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Neuroscience |
1 Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY 40292, USA
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Abstract |
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(Received 29 November 2005;
accepted after revision 27 January 2006;
first published online 2 February 2006)
Corresponding author C. H. Hubscher: Department of Anatomical Sciences and Neurobiology, University of Louisville, Louisville, KY 40292, USA. Email: chhubs01{at}louisville.edu
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Introduction |
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Another example in which coordination between the pelvic organs is important is during voiding of the urinary bladder, which requires contraction of the external anal sphincter, thereby preventing defaecation. In humans, distension of the urinary bladder produces contractions of the anal sphincter (Basinski et al. 2003). Experimental studies using cats have shown that distension of the urinary bladder both inhibits colonic contractions (Bouvier et al. 1990) and produces simultaneous contraction of the anal sphincter (Bouvier & Grimaud, 1984). The reverse also occurs, i.e. the urinary system is inhibited during defaecation. In humans, functional stimulation of the anal sphincter inhibits detrusor muscle contraction (Cheng et al. 2002). In animal studies, distension of the rectum has been shown to inhibit urinary bladder activity in female rats (Sugaya et al. 1998), and stimulation of colonic branches of the pelvic nerve in cats has been shown to have an inhibitory effect on micturition (Floyd et al. 1978).
Interactions and functional coordination between various organ systems creates a situation where a pathological condition in one pelvic/visceral organ can affect the normal function of another organ. For example, some patients who suffer from irritable bowel syndrome have micturition problems, such as voiding incontinence (Whorwell et al. 1986a). In addition, 46% of female patients who suffer from urinary tract problems have sexual dysfunction, such as decreased sexual activity, disorders in sexual arousal, and dyspareunia (pain with intercourse) (Salonia et al. 2004). In an experimental study using female rats, urinary bladder inflammation was shown to decrease uterine contractions (Dmitrieva et al. 2001), thereby demonstrating that the pathology of one organ, such as the urinary bladder, can affect the function of another.
The neural mechanisms underlying the interactions between the various pelvic/visceral organs are likely to be mediated by both the peripheral and central nervous systems. For the reflex circuitries to be efficient in coordinating pelvic/visceral functions there must be some sort of viscero-visceral convergence within the CNS, both in the spinal cord itself, as well as supraspinally. In the spinal cord, various neuroanatomical studies have shown innervation of different visceral organs by the same set of neurons (Russo & Conte, 1996; Nadelhaft & Vera, 2001). Also, various electrophysiological studies have shown that individual neurons in the spinal cord of rats (Berkley et al. 1993; Qin & Foreman, 2004), cats (Foreman et al. 1984) and primates (Milne et al. 1981) respond to different pelvic/visceral and somatic stimuli. At the brainstem level, numerous regions, including Barrington's nucleus, the solitary nucleus and the nucleus gracilis, have been shown to receive viscero-visceral convergent inputs (Hubscher & Berkley, 1994; Berkley & Hubscher, 1995; Rouzade-Dominguez et al. 2003b).
The medullary reticular formation (MRF) is another brainstem region that receives multiple pelvic/visceral organ inputs. The extensive connections of MRF neurons with the forebrain, limbic system, brainstem nuclei, cerebellum and spinal cord, are an indication of the potential importance of these neurons in the functional coordination between different systems (Brodal et al. 1980; Van Bockstaele et al. 1993; Tavares & Lima, 1994; Cobos et al. 2003; Sun & Panneton, 2005). MRF neurons, for example, that are responsive to electrical stimulation of dorsal nerve of penis (DNP) and mechanical stimulation of penis (low- and high-threshold stimuli) also respond to electrical stimulation of the pelvic nerve (PN), as well as to mechanical stimulation of the perineum and limbs (Hubscher & Johnson, 1996).
