Pleiotropy alleviates the fitness costs associated with resource allocation trade-offs in immune signalling networks.

Many genes and signalling pathways within plant and animal taxa drive the expression of multiple organismal traits. This form of genetic pleiotropy instigates trade-offs among life-history traits if a mutation in the pleiotropic gene improves the fitness contribution of one trait at the expense of another. Whether or not pleiotropy gives rise to conflict among traits, however, likely depends on the resource costs and timing of trait deployment during organismal development. To investigate factors that could influence the evolutionary maintenance of pleiotropy in gene networks, we developed an agent-based model of co-evolution between parasites and hosts. Hosts comprise signalling networks that must faithfully complete a developmental programme while also defending against parasites, and trait signalling networks could be independent or share a pleiotropic component as they evolved to improve host fitness. We found that hosts with independent developmental and immune networks were significantly more fit than hosts with pleiotropic networks when traits were deployed asynchronously during development. When host genotypes directly competed against each other, however, pleiotropic hosts were victorious regardless of trait synchrony because the pleiotropic networks were more robust to parasite manipulation, potentially explaining the abundance of pleiotropy in immune systems despite its contribution to life history trade-offs.

Pleiotropy promotes the evolution of inducible immune responses in a model of host-pathogen coevolution.

Components of immune systems face significant selective pressure to efficiently use organismal resources, mitigate infection, and resist parasitic manipulation. A theoretically optimal immune defense balances investment in constitutive and inducible immune components depending on the kinds of parasites encountered, but genetic and dynamic constraints can force deviation away from theoretical optima. One such potential constraint is pleiotropy, the phenomenon where a single gene affects multiple phenotypes. Although pleiotropy can prevent or dramatically slow adaptive evolution, it is prevalent in the signaling networks that compose metazoan immune systems. We hypothesized that pleiotropy is maintained in immune signaling networks despite slowed adaptive evolution because it provides some other advantage, such as forcing network evolution to compensate in ways that increase host fitness during infection. To study the effects of pleiotropy on the evolution of immune signaling networks, we used an agent-based modeling approach to evolve a population of host immune systems infected by simultaneously co-evolving parasites. Four kinds of pleiotropic restrictions on evolvability were incorporated into the networks, and their evolutionary outcomes were compared to, and competed against, non-pleiotropic networks. As the networks evolved, we tracked several metrics of immune network complexity, relative investment in inducible and constitutive defenses, and features associated with the winners and losers of competitive simulations. Our results suggest non-pleiotropic networks evolve to deploy highly constitutive immune responses regardless of parasite prevalence, but some implementations of pleiotropy favor the evolution of highly inducible immunity. These inducible pleiotropic networks are no less fit than non-pleiotropic networks and can out-compete non-pleiotropic networks in competitive simulations. These provide a theoretical explanation for the prevalence of pleiotropic genes in immune systems and highlight a mechanism that could facilitate the evolution of inducible immune responses.

Short-term changes in cortical physiological arousal measured by electroencephalography during thalamic centromedian deep brain stimulation.

OBJECTIVE: The intralaminar thalamus is well implicated in the processes of arousal and attention. Stimulation of the intralaminar thalamus has been used therapeutically to improve level of alertness in minimally conscious individuals and to reduce seizures in refractory epilepsy, both presumably through modulation of thalamocortical function. Little work exists that directly measures the effects of intralaminar thalamic stimulation on cortical physiological arousal in humans. Therefore, our goal was to quantify cortical physiological arousal in individuals with epilepsy receiving thalamic intralaminar deep brain stimulation. METHODS: We recorded scalp electroencephalogram (EEG) during thalamic intralaminar centromedian (CM) nucleus stimulation in 11 patients with medically refractory epilepsy. Participants underwent stimulation at 130 Hz and 300 µs for periods of 5 min alternating with 5 min of rest while stimulus voltage was titrated upward from 1 to 5 V. EEG signal power was analyzed in different frequency ranges in relation to stimulus strength and time. RESULTS: We found a progressive increase in broadband gamma (25-100 Hz) cortical EEG power (F = 7.64, p < .05) and decrease in alpha (8-13 Hz) power (F = 4.37, p < .05) with thalamic CM stimulation. Topographic maps showed these changes to be widely distributed across the cortical surface rather than localized to one region. SIGNIFICANCE: Previous work has shown that broadband increases in gamma frequency power and decreases in alpha frequency power are generally associated with states of cortical activation and increased arousal/attention. Our observed changes therefore support the possible role of cortical activation and increased physiological arousal in therapeutic effects of intralaminar thalamic stimulation for improving both epilepsy and attention. Further investigations with this approach may lead to methods for determining optimal deep brain stimulation parameters to improve clinical outcome in these disorders.