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Overview of cardiac innervation. (A) Schematic drawing of the cardiac visceral innervation system. Cardiac innervation starts with a signal from the heart or baroreceptors (e.g., on the aorta), relayed by sensory nerves (blue) giving feedback on, for instance, the levels of oxygen, carbon dioxide and blood pressure. The brain will give a signal to parasympathetic or sympathetic nerves to either relax or stimulate the heart. Parasympathetic innervation is achieved mainly via the vagal nerve (green) that will synapse in cardiac ganglia from where postganglionic nerves innervate the SA node and AV node, and potentially ventricular myocytes. Sympathetic neurons (red) start in the grey matter of the spinal cord, where interneurons (orange) from the brain project to the sympathetic neurons. Via the ventral root of the spinal cord, sympathetic nerves synapse in the sympathetic chain, from where postganglionic nerves will enter the heart; (B) This wax mold shows how cardiac nerves enter via the cardiac plexus and follow cardiac vessels over the heart. Courtesy of: Museo delle Cere Anatomiche " Luigi Cattaneo, " University Museum System, Alma Mater Studiorum—University of Bologna, picture taken by Dr. E.A.J.F. Lakke. Ao = aorta, DRG = dorsal root ganglion, LV = left ventricle, Pu = pulmonary artery, RA = right atrium, RV = right ventricle.
Source publication
The autonomic nervous system (cANS) is essential for proper heart function, and complications such as heart failure, arrhythmias and even sudden cardiac death are associated with an altered cANS function. A changed innervation state may underlie (part of) the atrial and ventricular arrhythmias observed after myocardial infarction. In other cardiac...
Citations
... Drugs targeting the CNS can decrease activation of sympathetic nerves but were shown to be ineffective in reducing arrhythmia risk (Cohn et al., 2003;Florea & Cohn, 2014), whereas peripheral blockade of sympathetic transmission decreases arrhythmias and prolongs life (Herring et al., 2019). Sympathetic ganglia were traditionally described as simple relays between cholinergic preganglionic neurons and noradrenergic postganglionic neurons that innervate peripheral tissues (Jänig, 2008;Vegh et al., 2016). Discrepancies from this simple organization suggest that additional steps may exist in sympathetic ganglionic neurocircuitry (Clyburn et al., 2022). ...
The sympathetic nervous system vitally regulates autonomic functions, including cardiac activity. Postganglionic neurons of the sympathetic chain ganglia relay signals from the central nervous system to autonomic peripheral targets. Disrupting this flow of information often dysregulates organ function and leads to poor health outcomes. Despite the importance of these sympathetic neurons, fundamental aspects of the neurocircuitry within peripheral ganglia remain poorly understood. Conventionally, simple monosynaptic cholinergic pathways from preganglionic neurons are thought to activate postganglionic sympathetic neurons. However, early studies suggested more complex neurocircuits may be present within sympathetic ganglia. The present study recorded synaptic responses in sympathetic stellate ganglia neurons following electrical activation of the pre‐ and postganglionic nerve trunks and used genetic strategies to assess the presence of collateral projections between postganglionic neurons of the stellate ganglia. Orthograde activation of the preganglionic nerve trunk, T‐2, uncovered high jitter synaptic latencies consistent with polysynaptic connections. Pharmacological inhibition of nicotinic acetylcholine receptors with hexamethonium blocked all synaptic events. To confirm that high jitter, polysynaptic events were due to the presence of cholinergic collaterals from postganglionic neurons within the stellate ganglion, we knocked out choline acetyltransferase in adult noradrenergic neurons. This genetic knockout eliminated orthograde high jitter synaptic events and EPSCs evoked by retrograde activation. These findings suggest that cholinergic collateral projections arise from noradrenergic neurons within sympathetic ganglia. Identifying the contributions of collateral excitation to normal physiology and pathophysiology is an important area of future study and may offer novel therapeutic targets for the treatment of autonomic imbalance. image
Key points
Electrical stimulation of a preganglionic nerve trunk evoked fast synaptic transmission in stellate ganglion neurons with low and high jitter latencies.
