DPP acutely defines the connectivity of central pacemaker neurons in Drosophila

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.

Download Full-text

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

Frontiers in Neuroscience ◽

10.3389/fnins.2020.00232 ◽

2020 ◽

Vol 14 ◽

Author(s):

Marlène Cassar ◽

Alexander D. Law ◽

Eileen S. Chow ◽

Jadwiga M. Giebultowicz ◽

Doris Kretzschmar

Keyword(s):

Pacemaker Neurons ◽

Circadian Changes ◽

Central Pacemaker

Download Full-text

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.

Download Full-text

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.

Download Full-text

Connectivity of pacemaker neurons in the neonatal rat superficial dorsal horn

The Journal of Comparative Neurology ◽

10.1002/cne.23706 ◽

2015 ◽

Vol 523 (7) ◽

pp. 1038-1053 ◽

Cited By ~ 7

Author(s):

Jie Li ◽

Elizabeth Kritzer ◽

Neil C. Ford ◽

Shahriar Arbabi ◽

Mark L. Baccei

Keyword(s):

Dorsal Horn ◽

Neonatal Rat ◽

Superficial Dorsal Horn ◽

Pacemaker Neurons

Download Full-text

Membrane Resonance in Bursting Pacemaker Neurons of an Oscillatory Network Is Correlated with Network Frequency

Journal of Neuroscience ◽

10.1523/jneurosci.0545-09.2009 ◽

2009 ◽

Vol 29 (20) ◽

pp. 6427-6435 ◽

Cited By ~ 42

Author(s):

V. Tohidi ◽

F. Nadim

Keyword(s):

Pacemaker Neurons ◽

Membrane Resonance ◽

Oscillatory Network

Download Full-text

PHASE DEPENDENT TRANSITION BETWEEN MULTISTABLE STATES IN A NEURAL NETWORK WITH RECIPROCAL INHIBITION

International Journal of Bifurcation and Chaos ◽

10.1142/s0218127404010138 ◽

2004 ◽

Vol 14 (05) ◽

pp. 1559-1575 ◽

Cited By ~ 4

Author(s):

KATSUMI TATENO ◽

HIDEYUKI TOMONARI ◽

HATSUO HAYASHI ◽

SATORU ISHIZUKA

Keyword(s):

Neural Network ◽

Network Model ◽

Neural Network Model ◽

Synaptic Input ◽

Reciprocal Inhibition ◽

Conduction Delay ◽

Inhibitory Connection ◽

Pacemaker Neurons ◽

Excitatory Synaptic Input ◽

Multistable State

We studied multistable oscillatory states of a small neural network model and switching of an oscillatory mode. In the present neural network model, two pacemaker neurons are reciprocally inhibited with conduction delay; one pacemaker neuron inhibits the other via an inhibitory nonpacemaker interneuron, and vice versa. The small network model shows bifurcations from quasi-periodic oscillation to chaos via period 3 with increase in the synaptic weight of the reciprocal inhibition. The route to chaos in the network model is different from that in the single pacemaker neuron. The network model exhibits several multistable states. In a regime of a weak inhibitory connection, in-phase beat, out-of-phase beat (period 3), and chaotic oscillation coexist at the multistable state. We can switch an oscillatory mode by an excitatory synaptic input to one of the pacemaker neurons through an afferent path. In a strong inhibitory connection regime, in-phase beat and out-of-phase beat (period 4) coexist at the multistable state. An excitatory synaptic input through the afferent path leads to the transition from the in-phase beat to the out-of-phase beat. The transition from the out-of-phase beat to the in-phase beat is induced by an inhibitory synaptic input via interneurons. A conduction delay, furthermore, causes the spontaneous transition from the in-phase beat to the out-of-phase beat. These transitions can be explained by phase response curves.

Download Full-text

Circadian Rhythms, the Mesolimbic Dopaminergic Circuit, and Drug Addiction

The Scientific World JOURNAL ◽

10.1100/tsw.2007.213 ◽

2007 ◽

Vol 7 ◽

pp. 194-202 ◽

Cited By ~ 65

Author(s):

Colleen A. McClung

Keyword(s):

Circadian Rhythms ◽

Drug Addiction ◽

Molecular Mechanisms ◽

Dopaminergic System ◽

Treatment Options ◽

Drug Induced ◽

Circadian Genes ◽

Dopaminergic Transmission ◽

Central Pacemaker

Drug addiction is a devastating disease that affects millions of individuals worldwide. Through better understanding of the genetic variations that create a vulnerability for addiction and the molecular mechanisms that underlie the progression of addiction, better treatment options can be created for those that suffer from this condition. Recent studies point to a link between abnormal or disrupted circadian rhythms and the development of addiction. In addition, studies suggest a role for specific genes that make up the molecular clock in the regulation of drug sensitivity, sensitization, and reward. The influence of circadian genes and rhythms on drug-induced behaviors may be mediated through the mesolimbic dopaminergic system. This system has long been implicated in the development of addiction, and recent evidence supports a regulatory role for the brain's central pacemaker and circadian gene expression in the regulation of dopaminergic transmission. This review highlights the association between circadian genes and drug addiction, and the possible role of the mesolimbic dopaminergic system in this association.

Download Full-text

Nonlinear Behavior of Sinusoidally Forced Pyloric Pacemaker Neurons

Journal of Neurophysiology ◽

10.1152/jn.2001.85.4.1623 ◽

2001 ◽

Vol 85 (4) ◽

pp. 1623-1638 ◽

Cited By ~ 35

Author(s):

Attila Szűcs ◽

Robert C. Elson ◽

Michail I. Rabinovich ◽

Henry D. I. Abarbanel ◽

Allen I. Selverston

Keyword(s):

Complex Dynamics ◽

Cooperative Behavior ◽

Model Neuron ◽

Nonlinear Behavior ◽

Periodic Forcing ◽

Pacemaker Neurons ◽

Strongly Coupled ◽

Electronic Model ◽

Group 2 ◽

Low Dimensional

Periodic current forcing was used to investigate the intrinsic dynamics of a small group of electrically coupled neurons in the pyloric central pattern generator (CPG) of the lobster. This group contains three neurons, namely the two pyloric dilator (PD) motoneurons and the anterior burster (AB) interneuron. Intracellular current injection, using sinusoidal waveforms of varying amplitude and frequency, was applied in three configurations of the pacemaker neurons: 1) the complete pacemaker group, 2) the two PDs without the AB, and 3) the AB neuron isolated from the PDs. Depending on the frequency and amplitude of the injected current, the intact pacemaker group exhibited a wide variety of nonlinear behaviors, including synchronization to the forcing, quasiperiodicity, and complex dynamics. In contrast, a single, broad 1:1 entrainment zone characterized the response of the PD neurons when isolated from the main pacemaker neuron AB. The isolated AB responded to periodic forcing in a manner similar to the complete pacemaker group, but with wider zones of synchronization. We have built an analog electronic circuit as an implementation of a modified Hindmarsh-Rose model for simulating the membrane potential activity of pyloric neurons. We subjected this electronic model neuron to the same periodic forcing as used in the biological experiments. This four-dimensional electronic model neuron reproduced the autonomous oscillatory firing patterns of biological pyloric pacemaker neurons, and it expressed the same stationary nonlinear responses to periodic forcing as its biological counterparts. This adds to our confidence in the model. These results strongly support the idea that the intact pyloric pacemaker group acts as a uniform low-dimensional deterministic nonlinear oscillator, and the regular pyloric oscillation is the outcome of cooperative behavior of strongly coupled neurons, having different dynamical and biophysical properties when isolated.

Download Full-text