeated, or chronic stress elicits a spectrum of cellular changes ranging from adaptive to maladaptive, including in the prefrontal cortex (PFC) where both neurons and astroglia undergo morphological, cellular and molecular remodeling. However, whether these alterations translate into altered cell activity and neuron-astroglia communication and how such changes evolve with recurrent stress or chronic stress exposure remains poorly understood. To address these questions, we used dual-color in vivo fiber photometry to longitudinally record PFC neuronal and astroglial calcium (Ca{superscript 2}) signals in the same mice during a brief (tail pinch), sustained (immobilization) acute stress, repeated homotypic stress across weeks, and unpredictable chronic mild stress (UCMS), tracking of same cellular network across time. We found that acute stressors elicited coordinated increases in neuronal and astroglial Ca{superscript 2} activity and enhanced their Ca2+ signal coupling. Repeated intermittent stress induced comparable per-cell-type responses but progressively strengthened coupling, suggesting adaptation. We also demonstrated that this trajectory is reversed under UCMS; neuronal Ca{superscript 2} reactivity to stress challenge was sensitized whereas astroglial reactivity was blunted. This was associated with a weakened intercellular coupling (-3.5 fold) and astroglia became progressively hyporesponsive to neuronal drive. UCMS-induced neuron-astroglia functional coupling impairment coincided with the onset of anhedonia- and anxiety-like behavioral deficits. These findings position impaired neuron-astroglial functional coupling as a potential substrate of stress-induced cortical dysfunction that may distinguish adaptive from maladaptive stress responses, offering a mechanistically tractable target for intervention in stress-related psychiatric disease such as depression, where dysfunction in both cell types has been consistently reported.

neuroscience↗

bioRxiv2025

Linking age changes in human cortical microcircuits to impaired brain function and EEG biomarkers

Human brain aging involves a variety of cellular and synaptic changes, but how these changes affect brain function and signals remains poorly understood due to experimental limitations in humans, meriting the use of detailed computational models. We identified key human cellular and synaptic changes occurring with age from previous studies, including a loss of inhibitory cells, NMDA receptors, and spines. We integrated these changes into our detailed human cortical microcircuit models and simulated activity in middle-age ([~]50 yrs) and older ([~]70 yrs) microcircuits, and linked the altered mechanisms to reduced spike rates and impaired signal detection. We then simulated EEG potentials arising from the microcircuit activity and found that the emergent power spectral changes due to these aging cellular mechanisms reproduced most of the resting-state EEG biomarkers seen in human aging, including reduced aperiodic offset, exponent, and periodic peak center frequency. Using machine learning, we demonstrated that the changes to the cellular and synaptic aging mechanisms can be estimated accurately from the simulated EEG aging biomarkers. Our results link cellular and synaptic mechanisms of aging with impaired cortical function and physiological biomarkers in clinically-relevant brain signals.

neuroscience↗

bioRxiv2024

Neurostructural and cognitive signatures of novel polygenic risk scores for molecular brain aging

The world population is shifting sharply toward an older-age demographic. To navigate the escalating burden of physical and cognitive decline common to aging, and heightened risk of neurodegenerative and neuropsychiatric disease, we require advances in treatment and prevention interventions. These advances are predicated on attaining a deeper understanding of the molecular processes underlying brain aging. Here, we employed novel GWAS and cis-eQTL-based polygenic risk scores (GWASAGE-PRS and cis-eQTLAGE-PRS) indexing genetic risk for accelerated molecular brain aging, and examined their associations with cortical thickness and performance in age-sensitive cognitive domains in 31 384 participants (16 392 women, age 64.1{+/-}7.65) from the UK Biobank. While GWASAGE-PRS was nominally associated with lower cortical thickness in frontotemporal regions, cis-eQTLAGE-PRS displayed robust associations with greater cortical thickness in age-sensitive frontal, temporal, and parietal regions, including the left and right precentral (pFDR<0.0001, pFDR=0.05), left insula (pFDR=0.05), as well as the right supramarginal (pFDR=0.05) and precuneus (pFDR=0.05) regions. Similar pFDR trending associations occurred bilaterally in the caudal middle frontal (pFDR=0.052, pFDR=0.078) and right insula (pFDR=0.071). These structural findings co-occurred alongside increased executive function performance on the Trail Making Test B (pFDR=0.035), suggesting a potential neurostructural and cognitive reserve phenotype. This resilience profile may reflect previously uncharacterized pathways of brain reserve in age-related pathology, informing future translational research identifying novel treatment and prevention targets.

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

Prefrontal Cortex Astroglia Modulate Anhedonia-like Behavior

Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.

neuroscience↗

bioRxiv2023

Ribosomal dysregulation: A conserved pathophysiological mechanism in human depression and mouse chronic stress.