Retrograde stimulation of a postganglionic nerve trunk evoked direct, all‐or‐none action currents and delayed nicotinic EPSCs indistinguishable from orthogradely‐evoked EPSCs in stellate neurons.
Nicotinic acetylcholine receptor blockade prevented all spontaneous and evoked synaptic activity.
Knockout of acetylcholine production in noradrenergic neurons eliminated all retrogradely‐evoked EPSCs but did not change retrograde action currents, indicating that noradrenergic neurons have cholinergic collaterals connecting neurons within the stellate ganglion.
... In the rat, there is a 6.2-fold increase in LV weight and a 69% increase in septum secundum length and width within the first 11-days postnatal, and myocyte cell volume increases up to 25-fold in the first 2 months of life (70)(71)(72). In humans and rodents alike, the innervation of the heart is relatively immature at birth and continues developing during childhood and early adolescence (68,(73)(74)(75). Regarding energy metabolism, there is a switch from preferential carbohydrate dependence to fatty acid oxidation within the first 30-days postnatal in rodents; in humans, this switch occurs before birth (76)(77)(78). ...
In recent decades, the scientific community has seen an increased interest in rigor and reproducibility. In 2017, concerns of methodological thoroughness and reporting practices were implicated as significant barriers to reproducibility within the preclinical cardiovascular literature, particularly in studies employing animal research. The Langendorff, whole-heart technique has proven to be an invaluable research tool, being modified in a myriad of ways to probe questions across the spectrum of physio- and pathophysiologic function of the heart. As a result, significant variability in the application of the Langendorff technique exists. This literature review quantifies the different methods employed in the implementation of the Langendorff technique and provides brief examples of how individual parametric differences can impact the outcomes and interpretation of studies. From 2017-2020, significant variability of animal models, anesthesia, cannulation time, and perfusate composition, pH, and temperature demonstrate that the technique has diversified to meet new challenges and answer different scientific questions. The review also reveals which individual methods are most frequently reported, even if there is no explicit agreement upon which parameters should be reported. The analysis of methods related to the Langendorff technique suggests a framework for considering methodological approach when interpreting seemingly contradictory results, rather than concluding that results are irreproducible.
... The nervous system affects the electrophysiological activities, as well as the bridge between neural activities and development of myocardial cells. Cardiac autonomic dysfunction is correlated with disease outcome [106] . Therefore, building high resolution ultrasonography targeting the heart segment of great subtlety is a potential therapeutic approach. ...
Significant advances in application of therapeutic ultrasound have been reported in the past decades. Therapeutic ultrasound is an emerging non-invasive stimulation technique. This approach has shown high potential for treatment of various disease including cardiovascular disease. In this review, application principle and significance of the basic parameters of therapeutic ultrasound are summarized. The effects of therapeutic ultrasound in myocardial ischemia, heart failure, myocarditis, arrhythmias, and hypertension are explored, with key focus on the underlying mechanism. Further, the limitations and challenges of ultrasound therapy on clinical translation are evaluated to promote application of the novel strategy in cardiovascular diseases.
... Cardiac function is modulated by the sympathetic and parasympathetic branches of the cardiac autonomic nervous system (cANS), which can stimulate or inhibit, e.g., the heart rate and contraction force. In vivo, neuronal axons innervate cardiac tissue [1][2][3], while neuronal somas reside in either central or peripheral nervous system (CNS and PNS, respectively) [1]. During embryonic cardiac innervation, neurons and cardiomyocytes (CMs) undergo comaturation, where the growth and transmission properties of the innervating neurons are regulated by signals from cardiac tissue and CM maturation is influenced by neuronal signals [2]. ...
... Cardiac function is modulated by the sympathetic and parasympathetic branches of the cardiac autonomic nervous system (cANS), which can stimulate or inhibit, e.g., the heart rate and contraction force. In vivo, neuronal axons innervate cardiac tissue [1][2][3], while neuronal somas reside in either central or peripheral nervous system (CNS and PNS, respectively) [1]. During embryonic cardiac innervation, neurons and cardiomyocytes (CMs) undergo comaturation, where the growth and transmission properties of the innervating neurons are regulated by signals from cardiac tissue and CM maturation is influenced by neuronal signals [2]. ...
