PIEZO2 in somatosensory neurons controls gastrointestinal transit.

The gastrointestinal tract is in a state of constant motion. These movements are tightly regulated by the presence of food and help digestion by mechanically breaking down and propelling gut content. Mechanical sensing in the gut is thought to be essential for regulating motility; however, the identity of the neuronal populations, the molecules involved, and the functional consequences of this sensation are unknown. Here, we show that humans lacking PIEZO2 exhibit impaired bowel sensation and motility. Piezo2 in mouse dorsal root, but not nodose ganglia is required to sense gut content, and this activity slows down food transit rates in the stomach, small intestine, and colon. Indeed, Piezo2 is directly required to detect colon distension in vivo. Our study unveils the mechanosensory mechanisms that regulate the transit of luminal contents throughout the gut, which is a critical process to ensure proper digestion, nutrient absorption, and waste removal.

An inter-organ neural circuit for appetite suppression.

Glucagon-like peptide-1 (GLP-1) is a signal peptide released from enteroendocrine cells of the lower intestine. GLP-1 exerts anorectic and antimotility actions that protect the body against nutrient malabsorption. However, little is known about how intestinal GLP-1 affects distant organs despite rapid enzymatic inactivation. We show that intestinal GLP-1 inhibits gastric emptying and eating via intestinofugal neurons, a subclass of myenteric neurons that project to abdominal sympathetic ganglia. Remarkably, cell-specific ablation of intestinofugal neurons eliminated intestinal GLP-1 effects, and their chemical activation functioned as a GLP-1 mimetic. GLP-1 sensing by intestinofugal neurons then engaged a sympatho-gastro-spinal-reticular-hypothalamic pathway that links abnormal stomach distension to craniofacial programs for food rejection. Within this pathway, cell-specific activation of discrete neuronal populations caused systemic GLP-1-like effects. These molecularly identified, delimited enteric circuits may be targeted to ameliorate the abdominal bloating and loss of appetite typical of gastric motility disorders.

An Airway Protection Program Revealed by Sweeping Genetic Control of Vagal Afferents.

Sensory neurons initiate defensive reflexes that ensure airway integrity. Dysfunction of laryngeal neurons is life-threatening, causing pulmonary aspiration, dysphagia, and choking, yet relevant sensory pathways remain poorly understood. Here, we discover rare throat-innervating neurons (∼100 neurons/mouse) that guard the airways against assault. We used genetic tools that broadly cover a vagal/glossopharyngeal sensory neuron atlas to map, ablate, and control specific afferent populations. Optogenetic activation of vagal P2RY1 neurons evokes a coordinated airway defense program-apnea, vocal fold adduction, swallowing, and expiratory reflexes. Ablation of vagal P2RY1 neurons eliminates protective responses to laryngeal water and acid challenge. Anatomical mapping revealed numerous laryngeal terminal types, with P2RY1 neurons forming corpuscular endings that appose laryngeal taste buds. Epithelial cells are primary airway sentinels that communicate with second-order P2RY1 neurons through ATP. These findings provide mechanistic insights into airway defense and a general molecular/genetic roadmap for internal organ sensation by the vagus nerve.

The Coding Logic of Interoception.

Interoception, the ability to precisely and timely sense internal body signals, is critical for life. The interoceptive system monitors a large variety of mechanical, chemical, hormonal, and pathological cues using specialized organ cells, organ innervating neurons, and brain sensory neurons. It is important for maintaining body homeostasis, providing motivational drives, and regulating autonomic, cognitive, and behavioral functions. However, compared to external sensory systems, our knowledge about how diverse body signals are coded at a system level is quite limited. In this review, we focus on the unique features of interoceptive signals and the organization of the interoceptive system, with the goal of better understanding the coding logic of interoception.

Evolutionarily conserved neural responses to affective touch in monkeys transcend consciousness and change with age.

