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Hypertension (Dallas, Tex. : 1979) Jul 2024The NET (norepinephrine transporter) is situated in the prejunctional plasma membrane of noradrenergic neurons. It is responsible for >90% of the norepinephrine uptake... (Review)
Review
The NET (norepinephrine transporter) is situated in the prejunctional plasma membrane of noradrenergic neurons. It is responsible for >90% of the norepinephrine uptake that is released in the autonomic neuroeffector junction. Inhibitors of this cell membrane transporter, known as norepinephrine reuptake inhibitors (NRIs), are commercially available for the treatment of depression and attention deficit hyperactivity disorder. These agents increase norepinephrine levels, potentiating its action in preganglionic and postganglionic adrenergic neurons, the latter through activation of α-1 adrenoreceptors. Previous studies found that patients with neurogenic orthostatic hypotension can improve standing blood pressure and reduce symptoms of neurogenic orthostatic hypotension after a single administration of the selective NRI atomoxetine. This effect was primarily observed in patients with impaired central autonomic pathways with otherwise normal postganglionic sympathetic fibers, known as multiple system atrophy. Likewise, patients with normal or high norepinephrine levels may benefit from NRIs. The long-term efficacy of NRIs for the treatment of neurogenic orthostatic hypotension-related symptoms is currently under investigation. In summary, an in-depth understanding of the pathophysiology of neurogenic orthostatic hypotension resulted in the discovery of a new therapeutic pathway targeted by NRI.
Topics: Humans; Hypotension, Orthostatic; Adrenergic Uptake Inhibitors; Norepinephrine; Atomoxetine Hydrochloride; Norepinephrine Plasma Membrane Transport Proteins; Blood Pressure
PubMed: 38766862
DOI: 10.1161/HYPERTENSIONAHA.124.22069 -
Cell Jun 2024Many behaviors require the coordinated actions of somatic and autonomic functions. However, the underlying mechanisms remain elusive. By opto-stimulating different...
Many behaviors require the coordinated actions of somatic and autonomic functions. However, the underlying mechanisms remain elusive. By opto-stimulating different populations of descending spinal projecting neurons (SPNs) in anesthetized mice, we show that stimulation of excitatory SPNs in the rostral ventromedial medulla (rVMM) resulted in a simultaneous increase in somatomotor and sympathetic activities. Conversely, opto-stimulation of rVMM inhibitory SPNs decreased both activities. Anatomically, these SPNs innervate both sympathetic preganglionic neurons and motor-related regions in the spinal cord. Fiber-photometry recording indicated that the activities of rVMM SPNs correlate with different levels of muscle and sympathetic tone during distinct arousal states. Inhibiting rVMM excitatory SPNs reduced basal muscle and sympathetic tone, impairing locomotion initiation and high-speed performance. In contrast, silencing the inhibitory population abolished muscle atonia and sympathetic hypoactivity during rapid eye movement (REM) sleep. Together, these results identify rVMM SPNs as descending spinal projecting pathways controlling the tone of both the somatomotor and sympathetic systems.
Topics: Animals; Male; Mice; Locomotion; Medulla Oblongata; Mice, Inbred C57BL; Motor Neurons; Neurons; Sleep, REM; Spinal Cord; Sympathetic Nervous System; Behavior, Animal; Cell Count; Muscle, Skeletal
PubMed: 38733990
DOI: 10.1016/j.cell.2024.04.022 -
ENeuro Apr 2024Neuromodulation of the peripheral nervous system (PNS) by electrical stimulation may augment autonomic function after injury or in neurodegenerative disorders. Nerve...
Neuromodulation of the peripheral nervous system (PNS) by electrical stimulation may augment autonomic function after injury or in neurodegenerative disorders. Nerve fiber size, myelination, and distance between individual fibers and the stimulation electrode may influence response thresholds to electrical stimulation. However, information on the spatial distribution of nerve fibers within the PNS is sparse. We developed a new two-dimensional (2D) morphological mapping tool to assess spatial heterogeneity and clustering of nerve fibers. The L6-S3 ventral roots (VRs) in rhesus macaques were used as a model system to map preganglionic parasympathetic, γ-motor, and α-motor fibers. Random and ground truth distributions of nerve fiber centroids were determined for each VR by light microscopy. The proposed tool allows for nonbinary determinations of fiber heterogeneity by defining the minimum distance between nerve fibers for cluster inclusion and comparisons with random fiber distributions for each VR. There was extensive variability in the relative composition of nerve fiber types and degree of 2D fiber heterogeneity between different L6-S3 VR levels within and across different animals. There was a positive correlation between the proportion of autonomic fibers and the degree of nerve fiber clustering. Nerve fiber cluster heterogeneity between VRs may contribute to varied functional outcomes from neuromodulation.
Topics: Animals; Macaca mulatta; Spinal Nerve Roots; Autonomic Pathways; Cluster Analysis
PubMed: 38548331
DOI: 10.1523/ENEURO.0009-23.2024 -
Clinical Autonomic Research : Official... Feb 2024We have re-evaluated the anatomical arguments that underlie the division of the spinal visceral outflow into sympathetic and parasympathetic divisions. (Review)
Review
PURPOSE
We have re-evaluated the anatomical arguments that underlie the division of the spinal visceral outflow into sympathetic and parasympathetic divisions.
METHODOLOGY
Using a systematic literature search, we mapped the location of catecholaminergic neurons throughout the mammalian peripheral nervous system. Subsequently, a narrative method was employed to characterize segment-dependent differences in the location of preganglionic cell bodies and the composition of white and gray rami communicantes.
