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1.  Diversity of sympathetic vasoconstrictor pathways and their plasticity after spinal cord injury 
Clinical Autonomic Research  2007;17(1):6-12.
Sympathetic vasoconstrictor pathways pass through paravertebral ganglia carrying ongoing and reflex activity arising within the central nervous system to their vascular targets. The pattern of reflex activity is selective for particular vascular beds and appropriate for the physiological outcome (vasoconstriction or vasodilation). The preganglionic signals are distributed to most postganglionic neurones in ganglia via synapses that are always suprathreshold for action potential initiation (like skeletal neuromuscular junctions).
Most postganglionic neurones receive only one of these “strong” inputs, other preganglionic connections being ineffective. Pre- and postganglionic neurones discharge normally at frequencies of 0.5–1 Hz and maximally in short bursts at <10 Hz. Animal experiments have revealed unexpected changes in these pathways following spinal cord injury. (1) After destruction of preganglionic neurones or axons, surviving terminals in ganglia sprout and rapidly re-establish strong connections, probably even to inappropriate postganglionic neurones. This could explain aberrant reflexes after spinal cord injury. (2) Cutaneous (tail) and splanchnic (mesenteric) arteries taken from below a spinal transection show dramatically enhanced responses in vitro to norepinephrine released from perivascular nerves. However the mechanisms that are modified differ between the two vessels, being mostly postjunctional in the tail artery and mostly prejunctional in the mesenteric artery. The changes are mimicked when postganglionic neurones are silenced by removal of their preganglionic input. Whether or not other arteries are also hyperresponsive to reflex activation, these observations suggest that the greatest contribution to raised peripheral resistance in autonomic dysreflexia follows the modifications of neurovascular transmission.
PMCID: PMC1797061  PMID: 17264977
sympathetic nervous system; sympathetic ganglia; autonomic dysreflexia; vasoconstriction; norepineph- rine; autonomic nervous system
2.  Chemical Coding for Cardiovascular Sympathetic Preganglionic Neurons in Rats 
Cocaine and amphetamine-regulated transcript peptide (CART) is present in a subset of sympathetic preganglionic neurons in the rat. We examined the distribution of CART-immunoreactive terminals in rat stellate and superior cervical ganglia and adrenal gland and found that they surround neuropeptide Y-immunoreactive postganglionic neurons and noradrenergic chromaffin cells. The targets of CART-immunoreactive preganglionic neurons in the stellate and superior cervical ganglia were shown to be vasoconstrictor neurons supplying muscle and skin and cardiac-projecting postganglionic neurons: they did not target non-vasoconstrictor neurons innervating salivary glands, piloerector muscle, brown fat or adrenergic chromaffin cells. Transneuronal tracing using pseudorabies virus demonstrated that many, but not all, preganglionic neurons in the vasoconstrictor pathway to forelimb skeletal muscle were CART-immunoreactive. Similarly, analysis with the confocal microscope confirmed that 70% of boutons in contact with vasoconstrictor ganglion cells contained CART, while 30% did not. Finally, we show that CART-immunoreactive cells represented 69% of the preganglionic neuron population expressing c-fos after systemic hypoxia. We conclude that CART is present in most, although not all, cardiovascular preganglionic neurons, but not thoracic preganglionic neurons with non-cardiovascular targets. We suggest that CART-immunoreactivity may identify the postulated “accessory” preganglionic neurons, whose actions may amplify vasomotor ganglionic transmission.
PMCID: PMC2947491  PMID: 20810898
Chemical coding; postganglionic neuron; vasoconstrictor; accessory pathway; c-fos; hypoxia; viral tracing
The Journal of General Physiology  1953;36(4):463-471.
The pedal ganglia of the terrestrial gastropod Ariolimax contain junctions between nerve fibers which are shown to be preferential points of fatigue and which exhibit facilitation (summation) of preganglionic impulses to produce a postganglionic spike. These characteristics in conjunction with others previously reported (reversible susceptibility to nicotine, convergence of preganglionic impulses, and inhibition of transmission through setting up a refractory state in the postganglionic fiber) are considered sufficient to indicate synaptic transmission in the pedal ganglia. The mean conduction velocity of the fastest fibers in the pedal nerves is 0.52 meter per second for preganglionic and 0.50 meter per second for postganglionic fibers at 7.56°C. The conduction rates at 21.76°C. are respectively 0.80 meter per second and 0.83 meter per second. The mean ganglionic delay is 0.033 second at 7.56°C. and 0.019 second at 21.76°C. The mean Q10's for conduction velocity are thus 1.37 for preganglionic and 1.42 for postganglionic fibers. The mean Q10 for ganglionic delay is 1.49. If the assumption is made that the Q10 for ganglionic delay is that of a limiting reaction, this figure then represents a value below which the Q10 for synaptic delay is statistically improbable.
