Biomedical subjects

Trese Leinders-Zufall

Publications and source records attributed to Trese Leinders-Zufall.

9 recordsLinked to original sources

PubMed2006

Essential role of the main olfactory system in social recognition of major histocompatibility complex peptide ligands.

Genes of the major histocompatibility complex (MHC), which play a critical role in immune recognition, influence mating preference and other social behaviors in fish, mice, and humans via chemical signals. The cellular and molecular mechanisms by which this occurs and the nature of these chemosignals remain unclear. In contrast to the widely held view that olfactory sensory neurons (OSNs) in the main olfactory epithelium (MOE) are stimulated by volatile chemosignals only, we show here that nonvolatile immune system molecules function as olfactory cues in the mammalian MOE. Using mice with targeted deletions in selected signal transduction genes (CNGA2, CNGA4), we used a combination of dye tracing, electrophysiological, Ca2+ imaging, and behavioral approaches to demonstrate that nonvolatile MHC class I peptides activate subsets of OSNs at subnanomolar concentrations in vitro and affect social preference of male mice in vivo. Both effects depend on the cyclic nucleotide-gated (CNG) channel gene CNGA2, the function of which in the nose is unique to the main population of OSNs. Disruption of the modulatory CNGA4 channel subunit reveals a profound defect in adaptation of peptide-evoked potentials in the MOE. Because sensory neurons in the vomeronasal organ (VNO) also respond to MHC peptides but do not express CNGA2, distinct mechanisms are used by the mammalian main and accessory olfactory systems for the detection of MHC peptide ligands. These results suggest a general role for MHC peptides in chemical communication even in those vertebrates that lack a functional VNO.

Animals↗

PubMed2006

Pheromonal recognition memory induced by TRPC2-independent vomeronasal sensing.

Detection and transduction of pheromonal signals by the mouse vomeronasal organ (VNO) is critical for the formation of a persistent memory required for mate recognition in the context of selective pregnancy failure (the Bruce effect). This pregnancy block can be mediated by peptide ligands of disparate major histocompatibility complex (MHC) molecules, but little is known about the molecular mechanisms underlying this effect. Given the proposed key role of the transient receptor potential channel, TRPC2, in VNO signal transduction, we tested whether TRPC2 is essential for memory formation in the context of the Bruce effect. Surprisingly, the loss of the TRPC2 channel did not significantly influence memory formation, whereas surgical lesions of the VNO caused a profound deficit. Furthermore, field potential and single-cell patch-clamp recordings showed that TRPC2 is dispensable for the transduction of MHC peptide ligands by sensory neurons in the basal zone of the VNO. This indicates that a previously unrecognized TRPC2-independent signal transduction mechanism in the VNO underlies the sensing of cues required for the formation of this pheromonal recognition memory.

Animals↗

PubMed2005

Neurobiology of TRPC2: from gene to behavior.

The mammalian vomeronasal organ (VNO), a part of the accessory olfactory system, plays an essential role in the sensing of pheromonal signals. The VNO has emerged as an excellent model to investigate the functional role of transient receptor potential (TRP) channels in intact neurons and intact physiological systems. TRPC2, a member of the (canonical) TRPC subfamily, is highly localized to the dendritic tip of vomeronasal sensory neurons. Phenotypic analysis of mice exhibiting a targeted deletion in the TRPC2 gene has established that TRPC2 occupies a fundamental role in the transduction machinery underlying the detection of pheromone signals by the VNO. TRPC2-deficient mice exhibit striking behavioral defects in the regulation of sexual and social behaviors. A previously unknown Ca(2+)-permeable, diacylglycerol (DAG)-activated cation channel found at the dendritic tip of vomeronasal neurons is severely defective in TRPC2 mutants, providing the first clear example for the existence of native DAG-gated cation channels in the mammalian nervous system. The experimental strategy employed in the mouse VNO now serves as a powerful model for examining the native functions of other TRP genes.

Aggression↗

PubMed2005

One neuron--multiple receptors: increased complexity in olfactory coding?

Olfaction--the sense of smell--is responsible for detecting molecules of immense structural variety. Precise recognition of such diverse stimuli requires a massive receptor repertoire. This functional challenge has been met by simultaneous expression of a multitude of odor-detecting receptors that all belong to the superfamily of heterotrimeric GTP-binding protein (G protein)-coupled receptors. Studies conducted over the past decade have led to the assumption that an individual olfactory sensory neuron expresses only a single odorant receptor, consequently giving rise to the "one receptor-one neuron" hypothesis. This idea is attractive because of its simplicity and has served as the basis for models of olfactory coding. However, recent reports regarding Drosophila have found exceptions to the rule that could have important implications for the logic of olfactory coding.

