Cortistatin deficiency reveals a dysfunctional brain endothelium with impaired gene pathways, exacerbated immune activation, and disrupted barrier integrity.

BACKGROUND: Brain activity governing cognition and behaviour depends on the fine-tuned microenvironment provided by a tightly controlled blood-brain barrier (BBB). Brain endothelium dysfunction is a hallmark of BBB breakdown in most neurodegenerative/neuroinflammatory disorders. Therefore, the identification of new endogenous molecules involved in endothelial cell disruption is essential to better understand BBB dynamics. Cortistatin is a neuroimmune mediator with anti-inflammatory and neuroprotective properties that exerts beneficial effects on the peripheral endothelium. However, its role in the healthy and injured brain endothelium remains to be evaluated. Herein, this study aimed to investigate the potential function of endogenous and therapeutic cortistatin in regulating brain endothelium dysfunction in a neuroinflammatory/neurodegenerative environment. METHODS: Wild-type and cortistatin-deficient murine brain endothelium and human cells were used for an in vitro barrier model, where a simulated ischemia-like environment was mimicked. Endothelial permeability, junction integrity, and immune response in the presence and absence of cortistatin were evaluated using different size tracers, immunofluorescence labelling, qPCR, and ELISA. Cortistatin molecular mechanisms underlying brain endothelium dynamics were assessed by RNA-sequencing analysis. Cortistatin role in BBB leakage was evaluated in adult mice injected with LPS. RESULTS: The endogenous lack of cortistatin predisposes endothelium weakening with increased permeability, tight-junctions breakdown, and dysregulated immune activity. We demonstrated that both damaged and uninjured brain endothelial cells isolated from cortistatin-deficient mice, present a dysregulated and/or deactivated genetic programming. These pathways, related to basic physiology but also crucial for the repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signalling, and metabolites transport), are dysfunctional and make brain endothelial barrier lacking cortistatin non-responsive to any further injury. Treatment with cortistatin reversed in vitro hyperpermeability, tight-junctions disruption, inflammatory response, and reduced in vivo BBB leakage. CONCLUSIONS: The neuropeptide cortistatin has a key role in the physiology of the cerebral microvasculature and its presence is crucial to develop a canonical balanced response to damage. The reparative effects of cortistatin in the brain endothelium were accompanied by the modulation of the immune function and the rescue of barrier integrity. Cortistatin-based therapies could emerge as a novel pleiotropic strategy to ameliorate neuroinflammatory/neurodegenerative disorders with disrupted BBB.

Empathy bodyssence: temporal dynamics of sensorimotor and physiological responses and the subjective experience in synchrony with the other's suffering.

Background: Empathy is foundational in our intersubjective interactions, connecting with others across bodily, emotional, and cognitive dimensions. Previous evidence suggests that observing individuals in painful situations elicits whole bodily responses, unveiling the interdependence of the body and empathy. Although the role of the body has been extensively described, the temporal structure of bodily responses and its association with the comprehension of subjective experiences remain unclear. Objective: Building upon the enactive approach, our study introduces and examines "bodyssence," a neologism formed from "body" and "essence." Our primary goal is to analyze the temporal dynamics, physiological, and phenomenological elements in synchrony with the experiences of sportspersons suffering physical accidents. Methods: Using the empirical 5E approach, a refinement of Varela's neurophenomenological program, we integrated both objective third-person measurements (postural sway, electrodermal response, and heart rate) and first-person descriptions (phenomenological data). Thirty-five participants watched videos of sportspersons experiencing physical accidents during extreme sports practice, as well as neutral videos, while standing on a force platform and wearing electrodermal and heart electrodes. Subsequently, micro-phenomenological interviews were conducted. Results: Bodyssence is composed of three distinct temporal dynamics. Forefeel marks the commencement phase, encapsulating the body's pre-reflective consciousness as participants anticipate impending physical accidents involving extreme sportspersons, manifested through minimal postural movement and high heart rate. Fullfeel, capturing the zenith of empathetic engagement, is defined by profound negative emotions, and significant bodily and kinesthetic sensations, with this stage notably featuring an increase in postural movement alongside a reduction in heart rate. In the Reliefeel phase, participants report a decrease in emotional intensity, feeling a sense of relief, as their postural control starts to reach a state of equilibrium, and heart rate remaining low. Throughout these phases, the level of electrodermal activity consistently remains high. Conclusion: This study through an enactive approach elucidates the temporal attunement of bodily experience to the pain experienced by others. The integration of both first and third-person perspectives through an empirical 5E approach reveals the intricate nature of bodyssence, offering an innovative approach to understanding the dynamic nature of empathy.