PMCID: PMC2147377  PMID: 13035063
4.  Weak and Straddling Secondary Nicotinic Synapses Can Drive Firing in Rat Sympathetic Neurons and Thereby Contribute to Ganglionic Amplification 
Interactions between nicotinic excitatory postsynaptic potentials (EPSPs) critically determine whether paravertebral sympathetic ganglia behave as simple synaptic relays or as integrative centers that amplify preganglionic activity. Synaptic connectivity in this system is characterized by an n + 1 pattern of convergence, where each ganglion cell receives one very strong primary input and a variable number (n) of weak secondary inputs that are subthreshold in strength. To test whether pairs of secondary nicotinic EPSPs can summate to fire action potentials (APs) and thus mediate ganglionic gain in the rat superior cervical ganglion, we recorded intracellularly at 34°C and used graded presynaptic stimulation to isolate individual secondary synapses. Weak EPSPs in 40 of 53 neurons had amplitudes of 0.5–7 mV (mean 3.5 ± 0.3 mV). EPSPs evoked by paired pulse stimulation were either depressing (n = 10), facilitating (n = 9), or borderline (n = 10). In 15 of 29 cells, pairs of weak secondary EPSPs initiated spikes when elicited within a temporal window <20 ms, irrespective of EPSP amplitude or paired pulse response type. In six other neurons, we observed novel secondary EPSPs that were strong enough to straddle spike threshold without summation. At stimulus rates <1 Hz straddling EPSPs appeared suprathreshold in strength. However, their limited ability to drive firing could be blocked by the afterhyperpolarization following an AP. When viewed in a computational context, these findings support the concept that weak and straddling secondary nicotinic synapses enable mammalian sympathetic ganglia to behave as use-dependent amplifiers of preganglionic activity.
PMCID: PMC2995956  PMID: 21173895
superior cervical ganglion; synaptic gain; summation; facilitation; depression
5.  Placodal sensory ganglia coordinate the formation of the cranial visceral motor pathway 
The parasympathetic reflex circuit is controlled by three basic neurons. In the vertebrate head, the sensory, pre- and post-ganglionic neurons that comprise each circuit have stereotypic positions along the anteroposterior (AP) axis, suggesting that the circuit arises from a common developmental plan. Here we show that precursors of the VIIth circuit are initially aligned along the AP axis, where the placode-derived sensory neurons provide a critical “guidepost” through which preganglionic axons and their neural crest-derived postganglionic targets navigate prior to reaching their distant target sites. In the absence of the placodal sensory ganglion, preganglionic axons terminate and the neural crest fated for postganglionic neurons undergo apoptosis at the site normally occupied by the placodal sensory ganglion. The stereotypic organization of the parasympathetic cranial sensory-motor circuit thus emerges from the initial alignment of its precursors along the AP axis, with the placodal sensory ganglion coordinating the formation of the motor pathway.
PMCID: PMC2948960  PMID: 20235227
epibranchial placode; neural crest; parasympathetic nervous system; branchial arch; rhombomere; migration; axon pathfinding; specification; differentiation; apoptosis; anteroposterior axis
6.  Effects of preganglionic denervation and postganglionic axotomy on acetylcholine receptors in the chick ciliary ganglion 
The Journal of Cell Biology  1987;105(4):1847-1854.
The regulation of nicotinic acetylcholine receptors (AChRs) in chick ciliary ganglia was examined by using a radiolabeled anti-AChR mAb to quantitate the amount of receptor in ganglion detergent extracts after preganglionic denervation or postganglionic axotomy. Surgical transection of the preganglionic input to the ciliary ganglion in newly hatched chicks caused a threefold reduction in the total number of AChRs within 10 d compared with that present in unoperated contralateral control ganglia. Surgical transection of both the choroid and ciliary nerves emerging from the ciliary ganglion in newly hatched chicks to establish postganglionic axotomy led to a nearly 10-fold reduction in AChRs within 5 d compared with unoperated contralateral ganglia. The declines were specific since they could not be accounted for by changes in ganglionic protein or by decreases in neuronal survival or size. Light microscopy revealed no gross morphological differences between neurons in operated and control ganglia. A second membrane component of cholinergic relevance on chick ciliary ganglion neurons is the alpha-bungarotoxin (alpha-Bgt)-binding component. The alpha-Bgt-binding component also declined in number after either postganglionic axotomy or preganglionic denervation, but appeared to do so with a more rapid time course than did ganglionic AChRs. The results imply that cell-cell interactions in vivo specifically regulate both the number of AChRs and the number of alpha-Bgt-binding components in the ganglion. Regulation of these neuronal cholinergic membrane components clearly differs from that previously described for muscle AChRs.
PMCID: PMC2114658  PMID: 3667699
7.  In Vivo Imaging of Presynaptic Terminals and Postsynaptic Sites in the Mouse Submandibular Ganglion 
Developmental neurobiology  2008;68(6):760-770.
