Kisspeptin fiber and receptor distribution analysis suggests its potential role in central sensorial processing and behavioral state control
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Wiley
Abstract
Kisspeptin (KP) signaling in the brain is defined by the anatomical distribution of KP-producing neurons, their fibers, receptors, and connectivity. Technological advances have prompted a re-evaluation of these chemoanatomical aspects, originally studied in the early years after the discovery of KP and its receptor Kiss1r. Previously, we characterized (Hernández et al. bioRxiv 2024) seven KP neuronal populations in the mouse brain at the mRNA level, including two novel populations, and examined their response to gonadectomy. In this study, we mapped KP fiber distribution in rats and mice using immunohistochemistry under intact as well as short- and long-term post-gonadectomy conditions. Kiss1r mRNA expression was examined via RNAscope, in relation to vesicular GABA transporter (Slc32a1) in whole mouse brain, and to KP and vesicular glutamate transporter 2 (Slc17a6), Kiss1, and Slc32a1 in hypothalamic RP3V and arcuate regions. We identified KP fibers in 118 brain regions, primarily in extra-hypothalamic areas associated with sensorial processing and behavioral state control. KP-immunoreactive fiber density and distribution were largely unchanged by gonadectomy. Kiss1r was expressed prominently in sensorial and state control regions such as the septal nuclei, the suprachiasmatic nucleus, locus coeruleus, hippocampal layers, thalamic nuclei, and cerebellar structures. Co-expression of Kiss1r and Kiss1 was observed in hypothalamic neurons, suggesting both autocrine and paracrine KP signaling mechanisms. These findings enhance our understanding of KP signaling beyond reproductive functions, particularly in sensorial processing and behavioral state regulation. This study opens new avenues for investigating KP's role in controlling complex physiological processes, including those unrelated to reproduction.
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DATA AVAILABILITY STATEMENT : The data that support the findings of this study are available from the corresponding author upon reasonable request.
SUPPORTING INFORMATION :
FIGURE S1. Comparison of cumulative (summed) fiber density charting of three young adult animals from each of the four experimental groups (male/female and intact/gonadectomized, N = 12) represented in six different parasagittal levels. Hand-made drawings under microscope observations highlight the fiber distributions abstracted from the three subjects of the same group. Lines (control: blue, GNX, red) representing the KP-ir fibers which are exaggerated in term of thickness, in relation to the section area, for visualization sake.
FIGURE S2. Projection targets of RP3V or Arc Kiss1-Cre neurons transfected with AAV. The data from two Kiss1-Cre mice injected in the arcuate nucleus (Arc, experiments 232311236 and 232310521) and two Kiss1-Cre mice injected in the rostral periventricular region (R3PV, experiments 299247009 and 301989585) injected with Cre-dependent tracer from the displayed in Allen Mouse Brain Connectivity Atlas this figure. Sagittal (A1), coronal (A2), and horizontal (A3) views of a 3D representation with 3D brain explorer of the innervation patterns of the two major populations of Kiss1 neurons. The VGAT-expressing RP3V neuronal population and its projections are represented in red, and the VGLUT2-expressing Arc population and its projections is represented in green. The different views show a reciprocal dense innervation between the Arc and the RP3V; additionally it is clear that the majority of regions in the striatum, septum, BNST, thalamus, hypothalamus, and amygdala, receive overlapping innervation from both regions. The ponto-mecencephalic region is mainly innervated by the RP3V. (B) Coronal sections at 17 rostro-caudal Bregma coordinates were selected from the animal that showed the best labeling for every level, for each level the left section from a RP3V injected mice was paired with a section from the Arc-injected mice. Some regions of interest are labeled in the RP3V sections, green-numbered arrows in the Arc sections indicate regions where there were differences in the innervation patterns between RP3V and Arc injected mice. Arrow no. 1: Some fibers were observed in the main stria terminalis and fimbria in the RP3V injected mice, but not in the Arc injected. Arrow no. 2: some fibers were observed in the stria medularis in the RP3V but not in the Arc injected mice. Arrow no. 3: The pattern of innervation of the paraventricular hypothalamic nucleus (PVN) is different between these experiments, the labeled axons of the mice injected in the RP3V innervate the magnocellular and parvocellular division, and the Arc injected neurons innervate preferentially the parvocellular region of the PVN. Also notice at this level and the following (Bregma −1.06) that for both injection targets, some axons travel laterally to reach the CeM. Arrow no. 4: the mice injected in the RP3V show innervation of the medial part of the lateral habenula (LHbm) specially the rostral part, thes fibers appear to travel via the stria medullaris (see arrow 2). No fibers in LHb were found in the Arc experiments. Arrow no. 5: A plexus of labeled fibers can be observed in the CA1 pyramidal layer of the ventral hippocampus, these fibers originate in the RP3V and travel through the stria terminalis (see arrow 1). No fibers were found at this location in the Arc injected mice. Arrow no. 6: Fibers from the RP3V reach the metencephalic region and innervate the periaquieductal gray region (PAG), the interfascicular nucleus (IF), the ventral tegmental area (VTA) and the median raphe (MnR). The mice injected in the Arc, show sparse axons and mainly innervate the PAG.
FIGURE S3. Kisspeptin pathways to regions involved in brain state control, as well as motor and sensorial processing. The maximum density found in males or females through all gonadal states is represented as a relative fiber density, color coded in two horizontal planes of rat brain (top panel, modified from Simerly and Swanson, 1988, JCN:270: 209-242; bottom panel, modified from Paxinos & Watson, The Rat Brain, 2007, interaural 5.26mm) where some of the most innervated regions related to brain state, sensorial processing and motor integration were found. The bottom halves of the two panels of the drawings represent the pathways that we identified using analysis of several consecutive immunoreacted slices in different planes, as well as data obtained from four experiments published in the Allen brain atlas. The seven KP populations symbolized with colored circles are based on the reference 1 of this paper.
Keywords
Autocrine, Behavior state system, Extrahypothalamic kisspeptin signaling, Kiss1r, Sensorial-motor circuits, Kisspeptin
Sustainable Development Goals
SDG-03: Good health and well-being
Citation
Zhang, L.M., Hernandez, V.S., Zetter, M.A. et al. 2025, 'Kisspeptin fiber and receptor distribution analysis suggests its potential role in central sensorial processing and behavioral state control', Journal of Neuroendocrinology, vol. 37, no. 5, art. e70007, pp. 1-32, doi : 10.1111/jne.70007.