Selective oxytocin receptor activation prevents prefrontal circuit dysfunction and social behavioral alterations in response to chronic prefrontal cortex activation in male rats

Philipp Janz; Frederic Knoflach; Konrad Bleicher; Sara Belli; Barbara Biemans; Patrick Schnider; Martin Ebeling; Christophe Grundschober; Madhurima Benekareddy

doi:10.3389/fncel.2023.1286552

Selective oxytocin receptor activation prevents prefrontal circuit dysfunction and social behavioral alterations in response to chronic prefrontal cortex activation in male rats

Front Cell Neurosci. 2023 Dec 7:17:1286552. doi: 10.3389/fncel.2023.1286552. eCollection 2023.

Authors

Philipp Janz¹, Frederic Knoflach¹, Konrad Bleicher², Sara Belli³, Barbara Biemans¹, Patrick Schnider², Martin Ebeling³, Christophe Grundschober¹, Madhurima Benekareddy^{1

4}

Affiliations

¹ Roche Pharma Research and Early Development, Neuroscience and Rare Diseases Discovery and Translational Area, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland.
² Roche Pharma Research and Early Development, Therapeutic Modalities, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland.
³ Roche Pharma Research and Early Development, Pharmaceutical Science, Roche Innovation Center Basel, F. Hoffmann-La Roche AG, Basel, Switzerland.
⁴ Calico Life Sciences, South San Francisco, CA, United States.

Abstract

Introduction: Social behavioral changes are a hallmark of several neurodevelopmental and neuropsychiatric conditions, nevertheless the underlying neural substrates of such dysfunction remain poorly understood. Building evidence points to the prefrontal cortex (PFC) as one of the key brain regions that orchestrates social behavior. We used this concept with the aim to develop a translational rat model of social-circuit dysfunction, the chronic PFC activation model (CPA).

Methods: Chemogenetic designer receptor hM3Dq was used to induce chronic activation of the PFC over 10 days, and the behavioral and electrophysiological signatures of prolonged PFC hyperactivity were evaluated. To test the sensitivity of this model to pharmacological interventions on longer timescales, and validate its translational potential, the rats were treated with our novel highly selective oxytocin receptor (OXTR) agonist RO6958375, which is not activating the related vasopressin V1a receptor.

Results: CPA rats showed reduced sociability in the three-chamber sociability test, and a concomitant decrease in neuronal excitability and synaptic transmission within the PFC as measured by electrophysiological recordings in acute slice preparation. Sub-chronic treatment with a low dose of the novel OXTR agonist following CPA interferes with the emergence of PFC circuit dysfunction, abnormal social behavior and specific transcriptomic changes.

Discussion: These results demonstrate that sustained PFC hyperactivity modifies circuit characteristics and social behaviors in ways that can be modulated by selective OXTR activation and that this model may be used to understand the circuit recruitment of prosocial therapies in drug discovery.

Keywords: chemogenetic; electrophysiology; oxytocin; pharmacology; prefrontal; social.

Grants and funding

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. PJ, FK, KB, SB, BB, PS, ME, CG, and MB were under paid employment by the company F. Hoffmann-La Roche (Roche) when the work was conducted. The funder provided support in the form of salaries and variable costs. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article, or the decision to submit it for publication.