Much of what is currently known about the behavior of synapses in vivo has been learned at the mammalian neuromuscular junction, because it is large and accessible and also its postsynaptic acetylcholine receptors (AChRs) are readily labeled with a specific, high-affinity probe, α-bungarotoxin (BTX). Neuron–neuron synapses have thus far been much less accessible. We therefore developed techniques for imaging interneuronal synapses in an accessible ganglion in the peripheral nervous system. In the submandibular ganglion, individual preganglionic axons establish large numbers of axo-somatic synapses with postganglionic neurons. To visualize these sites of synaptic contact, presynaptic axons were imaged by using transgenic mice that express fluorescent protein in preganglionic neurons. The postsynaptic sites were visualized by labeling the acetylcholine receptor (AChR) α7 subunit with fluorescently tagged BTX. We developed in vivo methods to acquire three-dimensional image stacks of the axons and postsynaptic sites and then follow them over time. The submandibular ganglion is an ideal site to study the formation, elimination, and maintenance of synaptic connections between neurons in vivo.
PMCID: PMC2583331  PMID: 18383540
timelapse; bungarotoxin; synapse; in vivo; submandibular
8.  5-HT1D receptor immunoreactivity in the sphenopalatine ganglion: Implications for the efficacy of triptans in the treatment of autonomic signs associated with cluster headache 
Headache  2011;51(3):392-402.
To determine if 5-HT1D receptors are located in the sphenopalatine ganglion.
While the 5-HT1D receptor has been described in sensory and sympathetic ganglia in the head, it was not known whether they were also located in parasympathetic ganglia.
We used retrograde labeling combined with immunohistochemistry to examine 5-HT1D receptor immunoreactivity in rat sphenopalatine ganglion neurons that project to the lacrimal gland, nasal mucosa, cerebral vasculature and trigeminal ganglion.
We found 5-HT1D receptor immunoreactivity in nerve terminals around postganglionic cell bodies within the sphenopalatine ganglion. All 5-HT1D immunoreactive terminals were also immunoreactive for calcitonin-gene related peptide but not vesicular acetylcholine transporter, suggesting that they were sensory and not preganglionic parasympathetic fibers. Our retrograde labeling studies showed that approximately 30% of sphenopalatine ganglion neurons innervating the lacrimal gland, 23% innervating the nasal mucosa and 39% innervating the trigeminal ganglion were in apparent contact with 5-HT1D receptor containing nerve terminals.
These data suggest that 5-HT1D receptors within primary afferent neurons that innervate the sphenopalatine ganglion are in a position to modulate the excitability of postganglionic parasympathetic neurons that innervate the lacrimal gland and nasal mucosa, as well as the trigeminal ganglion. This has implications for triptan (5-HT1D receptor agonist) actions on parasympathetic symptoms in cluster headache.
PMCID: PMC3073163  PMID: 21352213
parasympathetic; 5-HT1D; sumatriptan; trigeminal; axon reflex; calcitonin-gene related peptide
9.  Monoaminergic Modulation of Spinal Viscero-Sympathetic Function in the Neonatal Mouse Thoracic Spinal Cord 
PLoS ONE  2012;7(11):e47213.
Descending serotonergic, noradrenergic, and dopaminergic systems project diffusely to sensory, motor and autonomic spinal cord regions. Using neonatal mice, this study examined monoaminergic modulation of visceral sensory input and sympathetic preganglionic output. Whole-cell recordings from sympathetic preganglionic neurons (SPNs) in spinal cord slice demonstrated that serotonin, noradrenaline, and dopamine modulated SPN excitability. Serotonin depolarized all, while noradrenaline and dopamine depolarized most SPNs. Serotonin and noradrenaline also increased SPN current-evoked firing frequency, while both increases and decreases were seen with dopamine. In an in vitro thoracolumbar spinal cord/sympathetic chain preparation, stimulation of splanchnic nerve visceral afferents evoked reflexes and subthreshold population synaptic potentials in thoracic ventral roots that were dose-dependently depressed by the monoamines. Visceral afferent stimulation also evoked bicuculline-sensitive dorsal root potentials thought to reflect presynaptic inhibition via primary afferent depolarization. These dorsal root potentials were likewise dose-dependently depressed by the monoamines. Concomitant monoaminergic depression of population afferent synaptic transmission recorded as dorsal horn field potentials was also seen. Collectively, serotonin, norepinephrine and dopamine were shown to exert broad and comparable modulatory regulation of viscero-sympathetic function. The general facilitation of SPN efferent excitability with simultaneous depression of visceral afferent-evoked motor output suggests that descending monoaminergic systems reconfigure spinal cord autonomic function away from visceral sensory influence. Coincident monoaminergic reductions in dorsal horn responses support a multifaceted modulatory shift in the encoding of spinal visceral afferent activity. Similar monoamine-induced changes have been observed for somatic sensorimotor function, suggesting an integrative modulatory response on spinal autonomic and somatic function.