The cardiac autonomic nervous system (cANS) regulates cardiac function by innervating cardiac tissue with axons, and cardiomyocytes (CMs) and neurons undergo comaturation during the heart innervation in embryogenesis. As cANS is essential for cardiac function, its dysfunctions might be fatal; therefore, cardiac innervation models for studying embryogenesis, cardiac diseases, and drug screening are needed. However, previously reported neuron-cardiomyocyte (CM) coculture chips lack studies of functional neuron–CM interactions with completely human-based cell models. Here, we present a novel completely human cell-based and electrophysiologically functional cardiac innervation on a chip in which a compartmentalized microfluidic device, a 3D3C chip, was used to coculture human induced pluripotent stem cell (hiPSC)-derived neurons and CMs. The 3D3C chip enabled the coculture of both cell types with their respective culture media in their own compartments while allowing the neuronal axons to traverse between the compartments via microtunnels connecting the compartments. Furthermore, the 3D3C chip allowed the use of diverse analysis methods, including immunocytochemistry, RT-qPCR and video microscopy. This system resembled the in vivo axon-mediated neuron–CM interaction. In this study, the evaluation of the CM beating response during chemical stimulation of neurons showed that hiPSC-neurons and hiPSC-CMs formed electrophysiologically functional axon-mediated interactions.
... In addition to the ambiguity surrounding the anatomy of the sympathetic ganglia, the functional organization of the sympathetic neurocircuitry within these ganglia remains poorly defined. Current literature usually describes and illustrates the neurocircuitry within cervical sympathetic ganglia as simple monosynaptic connections from cholinergic preganglionic neurons to the noradrenergic postganglionic neurons that innervate visceral targets and the heart (21,22). However, Erulkar and Woodward (23) made intracellular recordings of postganglionic sympathetic neurons from rabbit superior cervical ganglia (SCG) in situ which suggest this neurocircuitry may be more complicated. ...
The sympathetic nervous system plays a critical role in regulating many autonomic functions, including cardiac rhythm. The postganglionic neurons in the sympathetic chain ganglia are essential components that relay sympathetic signals to target tissues and disruption of their activity leads to poor health outcomes. Despite this importance, the neurocircuitry within sympathetic ganglia is poorly understood. Canonically, postganglionic sympathetic neurons are thought to simply be activated by monosynaptic inputs from preganglionic cholinergic neurons of the intermediolateral cell columns of the spinal cord. Early electrophysiological studies of sympathetic ganglia where the peripheral nerve trunks were electrically stimulated identified excitatory cholinergic synaptic events in addition to retrograde action potentials, leading some to speculate that excitatory collateral projections are present. However, this seemed unlikely since sympathetic postganglionic neurons were known to synthesize and release norepinephrine and expression of dual neurochemical phenotypes had not been well recognized. In vitro studies clearly established the capacity of cultured sympathetic neurons to express and release acetylcholine and norepinephrine throughout development and even in pathophysiological conditions. Given this insight, we believe that the canonical view of ganglionic transmission needs to be reevaluated and may provide a mechanistic understanding of autonomic imbalance in disease. Further studies likely will require genetic models manipulating neurochemical phenotypes within sympathetic ganglia to resolve the function of cholinergic collateral projections between postganglionic neurons. In this perspective article, we will discuss the evidence for collateral projections in sympathetic ganglia, determine if current laboratory techniques could address these questions, and discuss potential obstacles and caveats.
... In the meanwhile, there was excessive ROS accumulated in the cells ( Figure 5B). It is widely accepted that catecholamine is biosynthesized from phenylalanine and tyrosine (Nazari et al. 2020;Végh et al. 2016). There is also evidence that the placenta could synthesize catecholamine from aromatic amino acids, and the abundance of catecholamine in the preeclampsia was signi cantly increased compared to the normal pregnancy (Turner et al. 2008). ...
Background
The forkhead box O3a protein (FoxO3a) has been reported to involve in the migration and invasion, but their underlying mechanisms in the trophoblast remain unknown. In this study, we aim to explore the transcriptional and metabolic regulations of FoxO3a on the migration and invasion of early placental development.