RESULTS AND CONCLUSION
One hundred seventy studies were included in the systematic review, providing information on 389 anatomical structures. Catecholaminergic nerve fibers are present in most spinal and all cranial nerves and ganglia, including those that are known for their parasympathetic function. Along the entire spinal autonomic outflow pathways, proximal and distal catecholaminergic cell bodies are common in the head, thoracic, and abdominal and pelvic region, which invalidates the "short-versus-long preganglionic neuron" argument. Contrary to the classically confined outflow levels T1-L2 and S2-S4, preganglionic neurons have been found in the resulting lumbar gap. Preganglionic cell bodies that are located in the intermediolateral zone of the thoracolumbar spinal cord gradually nest more ventrally within the ventral motor nuclei at the lumbar and sacral levels, and their fibers bypass the white ramus communicans and sympathetic trunk to emerge directly from the spinal roots. Bypassing the sympathetic trunk, therefore, is not exclusive for the sacral outflow. We conclude that the autonomic outflow displays a conserved architecture along the entire spinal axis, and that the perceived differences in the anatomy of the autonomic thoracolumbar and sacral outflow are quantitative.
Topics: Animals; Humans; Neurons; Sympathetic Nervous System; Ganglia, Sympathetic; Spinal Cord; Sacrum; Mammals
PubMed: 38403748
DOI: 10.1007/s10286-024-01023-6 -
Revue Neurologique 2024Autonomic failure is frequently encountered in synucleinopathies such as multiple system atrophy (MSA), Parkinson's disease (PD), Lewy body disease, and pure autonomic... (Review)
Review
Autonomic failure is frequently encountered in synucleinopathies such as multiple system atrophy (MSA), Parkinson's disease (PD), Lewy body disease, and pure autonomic failure (PAF). Cardiovascular autonomic failure affects quality of life and can be life threatening due to the risk of falls and the increased incidence of myocardial infarction, stroke, and heart failure. In PD and PAF, pathogenic involvement is mainly post-ganglionic, while in MSA, the involvement is mainly pre-ganglionic. Cardiovascular tests exploring the autonomic nervous system (ANS) are based on the analysis of continuous, non-invasive recordings of heart rate and digital blood pressure (BP). They assess facets of sympathetic and parasympathetic activities and provide indications on the integrity of the baroreflex arc. The tilt test is widely used in clinical practice. It can be combined with catecholamine level measurement and analysis of baroreflex activity and cardiac variability for a detailed analysis of cardiovascular damage. MIBG myocardial scintigraphy is the most sensitive test for early detection of autonomic dysfunction. It provides a useful measure of post-ganglionic sympathetic fiber integrity and function and is therefore an effective tool for distinguishing PD from other parkinsonian syndromes such as MSA. Autonomic cardiovascular investigations differentiate between certain parkinsonian syndromes that would otherwise be difficult to segregate, particularly in the early stages of the disease. Exploring autonomic failure by gathering information about residual sympathetic tone, low plasma norepinephrine levels, and supine hypertension can guide therapeutic management of orthostatic hypotension (OH).
Topics: Humans; Pure Autonomic Failure; Synucleinopathies; Quality of Life; Autonomic Nervous System Diseases; Multiple System Atrophy; Parkinson Disease
PubMed: 38216420
DOI: 10.1016/j.neurol.2023.12.004 -
Journal of Applied Physiology... Dec 2023Cervical spinal cord injury interrupts supraspinal pathways innervating thoracic sympathetic preganglionic neurons and results in cardiovascular dysfunction. Both...
Cervical spinal cord injury interrupts supraspinal pathways innervating thoracic sympathetic preganglionic neurons and results in cardiovascular dysfunction. Both respiratory and locomotor functions were also impaired due to damages of motoneuron pools controlling respiratory and forelimb muscles, respectively. However, no study has investigated autonomic and somatic motor functions in the same animal model. The present study aimed to establish a cervical spinal cord injury model to evaluate cardiorespiratory response and locomotor activity in unanesthetized rats. Cardiovascular response and respiratory behavior following laminectomy or cervical spinal contusion were measured using noninvasive blood pressure analyzer and plethysmography systems, respectively. Locomotor activity was evaluated by an open-field test and a locomotor rating scale. The results demonstrated that mean arterial blood pressure and heart rate were significantly reduced in contused rats compared with uninjured rats at the acute injured stage. Tidal volume was also significantly reduced during the acute and subchronic stages. Moreover, locomotor function was severely impaired, evidenced by decreasing moving ability and locomotor rating scores from the acute to chronic injured stages. Retrograde neurotracer results revealed that cervical spinal cord injury caused a reduction in number of phrenic and triceps motoneurons. Immunofluorescence staining revealed a significant attenuation of serotonergic, noradrenergic, glutamatergic, and GABAergic fibers innervating the thoracic sympathetic preganglionic neurons in chronically contused rats. These results revealed the pathological mechanism underlying the comorbidity of cardiorespiratory and locomotor dysfunction following cervical spinal cord injury. We proposed that this animal model can be used to evaluate the therapeutic efficacy of potential strategies to improve different physiological functions. The present study establishes a preclinical rodent model to comprehensively investigate physiological functions under unanesthetized condition following cervical spinal cord contusion. The results demonstrated that cervical spinal cord contusion is associated with impairments in cardiovascular, respiratory, and locomotor function. Respiratory and forelimb motoneurons and neurochemical innervations of sympathetic preganglionic neurons were damaged following injury. This animal model can be used to evaluate the therapeutic efficacy of potential strategies to improve different physiological functions.
Topics: Rats; Animals; Rats, Sprague-Dawley; Cervical Cord; Spinal Cord Injuries; Spinal Cord; Comorbidity; Cervical Vertebrae
PubMed: 37855033
DOI: 10.1152/japplphysiol.00473.2023