PMCID: PMC3489886  PMID: 23144807
10.  Characterization of the Vagal Motor Neurons Projecting to the Guinea Pig Airways and Esophagus 
Distinct parasympathetic postganglionic neurons mediate contractions and relaxations of the guinea pig airways. We set out to characterize the vagal inputs that regulate contractile and relaxant airway parasympathetic postganglionic neurons. Single and dual retrograde neuronal tracing from the airways and esophagus revealed that distinct, but intermingled, subsets of neurons in the compact formation of the nucleus ambiguus (nAmb) innervate these two tissues. Tracheal and esophageal neurons identified in the nAmb were cholinergic. Esophageal projecting neurons also preferentially (greater than 70%) expressed the neuropeptide CGRP, but could not otherwise be distinguished immunohistochemically from tracheal projecting preganglionic neurons. Few tracheal or esophageal neurons were located in the dorsal motor nucleus of the vagus. Electrical stimulation of the vagi in vitro elicited stimulus dependent tracheal and esophageal contractions and tracheal relaxations. The voltage required to evoke tracheal smooth muscle relaxation was significantly higher than that required for evoking either tracheal contractions or esophageal longitudinal striated muscle contractions. Together our data support the hypothesis that distinct vagal preganglionic pathways regulate airway contractile and relaxant postganglionic neurons. The relaxant preganglionic neurons can also be differentiated from the vagal motor neurons that innervate the esophageal striated muscle.
PMCID: PMC3007679  PMID: 21188271
airway innervation; parasympathetic nervous system; non-adrenergic non-cholinergic; esophageal motor neurons; nucleus ambiguus
11.  Testing a neural coding hypothesis using surrogate data 
Journal of neuroscience methods  2008;172(2):312-322.
Determining how a particular neuron, or population of neurons, encodes information in their spike trains is not a trivial problem, because multiple coding schemes exist and are not necessarily mutually exclusive. Coding schemes generally fall into one of two broad categories, which we refer to as rate and temporal coding. In rate coding schemes, information is encoded in the variations of the average firing rate of the spike train. In contrast, in temporal coding schemes, information is encoded in the specific timing of the individual spikes that comprise the train. Here, we describe a method for testing the presence of temporal encoding of information. Suppose that a set of original spike trains is given. First, surrogate spike trains are generated by randomizing each of the original spike trains subject to the following constraints: the local average firing rate is approximately preserved, while the overall average firing rate and the distribution of primary interspike intervals are perfectly preserved. These constraints ensure that any rate coding of information present in the original spike trains is preserved in the members of the surrogate population. The null-hypothesis is rejected when additional information is found to be present in the original spike trains, implying that temporal coding is present. The method is validated using artificial data, and then demonstrated using real neuronal data.
PMCID: PMC2529148  PMID: 18565591
Spike trains; rate coding; temporal coding; simultaneous coding; cricket; cerebellum; multielectrode; synchrony
12.  Immunohistochemical detection of connexin36 in sympathetic preganglionic and somatic motoneurons in the adult rat 
Autonomic Neuroscience  2008;139(1-2):15-23.
Gap junctional communication in the adult CNS plays an important role in the synchronization of neuronal activities. In vitro studies have shown evidence of electrotonic coupling through gap junctions between sympathetic preganglionic motoneurons and between somatic motoneurons in the neonatal and adult rat spinal cord. Electrotonic transmission of membrane oscillations might be an important mechanism for recruitment of neurons and result in the generation of rhythmic sympathetic and somato-motor activity at the population level. Gap junctions in the adult spinal cord are constituted principally by connexin36 (Cx36). However, the distribution of Cx36 in specific neuronal populations of the spinal cord is unknown. Here, we identify Cx36-like immunoreactivity in sympathetic preganglionic and somatic motoneurons in thoracic spinal cord segments of the adult rat. For this purpose, double immunostaining against Cx36 and choline acetyltransferase (ChAT) was performed on transverse sections (20 μm) taken from spinal segments T6–T8. Cx36 punctate immunostaining was detected in the majority of ChAT-immunoreactive (-ir) neurons from lamina VII [intermediolateral cell column (IML) and intercalated cell group (IC)], lamina X [central autonomic nucleus (CA)] and in ventral horn neurons from laminae VIII and IX. Cx36 puncta were distributed in the neuronal somata and along dendritic processes. The presence of Cx36 in ChAT-ir neurons is consistent with electrical coupling between sympathetic preganglionic motoneurons and between somatic motoneurons through gap junctions in the adult spinal cord.
PMCID: PMC2428072  PMID: 18280223
Sympathetic; Motoneurons; Gap junctions; Spinal cord; Rhythmic
13.  Neuron/glia relationships observed over intervals of several months in living mice 
The Journal of Cell Biology  1988;107(3):1167-1175.
