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<p>MicroRNA-148a (<i>miR-148a</i>) has been implicated in various neurological disorders, yet its specific function within the central nervous system remains elusive. In this study, conditional astrocyte-specific <i>miR-148a</i> knockout (cKO) and overexpression (KI) mouse models were established using CRISPR-Cas9 and Cre-loxP technology to elucidate its role in emotional and cognitive regulation. Behavioral analyses demonstrated that <i>miR-148a</i> overexpression induced marked anxiety- and depression-like behaviors, accompanied by astrocyte activation, neuronal ultrastructural damage, and disrupted synaptic morphology. Conversely, <i>miR-148a</i> deletion preserved neuronal integrity, improved synaptic architecture, and produced anxiolytic and antidepressant phenotypes with enhanced cognitive performance. Transcriptomic profiling identified the transcription factor <i>Otx2</i> as a direct target of <i>miR-148a</i>, mediating downstream modulation of dopaminergic signaling and neurodevelopmental genes. Integrative metabolomic analysis further revealed coordinated alterations in neuroendocrine and neurotransmitter-associated metabolic pathways. Collectively, these findings demonstrate that <i>miR-148a</i> critically modulates astrocyte-neuron interactions and dopaminergic homeostasis through the OTX2 axis, contributing to mood and cognitive disturbances. This work provides mechanistic insight into <i>miR-148a</i>-mediated neuroregulation and highlights its potential as a therapeutic target for affective and cognitive disorders.</p>

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MicroRNA-148a regulates depressive-like behaviors in mice via the Otx2/Dopaminergic signaling axis

  • 期刊论文

  • 发表日期：

    2026年7月31日

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  • Yifan Tang,
  • Huicong Feng,
  • Yue Li,
  • Lupeng Zhang,
  • Chiwen Qu,
  • Tianai Zhu,
  • Doudou Zhang,
  • Yi Wen,
  • Xiaomin Zeng,
  • Yong Zhang,
  • Xiaoning Peng

摘要

MicroRNA-148a (miR-148a) has been implicated in various neurological disorders, yet its specific function within the central nervous system remains elusive. In this study, conditional astrocyte-specific miR-148a knockout (cKO) and overexpression (KI) mouse models were established using CRISPR-Cas9 and Cre-loxP technology to elucidate its role in emotional and cognitive regulation. Behavioral analyses demonstrated that miR-148a overexpression induced marked anxiety- and depression-like behaviors, accompanied by astrocyte activation, neuronal ultrastructural damage, and disrupted synaptic morphology. Conversely, miR-148a deletion preserved neuronal integrity, improved synaptic architecture, and produced anxiolytic and antidepressant phenotypes with enhanced cognitive performance. Transcriptomic profiling identified the transcription factor Otx2 as a direct target of miR-148a, mediating downstream modulation of dopaminergic signaling and neurodevelopmental genes. Integrative metabolomic analysis further revealed coordinated alterations in neuroendocrine and neurotransmitter-associated metabolic pathways. Collectively, these findings demonstrate that miR-148a critically modulates astrocyte-neuron interactions and dopaminergic homeostasis through the OTX2 axis, contributing to mood and cognitive disturbances. This work provides mechanistic insight into miR-148a-mediated neuroregulation and highlights its potential as a therapeutic target for affective and cognitive disorders.