Affective touch-a slow, gentle, and pleasant form of touch-activates a different neural network than which is activated during discriminative touch in humans. Affective touch perception is enabled by specialized low-threshold mechanoreceptors in the skin with unmyelinated fibers called C tactile (CT) afferents. These CT afferents are conserved across mammalian species, including macaque monkeys. However, it is unknown whether the neural representation of affective touch is the same across species and whether affective touch's capacity to activate the hubs of the brain that compute socioaffective information requires conscious perception. Here, we used functional MRI to assess the preferential activation of neural hubs by slow (affective) vs. fast (discriminative) touch in anesthetized rhesus monkeys (Macaca mulatta). The insula, anterior cingulate cortex (ACC), amygdala, and secondary somatosensory cortex were all significantly more active during slow touch relative to fast touch, suggesting homologous activation of the interoceptive-allostatic network across primate species during affective touch. Further, we found that neural responses to affective vs. discriminative touch in the insula and ACC (the primary cortical hubs for interoceptive processing) changed significantly with age. Insula and ACC in younger animals differentiated between slow and fast touch, while activity was comparable between conditions for aged monkeys (equivalent to >70 y in humans). These results, together with prior studies establishing conserved peripheral nervous system mechanisms of affective touch transduction, suggest that neural responses to affective touch are evolutionarily conserved in monkeys, significantly impacted in old age, and do not necessitate conscious experience of touch.

Single neurons in the thalamus and subthalamic nucleus process cardiac and respiratory signals in humans.

Visceral signals are constantly processed by our central nervous system, enable homeostatic regulation, and influence perception, emotion, and cognition. While visceral processes at the cortical level have been extensively studied using non-invasive imaging techniques, very few studies have investigated how this information is processed at the single neuron level, both in humans and animals. Subcortical regions, relaying signals from peripheral interoceptors to cortical structures, are particularly understudied and how visceral information is processed in thalamic and subthalamic structures remains largely unknown. Here, we took advantage of intraoperative microelectrode recordings in patients undergoing surgery for deep brain stimulation (DBS) to investigate the activity of single neurons related to cardiac and respiratory functions in three subcortical regions: ventral intermedius nucleus (Vim) and ventral caudalis nucleus (Vc) of the thalamus, and subthalamic nucleus (STN). We report that the activity of a large portion of the recorded neurons (about 70%) was modulated by either the heartbeat, the cardiac inter-beat interval, or the respiration. These cardiac and respiratory response patterns varied largely across neurons both in terms of timing and their kind of modulation. A substantial proportion of these visceral neurons (30%) was responsive to more than one of the tested signals, underlining specialization and integration of cardiac and respiratory signals in STN and thalamic neurons. By extensively describing single unit activity related to cardiorespiratory function in thalamic and subthalamic neurons, our results highlight the major role of these subcortical regions in the processing of visceral signals.

The vagus nerve in cardiovascular physiology and pathophysiology: From evolutionary insights to clinical medicine.

The parasympathetic nervous system via the vagus nerve exerts profound influence over the heart. Together with the sympathetic nervous system, the parasympathetic nervous system is responsible for fine-tuned regulation of all aspects of cardiovascular function, including heart rate, rhythm, contractility, and blood pressure. In this review, we highlight vagal efferent and afferent innervation of the heart, with a focus on insights from comparative biology and advances in understanding the molecular and genetic diversity of vagal neurons, as well as interoception, parasympathetic dysfunction in heart disease, and the therapeutic potential of targeting the parasympathetic nervous system in cardiovascular disease.

Caresses, whispers and affective faces: A theoretical framework for a multimodal interoceptive mechanism underlying ASMR and affective touch: An evolutionary and developmental perspective for understanding ASMR and affective touch as complementary processes within affiliative interactions.

Autonomous sensory meridian response (ASMR) and affective touch (AT) are two phenomena that have been independently investigated from separate lines of research. In this article, I provide a unified theoretical framework for understanding and studying them as complementary processes. I highlight their shared biological basis and positive effects on emotional and psychophysiological regulation. Drawing from evolutionary and developmental theories, I propose that ASMR results from the development of biological mechanisms associated with early affiliative behaviour and self-regulation, similar to AT. I also propose a multimodal interoceptive mechanism underlying both phenomena, suggesting that different sensory systems could specifically respond to affective stimulation (caresses, whispers and affective faces), where the integration of those inputs occurs in the brain's interoceptive hubs, allowing physiological regulation. The implications of this proposal are discussed with a view to future research that jointly examines ASMR and AT, and their potential impact on improving emotional well-being and mental health.

Rhesus monkeys have an interoceptive sense of their beating hearts.

The sensation of internal bodily signals, such as when your stomach is contracting or your heart is beating, plays a critical role in broad biological and psychological functions ranging from homeostasis to emotional experience and self-awareness. The evolutionary origins of this capacity and, thus, the extent to which it is present in nonhuman animals remain unclear. Here, we show that rhesus monkeys (Macaca mulatta) spend significantly more time viewing stimuli presented asynchronously, as compared to synchronously, with their heartbeats. This is consistent with evidence previously shown in human infants using a nearly identical experimental paradigm, suggesting that rhesus monkeys have a human-like capacity to integrate interoceptive signals from the heart with exteroceptive audiovisual information. As no prior work has demonstrated behavioral evidence of innate cardiac interoceptive ability in nonhuman animals, these results have important implications for our understanding of the evolution of this ability and for establishing rhesus monkeys as an animal model for human interoceptive function and dysfunction. We anticipate that this work may also provide an important model for future psychiatric research, as disordered interoceptive processing is implicated in a wide variety of psychiatric conditions.