Identified neurons and glial cells in a parasympathetic ganglion were observed in situ with video-enhanced microscopy at intervals of up to 130 d in adult mice. Whereas the number and position of glial cells associated with particular neurons did not change over several hours, progressive differences were evident over intervals of weeks to months. These changes involved differences in the location of glial nuclei on the neuronal surface, differences in the apparent number of glial nuclei associated with each neuron, and often both. When we examined the arrangement of neurons and glial cells in the electron microscope, we also found that presynaptic nerve terminals are more prevalent in the vicinity of glial nuclei than elsewhere on the neuronal surface. The fact that glial nuclei are associated with preganglionic endings, together with the finding that the position and number of glial nuclei associated with identified neurons gradually changes, is in accord with the recent observation that synapses on these neurons are normally subject to ongoing rearrangement (Purves, D., J. T. Voyvodic, L. Magrassi, and H. Yawo. 1987. Science (Wash. DC). 238:1122-1126). By the same token, the present results suggest that glial cells are involved in synaptic remodeling.
PMCID: PMC2115292  PMID: 3417780
14.  Morphological studies of stimulated adrenergic axon varicosities in the mouse vas deferens 
The Journal of Cell Biology  1979;80(2):310-325.
The postganglionic axons of sympathetic neurons innervating the mouse vas deferens were stimulated transmurally in vitro by passing square pulses between two platinum electrodes. The ultrastructural appearance of the adrenergic nerve terminals was compared to samples fixed immediately after 30 min of stimulation and in samples allowed to recover for 2 h before fixation. The contralateral vasa deferentia served as controls, and these were incubated in Krebs solution for the same period as stimulated muscles. For each of four experiments, the mean number of large and small dense-core vesicles per square micrometer was calculated, as were the mean area and perimeter of the axon varicosities in each group. It was found that the number of small vesicles per square micrometer decreased by 60% during the stimulation period, but returned almost to control levels 2 h later. Large vesicles did not change in number during the stimulation or recovery periods. The proportion of vesicles containing cores was also determined for each group and found to decline just after stimulation in the small vesicle population, but to remain constant in the large vesicle population. The core depletion was partly reversed after 2 h. The vesicle recovery process was studied by use of the extracellular tracer horseradish peroxidase (HRP). When HRP was present in the extracellular space during stimulation, large numbers of vesicles contained the marker after recovery from stimulation. Thus, it is proposed that adrenergic axon varicosities recycle vesicle membrane through the plasma membrane in a manner similar to that already described for cholinergic nerve terminals.
PMCID: PMC2110335  PMID: 457747
15.  Systemic Postganglionic Adrenergic Studies Do Not Distinguish Parkinson's Disease From Multiple System Atrophy 
Multiple system atrophy (MSA) affects the preganglionic adrenergic neuron and Parkinson's disease (PD) involves the postganglionic counterpart. Widespread postganglionic denervation should result in denervation supersensitivity and a failure of the axon to release norepinephrine (NE). We examined if pharmacological dissection of the adrenergic neuron can distinguish between MSA and PD.
We measured blood pressure, heart rate, and plasma NE responses to direct (phenylephrine) and indirect (tyramine) acting adrenergic agonists in 15 patients with probable MSA, 16 patients with idiopathic PD, and 16 age- and gender-matched controls.
Baroreflex sensitivity was impaired in MSA and intact in PD. Pressor responses to phenylephrine (direct acting) were higher in MSA (p < 0.01) and PD patients (p = 0.04) than controls. Blood pressure responses to tyramine (indirect acting) were increased in MSA only (p < 0.01). Tyramine increased plasma catecholamine levels in all groups with no significant differences between groups.
There is denervation supersensitivity in PD patients that is, however, insufficient to shift the dose-response curve to the left. The excessive pressor responses to both tyramine and phenylephrine in MSA are due to baroreflex failure. We conclude that this diagnostic approach lacks sufficient sensitivity to differentiate PD and MSA.
PMCID: PMC2679853  PMID: 19345959
MSA; PD; baroreflex; tyramine; phenylephrine; autonomic; denervation supersensitivity
16.  Neuro-Anatomical Evidence Indicating Indirect Modulation of Macrophages by Vagal Efferents in the Intestine but Not in the Spleen 
PLoS ONE  2014;9(1):e87785.
Electrical stimulation of the vagus nerve suppresses intestinal inflammation and normalizes gut motility in a mouse model of postoperative ileus. The exact anatomical interaction between the vagus nerve and the intestinal immune system remains however a matter of debate. In the present study, we provide additional evidence on the direct and indirect vagal innervation of the spleen and analyzed the anatomical evidence for neuroimmune modulation of macrophages by vagal preganglionic and enteric postganglionic nerve fibers within the intestine.
Dextran conjugates were used to label vagal preganglionic (motor) fibers projecting to the small intestine and spleen. Moreover, identification of the neurochemical phenotype of the vagal efferent fibers and enteric neurons was performed by immunofluorescent labeling. F4/80 antibody was used to label resident macrophages.
