Mammalian Pheromones: From Genes to Behaviour

AbstractKnocking-out selected genes for receptors of the vomeronasal organ has been found to impair specific aspects of pheromone-induced behaviour in the mouse. This is not unexpected; less predictable is the finding that deleting the gene for a vomeronasal-organ-specific ion channel causes gender blindness

Resilience and Depressive Symptoms in Midlife Women

Rates of depression are increasing throughout the world, with women experiencing depression twice as often as men. This study utilized the Neuman Systems Model to examine the relationship in midlife women between depressive symptoms and resilience. Women ages 35-55, selected from four health care settings, completed written surveys on demographic information, life events, depression, and resilience. Results supported depressive symptoms as a health concern for mid-life women: 32% reporting current or previous treatment for depression, and 24% screening positive for depression. Resilience, measured by the Polk Resilience Patterns Scale, was related to education, perceived health, conflict in the living situation, and financial resources. It was inversely correlated with depressive symptoms. Depressive symptoms were related to perceived health, conflict in the living situation, financial resources, and sleep. Negative life events and the situational and philosophical resilience subscales contributed to 64% of the variance in the measure of depressive symptoms

The evolution of pheromonal communication

Small-brained rodents have been the principle focus for pheromonal research and have provided comprehensive insights into the chemosensory mechanisms that underpin pheromonal communication and the hugely important roles that pheromones play in behavioural regulation. However, pheromonal communication does not start or end with the mouse and the rat, and work in amphibians reveals much about the likely evolutionary origins of the chemosensory systems that mediate pheromonal effects. The dual olfactory organs (the main olfactory epithelium and the vomeronasal organ), their receptors and their separate projection pathways appear to have ancient evolutionary origins, appearing in the aquatic ancestors of all tetrapods during the Devonian period and so pre-dating the transition to land. While the vomeronasal organ has long been considered an exclusively pheromonal organ, accumulating evidence indicates that it is not the sole channel for the transduction of pheromonal information and that both olfactory systems have been co-opted for the detection of different pheromone signals over the course of evolution. This has also led to great diversity in the vomeronasal and olfactory receptor families, with enormous levels of gene diversity and inactivation of genes in different species. Finally, the evolution of trichromacy as well as huge increases in social complexity have minimised the role of pheromones in the lives of primates, leading to the total inactivation of the vomeronasal system in catarrhine primates while the brain increased in size and behaviour became emancipated from hormonal regulation. © 2008 Elsevier B.V. All rights reserved

Computational and experimental studies of novel β-adrenoceptor ligands

With over 30% of available drugs targeting them, G protein-coupled receptors (GPCRs) are of significant pharmaceutical interest. Efforts to understand protein-ligand interactions among this group of proteins have been aided by the increase in available x-ray crystallography structures. β1-Adrenergic receptor (β1-AR) antagonists are used as treatment in patients with cardiovascular and airway conditions. However, current widely used medications are considerably prone to off-target side effects due to the lack of selectivity between the β1- and β2-AR subtypes. Therefore, a deeper understanding into the structural differences in characteristics is necessary to utilise them as a means of increasing ligand selectivity and therefore reducing the prevalence of off-target side effects. Here, two characteristics of the β1-AR are targeted as a means of increasing receptor selectivity. The first being receptor plasticity - recent research has shown that β-ARs contain a fissure between transmembrane helices 4 and 5 (TM4, TM5) (dubbed the ‘keyhole’) that differ slightly between β-AR subtypes that may accommodate for extended moieties or ligand entry and exit via the intramembrane space. The second characteristic being receptor dimerization. Receptor dimerization among GPCRs remains an active area of research, that so far has many pharmacological implications. Targeting receptor homodimerization has been proposed to be a method of improving receptor specificity within GPCRs. Research into β-AR dimers and findings from X-ray crystallography have shown that β1-AR homodimers may indeed align with a TM4/TM5 interface, aligning the ‘keyhole’. By combining and exploring both characteristics, we designed and computationally validated bivalent ligands capable of taking advantage of two unique β1-AR structural features as a means of improving ligand selectivity. Most current attempts at bivalent ligands in GPCRs explore using the extracellular space as a spacing route, leading to longer ligands, undesirably affecting molecular weight, lipophilicity, and viability. However, to validate our ligand design, we computationally demonstrate – by analyzing all-atom molecular dynamics (MD) simulations – that those ligands long enough to extend beyond the receptor via the keyhole can bind canonically and maintain key interactions that have previously been pharmacologically verified, as well as investigate structure activity relationships (SARs) of differing steric and electronic configurations of ligand components exposed to the intramembrane space. Bivalent ligand linkers were designed and computationally investigated within a GPCR dimer system to determine whether flexibility of the linker impacts the pharmacophores’ ability to maintain key canonical interactions. Long timescale coarse grained simulations of a membrane-bound β1-AR dimer showed the dimer interface to be stable, so shorter all-atom simulations could be used with confidence to aid bivalent ligand design. Bivalent ligands of the nature discussed in this work required at least one pharmacophore to enter/exit the receptor orthosteric binding site via the keyhole route. In house enhanced sampling computational methods were developed to study and validate the feasibility of this entry and exit route. Ligand exit pathways were generated by performing self-avoiding walk MD on protein-ligand complexes, then used to define starting and end points for weighted ensemble molecular dynamics (WEMD) to predict kinetic rate constants. These rate constants were then verified against pharmacologically derived β-AR kinetics data to validate the method, model, and ligand entry/exit pathway. The designed ligands would then lead to shorter and less hindering spacing between orthosteric sites