Cerebellar Excitability Regulates Physical Fatigue Perception.

Fatigue is the subjective sensation of weariness, increased sense of effort, or exhaustion and is pervasive in neurologic illnesses. Despite its prevalence, we have a limited understanding of the neurophysiological mechanisms underlying fatigue. The cerebellum, known for its role in motor control and learning, is also involved in perceptual processes. However, the role of the cerebellum in fatigue remains largely unexplored. We performed two experiments to examine whether cerebellar excitability is affected after a fatiguing task and its association with fatigue. Using a crossover design, we assessed cerebellar inhibition (CBI) and perception of fatigue in humans before and after "fatigue" and "control" tasks. Thirty-three participants (16 males, 17 females) performed five isometric pinch trials with their thumb and index finger at 80% maximum voluntary capacity (MVC) until failure (force <40% MVC; fatigue) or at 5% MVC for 30 s (control). We found that reduced CBI after the fatigue task correlated with a milder perception of fatigue. In a follow-up experiment, we investigated the behavioral consequences of reduced CBI after fatigue. We measured CBI, perception of fatigue, and performance during a ballistic goal-directed task before and after the same fatigue and control tasks. We replicated the observation that reduced CBI after the fatigue task correlated with a milder perception of fatigue and found that greater endpoint variability after the fatigue task correlated with reduced CBI. The proportional relation between cerebellar excitability and fatigue indicates a role of the cerebellum in the perception of fatigue, which might come at the expense of motor control.SIGNIFICANCE STATEMENT Fatigue is one of the most common and debilitating symptoms in neurologic, neuropsychiatric, and chronic illnesses. Despite its epidemiological importance, there is a limited understanding of the neurophysiological mechanisms underlying fatigue. In a series of experiments, we demonstrate that decreased cerebellar excitability relates to lesser physical fatigue perception and worse motor control. These results showcase the role of the cerebellum in fatigue regulation and suggest that fatigue- and performance-related processes might compete for cerebellar resources.

PIEZO ion channels: force sensors of the interoceptive nervous system.

Many organs are designed to move: the heart pumps each second, the gastrointestinal tract squeezes and churns to digest food, and we contract and relax skeletal muscles to move our bodies. Sensory neurons of the peripheral nervous system detect signals from bodily tissues, including the forces generated by these movements, to control physiology. The processing of these internal signals is called interoception, but this is a broad term that includes a wide variety of both chemical and mechanical sensory processes. Mechanical senses are understudied, but rapid progress has been made in the last decade, thanks in part to the discovery of the mechanosensory PIEZO ion channels (Coste et al., 2010). The role of these mechanosensors within the interoceptive nervous system is the focus of this review. In defining the transduction molecules that govern mechanical interoception, we will have a better grasp of how these signals drive physiology.

Physiological Needs: Sensations and Predictions in the Insular Cortex.

Physiological needs create powerful motivations (e.g., thirst and hunger). Studies in humans and animal models have implicated the insular cortex in the neural regulation of physiological needs and need-driven behavior. We review prominent mechanistic models of how the insular cortex might achieve this regulation and present a conceptual and analytical framework for testing these models in healthy and pathological conditions.

Where alcohol use disorder meets interoception: A meta-analytic view on structural and functional neuroimaging data.

