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<p>Early vocal communication, such as isolation-induced ultrasonic vocalization (USV) in neonatal rodents, is critical for infant survival and represents a primary readout of early affective states. The patch/striosome compartment in the striatum has been proposed to serve as a limbic-motor interface integrating emotion and motivation. Developmentally, this compartment undergoes early maturation, during which activity-dependent transcription factors might enable the functional assembly of limbic-striosomal circuits to regulate infant vocal-motor behavior. <i>Npas4</i>, an activity-dependent early-response transcription factor, controls the developmental balance of excitatory and inhibitory synaptic activity. Here, we investigated how patch/ striosome compartment-expressing <i>Npas4</i> shapes early synaptic development and neonatal vocalization. We found that <i>Npas4</i> transcripts were transiently enriched in patch/striosomes at postnatal days (P) 4 and P8, before adopting a homogenous striatal distribution by P14. To investigate its biological function, we generated a patch/striosome-specific <i>Npas4</i> conditional knockout. Anatomically, <i>Npas4</i> deletion disrupted patch/striosomal synaptic balance, evidenced by a significant reduction in excitatory (Vglut1) and an increase in inhibitory (Vgat) presynaptic terminals. Behaviorally, acoustic and Markov-chain syntactical analyses of isolation-induced USVs revealed a hyper-vocal phenotype at P8, characterized by a significant increase in total USV call numbers and augmented temporal clustering of vocal bouts and sequences. Furthermore, acoustic analysis demonstrated a shift toward more complex syllable types. While the structure of global transition networks was preserved, <i>Npas4</i> knockout mice exhibited an elevated sequence entropy rate, indicating greater moment-to-moment structural variability. Our study suggests that <i>Npas4</i> shapes the development of limbic-striosomal circuits to provide top-down gating of early affective vocalization in neonates.</p>

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Npas4 regulates synaptic development in the patch/striosome compartment and early affective vocalization in neonatal mice

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月29日

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  • Yen-Hui Lee,
  • Hsiao-Ying Kuo,
  • Shih-Yun Chen,
  • Yu-Ning Chang,
  • Charles R. Gerfen,
  • Fu-Chin Liu

摘要

Early vocal communication, such as isolation-induced ultrasonic vocalization (USV) in neonatal rodents, is critical for infant survival and represents a primary readout of early affective states. The patch/striosome compartment in the striatum has been proposed to serve as a limbic-motor interface integrating emotion and motivation. Developmentally, this compartment undergoes early maturation, during which activity-dependent transcription factors might enable the functional assembly of limbic-striosomal circuits to regulate infant vocal-motor behavior. Npas4, an activity-dependent early-response transcription factor, controls the developmental balance of excitatory and inhibitory synaptic activity. Here, we investigated how patch/ striosome compartment-expressing Npas4 shapes early synaptic development and neonatal vocalization. We found that Npas4 transcripts were transiently enriched in patch/striosomes at postnatal days (P) 4 and P8, before adopting a homogenous striatal distribution by P14. To investigate its biological function, we generated a patch/striosome-specific Npas4 conditional knockout. Anatomically, Npas4 deletion disrupted patch/striosomal synaptic balance, evidenced by a significant reduction in excitatory (Vglut1) and an increase in inhibitory (Vgat) presynaptic terminals. Behaviorally, acoustic and Markov-chain syntactical analyses of isolation-induced USVs revealed a hyper-vocal phenotype at P8, characterized by a significant increase in total USV call numbers and augmented temporal clustering of vocal bouts and sequences. Furthermore, acoustic analysis demonstrated a shift toward more complex syllable types. While the structure of global transition networks was preserved, Npas4 knockout mice exhibited an elevated sequence entropy rate, indicating greater moment-to-moment structural variability. Our study suggests that Npas4 shapes the development of limbic-striosomal circuits to provide top-down gating of early affective vocalization in neonates.