The Paternally Expressed Gene Peg3 Regulates Sexual Experience-Dependent Preferences for Estrous Odors

Sexual experience has marked and long-lasting effects on male behavior in mammals, regulating traits such as the anticipation and display of sexual behavior, aggression and olfaction. We conducted urine preference, habituation-dishabituation and partner choice tests with sexually experienced and naïve male mice and found that wild-type males acquire adaptively significant preferences for the odors of receptive, estrous females with sexual experience, and that these preferences are matched by changes in main olfactory system responses involving the piriform cortex, as indicated by c-Fos expression. We also report that these experiential effects are disrupted in male mice carrying a knockout of the imprinted gene Peg3. This paternally expressed gene regulates maternal care and offspring development, but we here report that Peg3 mutant males suffer a complex olfactory deficit that affects estrous odor preferences and the responses of the main olfactory system to such odors. Peg3 appears to have evolved to regulate the experience-dependent preference for receptive females, an adaptive trait that would enhance male reproductive success and so potentially increase paternal transmission of this paternally expressed gene

GLIMPS: A Machine Learning Approach to Resolution Transformation for Multiscale Modeling

We describe a general approach to transforming molecular models between different levels of resolution, based on machine learning methods. The approach uses a matched set of models at both levels of resolution for training, but requires only the coordinates of their particles and no side information (e.g., templates for substructures, defined mappings, or molecular mechanics force fields). Once trained, the approach can transform further molecular models of the system between the two levels of resolution in either direction with equal facility

Social creatures: model animal systems for studying the neuroendocrine mechanisms of social behaviour

Work was supported by grants awarded to ML (BBSRC BB/S000224/1), OJB (BO 1958/8-2, GRK 2174), KEB (Wellcome Trust 109614/Z/15/Z, MRC MR/N004574/1), AJ (BBSRC BB/S000801) and GL (Israel Science Foundation #1511/16; United States-Israel Binational Science Foundation #2017325; Nella and Leon Benoziyo Center for Neurological Diseases, Richard F. Goodman Yale/Weizmann Exchange Program and Estate of Emile Mimran).The interaction of animals with conspecifics, termed social behaviour, has a major impact on the survival of many vertebrate species. Neuropeptide hormones modulate the underlying physiology that governs social interactions, and many findings concerning the neuroendocrine mechanisms of social behaviours have been extrapolated from animal models to humans. Neurones expressing neuropeptides show similar distribution patterns within the hypothalamic nucleus, even when evolutionarily distant species are compared. During evolution, hypothalamic neuropeptides and releasing hormones have retained not only their structures, but also their biological functions, including their effects on behaviour. Here, we review the current understanding of the mechanisms of social behaviours in several classes of animals, such as worms, insects and fish, as well as laboratory, wild and domesticated mammals.Publisher PDFPeer reviewe

More Functional V1R Genes Occur in Nest-Living and Nocturnal Terricolous Mammals

Size of the vomeronasal type 1 receptor (V1R) gene repertoire may be a good indicator for examining the relationship between animal genomes and their environmental niche specialization, especially the relationship between ecological factors and the molecular evolutionary history of the sensory system. Recently, Young et al. (Young JM, Massa HF, Hsu L, Trask BJ. 2009. Extreme variability among mammalian V1R gene families. Genome Res.) concluded that no single ecological factor could explain the extreme variability of the V1R gene repertoire in mammalian genomes. In contrast, we found a significant positive correlation between the size and percentage of intact V1R genes in 32 species that represent the phylogenetic diversity of terricolous mammals and two ecological factors: spatial activity and rhythm activity. Nest-living species possessed a greater number of intact V1R genes than open-living species, and nocturnal terricolous mammals tended to possess more intact V1R genes than did diurnal species. Moreover, our analysis reveals that the evolutionary mechanisms underlying these observations likely resulted from the rapid gene birth and accelerated amino acid substitutions in nest-living and nocturnal mammals, likely a functional requirement for exploiting narrow, dark environments. Taken together, these results reveal how adaptation to divergent circadian rhythms and spatial activity were manifested at the genomic scale. Size of the V1R gene family might have indicated how this gene family adapts to ecological factors

Neural mechanisms of social learning in the female mouse

Social interactions are often powerful drivers of learning. In female mice, mating creates a long-lasting sensory memory for the pheromones of the stud male that alters neuroendocrine responses to his chemosignals for many weeks. The cellular and synaptic correlates of pheromonal learning, however, remain unclear. We examined local circuit changes in the accessory olfactory bulb (AOB) using targeted ex vivo recordings of mating-activated neurons tagged with a fluorescent reporter. Imprinting led to striking plasticity in the intrinsic membrane excitability of projection neurons (mitral cells, MCs) that dramatically curtailed their responsiveness, suggesting a novel cellular substrate for pheromonal learning. Plasticity was selectively expressed in the MC ensembles activated by the stud male, consistent with formation of memories for specific individuals. Finally, MC excitability gained atypical activity-dependence whose slow dynamics strongly attenuated firing on timescales of several minutes. This unusual form of AOB plasticity may act to filter sustained or repetitive sensory signals.R21 DC013894 - NIDCD NIH HH