Alcohol use disorder (AUD) has been associated with changes in the processing of internal body signals, known as interoception. Changes in brain structure, particularly in the insula, are thought to underlie impaired interoception. As studies specifically investigating this association are largely lacking, this analysis takes an approach that compares meta-analytic results on interoception with recently published meta-analytic results on gray matter reduction in AUD. A systematic literature search identified 25 eligible interoception studies. Activation likelihood estimation (ALE) was used to test for spatial convergence of study results. Overlap between interoception and AUD clusters was tested using conjunction analysis. Meta-analytic connectivity modeling (MACM) and resting-state functional connectivity were used to identify the functional network of interoception and to test where this network overlapped with AUD meta-analytic clusters. The results were characterized using behavioral domain analysis. The interoception ALE identified a cluster in the left middle insula. There was no overlap with clusters of reduced gray matter in AUD. MACM analysis of the interoception cluster revealed a large network located in the insulae, thalami, basal nuclei, cingulate and medial frontal cortices, and pre- and postcentral gyri. Resting state analysis confirmed this result, showing the strongest connections to nodes of the salience- and somatomotor network. Five of the eight clusters that showed a structural reduction in AUD were located within these networks. The behavioral profiles of these clusters were suggestive of higher-level processes such as salience control, somatomotor functions, and skin sensations. The results suggest an altered salience mapping of interoceptive signals in AUD, consistent with current models. Connections to the somatomotor network may be related to action control and integration of skin sensations. Mindfulness-based interventions, pleasurable touch, and (deep) transcranial magnetic stimulation may be targeted interventions that reduce interoceptive deficits in AUD and thus contribute to drug use reduction and relapse prevention.

Revisiting prostaglandin E2: A promising therapeutic target for osteoarthritis.

Osteoarthritis (OA) is a complex disease characterized by cartilage degeneration and persistent pain. Prostaglandin E2 (PGE2) plays a significant role in OA inflammation and pain. Recent studies have revealed the significant role of PGE2-mediated skeletal interoception in the progression of OA, providing new insights into the pathogenesis and treatment of OA. This aspect also deserves special attention in this review. Additionally, PGE2 is directly involved in pathologic processes including aberrant subchondral bone remodeling, cartilage degeneration, and synovial inflammation. Therefore, celecoxib, a commonly used drug to alleviate inflammatory pain through inhibiting PGE2, serves not only as an analgesic for OA but also as a potential disease-modifying drug. This review provides a comprehensive overview of the discovery history, synthesis and release pathways, and common physiological roles of PGE2. We discuss the roles of PGE2 and celecoxib in OA and pain from skeletal interoception and multiple perspectives. The purpose of this review is to highlight PGE2-mediated skeletal interoception and refresh our understanding of celecoxib in the pathogenesis and treatment of OA.

The Gut-Brain Axis.

Preclinical evidence has firmly established bidirectional interactions among the brain, the gut, and the gut microbiome. Candidate signaling molecules and at least three communication channels have been identified. Communication within this system is nonlinear, is bidirectional with multiple feedback loops, and likely involves interactions between different channels. Alterations in gut-brain-microbiome interactions have been identified in rodent models of several digestive, psychiatric, and neurological disorders. While alterations in gut-brain interactions have clearly been established in irritable bowel syndrome, a causative role of the microbiome in irritable bowel syndrome remains to be determined. In the absence of specific microbial targets for more effective therapies, current approaches are limited to dietary interventions and centrally targeted pharmacological and behavioral approaches. A more comprehensive understanding of causative influences within the gut-brain-microbiome system and well-designed randomized controlled trials are needed to translate these exciting preclinical findings into effective therapies.

A framework for quantifying the coupling between brain connectivity and heartbeat dynamics: Insights into the disrupted network physiology in Parkinson's disease.

Parkinson's disease (PD) often shows disrupted brain connectivity and autonomic dysfunctions, progressing alongside with motor and cognitive decline. Recently, PD has been linked to a reduced sensitivity to cardiac inputs, that is, cardiac interoception. Altogether, those signs suggest that PD causes an altered brain-heart connection whose mechanisms remain unclear. Our study aimed to explore the large-scale network disruptions and the neurophysiology of disrupted interoceptive mechanisms in PD. We focused on examining the alterations in brain-heart coupling in PD and their potential connection to motor symptoms. We developed a proof-of-concept method to quantify relationships between the co-fluctuations of brain connectivity and cardiac sympathetic and parasympathetic activities. We quantified the brain-heart couplings from electroencephalogram and electrocardiogram recordings from PD patients on and off dopaminergic medication, as well as in healthy individuals at rest. Our results show that the couplings of fluctuating alpha and gamma connectivity with cardiac sympathetic dynamics are reduced in PD patients, as compared to healthy individuals. Furthermore, we show that PD patients under dopamine medication recover part of the brain-heart coupling, in proportion with the reduced motor symptoms. Our proposal offers a promising approach to unveil the physiopathology of PD and promoting the development of new evaluation methods for the early stages of the disease.

Transcutaneous auricular vagus nerve stimulation modulates the processing of interoceptive prediction error signals and their role in allostatic regulation.