The underlying biological mechanisms that contribute to the heterogeneity of major depressive disorder (MDD) presentation remain poorly understood, highlighting the need for a conceptual framework that can explain this variability and bridge the gap between animal models and clinical endpoints. Here, we hypothesize that comparative analysis of molecular data from different experimental systems of chronic stress and MDD has the potential to provide insight into these mechanisms and address this gap. Thus, we compared transcriptomic profiles of brain tissue from postmortem MDD subjects and from mice exposed to chronic variable stress (CVS) to identify orthologous genes. Ribosomal protein genes (RPGs) were downregulated, and associated RP-pseudogenes were upregulated in both conditions. Analysis across independent cohorts confirmed that this dysregulation was specific to the prefrontal cortex of both species. A seeded gene co-expression analysis using altered RPGs common between the MDD and CVS groups revealed that downregulated RPGs homeostatically regulated the synaptic changes in both groups through a RP-pseudogene-driven mechanism. In-vitro and in-silico analysis further demonstrated that the inverse RPG/RP-pseudogene association was a glucocorticoid-driven endocrine response to stress that was reversed during remission from MDD. This study provides the first evidence that ribosomal dysregulation during stress is a conserved phenotype in human MDD and CVS exposed mouse. Our results establish a foundation for the hypothesis that stress-induced alterations in RPGs and, consequently, ribosomes contribute to the synaptic dysregulation underlying MDD and chronic stress-related mood disorders. We discuss a ribosome-dependent mechanism for the variable presentations of depression and other mood disorders. Significance StatementThe presented study highlights the pressing need for a connection between animal models of depression and clinical endpoints. The lack of concordance between these two areas has hindered our understanding of MDDs biological underpinnings. The studys hypothesis that orthologous gene from experimental systems of chronic stress and MDD can bridge this gap is a major advance in this field. The study indicates that dysregulation of ribosomes in the synapse is a common feature in both human MDD and mice exposed to CVS. This dysregulation is a response to endocrine disturbances and is driven by mechanisms that involve pseudogenes. These findings support the hypothesis that stress-induced alterations in RPGs and, consequently, ribosomes may contribute to the variable presentations of depression.

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

Behavioral and Neurostructural changes associated with Chronic Amygdala Hyperactivation

BackgroundThe amygdala (AMY) is a key brain region of the limbic system that plays a critical role in emotion processing and stress response. Functional magnetic resonance imaging (fMRI) studies identified abnormal AMY activation in psychiatric illnesses including major depressive disorder (MDD). Stress exposure is a major precipitating factor of MDD episodes which are associated with AMY hyperactivity. Preclinical studies using of pharmacologic, opto- and chemogenetic approaches to activate AMY neurons have consistently demonstrated that acute AMY hyperactivation induces anxiety-like behaviors in mice. However, it remains unknown if chronic hyperactivation of the amygdala (cHOA) is sufficient to induce chronic stress-like deficits or is a susceptibility factor for chronic stress-induced behavioral, volumetric and synaptic deficits. MethodsUsing designer receptor exclusively activated by designer drug (DREADD) approach, basolateral amygdala (BLA) neurons of Camk2a-cre mice infected with a virus driving the expression of the Gq-coupled DREADD were activated with clozapine-N-oxide (in drink water for 5 weeks). Mice were then exposed to chronic restraint stress (CRS; 1X/day for 1hr) for 2 weeks. All mice were behaviorally assessed in the Phenotyper (PT), and sucrose consumption tests (SCT) each week and in the novelty supressed feeding (NSF, once at the end of the experiment). Animals were then perfused for ex vivo-MRI and puncta density analysis. ResultsWe found that mice with cHOA displayed a progressive increase in baseline anxiety-like deficits in the PT test and slightly more marked deficits following CRS compared to controls, but not statistically different from animals subjected to CRS alone. Also, cHOA did not exacerbate CRS effect in the NSF. No significant cAH effect was found in the SCT before or after CRS. MRI analysis revealed no statistical charges between groups, while increased synaptic puncta density was found in cHOA mice subjected to CRS compared to cHOA or CRS alone. ConclusionWe demonstrate that cAH is sufficient to induce anxiety and may exacerbate CRS effects on anxiety and synaptic measures. Results also suggest that cHOA was not sufficient to induce depressive-like behavior and was not a vulnerability factor for stress-induced depressive-like behavior in mice. Altogether, our findings imply that a strong causal link between AMY hyperactivity and elevated anxiety, but not depressive-like behaviors and provide critical information to clinical research focused on using AMY activity level as a biomarker in stress-related illnesses.

neuroscience↗