Chronic oxytocin-driven alternative splicing of Crfr2α induces anxiety

Area of Science:

• Neuroscience
• Molecular Biology
• Behavioral Science

Background:

• Oxytocin (OXT) is explored for psychiatric disorders like anxiety and autism.
• Long-term effects of chronic OXT and its receptor (OXTR) activation are understudied.
• Intranasal OXT shows potential for therapeutic long-term use.

Purpose of the Study:

• Investigate behavioral and molecular outcomes of chronic OXT administration.
• Examine the impact of chronic OXT on anxiety-like behaviors and related signaling pathways.
• Determine the role of corticotropin-releasing factor receptor 2α (Crfr2α) alternative splicing in OXT's chronic effects.

Main Methods:

• Administered chronic OXT to rats for two weeks.
• Analyzed anxiety-like behaviors and OXTR signaling pathways.
• Investigated alternative splicing of hypothalamic Crfr2α, specifically the shift towards soluble (sCRFR2α) forms.
• Assessed sCRFR2α levels in cerebrospinal fluid and correlated them with behavior.

Main Results:

• Chronic OXT increased anxiety-like behavior, particularly in female rats, an effect that was transient.
• OXT treatment shifted Crfr2α splicing from the membrane-bound (mCRFR2α) to the soluble (sCRFR2α) form.
• Experimental induction of this splicing change mimicked OXT's anxiogenic effects.
• sCRFR2α knockdown reduced anxiety in male rats, and elevated sCRFR2α in CSF correlated with anxiety.

Conclusions:

• Chronic OXT administration induces transient anxiogenic effects, contrasting acute anxiolytic actions.
• Altered alternative splicing of Crfr2α, favoring the anxiogenic sCRFR2α form, underlies these adverse effects.
• The findings highlight the importance of considering receptor splicing in OXT-based therapeutic strategies.