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Relative contributions of sympathetic, cholinergic, and myogenic mechanisms to cerebral autoregulation.

ABSTRACT: Prior work aimed at improving our understanding of human cerebral autoregulation has explored individual physiological mechanisms of autoregulation in isolation, but none has attempted to consolidate the individual roles of these mechanisms into a comprehensive model of the overall cerebral pressure-flow relationship.We retrospectively analyzed this relationship before and after pharmacological blockade of ?-adrenergic-, muscarinic-, and calcium channel-mediated mechanisms in 43 healthy volunteers to determine the relative contributions of the sympathetic, cholinergic, and myogenic controllers to cerebral autoregulation. Projection pursuit regression was used to assess the effect of pharmacological blockade on the cerebral pressure-flow relationship. Subsequently, ANCOVA decomposition was used to determine the cumulative effect of these 3 mechanisms on cerebral autoregulation and whether they can fully explain it.Sympathetic, cholinergic, and myogenic mechanisms together accounted for 62% of the cerebral pressure-flow relationship (P<0.05), with significant and distinct contributions from each of the 3 effectors. ANCOVA decomposition demonstrated that myogenic effectors were the largest determinant of the cerebral pressure-flow relationship, but their effect was outside of the autoregulatory region where neurogenic control appeared prepotent.Our results suggest that myogenic effects occur outside the active region of autoregulation, whereas neurogenic influences are largely responsible for cerebral blood flow control within it. However, our model of cerebral autoregulation left 38% of the cerebral pressure-flow relationship unexplained, suggesting that there are other physiological mechanisms that contribute to cerebral autoregulation.

SUBMITTER: Hamner JW

PROVIDER: S-EPMC4102642 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Relative contributions of sympathetic, cholinergic, and myogenic mechanisms to cerebral autoregulation.

Hamner J W JW Tan Can Ozan CO

Stroke 20140410 6

<h4>Background and purpose</h4>Prior work aimed at improving our understanding of human cerebral autoregulation has explored individual physiological mechanisms of autoregulation in isolation, but none has attempted to consolidate the individual roles of these mechanisms into a comprehensive model of the overall cerebral pressure-flow relationship.<h4>Methods</h4>We retrospectively analyzed this relationship before and after pharmacological blockade of α-adrenergic-, muscarinic-, and calcium cha ...[more]

PMID: 24723314

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Project description:The sympathetic nervous system vitally regulates autonomic functions, including cardiac activity. Postganglionic neurons of the sympathetic chain ganglia relay signals from the central nervous system to autonomic peripheral targets. Disrupting this flow of information often dysregulates organ function and leads to poor health outcomes. Despite the importance of these sympathetic neurons, fundamental aspects of the neurocircuitry within peripheral ganglia remain poorly understood. Conventionally, simple monosynaptic cholinergic pathways from preganglionic neurons are thought to activate postganglionic sympathetic neurons. However, early studies suggested more complex neurocircuits may be present within sympathetic ganglia. The present study recorded synaptic responses in sympathetic stellate ganglia neurons following electrical activation of the pre- and postganglionic nerve trunks and used genetic strategies to assess the presence of collateral projections between postganglionic neurons of the stellate ganglia. Orthograde activation of the preganglionic nerve trunk, T-2, uncovered high jitter synaptic latencies consistent with polysynaptic connections. Pharmacological inhibition of nicotinic acetylcholine receptors with hexamethonium blocked all synaptic events. To confirm that high jitter, polysynaptic events were due to the presence of cholinergic collaterals from postganglionic neurons within the stellate ganglion, we knocked out choline acetyltransferase in adult noradrenergic neurons. This genetic knockout eliminated orthograde high jitter synaptic events and EPSCs evoked by retrograde activation. These findings suggest that cholinergic collateral projections arise from noradrenergic neurons within sympathetic ganglia. Identifying the contributions of collateral excitation to normal physiology and pathophysiology is an important area of future study and may offer novel therapeutic targets for the treatment of autonomic imbalance. KEY POINTS: Electrical stimulation of a preganglionic nerve trunk evoked fast synaptic transmission in stellate ganglion neurons with low and high jitter latencies. Retrograde stimulation of a postganglionic nerve trunk evoked direct, all-or-none action currents and delayed nicotinic EPSCs indistinguishable from orthogradely-evoked EPSCs in stellate neurons. Nicotinic acetylcholine receptor blockade prevented all spontaneous and evoked synaptic activity. Knockout of acetylcholine production in noradrenergic neurons eliminated all retrogradely-evoked EPSCs but did not change retrograde action currents, indicating that noradrenergic neurons have cholinergic collaterals connecting neurons within the stellate ganglion.

Dataset Information

Relative contributions of sympathetic, cholinergic, and myogenic mechanisms to cerebral autoregulation.

Publications

Relative contributions of sympathetic, cholinergic, and myogenic mechanisms to cerebral autoregulation.

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