It has recently been suggested that predictive processing principles may apply to interoception, defined as the processing of hormonal, autonomic, visceral, and immunological signals. In the current study, we aimed at providing empirical evidence for the role of cardiac interoceptive prediction errors signals on allostatic adjustments, using transcutaneous auricular vagus nerve stimulation (taVNS) as a tool to modulate the processing of interoceptive afferents. In a within-subject design, participants performed a cardiac-related interoceptive task (heartbeat counting task) under taVNS and sham stimulation, spaced 1-week apart. We observed that taVNS, in contrast to sham stimulation, facilitated the maintenance of interoceptive accuracy levels over time (from the initial, stimulation-free, baseline block to subsequent stimulation blocks), suggesting that vagus nerve stimulation may have helped to maintain engagement to cardiac afferent signals. During the interoceptive task, taVNS compared to sham, produced higher heart-evoked potentials (HEP) amplitudes, a potential readout measure of cardiac-related prediction error processing. Further analyses revealed that the positive relation between interoceptive accuracy and allostatic adjustments-as measured by heart rate variability (HRV)-was mediated by HEP amplitudes. Providing initial support for predictive processing accounts of interoception, our results suggest that the stimulation of the vagus nerve may increase the precision with which interoceptive signals are processed, favoring their influence on allostatic adjustments.

Microbial influences on gut development and gut-brain communication.

The developmental programs that build and sustain animal forms also encode the capacity to sense and adapt to the microbial world within which they evolved. This is abundantly apparent in the development of the digestive tract, which typically harbors the densest microbial communities of the body. Here, we review studies in human, mouse, zebrafish and Drosophila that are revealing how the microbiota impacts the development of the gut and its communication with the nervous system, highlighting important implications for human and animal health.

Insights into interoceptive and emotional processing: Lessons from studies on insular HD-tDCS.

Interoception, the processing of internal bodily signals, is proposed as the fundamental mechanism underlying emotional experiences. Interoceptive and emotional processing appear distorted in psychiatric disorders. However, our understanding of the neural structures involved in both processes remains limited. To explore the feasibility of enhancing interoception and emotion, we conducted two studies using high-definition transcranial direct current stimulation (HD-tDCS) applied to the right anterior insula. In study one, we compared the effects of anodal HD-tDCS and sham tDCS on interoceptive abilities (sensibility, confidence, accuracy, emotional evaluation) in 52 healthy subjects. Study two additionally included physical activation through ergometer cycling at the beginning of HD-tDCS and examined changes in interoceptive and emotional processing in 39 healthy adults. In both studies, HD-tDCS was applied in a single-blind cross-over online design with two separate sessions. Study one yielded no significant effects of HD-tDCS on interoceptive dimensions. In study two, significant improvements in interoceptive sensibility and confidence were observed over time with physical preactivation, while no differential effects were found between sham and insula stimulation. The expected enhancement of interoceptive and emotional processing following insula stimulation was not observed. We conclude that HD-tDCS targeting the insula does not consistently increase interoceptive or emotional variables. The observed increase in interoceptive sensibility may be attributed to the activation of the interoceptive network through physical activity or training effects. Future research on HD-tDCS involving interoceptive network structures could benefit from protocols targeting larger regions within the network, rather than focusing solely on insula stimulation.

The duration discrimination respiratory task: A new test to measure respiratory interoceptive accuracy.

Interoception, which refers to the perception of body's internal state, is implicated in emotional processes and psychopathological disorders. Over the last decades, different tools have been developed to measure interoceptive accuracy, or the ability to accurately perceive physiological signals. Most of these tools have focused on cardiac interoception, but respiratory interoception has been less investigated due to the more complex and less portable equipment required. In this study, we suggest a new duration discrimination respiratory (DDR) task that does not require complex equipment. Using an adaptive staircase procedure, this task aims to determine an individual's ability to detect exhalation longer than their resting reference duration. One hundred and twenty-three healthy subjects completed the DDR task, an interoceptive task of heart rate discrimination, and filled out questionnaires on interoceptive awareness (Multidimensional Assessment of Interoceptive Awareness), alexithymia (Toronto Alexithymia Scale [TAS]), affects (Positive and Negative Affect Scale [PANAS]), and anamnestic. Results demonstrated a good internal consistency (Cronbach's alpha = .93) of the DDR task. On average, subjects needed 99.22% (SD = 36.38) of their reference exhalation time in addition to reference exhalation to detect a prolonged exhalation. Higher self-reported fitness levels, not counting during the DDR task and lower difficulty in describing feelings (TAS subscale), predicted higher respiratory discrimination duration. In conclusion, this study demonstrates the utility of the DDR task as a valid measure of interoception.