SK Current, Expressed During the Development and Regeneration of Chick Hair Cells, Contributes to the Patterning of Spontaneous Action Potentials

Chick hair cells display calcium (Ca2+)-sensitive spontaneous action potentials during development and regeneration. The role of this activity is unclear but thought to be involved in establishing proper synaptic connections and tonotopic maps, both of which are instrumental to normal hearing. Using an electrophysiological approach, this work investigated the functional expression of Ca2+-sensitive potassium [IK(Ca)] currents and their role in spontaneous electrical activity in the developing and regenerating hair cells (HCs) in the chick basilar papilla. The main IK(Ca) in developing and regenerating chick HCs is an SK current, based on its sensitivity to apamin. Analysis of the functional expression of SK current showed that most dramatic changes occurred between E8 and E16. Specifically, there is a developmental downregulation of the SK current after E16. The SK current gating was very sensitive to the availability of intracellular Ca2+ but showed very little sensitivity to T-type voltage-gated Ca2+ channels, which are one of the hallmarks of developing and regenerating hair cells. Additionally, apamin reduced the frequency of spontaneous electrical activity in HCs, suggesting that SK current participates in patterning the spontaneous electrical activity of HCs.

Even under majority influence, great apes fail to copy novel actions

It remains unclear when and why the ability to copy actions evolved and also its uniqueness to humans. Thus far, a lack of valid evidence for spontaneous action copying by other apes supports the view that only humans spontaneously copy actions. However, wild apes have access to multiple demonstrators and have been demonstrated to be affected by majority influences, thus raising the possibility that ape action copying might require a majority ratio of demonstrators to observers. We tested for spontaneous ape action copying across all four non-human great ape species using a demonstrator majority. Nineteen captive mother-reared apes (across 4 species) were tested (Raage=9-52; Mage=18.63; ♀=14; ♂=5). All failed to copy the demonstrated actions, despite observing it in a majority influence condition. We conclude that culture in non-human great apes is more likely supported by variants of social learning which regulate frequencies, rather than forms, of observed behaviours.

Ritual and Thought: Spirituality and Method in Philosophy of Religion

This paper outlines a strain of French Spiritualism, a philosophical tradition extending from Maine de Biran, Félix Ravaisson, and Jules Lachelier to their reception in the work of Maurice Blondel and his protégé Henry Duméry. In receiving and transforming this tradition, Blondel and Duméry have helped to provide a distinct philosophical paradigm in philosophy of religion, capable of providing insight into the spiritual nature of the human being, both in how spirituality relates to the advanced stages of religious culture in addition to its primitive presence in spontaneous action. As a tradition consecrated to the study of human consciousness, and the operations of the mind [l’esprit], the French spiritualist tradition provides a rich conceptual matrix for analyzing the nature of human thinking and its relationship to action. In such an analysis of human thought, Maurice Blondel set up a moral psychology and metaphysical anthropology, highlighting how the consciousness of the human being is linked to the objective order of existence, both in its material form and in the intelligible realities behind the nature of existence. This philosophical matrix helps to show how religious practices, through embodied engagement with the material world, are effective at generating a consciousness of metaphysical or transcendent realities. As such, this philosophical paradigm provides the means for constructing a theory of ritual, where ritual acts with symbols and signs may be rendered intelligible as the sensible means for the cognitive expression of spiritual activity.

The natural compound TMYX reduces SAN cells rate by antagonizing the cAMP modulation of f-channels

Tongmai Yangxin (TMYX), is a complex compound of a Traditional Chinese Medicine (TCM) used to treat several cardiac rhythm disorders; however, no information regarding its mechanism of action is available. In this study we provide a detailed characterization of the effects of TMYX on the electrical activity of pacemaker cells and unravel its mechanism of action. Single-cell electrophysiology revealed that TMYX elicits a reversible and dose-dependent (2/6 mg/ml) slowing of spontaneous action potentials rate (-20.8/-50.2%) by a selective reduction of the diastolic phase (-50.1/-76.0%). This action is mediated by a negative shift of the If activation curve (-6.7/-11.9 mV) and is caused by a reduction of the cAMP-induced stimulation of pacemaker channels. We provide evidence that TMYX acts by directly antagonizes the cAMP-induced allosteric modulation of the pacemaker channels. Noticeably, this mechanism functionally resembles the pharmacological actions of muscarinic stimulation or β-blockers, but it does not require generalized changes in cytoplasmic cAMP levels thus ensuring a selective action on rate. In agreement with a competitive inhibition mechanism, TMYX exerts its maximal antagonistic action at submaximal cAMP concentrations and then progressively becomes less effective thus ensuring a full contribution of If to pacemaker rate during high metabolic demand and sympathetic stimulation.

