In a groundbreaking study recently published in Translational Psychiatry, researchers have unveiled a compelling mechanism by which sex-specific differences in anxiety-like behaviors are modulated at the neuronal level within the forebrain. This pioneering work, led by Saleev, Getselter, and Elliott, provides novel insights into the complex interplay between genetic regulation and behavior, particularly focusing on the role of the Structural Maintenance of Chromosomes 3 (SMC3) protein in forebrain neurons of mice. The findings shed light on the molecular underpinnings that may explain why anxiety disorders often manifest differently between males and females, opening promising avenues for targeted therapeutic strategies.
Historically, anxiety disorders have presented considerable challenges in both diagnosis and treatment, partly due to evident sex biases in prevalence, symptomatology, and therapeutic response. Females tend to exhibit a higher incidence and severity of anxiety-related conditions, yet the biological basis for these disparities remains insufficiently understood. This study addresses this knowledge gap by investigating the contribution of SMC3, a component critical to chromosomal architecture and gene regulation, within excitatory forebrain neurons, illuminating how it differentially influences anxiety-like behaviors in male and female mice.
SMC3 belongs to the cohesin complex, a multiprotein assembly essential for ensuring proper sister chromatid cohesion during cell division and for regulating three-dimensional chromatin organization. Beyond its canonical roles, increasing evidence implicates cohesin components in modulating transcriptional dynamics in postmitotic neurons, thereby impacting neuronal function and behavior. This research leverages sophisticated genetic tools to dissect SMC3’s neuronal role, particularly focusing on excitatory neurons within the forebrain, a brain region integrally involved in emotional processing and regulation.
By employing conditional knockout strategies targeting SMC3 specifically in forebrain excitatory neurons, the investigators created a murine model with cell-type-specific depletion of the protein. Behavioral assays revealed striking sex-dependent effects: female mice lacking neuronal SMC3 exhibited heightened anxiety-like behaviors characterized by increased avoidance and risk assessment in elevated plus maze and open field tests, whereas male counterparts showed either no change or subtle reductions in anxiety-like responses. Such dichotomous outcomes underscore the protein’s complex role in neural circuits governing anxiety and highlight critical sex-specific regulatory mechanisms.
On a molecular level, transcriptomic analyses unveiled altered expression patterns of anxiety-related genes following SMC3 depletion, with marked differences between sexes. Female forebrain neurons deficient in SMC3 demonstrated upregulation of stress-response genes and alterations in synaptic plasticity markers that likely underpin their enhanced anxiety phenotype. Contrastingly, male neurons exhibited differential regulation of neuropeptides involved in anxiety suppression and reward processing. These sex-biased gene expression patterns offer profound insights into how epigenetic and chromatin remodeling factors mediate behavioral dimorphisms.
The anatomical localization of SMC3 within the forebrain also points to its pivotal influence on regions such as the prefrontal cortex, hippocampus, and amygdala—key nodes in the neural circuitry orchestrating fear and anxiety responses. Imaging and electrophysiological analyses indicated that SMC3 loss disrupts synaptic transmission and dendritic spine morphology selectively in females, potentially leading to increased neuronal excitability and altered network dynamics conducive to anxiety. Conversely, male neural circuits displayed differential plasticity adjustments that might confer resilience or compensatory behavioral effects.
Importantly, this study contributes to the burgeoning understanding of how chromatin architectural proteins like SMC3 extend their function beyond canonical cell cycle roles into modulating adult brain function and behavior. The sex-specific nature of these effects hints at intricate interplay between hormonal milieus, sex chromosome-linked factors, and chromatin regulatory machinery, emphasizing the need for sex-informed approaches in neuroscience research and pharmacology. It also provides a conceptual framework for re-examining other chromatin modifiers in context-specific behavioral outcomes.
