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Heart rate (HR) and HR variability (HRV), predictors of over-all organism health, are widely believed to be driven by autonomic input to the sinoatrial node (SAN), with sympathetic input increasing HR and reducing HRV. However, variability in spontaneous beating intervals in isolated SAN tissue and single SAN cells, devoid of autonomic neural input, suggests that clocks intrinsic to SAN cells may also contribute to HR and HRV in vivo. We assessed contributions of both intrinsic and autonomic neuronal input mechanisms of SAN cell function on HR and HRV via in vivo, telemetric EKG recordings. This was done in both wild type (WT) mice, and those in which adenylyl cyclase type 8 (ADCY8), a main driver of intrinsic cAMP-PKA-Ca2+ mediated pacemaker function, was overexpressed exclusively in the heart (TGAC8). We hypothesized that TGAC8 mice would: (1) manifest a more coherent pattern of HRV in vivo, i.e., a reduced HRV driven by mechanisms intrinsic to SAN cells, and less so to modulation by autonomic input and (2) utilize unique adaptations to limit sympathetic input to a heart with high levels of intrinsic cAMP-Ca2+ signaling. Increased adenylyl cyclase (AC) activity in TGAC8 SAN tissue was accompanied by a marked increase in HR and a concurrent marked reduction in HRV, both in the absence or presence of dual autonomic blockade. The marked increase in intrinsic HR and coherence of HRV in TGAC8 mice occurred in the context of: (1) reduced HR and HRV responses to β-adrenergic receptor (β-AR) stimulation; (2) increased transcription of genes and expression of proteins [β-Arrestin, G Protein-Coupled Receptor Kinase 5 (GRK5) and Clathrin Adaptor Protein (Dab2)] that desensitize β-AR signaling within SAN tissue, (3) reduced transcripts or protein levels of enzymes [dopamine beta-hydorxylase (DBH) and phenylethanolamine N-methyltransferase (PNMT)] required for catecholamine production in intrinsic cardiac adrenergic cells, and (4) substantially reduced plasma catecholamine levels. Thus, mechanisms driven by cAMP-PKA-Ca2+ signaling intrinsic to SAN cells underlie the marked coherence of TGAC8 mice HRV. Adaptations to limit additional activation of AC signaling, via decreased neuronal sympathetic input, are utilized to ensure the hearts survival and prevent Ca2+ overload.

Heart rate (HR) and HR variability (HRV), predictors of over-all organism health, are widely believed to be driven by autonomic input to the sinoatrial node (SAN), with sympathetic input increasing HR and reducing HRV. However, variability in spontaneous beating intervals in isolated SAN tissue and single SAN cells, devoid of autonomic neural input, suggests that clocks intrinsic to SAN cells may also contribute to HR and HRV in vivo. We assessed contributions of both intrinsic and autonomic neuronal input mechanisms of SAN cell function on HR and HRV via in vivo , telemetric EKG recordings. This was done in both wild type (WT) mice, and those in which adenylyl cyclase type 8 (ADCY8), a main driver of intrinsic cAMP-PKA-Ca2+ mediated pacemaker function, was overexpressed exclusively in the heart (TGAC8). We hypothesized that TGAC8 mice would: (1) manifest a more coherent pattern of HRV in vivo , i.e., a reduced HRV driven by mechanisms intrinsic to SAN cells, and less so to modulation by autonomic input and (2) utilize unique adaptations to limit sympathetic input to a heart with high levels of intrinsic cAMP-Ca2+ signaling. Increased adenylyl cyclase (AC) activity in TGAC8 SAN tissue was accompanied by a marked increase in HR and a concurrent marked reduction in HRV, both in the absence or presence of dual autonomic blockade. The marked increase in intrinsic HR and coherence of HRV in TGAC8 mice occurred in the context of: (1) reduced HR and HRV responses to β-adrenergic receptor (β-AR) stimulation; (2) increased transcription of genes and expression of proteins [β-Arrestin, G Protein-Coupled Receptor Kinase 5 (GRK5) and Clathrin Adaptor Protein (Dab2)] that desensitize β-AR signaling within SAN tissue, (3) reduced transcripts or protein levels of enzymes [dopamine beta-hydorxylase (DBH) and phenylethanolamine N -methyltransferase (PNMT)] required for catecholamine production in intrinsic cardiac adrenergic cells, and (4) substantially reduced plasma catecholamine levels. Thus, mechanisms driven by cAMP-PKA-Ca2+ signaling intrinsic to SAN cells underlie the marked coherence of TGAC8 mice HRV. Adaptations to limit additional activation of AC signaling, via decreased neuronal sympathetic input, are utilized to ensure the hearts survival and prevent Ca2+ overload. [ABSTRACT FROM AUTHOR]