Experience-Specific Dimensions of Consciousness (Observable in Flexible and Spontaneous Action Planning Among Animals)

The multidimensional framework to the study of consciousness, which comes as an alternative to a single sliding scale model, offers a set of experimental paradigms for investigating dimensions of animal consciousness, acknowledging the compelling urge for a novel approach. One of these dimensions investigates whether non-human animals can flexibly and spontaneously plan for a future event, and for future desires, without relying on reinforcement learning. This is a critical question since different intentional structures for action in non-human animals are described as served by different neural mechanisms underpinning the capacity to represent temporal properties. And a lack of appreciation of this variety of intentional structures and neural correlates has led many experts to doubt that animals have access to temporal reasoning and to not recognize temporality as a mark of consciousness, and as a psychological resource for their life. With respect to this, there is a significant body of ethological evidence for planning abilities in non-human animals, too often overlooked, and that instead should be taken into serious account. This could contribute to assigning consciousness profiles, across and within species, that should be tailored according to an implemented and expansive use of the multidimensional framework. This cannot be fully operational in the absence of an additional tag to its dimensions of variations: the experience-specificity of consciousness.

Acute Genetic Ablation of Cardiac Sodium/Calcium Exchange in Adult Mice: Implications for Cardiomyocyte Calcium Regulation, Cardioprotection, and Arrhythmia

Background Sodium‐calcium (Ca 2+ ) exchanger isoform 1 (NCX1) is the dominant Ca 2+ efflux mechanism in cardiomyocytes and is critical to maintaining Ca 2+ homeostasis during excitation‐contraction coupling. NCX1 activity has been implicated in the pathogenesis of cardiovascular diseases, but a lack of specific NCX1 blockers complicates experimental interpretation. Our aim was to develop a tamoxifen‐inducible NCX1 knockout (KO) mouse to investigate compensatory adaptations of acute ablation of NCX1 on excitation‐contraction coupling and intracellular Ca 2+ regulation, and to examine whether acute KO of NCX1 confers resistance to triggered arrhythmia and ischemia/reperfusion injury. Methods and Results We used the α‐myosin heavy chain promoter (Myh6)‐MerCreMer promoter to create a tamoxifen‐inducible cardiac‐specific NCX1 KO mouse. Within 1 week of tamoxifen injection, NCX1 protein expression and current were dramatically reduced. Diastolic Ca 2+ increased despite adaptive reductions in Ca 2+ current and action potential duration and compensatory increases in excitation‐contraction coupling gain, sarcoplasmic reticulum Ca 2+ ATPase 2 and plasma membrane Ca2+ ATPase. As these adaptations progressed over 4 weeks, diastolic Ca 2+ normalized and SR Ca 2+ load increased. Left ventricular function remained normal, but mild fibrosis and hypertrophy developed. Transcriptomics revealed modification of cardiovascular‐related gene networks including cell growth and fibrosis. NCX1 KO reduced spontaneous action potentials triggered by delayed afterdepolarizations and reduced scar size in response to ischemia/reperfusion. Conclusions Tamoxifen‐inducible NCX1 KO mice adapt to acute genetic ablation of NCX1 by reducing Ca 2+ influx, increasing alternative Ca 2+ efflux pathways, and increasing excitation‐contraction coupling gain to maintain contractility at the cost of mild Ca 2+ ‐activated hypertrophy and fibrosis and decreased survival. Nevertheless, KO myocytes are protected against spontaneous action potentials and ischemia/reperfusion injury.

