Unveiling a Novel Memory Center in Humans: Neurochemical Identification of the Nucleus Incertus, a Key Pontine Locus Implicated in Stress and Neuropathology

de Avila, C.; Gugula, A.; Trenk, A.; Intorcia, A. J.; Suazo, C.; Nolz, J.; Plamondon, J.; Khatri, D.; Tallant, L.; Caron, A.; Blasiak, A.; Serrano, G. E.; Beach, T. G.; Gundlach, A. L.; Mastroeni, D.

doi:10.1101/2023.09.08.556922

bioRxiv · 10.1101/2023.09.08.556922

Unveiling a Novel Memory Center in Humans: Neurochemical Identification of the Nucleus Incertus, a Key Pontine Locus Implicated in Stress and Neuropathology

de Avila, C.·Gugula, A.·Trenk, A.·Intorcia, A. J.·Suazo, C.·Nolz, J.·Plamondon, J.·Khatri, D.·Tallant, L.·Caron, A.·Blasiak, A.·Serrano, G. E.·Beach, T. G.·Gundlach, A. L.·Mastroeni, D.

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Abstract

BackgroundThe nucleus incertus (NI) was originally described by Streeter in 1903, as a midline region in the floor of the fourth ventricle (4V) of the human brain with an unknown function. More than a century later, the neuroanatomy of the NI including its forebrain target regions has been described in lower vertebrates, but not in humans. Therefore, we examined the neurochemical anatomy of the human NI using several markers, including the neuropeptide, relaxin-3 (RLN3), and began to explore the distribution of the NI-related RLN3 innervation of the hippocampus. MethodsHistochemical staining of serial, coronal sections (30 {micro}m) of control human postmortem pons was conducted to reveal the presence of the NI by detection of immunoreactivity (IR) for the neuronal marker, microtubule-associated protein-2 (MAP2), two markers present in rat NI, glutamic acid dehydrogenase (GAD)-65/67 and corticotrophin releasing hormone receptor 1 (CRHR1), and RLN3, which is highly expressed in a major population of NI neurons in diverse species. RLN3 and vesicular GABA transporter 1 (vGAT1) mRNA was detected by multiplex, fluorescence in situ hybridization. Postmortem pons sections containing the NI from an Alzheimers disease (AD) case were immunostained for phosphorylated-tau (AT8 antibody), to explore potential relevance to neurodegenerative diseases. Lastly, sections of human hippocampus were stained to detect RLN3-IR and somatostatin (SST)-IR, as SST is expressed in interneurons targeted by RLN3 projections in rodents. ResultsIn the dorsal, anterior-medial region of the human pons, neurons containing RLN3- and MAP2-IR, and RLN3/vGAT1 mRNA-positive neurons were observed in an anatomical pattern consistent with that of the NI in other species. GAD65/67- and CRHR1-immunopositive neurons were also detected within this area. Furthermore, RLN3- and AT8-IR were co-localized within NI neurons of an AD subject. Lastly, RLN3-IR was detected in neurons within the CA1, CA2, CA3, and DG areas of the hippocampus, in the absence of RLN3 mRNA. In the DG, RLN3- and SST-IR were co-localized in a small population of neurons. ConclusionsAspects of the anatomy of the human NI are shared across species, including a population of RLN3-expressing neurons and a RLN3 innervation of the hippocampus. Accumulation of phosphorylated-tau in the NI suggests its possible involvement in AD pathology. Further characterization of the neurochemistry of the human NI will increase our understanding of its functional role in health and disease. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=75 SRC="FIGDIR/small/556922v1_ufig1.gif" ALT="Figure 1"> View larger version (24K): org.highwire.dtl.DTLVardef@f4c439org.highwire.dtl.DTLVardef@17e85f5org.highwire.dtl.DTLVardef@18ca7faorg.highwire.dtl.DTLVardef@168246c_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract Created with BioRender.com C_FIG

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de Avila, C., Gugula, A., Trenk, A., Intorcia, A. J., Suazo, C., Nolz, J., Plamondon, J., Khatri, D., Tallant, L., Caron, A., Blasiak, A., Serrano, G. E., Beach, T. G., Gundlach, A. L., Mastroeni, D.. 2023-09-09. Unveiling a Novel Memory Center in Humans: Neurochemical Identification of the Nucleus Incertus, a Key Pontine Locus Implicated in Stress and Neuropathology. https://doi.org/10.1101/2023.09.08.556922

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