Cardiovascular Brain Circuits

Abstract

The cardiovascular system is hardwired to the brain via multilayered afferent and efferent polysynaptic axonal connections. Two major anatomically and functionally distinct though closely interacting subcircuits within the cardiovascular system have recently been defined: The artery-brain circuit and the heart-brain circuit. However, how the nervous system impacts cardiovascular disease progression remains poorly understood. Here, we review recent findings on the anatomy, structures, and inner workings of the lesser-known artery-brain circuit and the better-established heart-brain circuit. We explore the evidence that signals from arteries or the heart form a systemic and finely tuned cardiovascular brain circuit: afferent inputs originating in the arterial tree or the heart are conveyed to distinct sensory neurons in the brain. There, primary integration centers act as hubs that receive and integrate artery-brain circuit-derived and heart-brain circuit-derived signals and process them together with axonal connections and humoral cues from distant brain regions. To conclude the cardiovascular brain circuit, integration centers transmit the constantly modified signals to efferent neurons which transfer them back to the cardiovascular system. Importantly, primary integration centers are wired to and receive information from secondary brain centers that control a wide variety of brain traits encoded in engrams including immune memory, stress-regulating hormone release, pain, reward, emotions, and even motivated types of behavior. Finally, we explore the important possibility that brain effector neurons in the cardiovascular brain circuit network connect efferent signals to other peripheral organs including the immune system, the gut, the liver, and adipose tissue. The enormous recent progress vis-à-vis the cardiovascular brain circuit allows us to propose a novel neurobiology-centered cardiovascular disease hypothesis that we term the neuroimmune cardiovascular circuit hypothesis.

Keywords: brain; cardiovascular diseases; heart; infarctions; neurons.

Figure 1.. The ABC sensor.

We propose that the ABC is initiated in the adventitia of diseased artery segments establishing a tridirectional communication network between innate immune cells, the arterial wall, and the peripheral nervous system. Inflammatory mediators may activate nociceptive receptors, for example, TRPV1 (transient receptor potential vanilloid 1), ion channel receptor, for example, Nav1.8 (voltage-gated sodium channel 1.8), P2X3 (P2X purinoceptor 3), cytokine receptors and GPCRs (G protein-coupled receptors) at axon endings of sensory neurons resulting in action potentials that are transduced to dorsal root ganglia to enter the spinal cord to be conveyed to brain nuclei (see below).

Figure 2.. The ABC effector.

Sympathetic nervous system neurons are projected via the spinal cord to the periphery. Sympathetic nerves of celiac ganglion neurons directly innervate the adventitia.

Figure 3.. The HBC.

The HBC is composed of a sensory arm through vagal and spinal afferents reaching the brain either via DRGs and the spinal cord or via the nodose ganglia; the motor arm contains sympathetic and parasympathetic efferents. The ICN communicates with the heart and the vagus and the sympathetic nervous system. The ICN is preferentially present in the atria (inset above the heart symbol). RA, right atrium; LA, left atrium; ICN, intrinsic cardiac nervous system.

Figure 4.. Neuroimmune interactions regulate CVD progression via long-distance brain-body axes.

Long-distance neuroimmune circuits allow for the integration of exteroceptive and interoceptive cues in health and disease. Bidirectional connections between immune cells and the nervous system empowers neuroimmune axes with the unique capacity to efficiently perceive, integrate and respond to the ever changing external and internal environmental perturbations. We hypothesise that neuroimmune circuits operate in the heart and arteries to orchestrate cardiovascular physiology, health and disease.

Figure 5.. The ABC and the HBC share large functionally diverse brain areas but whether identical neuron subtypes are shared remains unknwon.

Major multifunctional and markedly heterogeneously brain areas are shared by the ABC and the HBC. However, whether neuron subtypes connect to arteries and the heart remains to be defined. Here we list broad functions that have been assigned to these brain nuclei with the potential to regulate CVDs: Insula (emotions)^{, , , ,} , Amygdala (memory)^, , Hypothalamus (stress), Rostral Ventrolateral Medulla^, (stress), Nucleus Tractus Solitarius (body weight)^, , and Dorsal Motor Nucleus of the Vagus (metabolism)^, . Many other impacts and connections of these nuclei are not depicted for ease of reading.

Figure 6.. Organ to brain connections form a CBC sensor and program engrams.

Focusing on the upper abdominal aorta, virus tracing has shown that the adventitia is directly innervated by neurons of DRG segments T6–12, while sensory neurons in the nodose ganglia of the vagus nerve and different DRGs innervate the heart (Figure 3)^{, , , , , ,} . Both routes of cardiovascular innervation gain access to the brainstem to be projected to higher brain areas along the pain pathway. The chronic flow of organ-to-brain signals may form sensory engrams of the cardiovascular system.

Figure 7.. Brain to organ connections form a CBC effector and yield engram-derived cues back to the cardiovascular system.

Retrograde virus tracing from the adventitia of the abdominal aorta segment revealed direct polysynaptic efferent connections of autonomic brain nuclei via the brainstem and the spinal cord to the celiac ganglion, while similar studies of heart innervation showed vagus efferent neurons in the brain stem innervating the aortic arch and the heart including the atria (location of the ICN) and ventricles^, . In addition, it is known that spinal cord sympathetic nervous system innervation involves the bone marrow, the adrenal gland, the spleen and other internal organs. These brain-to-organ efferents contain information from cardiovascular injury or other types of past tissue injuries what can be defined as engrams^{, , , ,} .

Figure 8.. Toolbox to investigate the CBC.

Progress in understanding the CBC requires state-of-the-art tools that exploit neurobiology approaches including tissue clearing, multiomics^, , optogenetics^{, ,} , chemogenetics^, , electrophysiology^{, ,} , and multiple tracing methods^{, , ,} . We refer to excellent recent reviews covering each of the methods here for the interested reader.

Figure 9.. The Neuroimmune Cardiovascular Circuit Hypothesis.

The neuroimmune cardiovascular circuit hypothesis emphasizes the central role of the brain in affecting CVD progression. It incorporates several components: The interoceptive impacts of arteries and the heart on the CBC in addition to the genetic background and lifestyle exteroceptive impacts on each individual human. Depending on the composition of these inputs and actions of - at times opposite - factors, cardiovascular homeostasis may be either maintained or disrupted to accelerate CVD progression.