Bidirectional flow of the funny current (If) during the pacemaking cycle in murine sinoatrial node myocytes

Sinoatrial node myocytes (SAMs) act as cardiac pacemaker cells by firing spontaneous action potentials (APs) that initiate each heartbeat. The funny current (If) is critical for the generation of these spontaneous APs; however, its precise role during the pacemaking cycle remains unresolved. Here, we used the AP-clamp technique to quantify If during the cardiac cycle in mouse SAMs. We found that If is persistently active throughout the sinoatrial AP, with surprisingly little voltage-dependent gating. As a consequence, it carries both inward and outward current around its reversal potential of −30 mV. Despite operating at only 2 to 5% of its maximal conductance, If carries a substantial fraction of both depolarizing and repolarizing net charge movement during the firing cycle. We also show that β-adrenergic receptor stimulation increases the percentage of net depolarizing charge moved by If, consistent with a contribution of If to the fight-or-flight increase in heart rate. These properties were confirmed by heterologously expressed HCN4 channels and by mathematical models of If. Modeling further suggested that the slow rates of activation and deactivation of the HCN4 isoform underlie the persistent activity of If during the sinoatrial AP. These results establish a new conceptual framework for the role of If in pacemaking, in which it operates at a very small fraction of maximal activation but nevertheless drives membrane potential oscillations in SAMs by providing substantial driving force in both inward and outward directions.

AT1a dependent GABAA inhibition in the MnPO following chronic intermittent hypoxia

Chronic intermittent hypoxia (CIH) is associated with diurnal hypertension, increased sympathetic nerve activity (SNA), and increases in circulating angiotensin II (ANG II). In rats, CIH increases angiotensin type 1 (AT1a) receptor expression in the median preoptic nucleus (MnPO), and pharmacological blockade or viral knockdown of this receptor prevents CIH dependent increases in diurnal blood pressure. The current study investigates the role of AT1a receptor in modulating the activity of MnPO neurons following 7 days of CIH. Male Sprague-Dawley rats received MnPO injections of an adeno-associated virus with a shRNA against the AT1a receptor or a scrambled control. Rats were then exposed to CIH 8 h a day for 7 days. In vitro loose patch recordings of spontaneous action potential activity were made from labeled MnPO neurons in response to brief focal application of ANG II or the GABAA receptor agonist muscimol. Additionally, MnPO KCC2 protein expression was assessed using Western blot. CIH impaired the duration but not the magnitude of ANG II mediated excitation in the MnPO. Both CIH and AT1a knockdown also impaired GABAA mediated inhibition and CIH with AT1a knockdown produced GABAA mediated excitation. Recordings using the ratiometric Cl- indicator ClopHensorN showed CIH was associated with Cl- efflux in MnPO neurons that was associated with decreased KCC2 phosphorylation. The combination of CIH and AT1a knockdown attenuated reduced KCC2 phosphorylation seen with CIH alone. The current study shows that CIH, through the activity of AT1a receptors, can impair GABAA mediated inhibition in the MnPO contributing sustained hypertension.

Democratic Action, Spontaneity, and the Intermediating Practices of Political Friendship

This chapter accomplishes two goals. First, it critically engages with the contemporary debates on the last decade’s democratic uprisings to demonstrate the ongoing influence of Rousseau’s emphasis on immediacy in democratic theory. By casting organization as that which precedes politics and moments of spontaneous action as sudden explosions, contemporary accounts reduce spontaneity to immediacy. Thus, they both erase on-the-ground practices of the political actors, and, taking an antidemocratic Rousseauian turn, construe the transience and unpredictability of democratic events as problems to be resolved under the guidance of the theorist. Second, the chapter appropriates Aristotle’s notion of political friendship, laying the groundwork for the conception of democratic action developed in the book, and arguing that democratic events are created in and through “intermediating practices,” including deliberation, judging, negotiation, artistic production, and common use. Through intermediating practices, people establish relations with strangers, constitute a common amid disagreements, and stage their equality as political friends.

Jean-Jacques Rousseau

This chapter offers an innovative interpretive analysis of Rousseau’s literary and political works, highlighting how his formulation of popular sovereignty as the immediate expression of the people rests on a critique of the theater’s conspicuous artificiality. Contrary to the established reading, Rousseau’s alternative to the theater is not the public festival, which he finds unpredictable and fragile due to its performative nature. Rousseau models his conception of politics on a different form of aesthetic experience, which he develops in Pygmalion—a monodrama that depicts the encounter between a sculptor and his work of art. The Social Contract embodies this aesthetic experience whose paradigmatic example comes from plastic arts. The chapter concludes with an exploration of the antidemocratic implications of this turn to plastic arts, which resurfaces in the works of contemporary theorists who share Rousseau’s idealization of the supposed immediacy of spontaneous action and his desire to remedy its fragility and unpredictability.