Our anterograde tracing experiments did not reveal dextran-labeled vagal fibers or terminals in the mesenteric ganglion or spleen. Vagal efferent fibers were confined within the myenteric plexus region of the small intestine and mainly endings around nNOS, VIP and ChAT positive enteric neurons. nNOS, VIP and ChAT positive fibers were found in close proximity of intestinal resident macrophages carrying α7 nicotinic receptors. Of note, VIP receptors were found on resident macrophages located in close proximity of VIP positive nerve fibers.
In the present study, we show that the vagus nerve does not directly interact with resident macrophages in the gut or spleen. Instead, the vagus nerve preferentially interacts with nNOS, VIP and ChAT enteric neurons located within the gut muscularis with nerve endings in close proximity of the resident macrophages.
PMCID: PMC3906221  PMID: 24489965
17.  Role of cGMP and cAMP in the hemodynamic response to intrathecal sildenafil administration 
Clinics  2011;66(8):1407-1411.
Results from our laboratory have demonstrated that intracerebroventricular administration of sildenafil to conscious rats promoted a noticeable increase in both lumbar sympathetic activity and heart rate, with no change in the mean arterial pressure. The intracerebroventricular administration of sildenafil may have produced the hemodynamic effects by activating sympathetic preganglionic neurons in the supraspinal regions and spinal cord. It is well documented that sildenafil increases intracellular cGMP levels by inhibiting phosphodiesterase type 5 and increases cAMP levels by inhibiting other phosphodiesterases.
To examine and compare, in conscious rats, the hemodynamic response following the intrathecal administration of sildenafil, 8-bromo-cGMP (an analog of cGMP), forskolin (an activator of adenylate cyclase), or dibutyryl-cAMP (an analog of cAMP) in order to elucidate the possible role of the sympathetic preganglionic neurons in the observed hemodynamic response.
The hemodynamic responses observed following intrathecal administration of the studied drugs demonstrated the following: 1) sildenafil increased the mean arterial pressure and heart rate in a dose-dependent manner, 2) increasing doses of 8-bromo-cGMP did not alter the mean arterial pressure and heart rate, 3) forskolin did not affect the mean arterial pressure but did increase the heart rate and 4) dibutyryl-cAMP increased the mean arterial pressure and heart rate, similar to the effect observed following the intrathecal injection of the highest dose of sildenafil.
Overall, the findings of the current study suggest that the cardiovascular response following the intrathecal administration of sildenafil to conscious rats involves the inhibition of phosphodiesterases other than phosphodiesterase type 5 that increase the cAMP level and the activation of sympathetic preganglionic neurons.
PMCID: PMC3161220  PMID: 21915492
Sympathetic preganglionic neurons; Lumbar sympathetic activity; Forskolin; Phosphodiesterase 5; Spinal cord
18.  Regular Patterns in Cerebellar Purkinje Cell Simple Spike Trains 
PLoS ONE  2007;2(5):e485.
Cerebellar Purkinje cells (PC) in vivo are commonly reported to generate irregular spike trains, documented by high coefficients of variation of interspike-intervals (ISI). In strong contrast, they fire very regularly in the in vitro slice preparation. We studied the nature of this difference in firing properties by focusing on short-term variability and its dependence on behavioral state.
Methodology/Principal Findings
Using an analysis based on CV2 values, we could isolate precise regular spiking patterns, lasting up to hundreds of milliseconds, in PC simple spike trains recorded in both anesthetized and awake rodents. Regular spike patterns, defined by low variability of successive ISIs, comprised over half of the spikes, showed a wide range of mean ISIs, and were affected by behavioral state and tactile stimulation. Interestingly, regular patterns often coincided in nearby Purkinje cells without precise synchronization of individual spikes. Regular patterns exclusively appeared during the up state of the PC membrane potential, while single ISIs occurred both during up and down states. Possible functional consequences of regular spike patterns were investigated by modeling the synaptic conductance in neurons of the deep cerebellar nuclei (DCN). Simulations showed that these regular patterns caused epochs of relatively constant synaptic conductance in DCN neurons.
Our findings indicate that the apparent irregularity in cerebellar PC simple spike trains in vivo is most likely caused by mixing of different regular spike patterns, separated by single long intervals, over time. We propose that PCs may signal information, at least in part, in regular spike patterns to downstream DCN neurons.
