Scientists uncover excessive maturation and aging in the hippocampus

In a groundbreaking study, researchers at Fujita Health University and the Tokyo Metropolitan Institute of Medical Science have uncovered a previously overlooked form of brain abnormality linked to anxiety: excessive maturation and aging in the hippocampus, a state they term “hyper-maturity.” Published in Neuropsychopharmacology, the study systematically screened publicly available omics datasets and identified gene expression signatures of hippocampal hyper-maturity in 17 datasets across 16 mouse models of neuropsychiatric disorders, including models of anxiety, depression, schizophrenia, and neurodegeneration.

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.”

Dr. Tsuyoshi Miyakawa, senior author of the study

Synaptic pathways drive hyper-maturity in the anxious brain

The researchers identified 16 mouse models exhibiting excessively enhanced gene expression patterns of typical postnatal development in the hippocampus, referred to as hyper-maturity model mice. Pathway enrichment analysis revealed 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, a brain region crucial for emotion and memory, is known for its remarkable plasticity. To quantify the degree of cellular maturation, the team developed a “maturity index” based on gene expression patterns and assessed its relationship with anxiety-like behavior. A positive correlation emerged: hippocampal hyper-maturity was associated with increased anxiety-like behaviors, while previously established models characterized by hippocampal immaturity were linked to reduced anxiety. Notably, mice chronically exposed to corticosterone, a key stress hormone, also displayed both hippocampal hyper-maturity and increased anxiety, underscoring contribution of stress to these brain and behavioral abnormalities.

These findings suggest that dysregulation of hippocampal maturation, whether toward immaturity or hyper-maturity, may influence emotional behavior through alterations in synaptic gene expression and function. At present, however, the causal relationship between hippocampal maturational abnormalities and anxiety remains to be clarified.

Aging before its time

Postnatal development (from infancy to adulthood) and aging (from adulthood to old age) are continuous biological processes. The researchers investigated whether the gene expression profiles of hyper-maturity model mice more closely resembled patterns associated with postnatal development or aging. They found that individual models tended to greater similarity to one of the two trajectories:

• Enhanced Postnatal Development, as observed in models such as serotonin transporter (Sert) knockout and senescence-prone SAMP8 mice.
• Accelerated Aging, as seen in models including corticosterone-treated mice and those with lysosomal storage disorders.

Further cell-type-specific analyses suggested that microglia, astrocytes, and granule cells might contribute to the aging-related gene expression changes in these models.

Translational relevance in humans

The team also analyzed 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 the 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.

“This suggests that brain hyper-maturity may, at least in certain populations, represent a shared molecular signature across multiple psychiatric disorders,” said Dr. Hideo Hagihara, lead author. “Among the affected genes are candidates that could potentially serve as transdiagnostic markers or even targets for novel therapies.”

Mechanisms and future implications

“We do not yet fully understand the shared molecular mechanisms by which diverse genetic and environmental factors give rise to hyper-maturity,” said Dr. Miyakawa. “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.