Researchers at Fujita Health University and the Tokyo Metropolitan Institute of Medical Science have identified a novel form of brain abnormality linked to anxiety, termed “hyper-maturity,” characterised by excessive maturation and aging in the hippocampus. This discovery, published in Neuropsychopharmacology, involved a systematic screening of publicly available omics datasets, revealing gene expression signatures of hippocampal hyper-maturity in 17 datasets across 16 mouse models of neuropsychiatric disorders, including anxiety, depression, schizophrenia, and neurodegeneration.
Dr. Tsuyoshi Miyakawa, senior author of the study, noted, “While our previous research has largely focused on neuronal immaturity in neuropsychiatric conditions, we found that some models instead exhibited the opposite, showing gene expression profiles indicative of an over-advanced state of development and aging.”
The researchers identified 16 mouse models showing enhanced gene expression patterns typical of postnatal development in the hippocampus, referred to as hyper-maturity model mice. Pathway enrichment analysis indicated that genes associated with hyper-maturity were heavily enriched in synaptic processes, with key synaptic genes like Camk2a and Grin2b consistently upregulated across multiple models.
The hippocampus, crucial for emotion and memory, is known for its remarkable plasticity. To quantify cellular maturation, the team developed a “maturity index” based on gene expression patterns, assessing its relationship with anxiety-like behaviour. A positive correlation emerged: hippocampal hyper-maturity was associated with increased anxiety-like behaviours, while models characterised by hippocampal immaturity were linked to reduced anxiety. Mice chronically exposed to corticosterone, a key stress hormone, also displayed hippocampal hyper-maturity and increased anxiety, highlighting the role of stress in these abnormalities.
These findings suggest that dysregulation of hippocampal maturation, whether towards immaturity or hyper-maturity, may influence emotional behaviour through alterations in synaptic gene expression and function. However, the causal relationship between hippocampal maturational abnormalities and anxiety remains to be clarified.
The researchers investigated whether the gene expression profiles of hyper-maturity model mice more closely resembled postnatal development or aging. They found individual models showed greater similarity to one of the two trajectories: enhanced postnatal development, as observed in serotonin transporter (Sert) knockout and senescence-prone SAMP8 mice, or accelerated aging, as seen in corticosterone-treated mice and those with lysosomal storage disorders. Further analyses suggested that microglia, astrocytes, and granule cells might contribute to aging-related gene expression changes in these models.
The team also analysed hippocampal transcriptomes from postmortem brains of patients with depression, bipolar disorder, and schizophrenia, identifying partial overlaps with hyper-maturity and aging-like gene expression profiles. Although patterns varied across datasets, likely due to the heterogeneity of human conditions, the observed accelerated aging signatures aligned with previous reports that psychological stress can hasten biological aging.
Dr. Hideo Hagihara, lead author, remarked, “This suggests that brain hyper-maturity may, at least in certain populations, represent a shared molecular signature across multiple psychiatric disorders. Among the affected genes are candidates that could potentially serve as transdiagnostic markers or even targets for novel therapies.”
Dr. Miyakawa added, “We do not yet fully understand the shared molecular mechanisms by which diverse genetic and environmental factors give rise to hyper-maturity. Brain development and aging are not fixed or linear processes; rather, they are dynamically regulated by factors such as neuronal activity, stress, and inflammation. If we can unravel these mechanisms and discover ways to modulate them, it may ultimately open the door to brain rejuvenation strategies, with potential applications in both psychiatric treatment and anti-aging interventions.”
This research not only deepens our understanding of psychiatric disorders but also broadens the scope of anti-aging neuroscience by highlighting the importance of maturation trajectories, which are dynamically and plastically regulated in postmitotic neurons, beyond just neurodegeneration or reduced adult neurogenesis.
For further details, refer to the study published in Neuropsychopharmacology: doi.org/10.1038/s41386-025-02237-6.