Moving beyond the lab: investigating empathy through the Empirical 5E approach.

Empathy is a complex and multifaceted phenomenon that plays a crucial role in human social interactions. Recent developments in social neuroscience have provided valuable insights into the neural underpinnings and bodily mechanisms underlying empathy. This methodology often prioritizes precision, replicability, internal validity, and confound control. However, fully understanding the complexity of empathy seems unattainable by solely relying on artificial and controlled laboratory settings, while overlooking a comprehensive view of empathy through an ecological experimental approach. In this article, we propose articulating an integrative theoretical and methodological framework based on the 5E approach (the "E"s stand for embodied, embedded, enacted, emotional, and extended perspectives of empathy), highlighting the relevance of studying empathy as an active interaction between embodied agents, embedded in a shared real-world environment. In addition, we illustrate how a novel multimodal approach including mobile brain and body imaging (MoBi) combined with phenomenological methods, and the implementation of interactive paradigms in a natural context, are adequate procedures to study empathy from the 5E approach. In doing so, we present the Empirical 5E approach (E5E) as an integrative scientific framework to bridge brain/body and phenomenological attributes in an interbody interactive setting. Progressing toward an E5E approach can be crucial to understanding empathy in accordance with the complexity of how it is experienced in the real world.

"I am feeling tension in my whole body": An experimental phenomenological study of empathy for pain.

Introduction: Traditionally, empathy has been studied from two main perspectives: the theory-theory approach and the simulation theory approach. These theories claim that social emotions are fundamentally constituted by mind states in the brain. In contrast, classical phenomenology and recent research based on the enactive theories consider empathy as the basic process of contacting others' emotional experiences through direct bodily perception and sensation. Objective: This study aims to enrich the knowledge of the empathic experience of pain using an experimental phenomenological method. Materials and methods: Implementing an experimental paradigm used in affective neuroscience, we exposed 28 healthy adults to a video of sportspersons suffering physical accidents while practicing extreme sports. Immediately after watching the video, each participant underwent a phenomenological interview to gather data on embodied, multi-layered dimensions (bodily sensations, emotions, and motivations) and temporal aspects of empathic experience. We also performed quantitative analyses of the phenomenological categories. Results: Experiential access to the other person's painful experience involves four main themes. Bodily resonance: participants felt a multiplicity of bodily, affective, and kinesthetic sensations in coordination with the sportsperson's bodily actions. Attentional focus: some participants centered their attention more on their own personal discomfort and sensations of rejection, while others on the pain and suffering experienced by the sportspersons. Kinesthetic motivation: some participants experienced the feeling in their bodies to avoid or escape from watching the video, while others experienced the need to help the sportspersons avoid suffering any injury while practicing extreme sports. The temporality of experience: participants witnessed temporal fluctuations in their experiences, bringing intensity changes in their bodily resonance, attentional focus, and kinesthetic motivation. Finally, two experiential structures were found: one structure is self-centered empathic experience, characterized by bodily resonance, attentional focus centered on the participant's own experience of seeing the sportsperson suffering, and self-protective kinesthetic motivation; the other structure is other-centered empathic experience, characterized by bodily resonance, attentional focus centered on the sportsperson, and prosocial kinesthetic motivation to help them. Discussion: We show how phenomenological data may contribute to comprehending empathy for pain in social neuroscience. In addition, we address the phenomenological aspect of the enactive approach to the three dimensions of an embodiment of human consciousness, especially the intersubjective dimension. Also, based on our results, we suggest an extension of the enactive theory of non-interactive social experience.