Animals↗

PubMed2004

MHC class I peptides as chemosensory signals in the vomeronasal organ.

The mammalian vomeronasal organ detects social information about gender, status, and individuality. The molecular cues carrying this information remain largely unknown. Here, we show that small peptides that serve as ligands for major histocompatibility complex (MHC) class I molecules function also as sensory stimuli for a subset of vomeronasal sensory neurons located in the basal Gao- and V2R receptor-expressing zone of the vomeronasal epithelium. In behaving mice, the same peptides function as individuality signals underlying mate recognition in the context of pregnancy block. MHC peptides constitute a previously unknown family of chemosensory stimuli by which MHC genotypic diversity can influence social behavior.

Action Potentials↗

PubMed2003

A diacylglycerol-gated cation channel in vomeronasal neuron dendrites is impaired in TRPC2 mutant mice: mechanism of pheromone transduction.

Vomeronasal sensory neurons play a crucial role in detecting pheromones, but the chemoelectrical transduction mechanism remains unclear and controversial. A major barrier to the resolution of this question has been the lack of an activation mechanism of a key transduction component, the TRPC2 channel. We have identified a Ca(2+)-permeable cation channel in vomeronasal neuron dendrites that is gated by the lipid messenger diacylglycerol (DAG), independently of Ca(2+) or protein kinase C. We demonstrate that ablation of the TRPC2 gene causes a severe deficit in the DAG-gated channel, indicating that TRPC2 encodes a principal subunit of this channel and that the primary electrical response to pheromones depends on DAG but not Ins(1,4,5)P(3), Ca(2+) stores, or arachidonic acid. Thus, a previously unanticipated mechanism involving direct channel opening by DAG underlies the transduction of sensory cues in the accessory olfactory system.

Alkaloids↗

PubMed2002

Deficient pheromone responses in mice lacking a cluster of vomeronasal receptor genes.

The mammalian vomeronasal organ (VNO), a part of the olfactory system, detects pheromones--chemical signals that modulate social and reproductive behaviours. But the molecular receptors in the VNO that detect these chemosensory stimuli remain undefined. Candidate pheromone receptors are encoded by two distinct and complex superfamilies of genes, V1r and V2r (refs 3 and 4), which code for receptors with seven transmembrane domains. These genes are selectively expressed in sensory neurons of the VNO. However, there is at present no functional evidence for a role of these genes in pheromone responses. Here, using chromosome engineering technology, we delete in the germ line of mice an approximately 600-kilobase genomic region that contains a cluster of 16 intact V1r genes. These genes comprise two of the 12 described V1r gene families, and represent approximately 12% of the V1r repertoire. The mutant mice display deficits in a subset of VNO-dependent behaviours: the expression of male sexual behaviour and maternal aggression is substantially altered. Electrophysiologically, the epithelium of the VNO of such mice does not respond detectably to specific pheromonal ligands. The behavioural impairment and chemosensory deficit support a role of V1r receptors as pheromone receptors.

Aggression↗

PubMed2002

Pheromone detection by mammalian vomeronasal neurons.

The vomeronasal organ (VNO) of mammals plays an essential role in the perception of chemical stimuli of social nature including pheromone-like signals but direct evidence for the transduction of pheromones by vomeronasal sensory neurons has been lacking. The recent development of electrophysiological and optical imaging methods using confocal microscopy has enabled researchers to systematically analyze sensory responses in large populations of mouse vomeronasal neurons. These experiments revealed that vomeronasal neurons are surprisingly sensitive and highly discriminative detectors of volatile, urinary metabolites that have pheromonal activity in recipient mice. Functional mapping studies of pheromone receptor activation have uncovered the basic principles of sensory processing by vomeronasal neurons and revealed striking differences in the neural mechanisms by which chemosensory information is detected by receptor neurons in the VNO and the main olfactory epithelium. These advances offer the opportunity to decipher the logic of mammalian pheromonal communication.

Animals↗

PubMed2002

Altered sexual and social behaviors in trp2 mutant mice.

We have used gene targeting to generate mice with a homozygous deficiency in trp2, a cation channel expressed in the vomeronasal organ (VNO). Trp2 mutant animals reveal a striking reduction in the electrophysiological response to pheromones in the VNO, suggesting that trp2 plays a central role in mediating the pheromone response. These mutants therefore afford the opportunity to examine the role of the VNO in the generation of innate sexual and social behaviors in mice. Trp2 mutant males and nursing females are docile and fail to initiate aggressive attacks on intruder males. Male-female sexual behavior appears normal, but trp2 mutant males also vigorously mount other males. These results suggest that the cation channel trp2 is required in the VNO to detect male-specific pheromones that elicit aggressive behaviors and dictate the choice of sexual partners.

Aggression↗