Conditional `Cc2d1a` deletion increases irritability-like behavior by decreasing oxytocin via prelimbic-hypothalamic pathway

Dysregulation of the oxytocin (OXT) system is strongly implicated in the pathophysiology of several neuropsychiatric disorders, particularly autism spectrum disorder (ASD). While previous work showed that restoring OXT levels can ameliorate irritability-like behavior in Cc2d1a conditional knockout (cKO) mice, the precise mechanisms by which loss of Cc2d1a in forebrain excitatory neurons leads to reduced OXT expression in the paraventricular nucleus of the hypothalamus (PVN) remained unclear. Understanding this pathway is crucial for developing targeted interventions for ASD-related irritability.

Researchers utilized Cc2d1a cKO mice and wild-type (WT) controls to assess irritability-like behavior using the bottle-brush test (BBT). To map neural circuits, they employed retrograde and anterograde trans-synaptic viral tracing. Chemogenetic methods were used to modify neuronal activity within identified pathways. Fiber photometry monitored real-time OXT dynamics, and whole-cell voltage-clamp recordings in ex vivo brain slices assessed synaptic transmission onto PVN OXT neurons. The study focused on adult male mice.

Decreased OXT expression was observed in both magnocellular and parvocellular PVN neurons in adult male Cc2d1a cKO mice, notably without corresponding changes in mRNA levels. Chronic silencing of PVN OXT neurons during adolescence in WT mice led to fewer OXT-immunoreactive neurons and heightened irritability-like behavior in adulthood. Viral tracing identified the prelimbic cortex (PrL) as an indirect regulator of 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 revealed:

Reduced OXT release during the BBT in the posteroventral medial amygdala of male Cc2d1a cKO mice. Chronic chemogenetic silencing of the PrL-PVN pathway during adolescence successfully reduced irritability-like behavior in adult male Cc2d1a cKO mice.