The aim of this paper is to set the stage for the vagal tank theory, showcasing a functional resource account for self-regulation. The vagal tank theory, building on neurophysiological, cognitive and social psychology approaches, will introduce a physiological indicator for self-regulation that has mainly been ignored from cognitive and social psychology, cardiac vagal control (also referred to as cardiac vagal activity). Cardiac vagal control reflects the contribution of the vagus nerve, the main nerve of the parasympathetic nervous system, to cardiac regulation. We propose cardiac vagal control to be an indicator of how efficiently self-regulatory resources are mobilized and used. Three systematic levels of cardiac vagal control analysis are suggested: resting, reactivity, and recovery. Based on this physiological indicator we derive the metaphor of the vagal tank, which can get depleted and replenished. Overall, the vagal tank theory will enable to integrate previous findings from different disciplines and to stimulate new research questions, predictions, and designs regarding self-regulation.

There is evidence that accumulated senescent cells drive age-related pathologies, but the antecedents to the cellular stressors that induce senescence remain poorly understood. Previous research suggests that there is a relationship between shorter telomere length, an antecedent to cellular senescence, and psychological stress. Existing models do not sufficiently account for the specific pathways from which psychological stress regulation is converted into production of reactive oxygen species. We propose the neuro-immuno-senescence integrative model (NISIM) suggesting how vagally mediated heart rate variability (HRV) might be related to cellular senescence. Prefrontally modulated, and vagally mediated cortical influences on the autonomic nervous system, expressed as HRV, affects the immune system by adrenergic stimulation and cholinergic inhibition of cytokine production in macrophages and neutrophils. Previous findings indicate that low HRV is associated with increased production of the pro-inflammatory cytokines IL-6 and TNF-α. IL-6 and TNF-α can activate the NFκB pathway, increasing production of reactive oxygen species that can cause DNA damage. Vagally mediated HRV has been related to an individual's ability to regulate stress, and is lower in people with shorter telomeres. Based on these previous findings, the NISIM suggest that the main pathway from psychological stress to individual differences in oxidative telomere damage originates in the neuroanatomical components that modulate HRV, and culminates in the cytokine-induced activation of NFκB. Accumulated senescent cells in the brain is hypothesized to promote age-related neurodegenerative disease, and previous reports suggest an association between low HRV and onset of Alzheimer's and Parkinson's disease. Accumulating senescent cells in peripheral tissues secreting senescence-associated secretory phenotype factors can alter tissue structure and function which can induce cancer and promote tumor growth and metastasis in old age, and previous research suggested that ability to regulate psychological stress has a negative association with cancer onset. We therefore conclude that the NISIM can account for a large proportion of the individual differences in the psychological stress-related antecedents to cellular senescence, and suggest that it can be useful in providing a dynamic framework for understanding the pathways by which psychological stress induce pathologies in old age. [ABSTRACT FROM AUTHOR]

The aim of this paper is to set the stage for the vagal tank theory, showcasing a functional resource account for self-regulation. The vagal tank theory, building on neurophysiological, cognitive and social psychology approaches, will introduce a physiological indicator for self-regulation that has mainly been ignored from cognitive and social psychology, cardiac vagal control (also referred to as cardiac vagal activity). Cardiac vagal control reflects the contribution of the vagus nerve, the main nerve of the parasympathetic nervous system, to cardiac regulation. We propose cardiac vagal control to be an indicator of how efficiently self-regulatory resources are mobilized and used. Three systematic levels of cardiac vagal control analysis are suggested: resting, reactivity, and recovery. Based on this physiological indicator we derive the metaphor of the vagal tank, which can get depleted and replenished. Overall, the vagal tank theory will enable to integrate previous findings from different disciplines and to stimulate new research questions, predictions, and designs regarding self-regulation. [ABSTRACT FROM AUTHOR]