PMCID: PMC1868782  PMID: 17534435
19.  Dynamic Clamp Analysis of Synaptic Integration in Sympathetic Ganglia 
Advances in modern neuroscience require the identification of principles that connect different levels of experimental analysis, from molecular mechanisms to explanations of cellular functions, then to circuits, and, ultimately, to systems and behavior. Here, we examine how synaptic organization of the sympathetic ganglia may enable them to function as use-dependent amplifiers of preganglionic activity and how the gain of this amplification may be modulated by metabotropic signaling mechanisms. The approach combines a general computational model of ganglionic integration together with experimental tests of the model using the dynamic clamp method. In these experiments, we recorded intracellularly from dissociated bullfrog sympathetic neurons and then mimicked physiological synapses with virtual computer-generated synapses. It thus became possible to analyze the synaptic gain by recording cellular responses to complex patterns of synaptic activity that normally arise in vivo from convergent nicotinic and muscarinic synapses. The results of these studies are significant because they illustrate how gain generated through ganglionic integration may contribute to the feedback control of important autonomic behaviors, in particular to the control of the blood pressure. We dedicate this paper to the memory of Professor Vladimir Skok, whose rich legacy in synaptic physiology helped establish the modern paradigm for connecting multiple levels of analysis in studies of the nervous system.
PMCID: PMC2743268  PMID: 19756262
nicotinic synapses; muscarinic receptors; neuropeptides; bullfrog sympathetic ganglia; conductance-based models; baroreceptor reflex
20.  Melanocortin 4 Receptors Reciprocally Regulate Sympathetic and Parasympathetic - Preganglionic Neurons 
Cell  2013;152(3):612-619.
Melanocortin 4 receptors (MC4Rs) in the central nervous system are key regulators of energy and glucose homeostasis. Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obesity-induced hypertension. Although these effects are likely dependent upon the activity of the autonomic nervous system, the cellular effects of MC4Rs on parasympathetic and sympathetic neurons remain undefined. Here, we show that MC4R agonists inhibit parasympathetic preganglionic neurons in the brainstem. In contrast, MC4R agonists activate sympathetic preganglionic neurons in the spinal cord. Deletion of MC4Rs in cholinergic neurons resulted in elevated levels of insulin. Furthermore, re-expression of MC4Rs specifically in cholinergic neurons (including sympathetic preganglionic neurons) restores obesity-associated hypertension in MC4R null mice. These findings provide a cellular correlate of the autonomic side effects associated with MC4R agonists and demonstrate a role for MC4Rs expressed in cholinergic neurons in the regulation of insulin levels and in the development of obesity-induced hypertension.
PMCID: PMC3711728  PMID: 23374353
21.  Firing Patterns of Muscle Vasoconstrictor Neurons in Respiratory Disease 
Because the cardiovascular system and respiration are so intimately coupled, disturbances in respiratory control often lead to disturbances in cardiovascular control. Obstructive Sleep Apnea (OSA), Chronic Obstructive Pulmonary Disease (COPD), and Bronchiectasis (BE) are all associated with a greatly elevated muscle vasoconstrictor drive (muscle sympathetic nerve activity, MSNA). Indeed, the increase in MSNA is comparable to that seen in congestive heart failure (CHF), in which the increase in MSNA compensates for the reduced cardiac output and thereby assists in maintaining blood pressure. However, in OSA – but not COPD or BE – the increase in MSNA can lead to hypertension. Here, the features of the sympathoexcitation in OSA, COPD, and BE are reviewed in terms of the firing properties of post-ganglionic muscle vasoconstrictor neurons. Compared to healthy subjects with low levels of resting MSNA, single-unit recordings revealed that the augmented MSNA seen in OSA, BE, COPD, and CHF were each associated with an increase in firing probability and mean firing rates of individual neurons. However, unlike patients with heart failure, all patients with respiratory disease exhibited an increase in multiple within-burst firing which, it is argued, reflects an increase in central sympathetic drive. Similar patterns to those seen in OSA, COPD, and BE were seen in healthy subjects during an acute increase in muscle vasoconstrictor drive. These observations emphasize the differences by which the sympathetic nervous system grades its output in health and disease, with an increase in firing probability of active neurons and recruitment of additional neurons being the dominant mechanisms.
PMCID: PMC3358712  PMID: 22654767
bronchiectasis; chronic obstructive pulmonary disease; obstructive sleep apnea; microneurography; single-unit; sympathoexcitation
22.  Branching projections of ventrolateral reticular neurons to the medial preoptic area and lumbo-sacral spinal cord 
Different findings indicate that rostral ventrolateral reticular nucleus (RVL) is neuronal substrate of integration and regulation of the cardiovascular functions. Some efferent RVL neurons project to the thoraco-lumbar spinal cord and excite preganglionic sympathetic neurons, to the spinal phrenic motor neurons involved in inspiratory function and increase the activity of vasoconstrictor fibres innervating blood vessels in the skin and skeletal muscle. Our study was aimed at revealing presence of neurons within RVL supplying branching collateral input to the medial preoptic area (MPA) and to the lumbo-sacral spinal cord (SC-L) in the rat. All animal experiments were carried out in accordance with current institutional guidelines for the care and use of experimental animals. We have employed double fluorescent-labelling procedure: the projections were defined by injections of two retrograde tracers: Rhodamine Labelled Bead (RBL) and Fluoro Gold (FG) in the MPA and SC-L, respectively. Our results showed the presence of few single FG neurons and single RBL neurons in the RVL. The size of FG-neurons and RBL-neurons was medium (25–30 μm) and large (50 μm).
