Placental senescence pathophysiology is shared between peripartum cardiomyopathy and preeclampsia in mouse and human.

Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator-activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.

Past, present and future of zebrafish in epilepsy research.

Animal models contribute greatly to our understanding of brain development and function as well as its dysfunction in neurological diseases. Epilepsy research is a very good example of how animal models can provide us with a mechanistic understanding of the genes, molecules, and pathophysiological processes involved in disease. Over the course of the last two decades, zebrafish came in as a new player in epilepsy research, with an expanding number of laboratories using this animal to understand epilepsy and to discover new strategies for preventing seizures. Yet, zebrafish as a model offers a lot more for epilepsy research. In this viewpoint, we aim to highlight some key contributions of zebrafish to epilepsy research, and we want to emphasize the great untapped potential of this animal model for expanding these contributions. We hope that our suggestions will trigger further discussions between clinicians and researchers with a common goal to understand and cure epilepsy.

Mating Suppresses Alarm Response in Zebrafish.

Mating and flight from threats are innate behaviors that enhance species survival [1, 2]. Stimuli to these behaviors often are contemporaneous and conflicting [3, 4]. Both how such conflicts are resolved and where in the brain such decisions are made are poorly understood. For teleosts, olfactory stimuli are key elements of mating and threat responses [5-7]. For example, zebrafish manifest a stereotypical escape response when exposed to an alarm substance released from injured conspecific skin ("skin extract") [8, 9]. We find that when mating, fish ignore this threatening stimulus. Water conditioned by the mating fish ("mating water") suffices to suppress much of the alarm-response behavior. By 2-photon imaging of calcium transients [10], we mapped the regions of the brain responding to skin extract and to mating water. In the telencephalon, we found regions where the responses overlap, one region (medial Dp) to be predominantly activated by skin extract, and another, Vs, to be predominantly activated by mating water. When mating water and skin extract were applied simultaneously, the alarm-specific response was suppressed, while the mating-water-specific response was retained, corresponding to the dominance of mating over flight behavior. The choice made, for reproduction over escape, is opposite to that of mammals, presumably reflecting how the balance affects species survival.

Glia-neuron interactions underlie state transitions to generalized seizures.

Brain activity and connectivity alter drastically during epileptic seizures. The brain networks shift from a balanced resting state to a hyperactive and hypersynchronous state. It is, however, less clear which mechanisms underlie the state transitions. By studying neural and glial activity in zebrafish models of epileptic seizures, we observe striking differences between these networks. During the preictal period, neurons display a small increase in synchronous activity only locally, while the gap-junction-coupled glial network was highly active and strongly synchronized across large distances. The transition from a preictal state to a generalized seizure leads to an abrupt increase in neural activity and connectivity, which is accompanied by a strong alteration in glia-neuron interactions and a massive increase in extracellular glutamate. Optogenetic activation of glia excites nearby neurons through the action of glutamate and gap junctions, emphasizing a potential role for glia-glia and glia-neuron connections in the generation of epileptic seizures.

Motile-Cilia-Mediated Flow Improves Sensitivity and Temporal Resolution of Olfactory Computations.

Motile cilia are actively beating hair-like structures that cover the surface of multiple epithelia. The flow that ciliary beating generates is utilized for diverse functions and depends on the spatial location and biophysical properties of cilia. Here we show that the motile cilia in the nose of aquatic vertebrates are spatially organized and stably beat with an asymmetric pattern, resulting in a robust and stereotypical flow around the nose. Our results demonstrate that these flow fields attract odors to the nose pit and facilitate detection of odors by the olfactory system in stagnant environments. Moreover, we show that ciliary beating quickly exchanges the content of the nose, thereby improving the temporal resolution of the olfactory system for detecting dynamic changes of odor plumes in turbulent environments. Altogether, our work unravels a central function of ciliary beating for generating flow fields that increase the sensitivity and the temporal resolution of olfactory computations in the vertebrate brain.