Previous neuroanatomical and electrophysiological studies have, however, focused primarily on either inputs to MRF from territories involved with one pelvic organ system (such as from either the bladder and urethra or from the colon and rectum or from the genitalia) or on somato-visceral convergence (Roy et al. 1992; Hubscher & Johnson, 1996, 2004; Almeida & Lima, 1997; Nadelhaft & Vera, 2001; Hubscher et al. 2004). Given the vast array of inputs that have been shown to go to the MRF from the pelvic viscera, as well as convergent inputs from widespread somatic territories, it is hypothesized that there is a significant degree of overlap from different pelvic territories onto individual MRF neurons. Using electrophysiological studies, a defined region of the MRF was searched for neurons responsive to PN stimulation. Each PN-responsive neuron was then tested for responsiveness to urinary bladder (UB) distension and urethral stimulation, electrical stimulation of the DNP and abdominal branches of the vagus, mechanical stimulation of the genitalia, and distension of the distal colon.
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Methods |
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A total of 12 male Wister rats (120 days of age) were used. Each animal was anaesthetized with 50% urethane (1.2 g kg–1). The jugular vein, carotid artery and trachea were exposed and intubated for anaesthetic supplement (5% urethane, as needed, based on assessing withdrawal reflexes), blood pressure monitoring, and respiratory rate/end-expired PCO2 level monitoring, respectively. Using an oesophageal heat sensor probe connected to a thermometer, the animal temperature was monitored throughout the experiment, and maintained at around 37°C using a circulating water-heating pad.
Each animal was mounted onto a stereotaxic device. A dorsal incision was made to gain access to the brainstem. The dorsal surface of rostral medulla was exposed by removing some occipital bone and suctioning the caudal midline portion of the cerebellum (Hubscher & Johnson, 1996, 1999).
Electrical nerve stimulation
A dorsal incision, through the gluteus superficialis and biceps femoris muscles, was made in each animal to expose the PN and DNP bilaterally. The somato-motor branch of the PN was cut and a portion removed to avoid undesirable contractions; only the viscerocutaneous branch was prepared for stimulation. The nerves were separated from the connective tissues and placed on specially fabricated bipolar electrodes (Hubscher & Johnson, 1996). The stimulus intensity, for both nerves, was set at 30–50 µA, 0.1 ms duration, with trains of 14 pulses at 70 pulses s–1, 100 ms train duration, 1 train s–1 (Hubscher & Johnson, 1996).
A bipolar electrode was introduced alongside the oesophageal thermometer probe, just caudal to the oesophageal hiatus, in order to stimulate the abdominal branches of the vagus nerve that are situated on the external wall of the oesophagus (Hubscher et al. 2004). The stimulus intensity was set at 8 mA for 2 ms duration. This stimulus intensity produces compound action potentials in the vagus nerve, as recorded with bipolar hook electrodes in the neck where the vagus runs along the common carotid artery (Hubscher et al. 2004).
Mechanical stimulation of pelvic/visceral organs
A midline abdominal incision was made to expose the UB and proximal urethra. UB and urethral catheters, comprising PE 60 tubing attached to a syringe, were implanted through an incision in the proximal urethra, with the UB catheter directed rostrally toward the UB, and the urethral catheter directed caudally toward the distal urethra (see Fig. 1). The ureters were tied close to the UB and were cut proximal to the suture and drained externally using PE 10 tubing (Kakizaki & de Groat, 1997). The abdominal incision was then closed.
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Electrophysiological recordings
An epoxylite-insulated tungsten microelectrode with standard tip (Frederick Haer and Co., Bowdoinham, ME, USA) was lowered from the dorsal surface with a motorized drive (Frederick Haer and Co.) into the MRF. Stereotaxic coordinates were 3400 µm rostral to obex and 400 µm and 800 µm lateral to midline on both sides of the brainstem (four tracks per animal, in total). The search area for each dorso-ventral track covered a length of 2800–3000 µm, which penetrated the rostral part of the nucleus reticularis gigantocellularis (Gi), the Gi pars alpha (GiA) and the medial part of lateral paragigantocellular nucleus (LPGi) (Hubscher & Johnson, 1999).
