From models to mechanisms: Odorant communication as a key determinant of social behavior in rodents during illness-associated states

Arakawa, Hiroyuki; Cruz, Stephanie M.; Deak, Terrence

doi:10.1016/j.neubiorev.2011.03.007

Cited by 118 publications

(87 citation statements)

References 242 publications

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“…When comparing the procedures for social behavior assessment used in our prior work to the present studies, it should be noted that Arakawa et al (2009) used a slightly different procedure that assessed social investigation under conditions in which rats were in close proximity but not able to interact directly. A more detailed description and validation of the restricted-access social investigation model can be found in our recent publications Arakawa et al, 2011). Briefly, the limited-access test used previously sustains much higher levels of social investigation initially that then dissipate precipitously because there is no reinforcement provided through actual physical contact.…”

Section: Discussionmentioning

confidence: 99%

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Lord

Aluisio

Shoblock

et al. 2014

J Pharmacol Exp Ther

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In the central nervous system, the ATP-gated Purinergic receptor P2X ligand-gated ion channel 7 (P2X7) is expressed in glial cells and modulates neurophysiology via release of gliotransmitters, including the proinflammatory cytokine interleukin (IL)-1b. In this study, we characterized JNJ-42253432 [2-methyl-N-([1-(4-phenylpiperazin-1-yl)cyclohexyl]methyl)-1,2,3,4-tetrahydroisoquinoline-5-carboxamide] as a centrally permeable (brain-to-plasma ratio of 1), high-affinity P2X7 antagonist with desirable pharmacokinetic and pharmacodynamic properties for in vivo testing in rodents. JNJ-42253432 is a high-affinity antagonist for the rat (pK i 9.1 6 0.07) and human (pK i 7.9 6 0.08) P2X7 channel. The compound blocked the ATPinduced current and Bz-ATP [29(39)-O-(4-benzoylbenzoyl)adenosine-59-triphosphate tri(triethylammonium)]-induced release of IL-1b in a concentration-dependent manner. When dosed in rats, JNJ-42253432 occupied the brain P2X7 channel with an ED 50 of 0.3 mg/kg, corresponding to a mean plasma concentration of 42 ng/ml. The compound blocked the release of IL-1b induced by Bz-ATP in freely moving rat brain. At higher doses/exposure, JNJ-42253432 also increased serotonin levels in the rat brain, which is due to antagonism of the serotonin transporter (SERT) resulting in an ED 50 of 10 mg/kg for SERT occupancy. JNJ-42253432 reduced electroencephalography spectral power in the a-1 band in a dose-dependent manner; the compound also attenuated amphetamine-induced hyperactivity. JNJ-42253432 significantly increased both overall social interaction and social preference, an effect that was independent of stress induced by foot-shock. Surprisingly, there was no effect of the compound on either neuropathic pain or inflammatory pain behaviors. In summary, in this study, we characterize JNJ-42253432 as a novel brain-penetrant P2X7 antagonist with high affinity and selectivity for the P2X7 channel.

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Section: Discussionmentioning

confidence: 99%

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Lord

Aluisio

Shoblock

et al. 2014

J Pharmacol Exp Ther

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“…Here, the exposure to disease cues in other individuals is proposed to facilitate certain cognitive and emotional responses, consequently provoking social avoidance and certain immune markers (3,5). Many animals can detect sick individuals via odor cues such as volatiles in urine and feces (6), and sickness detection leads to constrained social investigations in healthy conspecifics, possibly minimizing disease transmission. However, only a few studies have assessed a sensory-mediated sicknessdetection mechanism in humans, and essentially nothing is known about the neural mechanisms underlying the detection of sick individuals and potential subsequent social avoidance tendencies toward them.…”