Methods
Lentiviral vectors were used to knock down the expression of FoxO3a of the HTR8/SVneo cells. Western blot, matrigel invasion assay, wound healing assay, seahorse, gas-chromatography-mass spectrometry (GC-MS) based metabolomics, fluxomics, and RNA-seq transcriptomics were performed.
Results
We found that FoxO3a depletion restrained the migration and invasion of HTR8/SVneo cells. Metabolomics, fluxomics, and seahorse demonstrated that FoxO3a knockdown resulted in a switch from aerobic to anaerobic respiration and increased utilization of aromatic amino acids and long-chain fatty acids from extracellular nutrients. Furthermore, our RNA-seq also demonstrated that the expression of COX-2 and MMP9 decreased after FoxO3a knockdown, and these two genes were closely associated with the migration/invasion progress of trophoblast cells.
Conclusions
Our results suggested novel biological roles of FoxO3a in early placental development. FoxO3a exerts an essential effect on trophoblast migration and invasion owing to the regulations of COX2, MMP9, aromatic amino acids, energy metabolism, and oxidative stress.
... In mice, cardiac innervation starts at embryonic days 10-11 (E10-11) [14]. Therefore, although neurons play important roles in functional maturation of the heart through direct connections of the autonomic nerves, cardiac morphogenesis is commonly thought not to be under influence of the developing nervous system [15]. During the early postnatal period when cardiac sympathetic innervation is established, neurogenic inputs become fundamental for the organization of myocardial architecture. ...
Development of the heart, from early morphogenesis to functional maturation, as well as maintenance of its homeostasis are tasks requiring collaborative efforts of cardiac tissue and different extra‐cardiac organ systems. The brain, lymphoid organs, and gut are among the interaction partners that can communicate with the heart through a wide array of paracrine signals acting at local or systemic level. Disturbance of cardiac homeostasis following ischemic injury also needs immediate response from these distant organs. Our hearts replace dead muscles with non‐contractile fibrotic scars. We have learned from animal models capable of scarless repair that regenerative capability of the heart does not depend only on competency of the myocardium and cardiac‐intrinsic factors but also on long‐range molecular signals originating in other parts of the body. Here, we provide an overview of inter‐organ signals that take part in development and regeneration of the heart. We highlight recent findings and remaining questions. Finally, we discuss the potential of inter‐organ modulatory approaches for possible therapeutic use.
... The autonomic nervous system includes a sympathetic and a parasympathetic branch with opposing effects on heart rate, conduction velocity, contraction force, and relaxation (1)(2)(3)(4). Increased activation of the sympathetic nervous system in adults is associated with a higher incidence of arrhythmogenesis, worsening heart failure, hypertension, and sudden cardiac death (1)(2)(3). In addition, incomplete sympathetic innervation of premature infants as documented by increased heart rate variability is associated with sudden infant death syndrome, increased incidence of coronary heart disease, hypertension, and changes in cardiac geometry and function (5)(6)(7). ...
... The autonomic nervous system includes a sympathetic and a parasympathetic branch with opposing effects on heart rate, conduction velocity, contraction force, and relaxation (1)(2)(3)(4). Increased activation of the sympathetic nervous system in adults is associated with a higher incidence of arrhythmogenesis, worsening heart failure, hypertension, and sudden cardiac death (1)(2)(3). In addition, incomplete sympathetic innervation of premature infants as documented by increased heart rate variability is associated with sudden infant death syndrome, increased incidence of coronary heart disease, hypertension, and changes in cardiac geometry and function (5)(6)(7). ...
... The mouse heart is innervated by SNs from midgestation [embryonic day 13.5 (E13.5)], and this continues throughout the postnatal stages (2 to 3 weeks) (1)(2)(3)22). During this period, developmental adjustments in cardiomyocyte function, morphology, and metabolism coincide with maturational changes of heart's SNs after birth (23,24). ...
