Glutamatergic heterogeneity in the neuropeptide projections from the lateral hypothalamus to the mouse olfactory bulb

Qi, M.; Won, J.; Rodriguez, C.; Storace, D. A.

doi:10.1101/2025.02.16.638511

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bioRxiv · 10.1101/2025.02.16.638511

Glutamatergic heterogeneity in the neuropeptide projections from the lateral hypothalamus to the mouse olfactory bulb

Qi, M.·Won, J.·Rodriguez, C.·Storace, D. A.

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Abstract

The direct pathway from the lateral hypothalamus to the mouse olfactory bulb (OB) includes neurons that express the neuropeptide orexin-A, and others that do not. The OB-projecting neurons that do not express orexin-A are present in an area of the lateral hypothalamus known to contain neurons that express the neuropeptide melanin-concentrating hormone (MCH). We used virally mediated anterograde tract tracing and immunohistochemistry for orexin-A and MCH to demonstrate that the OB is broadly innervated by axon projections from both populations of neurons. Orexin-A and MCH were expressed in each OB layer across its anterior to posterior axis. Both orexin-A and MCH neurons are genetically heterogeneous, with subsets that co-express an isoform of vesicular glutamate transporter (VGLUT). We used high-resolution confocal imaging to test whether the projections from orexin-A and MCH neurons to the OB reflect this glutamatergic heterogeneity. The majority ([~]57%) of putative orexin-A axon terminals overlapped with VGLUT2, with smaller proportions that co-expressed VGLUT1, or that did not overlap with either VGLUT1 or VGLUT2. In contrast, only [~]26% of putative MCH axon terminals overlapped with VGLUT2, with the majority not overlapping with either VGLUT. Therefore, the projections from the lateral hypothalamus to the OB are genetically heterogeneous and include neurons that can release two different neuropeptides. The projections from both populations are themselves genetically heterogeneous with distinct ratios of glutamatergic and non-glutamatergic axon terminals. Three Key PointsO_LIA direct anterograde projection from orexin-A-expressing neurons in the hypothalamus to the mouse olfactory bulb (OB) was confirmed using virally mediated tract tracing. C_LIO_LIOrexin-A and melanin-concentrating hormone (MCH), two neuropeptides primarily produced in the lateral hypothalamus are broadly expressed throughout the mouse OB. C_LIO_LIApproximately 64% of putative orexin-A axon terminals overlapped with vesicular glutamate transporter type 1 (VGLUT1) or type 2 (VGLUT2). In contrast, only 25% of putative MCH axon terminals overlapped with VGLUT2. C_LI

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Qi, M., Won, J., Rodriguez, C., Storace, D. A.. 2025-02-16. Glutamatergic heterogeneity in the neuropeptide projections from the lateral hypothalamus to the mouse olfactory bulb. https://doi.org/10.1101/2025.02.16.638511

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