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confidence: 99%

Behavioral and neural correlates to multisensory detection of sick humans

Regenbogen

Axelsson

Lasselin

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

110

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Throughout human evolution, infectious diseases have been a primary cause of death. Detection of subtle cues indicating sickness and avoidance of sick conspecifics would therefore be an adaptive way of coping with an environment fraught with pathogens. This study determines how humans perceive and integrate early cues of sickness in conspecifics sampled just hours after the induction of immune system activation, and the underlying neural mechanisms for this detection. In a double-blind placebo-controlled crossover design, the immune system in 22 sample donors was transiently activated with an endotoxin injection [lipopolysaccharide (LPS)]. Facial photographs and body odor samples were taken from the same donors when "sick" (LPS-injected) and when "healthy" (saline-injected) and subsequently were presented to a separate group of participants (n = 30) who rated their liking of the presented person during fMRI scanning. Faces were less socially desirable when sick, and sick body odors tended to lower liking of the faces. Sickness status presented by odor and facial photograph resulted in increased neural activation of odor-and faceperception networks, respectively. A superadditive effect of olfactory-visual integration of sickness cues was found in the intraparietal sulcus, which was functionally connected to core areas of multisensory integration in the superior temporal sulcus and orbitofrontal cortex. Taken together, the results outline a disease-avoidance model in which neural mechanisms involved in the detection of disease cues and multisensory integration are vital parts.body odor | lipopolysaccharide | endotoxin | sickness cues | disease avoidance

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“…For example, rodents use such chemical signals to distinguish between parasitized individuals, recognize infected conspecifics, and avoid and display aversive responses to infected individuals (7)(8)(9). Defining the cellular and molecular mechanisms and neural circuits underlying the detection of infection-and illness-associated states is not only crucial for understanding the sensing of health status in animals but also for advancing our knowledge of disease-related odors and diagnostic olfactory biomarkers in humans (10,11).…”

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confidence: 99%

Strain-specific Loss of Formyl Peptide Receptor 3 in the Murine Vomeronasal and Immune Systems

Stempel¹,

Jung

Pérez-Gómez³

et al. 2016

Journal of Biological Chemistry

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Social animals benefit from sharing information that promotes fitness and survival (1-3). In rodents, there is extensive evidence that the detection of chemosensory cues emitted by other individuals is a fundamental feature of social recognition and a prerequisite for a wide range of social behaviors (4 -6).For example, rodents use such chemical signals to distinguish between parasitized individuals, recognize infected conspecifics, and avoid and display aversive responses to infected individuals (7-9). Defining the cellular and molecular mechanisms and neural circuits underlying the detection of infection-and illness-associated states is not only crucial for understanding the sensing of health status in animals but also for advancing our knowledge of disease-related odors and diagnostic olfactory biomarkers in humans (10, 11).The vomeronasal organ (VNO) 4 is an olfactory substructure of the mammalian nose that is essential for social recognition and chemical communication (12). The VNO houses vomeronasal sensory neurons (VSNs), specialized nerve cells that detect a wide range of volatile and non-volatile molecular cues, including pheromones and predator odors (13-15). Among these cues are major histocompatibility complex class I binding peptides (antigens) and other small urinary peptides (16 -18) thus providing initial support for an evolutionary link between recognition mechanisms in immune cells and subsets of VSNs (14, 19). More recently, clear evidence has emerged that the VNO plays an important role in mediating sick conspecific avoidance and thus seems to function as a sensor of infection (20), but the underlying cellular and molecular basis for this function remains unclear. VSNs are characterized by the expression of large families of G protein-coupled receptors, vomeronasal type 1 receptors (Vmn1r) expressed in the apical vomeronasal layer and vomeronasal type 2 receptor (Vmn2r) that function together with non-classical class I major histocompatibility complex receptors of the H2-Mv subtype in the basal layer (21, 22). An important development has been the identification of a third family of G protein-coupled receptors expressed in subsets of VSNs as follows: the formyl peptide receptors (Fprs) (23,24). Fprs are primarily known from the innate immune system where they are involved in chemoattraction of phagocytic immune cells to sites of infection mediating host defense against invading microorganisms (25-28). Fprs detect a wide range of inflammation markers as well as bacterial and mitochondrial peptides (25-28), and consistent with the results from immune cells, some of these ligands have also been shown to activate specific VSNs (23,29). Hence, members of the Fpr family are currently prime candidates for mediating VNO pathogen sensing, although it cannot be ruled out that

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From models to mechanisms: Odorant communication as a key determinant of social behavior in rodents during illness-associated states

Cited by 118 publications

References 242 publications

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Pharmacology of a Novel Central Nervous System–Penetrant P2X7 Antagonist JNJ-42253432

Behavioral and neural correlates to multisensory detection of sick humans

Strain-specific Loss of Formyl Peptide Receptor 3 in the Murine Vomeronasal and Immune Systems

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