P3.34. EXPLORING THE NEUROCHEMICAL PROFILE AND FUNCTIONAL CONNECTIVITY OF THE NUCLEUS INCERTUS–VENTRAL HIPPOCAMPUS CIRCUIT: POTENTIAL ROLE IN ANXIETY REGULATION IN RATS AND HUMANS
Kinga Przybylska1,2, Aleksandra Trenk1, Anna Gugula1, Aleksandra Nogaj1,2, Gabriela Czerniak1, Camila de Ávila3, Anthony J. Intorcia4, Geidy E. Serrano4, Thomas G. Beach4, Diego F. Mastroeni3, Anna Blasiak1
1 Department of Neurophysiology and Chronobiology, Institute of Zoology and Biomedical Research, Jagiellonian University, Cracow, Poland
2 Doctoral School of Exact and Natural Sciences, Jagiellonian University, Cracow, Poland
3 ASU-Banner Neurodegenerative Disease Research Center, Biodesign Institute, and School of Life Sciences, Tempe, Arizona, USA
4 Neuropathology Laboratory, Banner Sun Health Research Institute, Sun City, Arizona, USA
INTRODUCTION: The ventral hippocampus (vHPC) plays a pivotal role in regulating stress and anxiety responses, with disruptions within its interneuron network strongly linked to clinical anxiety-related disorders. One major input to the vHPC originates from the pontine tegmental nucleus incertus (NI), which is the main source of the neuropeptide relaxin-3 (RLN3) in the rat brain. Notably, sustained activation of the RLN3 receptor, RXFP3, in the vHPC has been shown to increase anxiety and social avoidance, though the underlying neurobiological mechanisms remain unclear.
AIM(S): Therefore, this study aimed to investigate the neurochemical profile and functional connectivity of the NI-vHPC pathway in the rat brain, alongside anatomical investigations in the human hippocampus.
METHOD(S): RLN3 fiber distribution and their origin in the ventral dentate gyrus (vDG) were investigated using immunohistochemistry and viral-based neural tract-tracing. RXFP3 mRNA-expressing neurons were characterized using HiPlex in situ hybridization (ISH) and their sensitivity to RLN3 was examined using ex vivo multi-electrode array recordings.
RESULTS: Immunohistochemistry revealed abundant RLN3-positive fiber innervation in the vDG of the rat hippocampus. Viral-based neural tract-tracing further confirmed a predominantly ipsilateral innervation of the rat vDG by RLN3 NI neurons. ISH studies showed that RXFP3 mRNA-expressing neurons in the rat vDG co-express vesicular GABA transporter (vGAT) and somatostatin mRNA. Importantly, ISH with human anterior hippocampal sections also revealed co-expression of RXFP3 and somatostatin mRNA. Finally, electrophysiological recordings ex vivo using multi-electrode arrays demonstrated an inhibitory effect of RXFP3 activation on the rat vDG network activity.
CONCLUSIONS: Collectively, these findings indicate a direct influence of RLN3 on GABAergic vDG interneurons in rat and human, which may underlie the effects of RLN3/RXFP3 signalling on anxiety-related behaviours.
FINANCIAL SUPPORT: National_Science_Centre_Poland UMO-2023/49/B/NZ4/01885, MiniGrant2023 ID.UJ; U1U/W18/NO/28.55 RSM ID.UJ, BrightFocus Foundation A2021006; Alzheimer’s Association AARFD-22-972099