Hemoglobin in the blood acts as a chemosensory signal via the mouse vomeronasal system

Osakada, Takuya; Abe, Takayuki; Itakura, Takumi; Mori, Hiromi; Ishii, Kaneo; Eguchi, Ryo; Murata, Ken T.; Saito, Kosuke; Haga-Yamanaka, Sachiko; Kimoto, Hiroko; Yoshihara, Yoshihiro; Miyamichi, Kazunari; Touhara, Kazushige

doi:10.1038/s41467-022-28118-w

Cited by 19 publications

(14 citation statements)

References 43 publications

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“…To investigate if VNO neurons are indeed activated by cat saliva, we analyzed immunoreactivity (IR) of phosphorylated ribosomal protein S6 subunit, pS6, in the VNO of mice exposed to cat saliva. As the cellular pS6 level is greatly upregulated upon activation of VNO neurons, it has been used as a sensitive marker to examine neural activation in the VNO (Carvalho et al, 2020; Itakura et al, 2022; Osakada et al, 2022; Tsunoda et al, 2018). We observed that exposure to both fresh and old cat saliva induced an increase in pS6-IR in the basal VNO neurons that express Gαo protein (Figure 2E, G).…”

Section: Resultsmentioning

confidence: 99%

“…These approaches are technically challenging and may provide false positive results. Therefore, identified receptors need to be further confirmed by examining necessity and sufficiency for detecting cat saliva using genetically modified mouse lines (Haga et al, 2010;Haga-Yamanaka et al, 2014;Isogai et al, 2018;Itakura et al, 2022;Osakada et al, 2022Osakada et al, , 2018Tsunoda et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Potential approaches include receptor mRNA profiling with pS6 immunoprecipitation from the VNO of mice stimulated by cat saliva (Isogai et al, 2018; Jiang et al, 2015), as well as receptor mRNA profiling from isolated single cells activated by cat saliva in GcaMP imaging using the VNO slices in vitro (Haga-Yamanaka et al, 2014; Wong et al, 2020). Receptor candidates identified using either of the methods can be further confirmed by examining necessity and sufficiency for detecting cat saliva using genetically modified mouse lines (Haga et al, 2010; Haga-Yamanaka et al, 2014; Isogai et al, 2018; Itakura et al, 2022; Osakada et al, 2022, 2018; Tsunoda et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

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Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice

Nguyen,

Rocha,

Chhor

et al. 2023

Preprint

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Animals have the innate ability to select optimal defensive behavioral outputs with an appropriate intensity in response to predator threat in specific contexts. Such innate behavioral decisions are thought to be computed in the medial hypothalamic nuclei that contain neural populations directly controlling defensive behavioral outputs. The vomeronasal organ (VNO) is one of the major sensory input channels through which predator cues are detected with ascending inputs to the medial hypothalamic nuclei, especially to the ventromedial hypothalamus (VMH). Here, we show that cat saliva contains predator cues that signal imminence of predator threat and regulate the robustness of freezing behavior through the VNO in mice. Cat saliva activates neurons expressing the V2R-A4 subfamily of sensory receptors, suggesting the existence of specific receptor groups responsible for freezing behavior induced by the predator cues. The number of VNO neurons activated in response to saliva correlates with the freshness of saliva and the intensity of freezing behavior, while the downstream neurons in the accessory olfactory bulb (AOB) and VMH are quantitatively equally activated by fresh and old saliva. Strikingly, however, only the number of VMH neurons activated by fresh saliva positively correlates with intensity of freezing behavior. Detailed analysis of the spatial distribution of fresh and old saliva-responding neurons revealed a neuronal population within the VMH that is more sensitive to fresh saliva than old saliva. Taken together, this study demonstrates that predator cues in cat saliva change over time and differentially activate the sensory-to-hypothalamus pathway. More specifically, the imminent predator signal predominantly activates V2R-A4 receptors, which results in the activation of freezing-correlated neurons in the VMH. In contrast, the less imminent predator signal activates V2R-A4 receptors to a lesser extent, which in turn results in the activation of distinct populations of neurons in the VMH that are not correlated to freezing.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice

