Disease-Associated Mutant Tau Prevents Circadian Changes in the Cytoskeleton of Central Pacemaker Neurons

Autonomic cardiovascular regulation involves sympathetic rhythms that contribute to blood pressure fluctuations in the low frequency range. It has been suggested that fluctuations in sympathetic vasomotor tone reflect a resonance phenomenon due to interplay between the vasculature and baroreflex. Alternatively, this could reflect an intrinsic rhythm of pacemaker neurons. To dissect the autonomic origin of this cardiovascular rhythm, we studied autonomic failure patients with loss of baroreflex buffering. We hypothesized that if this rhythm originates in pacemaker neurons, it would be present in multiple systems atrophy (MSA) patients in whom residual sympathetic tone is intact but not regulated by the baroreflex, and absent in pure autonomic failure (PAF) patients with postganglionic sympathetic denervation. We studied 28 MSA and 34 PAF patients with severe autonomic impairment and neurogenic orthostatic hypotension. Low-frequency systolic blood pressure variability (LFSBP), an index of sympathetic modulation of vasomotor tone, and baroreflex sensitivity (BRS) were assessed by spectral analysis of continuous blood pressure and heart rate recordings. MSA patients had higher LFSBP during supine rest compared with PAF patients (3.3±0.5 versus 1.5±0.2 mmHg2, respectively; p=0.003), despite similarly low BRS (3.6±0.6 PAF versus 4.3±0.7 msec/mmHg MSA; p=0.380). LFSBP was higher in MSA patients with supine hypertension compared with normotensive patients (4.1±0.6 versus 2.3±0.6 mmHg2; p=0.041), with no differences in PAF patients (1.5±0.2 hypertensive versus 1.6±0.3 mmHg2 normotensive, respectively; p=0.984). These findings suggest that LFSBP is driven by an intrinsic rhythm originating in central sympathetic pathways in MSA patients, independent of baroreflex-mediated blood pressure fluctuations. The precise origin of this rhythm is unclear but may include central pacemaker neurons, spinal cord neurons or loops, or hormonal mechanisms. In addition, LFSBP is higher in MSA patients with sympathetically-mediated hypertension, but low and fixed in PAF patients with sympathetic-independent hypertension. Overall, these findings provide new insight into neural regulatory mechanisms involved in blood pressure control.

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Clock genes and metabolic disease

Journal of Applied Physiology ◽

10.1152/japplphysiol.00698.2009 ◽

2009 ◽

Vol 107 (5) ◽

pp. 1638-1646 ◽

Cited By ~ 47

Author(s):

Biliana Marcheva ◽

Kathryn Moynihan Ramsey ◽

Alison Affinati ◽

Joseph Bass

Keyword(s):

Metabolic Networks ◽

Clock Genes ◽

Pacemaker Neurons ◽

Peripheral Tissues ◽

Physiological Processes ◽

The Earth ◽

Metabolic Systems ◽

Rotation Of The Earth ◽

Central Pacemaker ◽

Feedback Networks

The circadian system is a key integrator of behavior and metabolism that synchronizes physiological processes with the rotation of the Earth on its axis. In mammals, the clock is present not only within the central pacemaker neurons of the hypothalamus, but also within extra-suprachiasmatic nucleus (SCN) regions of brain and nearly all peripheral tissues. Recent evidence suggests that the complex feedback networks that encompass both the circadian and metabolic systems are intimately intertwined and that disruption of either system leads to reciprocal disturbances in the other. We anticipate that improved understanding of the interconnections between the circadian and metabolic networks will open new windows on the treatment of sleep and metabolic disorders, including diabetes mellitus and obesity.

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Uncovering the Roles of Clocks and Neural Transmission in the Resilience of Drosophila Circadian Network

Frontiers in Physiology ◽

10.3389/fphys.2021.663339 ◽

2021 ◽

Vol 12 ◽

Author(s):

Edouard Jaumouillé ◽

Rafael Koch ◽

Emi Nagoshi

Keyword(s):

Constant Darkness ◽

Molecular Clocks ◽

Pacemaker Neurons ◽

Molecular Oscillator ◽

Neural Communication ◽

Theoretical Predictions ◽

Neural Transmission ◽

Free Running ◽

Locomotor Rhythms ◽

Central Pacemaker

Studies of circadian locomotor rhythms in Drosophila melanogaster gave evidence to the preceding theoretical predictions on circadian rhythms. The molecular oscillator in flies, as in virtually all organisms, operates using transcriptional-translational feedback loops together with intricate post-transcriptional processes. Approximately150 pacemaker neurons, each equipped with a molecular oscillator, form a circuit that functions as the central pacemaker for locomotor rhythms. Input and output pathways to and from the pacemaker circuit are dissected to the level of individual neurons. Pacemaker neurons consist of functionally diverse subclasses, including those designated as the Morning/Master (M)-oscillator essential for driving free-running locomotor rhythms in constant darkness and the Evening (E)-oscillator that drives evening activity. However, accumulating evidence challenges this dual-oscillator model for the circadian circuit organization and propose the view that multiple oscillators are coordinated through network interactions. Here we attempt to provide further evidence to the revised model of the circadian network. We demonstrate that the disruption of molecular clocks or neural output of the M-oscillator during adulthood dampens free-running behavior surprisingly slowly, whereas the disruption of both functions results in an immediate arrhythmia. Therefore, clocks and neural communication of the M-oscillator act additively to sustain rhythmic locomotor output. This phenomenon also suggests that M-oscillator can be a pacemaker or a downstream path that passively receives rhythmic inputs from another pacemaker and convey output signals. Our results support the distributed network model and highlight the remarkable resilience of the Drosophila circadian pacemaker circuit, which can alter its topology to maintain locomotor rhythms.

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