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Background <p>Dysregulation of the oxytocin (OXT) system is implicated in the pathophysiology of several neuropsychiatric and neurological disorders, particularly autism spectrum disorder (ASD). Our previous study using the <i>Coiled-coil and C2 domain containing 1a</i> (<i>Cc2d1a</i>) conditional knockout (cKO) mouse model of ASD showed that restoring OXT levels effectively ameliorates irritability-like behavior; however, the mechanisms by which loss of <i>Cc2d1a</i> in forebrain excitatory neurons leads to decreased OXT expression in the paraventricular nucleus of the hypothalamus (PVN) remain elusive.</p> Methods <p>We used the bottle-brush test (BBT) to assess irritability-like behavior in wild-type (WT) and <i>Cc2d1a</i> cKO mice. Retrograde and anterograde trans-synaptic viral tracing were used to map associated neural circuits, and chemogenetic methods were employed to modify neuronal activity. Fiber photometry monitored OXT dynamics in situ, and whole-cell voltage-clamp recordings in ex vivo brain slices assessed synaptic transmission onto PVN OXT neurons.</p> Results <p>We found that decreased OXT expression in both magnocellular and parvocellular PVN neurons is evident in adult male <i>Cc2d1a</i> cKO mice, without corresponding changes in mRNA levels. Chronic silencing of PVN OXT neurons during adolescence leads to fewer OXT-immunoreactive neurons and heightened irritability-like behavior in adult male WT mice. Using both retrograde and anterograde trans-synaptic viral tracing techniques, we identified that the prelimbic cortex (PrL) indirectly regulates PVN OXT neuronal activity. In male <i>Cc2d1a</i> cKO mice, there was a preferential decrease in excitatory synaptic transmission onto PVN OXT neurons. In vivo real-time measurements of OXT dynamics in the posteroventral medial amygdala revealed reduced OXT release during the BBT in male <i>Cc2d1a</i> cKO mice. Chronic chemogenetic silencing of the PrL-PVN pathway during adolescence reduces irritability-like behavior in adult male <i>Cc2d1a</i> cKO mice.</p> Conclusions <p>Our study unveils how forebrain <i>Cc2d1a</i> loss reduces OXT expression in the PVN at both molecular and circuit levels, underscoring the critical role of the OXT system as a potential therapeutic target for managing irritability in individuals with ASD.</p>

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Conditional deletion of Cc2d1a increases irritability-like behavior by decreasing oxytocin expression via the prelimbic-hypothalamic pathway

  • 期刊论文

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  • 发表日期：

    2026年6月1日

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  • Kuan-Hsiang Cheng,
  • Yu-Chieh Hung,
  • Pin Ling,
  • Kuei-Sen Hsu

摘要

Background

Dysregulation of the oxytocin (OXT) system is implicated in the pathophysiology of several neuropsychiatric and neurological disorders, particularly autism spectrum disorder (ASD). Our previous study using the Coiled-coil and C2 domain containing 1a (Cc2d1a) conditional knockout (cKO) mouse model of ASD showed that restoring OXT levels effectively ameliorates irritability-like behavior; however, the mechanisms by which loss of Cc2d1a in forebrain excitatory neurons leads to decreased OXT expression in the paraventricular nucleus of the hypothalamus (PVN) remain elusive.

Methods

We used the bottle-brush test (BBT) to assess irritability-like behavior in wild-type (WT) and Cc2d1a cKO mice. Retrograde and anterograde trans-synaptic viral tracing were used to map associated neural circuits, and chemogenetic methods were employed to modify neuronal activity. Fiber photometry monitored OXT dynamics in situ, and whole-cell voltage-clamp recordings in ex vivo brain slices assessed synaptic transmission onto PVN OXT neurons.

Results

We found that decreased OXT expression in both magnocellular and parvocellular PVN neurons is evident in adult male Cc2d1a cKO mice, without corresponding changes in mRNA levels. Chronic silencing of PVN OXT neurons during adolescence leads to fewer OXT-immunoreactive neurons and heightened irritability-like behavior in adult male WT mice. Using both retrograde and anterograde trans-synaptic viral tracing techniques, we identified that the prelimbic cortex (PrL) indirectly regulates PVN OXT neuronal activity. In male Cc2d1a cKO mice, there was a preferential decrease in excitatory synaptic transmission onto PVN OXT neurons. In vivo real-time measurements of OXT dynamics in the posteroventral medial amygdala revealed reduced OXT release during the BBT in male Cc2d1a cKO mice. Chronic chemogenetic silencing of the PrL-PVN pathway during adolescence reduces irritability-like behavior in adult male Cc2d1a cKO mice.

Conclusions

Our study unveils how forebrain Cc2d1a loss reduces OXT expression in the PVN at both molecular and circuit levels, underscoring the critical role of the OXT system as a potential therapeutic target for managing irritability in individuals with ASD.