The hypothalamic vasopressin circuit drives lateralized endocrine signaling

Traumatic brain injury and stroke often result in contralateral sensorimotor deficits, including asymmetric posture. While these lateralized effects are classically attributed to neural tract disruption, recent evidence supports the existence of a complementary humoral pathway. Our previous work demonstrated that the neurohormone Arg-vasopressin (AVP) mediates right hindlimb responses to left-sided brain injury, whereas the dynorphin - κ-opioid receptor system is involved in regulation of left hindlimb reflexes following right-sided lesions. We hypothesized that AVP-expressing hypothalamic neuroendocrine circuits function to maintain left-right balance in peripheral regulation while their selective activation disrupts this equilibrium producing asymmetric outcomes, and that dynorphins may counteract these processes. To address this hypothesis, we used transgenic rats expressing the Gq-coupled Designer Receptor Exclusively Activated by Designer Drugs (DREADD) receptor hM3Dq in AVP-neurons. Functional outcomes were assessed using hindlimb postural asymmetry (HL-PA) model, a proxy for lateralized peripheral responses. The DREADD ligand clozapine-N-oxide (CNO) activation of AVP neurons alone did not induce asymmetry. However, following κ-opioid receptor inactivation with nor-binaltorphimine, CNO administration produced right hindlimb flexion in rats with completely transected spinal cords-an effect abolished by SSR-149415, an antagonist of AVP V1B receptors. These findings suggest that the AVP neurocircuit is a regulator of left-right balance in the body, and its side-specific actions are mediated through the release of the hypothalamic-pituitary hormones into the circulation and counterbalanced by dynorphins. This novel rat model recapitulates side-specific aspects of unilateral brain injury and highlight AVP circuitry for physiological control of the left and right body sides.