Biology subjects

Nikolova, Y.

Publications and source records attributed to Nikolova, Y..

6 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↗

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↗

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↗

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↗

bioRxiv2020

Reduced anterior cingulate cortex volume induced by chronic stress correlates with increased behavioral emotionality and decreased synaptic puncta density

Clinical and preclinical studies report that chronic stress induces behavioral deficits as well as volumetric and synaptic alterations in corticolimbic brain regions including the anterior cingulate cortex (ACC), amygdala (AMY), nucleus accumbens (NAc) and hippocampus (HPC). Here, we aimed to investigate the volumetric changes associated with chronic restraint stress (CRS) and link these changes to the CRS-induced behavioral and synaptic deficits. We first confirmed that CRS increases behavioral emotionality, defined as collective scoring of anxiety- and anhedonia-like behaviors. We then demonstrated that CRS induced a reduction of total brain volume which negatively correlated with behavioral emotionality. Region-specific analysis identified that only the ACC showed significant decrease in volume following CRS (p<0.05). Reduced ACC correlated with increased behavioral emotionality (r=-0.56; p=0.0003). Although not significantly altered by CRS, AMY and NAc (but not the HPC) volumes were negatively correlated with behavioral emotionality. Finally, using structural covariance network analysis to assess shared volumetric variances between the corticolimbic brain regions and associated structures, we found a progressive decreased ACC degree and increased AMY degree following CRS. At the cellular level, reduced ACC volume correlated with decreased PSD95 (but not VGLUT1) puncta density (r=0.35, p<0.05), which also correlated with increased behavioral emotionality (r=-0.44, p<0.01), suggesting that altered synaptic strength is an underlying substrate of CRS volumetric and behavioral effects. Our results demonstrate that CRS effects on ACC volume and synaptic density are linked to behavioral emotionality and highlight key ACC structural and morphological alterations relevant to stress-related illnesses including mood and anxiety disorders. HighlightsO_LIChronic restraint stress (CRS) decreases anterior cingulate cortex (ACC) volume C_LIO_LIACC and amygdala (AMY) volumes negatively correlate with behavioral emotionality C_LIO_LICRS decreased the strength and degree of the ACC structural covariance network C_LIO_LICRS increased the strength and degree of the AMY structural covariance network C_LIO_LIPSD95 puncta density correlates with behavioral emotionality and ACC volume. C_LI

neuroscience↗

bioRxiv2019

Novel transcriptome-based polygenic risk score for depression is associated with neural processing of social stimuli

Convergent data from imaging and postmortem brain transcriptome studies implicate corticolimbic circuit (CLC) dysregulation in the pathophysiology of depression. To more directly bridge these lines of work, we generated a novel transcriptome-based polygenic risk score (T-PRS), capturing subtle shifts towards depression-like gene expression patterns in key CLC regions, and mapped this T-PRS onto brain function and related depressive symptoms in a non-clinical sample of 478 young adults (225 men; age 19.79+/-1.24) from the Duke Neurogenetics Study. First, T-PRS was generated based on common functional SNPs shifting CLC gene expression towards a depression-like state. Next, we used multivariate partial least squares regression to map T-PRS onto whole-brain activity patterns during perceptual processing of social stimuli (i.e., human faces). For validation, we conducted a comparative analysis with a PRS summarizing depression risk variants identified by the Psychiatric Genomics Consortium (PGC-PRS). Sex was modeled as moderating factor. We showed that T-PRS was associated with widespread reductions in neural response to neutral faces in women and to emotional faces and shapes in men (multivariate p<0.01). This female-specific reductions in neural response to neutral faces was also associated with PGC-PRS (multivariate p<0.03). Reduced reactivity to neutral faces was further associated with increased self-reported anhedonia. We conclude that women with functional alleles mimicking the postmortem transcriptomic CLC signature of depression have blunted neural activity to social stimuli, which may be expressed as higher anhedonia.

neuroscience↗