Few double-projecting neurons were distributed in the middle third of RVL nucleus, their size was 30–40 μm. The results demonstrate that pools of neurons in the RVL have collateral projections to the MPA and SC-L and they are involved in ascending and descending pathway. These data suggest that these neurons could play a role in maintaining activity of central and peripheral blood flow.
PMCID: PMC1262690  PMID: 16212663
ventrolateral reticular nucleus (RVL); retrograde fluorescent tracer; medial preoptic area; spinal cord; rat.
23.  Stochasticity, spikes and decoding: sufficiency and utility of order statistics 
Biological cybernetics  2009;100(6):447-457.
For over 75 years it has been clear that the number of spikes in a neural response is an important part of the neuronal code. Starting as early as the 1950’s with MacKay and McCullough, there has been speculation over whether each spike and its exact time of occurrence carry information. Although it is obvious that the firing rate carries information, it has been less clear as to whether there is information in exactly timed patterns, when they arise from the dynamics of the neurons and networks, as opposed to when they represent some strong external drive that entrains them. One strong null hypothesis that can be applied is that spike trains arise from stochastic sampling of an underlying deterministic temporally modulated rate function, that is, there is a time-varying rate function. In this view, order statistics seem to provide a sufficient theoretical construct to both generate simulated spike trains that are indistinguishable from those observed experimentally, and to evaluate (decode) the data recovered from experiments. It remains to learn whether there are physiologically important signals that are not described by such a null hypothesis.
PMCID: PMC2745726  PMID: 19517130
24.  Extracting non-linear integrate-and-fire models from experimental data using dynamic I–V curves 
Biological Cybernetics  2008;99(4-5):361-370.
The dynamic I–V curve method was recently introduced for the efficient experimental generation of reduced neuron models. The method extracts the response properties of a neuron while it is subject to a naturalistic stimulus that mimics in vivo-like fluctuating synaptic drive. The resulting history-dependent, transmembrane current is then projected onto a one-dimensional current–voltage relation that provides the basis for a tractable non-linear integrate-and-fire model. An attractive feature of the method is that it can be used in spike-triggered mode to quantify the distinct patterns of post-spike refractoriness seen in different classes of cortical neuron. The method is first illustrated using a conductance-based model and is then applied experimentally to generate reduced models of cortical layer-5 pyramidal cells and interneurons, in injected-current and injected- conductance protocols. The resulting low-dimensional neuron models—of the refractory exponential integrate-and-fire type—provide highly accurate predictions for spike-times. The method therefore provides a useful tool for the construction of tractable models and rapid experimental classification of cortical neurons.
PMCID: PMC2798053  PMID: 19011924
I-V curve; Exponential integrate-and-fire; Refractoriness
Neuroscience  2012;217:154-171.
This study examined responsiveness to acoustic stimuli among neurons of the basolateral amygdala. While recording from single neurons in awake mustached bats (Pteronotus parnellii), we presented a wide range of acoustic stimuli including tonal, noise, and vocal signals. While many neurons displayed phasic or sustained responses locked to effective auditory stimuli, the majority of neurons (n = 58) displayed a persistent excitatory discharge that lasted well beyond stimulus duration and filled the interval between successive stimuli. Persistent firing usually began seconds (median value, 5.4 s) after the initiation of a train of repeated stimuli and lasted, in the majority of neurons, for at least 2 min after the end of the stimulus train. Auditory-responsive amygdalar neurons were generally excited by one stimulus or very few stimuli. Most neurons did not respond well to synthetic stimuli including tones, noise bursts or frequency-modulated sweeps, but instead responded only to vocal stimuli (82 of 87 neurons). Furthermore, most neurons were highly selective among vocal stimuli. On average, neurons responded to 1.7 of 15 different syllables or syllable sequences. The largest percentage of neurons responded to a hiss-like rectangular broadband noise burst (rBNB) call associated with aggressive interactions. Responsiveness to effective vocal stimuli was reduced or eliminated when the spectrotemporal features of the stimuli were altered in a subset of neurons. Chemical activation of the medial geniculate body (MG) increased both background and evoked firing. Among 39 histologically localized recording sites, we saw no evidence of topographic organization in terms of temporal response pattern, habituation, or the affect of calls to which neurons responded. Overall, these studies demonstrate that amygdalar neurons in the mustached bat show high selectivity to vocal stimuli, and suggest that persistent firing may be an important feature of amygdalar responses to social vocalizations.
PMCID: PMC3586201  PMID: 22569154
bat; Pteronotus parnellii; persistent firing; acoustic communication; basolateral amygdala

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