Cardiogenic control of affective behavioural state

Abstract

Emotional states influence bodily physiology, as exemplified in the top-down process by which anxiety causes faster beating of the heart1–3. However, whether an increased heart rate might itself induce anxiety or fear responses is unclear3–8. Physiological theories of emotion, proposed over a century ago, have considered that in general, there could be an important and even dominant flow of information from the body to the brain9. Here, to formally test this idea, we developed a noninvasive optogenetic pacemaker for precise, cell-type-specific control of cardiac rhythms of up to 900 beats per minute in freely moving mice, enabled by a wearable micro-LED harness and the systemic viral delivery of a potent pump-like channelrhodopsin. We found that optically evoked tachycardia potently enhanced anxiety-like behaviour, but crucially only in risky contexts, indicating that both central (brain) and peripheral (body) processes may be involved in the development of emotional states. To identify potential mechanisms, we used whole-brain activity screening and electrophysiology to find brain regions that were activated by imposed cardiac rhythms. We identified the posterior insular cortex as a potential mediator of bottom-up cardiac interoceptive processing, and found that optogenetic inhibition of this brain region attenuated the anxiety-like behaviour that was induced by optical cardiac pacing. Together, these findings reveal that cells of both the body and the brain must be considered together to understand the origins of emotional or affective states. More broadly, our results define a generalizable approach for noninvasive, temporally precise functional investigations of joint organism-wide interactions among targeted cells during behaviour.

Cerebellar contribution to the regulation of defensive states

“…As a result, the system adapts expression of defensive state dynamics to the current and anticipated threat level. Defensive state dynamics are not only determined by exteroceptive sensory inputs, but also crucially by interoceptive feedback from the body (Hsueh et al, 2023), two information streams that have to be integrated into an internal model to predict and adequately respond to threats (Barrett, 2017;Kleckner et al, 2017). Based on the evidence presented in this review, it is likely that both, intracerebellar circuits as well as cerebellar connections to classic defensive circuits crucially contribute to these integrative and regulatory processes.…”

Cardiovascular Brain Circuits

“…Now, time has come to bring artery and heart innervation together and begin to appreciate the role of the brain to power the CBC network and its subcircuits. 1,5,25,26,36,55,191,193 Broadly, the CBC can be functionally divided into CBC sensors (Figure 6) and CBC effectors (Figure 7). It should be noted that each of the participants of the CBC consist of multiple genetically, functionally, and territorialized distinct subcircuits to provide well-organized neuronal control nodes depending on specific requirements of the various artery segments and heart compartments.…”

“…56,58,61,129,131,[210][211][212][213] As reviewed above, recent research into the pathogenesis of atherosclerotic coronary artery disease and other segments of the arterial tree together with a better understanding of the innervation of the heart suggests the existence of an ABC and an HBC. 1,6,25,26,36,46,[52][53][54][55]163,184,214 Moreover, the ABC and the HBC form a global CBC network regulating both physiological and pathophysiological responses of the cardiovascular system. The understanding of the workings of the CBC is still in an infant stage requiring application of state-of-the art toolboxes to progress (Figure 8).…”

“…1–35 Indeed, if challenges can be overcome to make steps towards a better understanding of the brain, groundbreaking advances into human development and conceivably the pathogeneses of a large number of clinically important cardiovascular diseases (CVDs) may be within reach. 36 Defining control of physiological responses such as stress-related circuits have already uncovered aberrant interactions between the brain and peripheral organ dysfunction in diseases as diverse as cancer, 37 obesity, 24 metabolism and diabetes, 38 chronic lung diseases, 39,40 inflammatory bowel diseases, 20,41 autoimmune diseases, 42 psychiatric disorders, 43,44 and neural control of infectious diseases. 3,28 It is important to distinguish these types of circuits as hardwired bona fide circuits from interactions mediated by soluble molecules including neurotransmitters and hormones produced by the immune, endocrine, or the nervous systems, respectively.…”

Long COVID is primarily a Spike protein Induced Thrombotic Vasculitis

“…Downregulation of ACE2 and tissue hypoxia can both reduce serotonin synthesis [156,157], whilst hyperactive platelets (which store serotonin) may cause serotonin depletion [113]. Thus, anxiety may be a consequence of coagulopathy and dysautonomia [158].…”