Nguyen,

Rocha,

Chhor

et al. 2023

Preprint

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“…Notably, Vmn2r114, close homolog of Vmn2r115 and Vmn2r116, is also expressed by large numbers of cells. Vmn2r88, a hemoglobin receptor 101 , was not identified as a highly expressed gene. The functions of other highly expressed receptors are not known.…”

Section: E)mentioning

confidence: 96%

Molecular, Cellular, and Developmental Organization of the Mouse Vomeronasal organ at Single Cell Resolution

Hills,

Ma,

Fang

et al. 2024

Preprint

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SUMMARYWe have generated single cell transcriptomic atlases of vomeronasal organs (VNO) from juvenile and adult mice. Combined with spatial molecular imaging, we uncover a distinct, previously unidentified class of cells that express the vomeronasal receptors and a population of canonical olfactory sensory neurons in the VNO. High resolution trajectory and cluster analyses reveal the lineage relationship, spatial distribution of cell types, and a putative cascade of molecular events that specify the V1r, V2r, and OR lineages from a common stem cell population. The expression of vomeronasal and olfactory receptors follow power law distributions, but there is high variability in average expression levels between individual receptor and cell types. Substantial co-expression is found between receptors across clades, from different classes, and between olfactory and vomeronasal receptors, with nearly half from pairs located on the same chromosome. Interestingly, the expression of V2r, but not V1r, genes is associated with various transcription factors, suggesting distinct mechanisms of receptor choice associated with the two cell types. We identify association between transcription factors, surface axon guidance molecules, and individual VRs, thereby uncovering a molecular code that guides the specification of the vomeronasal circuitry. Our study provides a wealth of data on the development and organization of the accessory olfactory system at both cellular and molecular levels to enable a deeper understanding of vomeronasal system function.

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“…Nevertheless, significant progress has been made in associating various pheromones with specific VRs and their resultant behavioral responses, which were further confirmed by VR knockout mouse studies. A number of studies have identified specific ligand-receptor pairs that mediate behaviors through the VNO (see Table 1) (Bufe et al, 2019;Haga et al, 2010;Isogai et al, 2018;Itakura et al, 2022;Kimoto et al, 2005;Osakada et al, 2022Osakada et al, , 2018. Moreover, several groups of chemicals and proteins have been identified to activate VSNs that express specific VRs, potentially influencing mouse behaviors.…”

mentioning

confidence: 99%

Type 2 vomeronasal receptor‐A4 subfamily: Potential predator sensors in mice

Rocha,

Nguyen,

Haga‐Yamanaka

2024

Genesis

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SummarySensory signals detected by olfactory sensory organs are critical regulators of animal behavior. An accessory olfactory organ, the vomeronasal organ, detects cues from other animals and plays a pivotal role in intra‐ and inter‐species interactions in mice. However, how ethologically relevant cues control mouse behavior through approximately 350 vomeronasal sensory receptor proteins largely remains elusive. The type 2 vomeronasal receptor‐A4 (V2R‐A4) subfamily members have been repeatedly detected from vomeronasal sensory neurons responsive to predator cues, suggesting a potential role of this receptor subfamily as a sensor for predators. This review focuses on this intriguing subfamily, delving into its receptor functions and genetic characteristics.

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Hemoglobin in the blood acts as a chemosensory signal via the mouse vomeronasal system

Cited by 19 publications

References 43 publications

Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice

Hypothalamic representation of the imminence of predator threat detected by the vomeronasal organ in mice

Molecular, Cellular, and Developmental Organization of the Mouse Vomeronasal organ at Single Cell Resolution

Type 2 vomeronasal receptor‐A4 subfamily: Potential predator sensors in mice

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