Neurons can regulate the development, pathogenesis, and regeneration of target organs. However, the role of neurons during heart development and regeneration remains unclear. We genetically inhibited sympathetic innervation in vivo, which resulted in heart enlargement with an increase in cardiomyocyte number. Transcriptomic and protein analysis showed down-regulation of the two clock gene homologs Period1/Period2 (Per1/Per2) accompanied by up-regulation of cell cycle genes. Per1/Per2 deletion increased heart size and cardiomyocyte proliferation, recapitulating sympathetic neuron–deficient hearts. Conversely, increasing sympathetic activity by norepinephrine treatment induced Per1/Per2 and suppressed cardiomyocyte proliferation. We further found that the two clock genes negatively regulate myocyte mitosis entry through the Wee1 kinase pathway. Our findings demonstrate a previously unknown link between cardiac neurons and clock genes in regulation of cardiomyocyte proliferation and heart size and provide mechanistic insights for developing neuromodulation strategies for cardiac regen5eration.
... The autonomic nervous system includes a sympathetic and a parasympathetic branch with opposing effects on heart rate, conduction velocity, contraction force, and relaxation (1)(2)(3)(4). Increased activation of the sympathetic nervous system in adults is associated with a higher incidence of arrhythmogenesis, worsening heart failure, hypertension, and sudden cardiac death (1)(2)(3). In addition, incomplete sympathetic innervation of premature infants as documented by increased heart rate variability is associated with sudden infant death syndrome, increased incidence of coronary heart disease, hypertension, and changes in cardiac geometry and function (5)(6)(7). ...
... The autonomic nervous system includes a sympathetic and a parasympathetic branch with opposing effects on heart rate, conduction velocity, contraction force, and relaxation (1)(2)(3)(4). Increased activation of the sympathetic nervous system in adults is associated with a higher incidence of arrhythmogenesis, worsening heart failure, hypertension, and sudden cardiac death (1)(2)(3). In addition, incomplete sympathetic innervation of premature infants as documented by increased heart rate variability is associated with sudden infant death syndrome, increased incidence of coronary heart disease, hypertension, and changes in cardiac geometry and function (5)(6)(7). ...
... The mouse heart is innervated by SNs from midgestation [embryonic day 13.5 (E13.5)], and this continues throughout the postnatal stages (2 to 3 weeks) (1)(2)(3)22). During this period, developmental adjustments in cardiomyocyte function, morphology, and metabolism coincide with maturational changes of heart's SNs after birth (23,24). ...
... Intracardiac neurons derive primarily from neural crest cells (NCC) that migrate to the developing heart (~5th week in humans and~E8.5-9.5 in mice [10,28,29]) giving rise to sympathetic, parasympathetic, and afferent sensory neurons [10,28]. Currently much of what is known of embryonic and fetal development of IcNS neurons and their subsequent postnatal maturation is derived from studies in mice. ...
... Sympathetic intracardiac neurons originate from trunk NCC that first migrate ventrally towards the dorsal aorta, and then rostrally and caudally, forming the paravertebral sympathetic chain [10]. NCC, which ultimately derive sympathetic components, have been shown to reach the dorsal aorta and outflow tract between E9.5-E10.5 [29]. By E13.5-E15.5, sympathetic axons begin to extend along coronary veins and penetrate the subepicardium, but it is not until E17.5 that these axons infiltrate the myocardium [30]. ...
The intracardiac nervous system (IcNS), sometimes referred to as the “little brain” of the heart, is involved in modulating many aspects of cardiac physiology. In recent years our fundamental understanding of autonomic control of the heart has drastically improved, and the IcNS is increasingly being viewed as a therapeutic target in cardiovascular disease. However, investigations of the physiology and specific roles of intracardiac neurons within the neural circuitry mediating cardiac control has been hampered by an incomplete knowledge of the anatomical organisation of the IcNS. A more thorough understanding of the IcNS is hoped to promote the development of new, highly targeted therapies to modulate IcNS activity in cardiovascular disease. In this paper, we first provide an overview of IcNS anatomy and function derived from experiments in mammals. We then provide descriptions of alternate experimental models for investigation of the IcNS, focusing on a non-mammalian model (zebrafish), neuron-cardiomyocyte co-cultures, and computational models to demonstrate how the similarity of the relevant processes in each model can help to further our understanding of the IcNS in health and disease.