Moreover, the use of state-of-the-art single-cell RNA sequencing techniques allowed high-resolution dissection of cell-type-specific gene expression changes upon SMC3 depletion, reinforcing the notion that subtle chromatin alterations can exert profound effects on behavioral phenotypes. This technological integration underscores how molecular neuroscience is capitalizing on genomics and epigenomics to decode the cellular basis of complex psychiatric disorders, steering the field towards precision medicine.
Beyond fundamental insights, these findings bear translational potential. Given the role of SMC3 and the cohesin complex in human neurodevelopmental and psychiatric disorders, understanding how its modulation affects anxiety provides candidate pathways for pharmacological targeting. The sex-specific outcomes further suggest that treatments could be tailored according to sex to optimize efficacy, a crucial consideration often overlooked in clinical practice but vital for addressing the sex disparities in anxiety disorders globally.
Additionally, this research raises intriguing questions about developmental timing and environmental influences on SMC3’s role in anxiety regulation. Future studies could explore whether embryonic or postnatal alterations in cohesin function differentially impact sex-specific brain maturation trajectories and vulnerability to stress-related disorders, thereby refining intervention windows. The potential interdependence between SMC3-mediated chromatin dynamics and hormonal fluctuations across the lifespan also represents a fertile ground for deeper inquiry.
The implications also extend into the realm of neuropsychiatric genetics, where polymorphisms or mutations in cohesin-related genes might predispose individuals to anxiety spectrum conditions with sex-biased penetrance. Investigating such genetic variants in human populations, alongside mechanistic studies in animal models, could unravel the intricate genetics-epigenetics-behavior axis, empowering the development of genetic screening tools and risk stratification protocols incorporating sex as a biological variable.
Furthermore, the methodological rigor of this study, including behavioral phenotyping under diverse anxiety paradigms, precise genetic manipulations, and integrative molecular analyses, sets a new standard for investigations aiming to dissect the neural circuitry and molecular substrates of psychiatric disease. The depth of interrogation into both cellular and behavioral phenotypes exemplifies how bridging multiple scales of biology can illuminate the complex etiology of anxiety with unprecedented clarity.
This research also invites a re-examination of existing therapeutic approaches. For instance, if SMC3 and associated chromatin remodeling processes modulate synaptic plasticity distinctly in males and females, interventions enhancing or mimicking SMC3 function may require sex-specific formulation or dosing. Additionally, pharmacological agents targeting upstream regulators or downstream effectors identified through transcriptomic changes could offer novel anxiolytic modalities, better aligned with individual molecular profiles.
In sum, the comprehensive and nuanced investigation by Saleev, Getselter, and Elliott advances our understanding of the molecular architecture underlying sex differences in anxiety-like behavior. By highlighting SMC3’s pivotal and sex-dependent role in forebrain neurons, the study provides a compelling narrative that integrates chromatin biology, neurocircuitry, and behavioral neuroscience. These insights not only deepen fundamental knowledge but also pave the way for revolutionary, sex-informed strategies to alleviate anxiety disorders, which continue to impose a significant global mental health burden.
As scientific inquiry increasingly prioritizes sex as a biological variable, studies like this catalyze transformative change in psychiatric research paradigms. The precise dissection of chromatin-mediated gene regulation within discrete neuronal populations stands as a beacon for future endeavors, promising breakthroughs in how we conceptualize and remediate complex neuropsychiatric conditions, moving us closer to truly personalized mental health care.
Subject of Research:
Sex-specific molecular mechanisms regulating anxiety-like behavior mediated by neuronal SMC3 in the forebrain of mice.
Article Title:
Sex-specific modulation of anxiety-like behavior by forebrain neuronal SMC3 in mice.
Article References:
Saleev, N., Getselter, D. & Elliott, E. Sex-specific modulation of anxiety-like behavior by forebrain neuronal SMC3 in mice. Transl Psychiatry 15, 266 (2025). https://doi.org/10.1038/s41398-025-03494-1
Image Credits: AI Generated