Bilateral electrical stimulation of the PN (bPN) was used as the search stimulus. Once a neuron was found to be responsive to bPN (twice- or half-background activity for excitatory and inhibitory responses, respectively, and at least three spikes for non-spontaneous units; Hubscher & Johnson, 2003, 2004), responses of that neuron to distension of the UB and colon were tested, as well as infusion of the urethra. Responses to electrical stimulation of the DNP and the abdominal branches of the vagus nerve were then tested. In addition, the responses to mechanical (stroke and pinch) stimulation of different somatic regions, such as the penis, scrotum, trunk, upper and lower limbs, ears, eyelids and face, were tested. All of the spike recordings made while testing the PN-responsive MRF neurons were recorded to videotape and analysed offline using Data Wave software.
Histology
At the end of the experiment, each animal was perfused using 0.9% normal saline followed by 4% paraformaldehyde introduced through the left ventricle. The brainstem was extracted from each animal and sectioned at 100 µm thickness on a vibratome, and then processed histologically and stained with cresyl violet. The electrophysiological tracks were visualized in these sections under the light microscope, thereby confirming the location of each electrode track (Hubscher & Johnson, 1999). Stereotaxic depth measurements obtained relative to the dorsal surface were used to plot the location of each PN-responsive neuron that was recorded along each of the electrode tracks.
Data analysis
Data was analysed for significance using Student's t test and the 
2 test. Results were considered significant when P < 0.05. Spike histograms were generated using the Data Wave program. The study was performed in accordance with guidelines of the Animal Care and Use Committee (IACUC) of the University of Louisville School of Medicine, and the Guide for the Care and Use of Laboratory Animals (National Academy of Sciences, publication no. 0-309-05377-3).
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Results |
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Many of the PN-responsive MRF neurons studied that were excited or inhibited by UB distension also responded to stimulation of other organs/nerves (urethral infusion, colon distension, penis stimulation, DNP and abdominal branches of the vagus stimulation – 62% responded to all of these stimuli) as well as numerous cutaneous territories (face, eyelid and trunk). A summary comparing the convergent responses of PN-responsive MRF neurons that did and did not respond to UB distension is presented in Table 3. Note that the degree of convergence from multiple pelvic/visceral territories was significantly greater for those neurons responding to UB distension. In fact, the amount of convergence for those responding to all the other pelvic/visceral territories tested was quite different for the subsets of neurons responding and not responding to UB distension (62 versus 0%, respectively, responded to urethra as well as colon and vagal stimulation).
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Most MRF neurons that responded to the stimulation of one visceral organ responded to stimulation of other visceral organs (i.e. viscero-visceral convergence). The degree of viscero-visceral convergence in the MRF is illustrated graphically in Fig. 6. Note that many responses were found for electrical stimulation of the abdominal branches of the vagus nerve, which is known to innervate a number of pelvic/visceral organs, including the stomach, liver, pancreas, colon and the female reproductive organs (Sauter et al. 1983; Prechtl & Powley, 1985; Schoenen et al. 1992; Altschuler et al. 1993; Hubscher & Berkley, 1995). Examples illustrating varying degrees of viscero-visceral convergence onto individual PN-responsive MRF neurons can be seen by comparing responses shown in Figs 3, 4, 5 and 7.
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Somato-visceral convergence into MRF
All of the PN-responsive MRF neurons had convergent input from somatic territories (bilateral). Of the 94 PN-responsive MRF neurons, 27.7% responded to both low- and high-threshold stimulation of somatic receptive fields, whereas 72.3% responded to high-threshold levels of stimulation only. The subregion distribution of PN-responsive MRF neurons with responses to both low- and high-threshold levels of stimulation was as follows: 73.0% located in Gi, 11.5% located in DPGi, and 15.4% located in GiA and raphe magnus nucleus; these levels were not significantly different from the distribution of the PN-responsive MRF neurons that only had responses to high-threshold levels of stimulation. The PN-responsive MRF neurons that responded to UB distension were more responsive to low-threshold stimulation of several different somatic territories (see Fig. 8) compared with the neurons that did not respond to UB distension (43.8 versus 10.9%, respectively).
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Discussion |
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UB/urethral input to MRF
More than half of the PN-responsive MRF neurons responded to distension of the UB. Most of these neurons were also responsive to urethral stimulation. The high degree of convergence from UB and urethra to single MRF neurons indicates that these neurons may play a role in coordinating or modulating the micturition process. Neuroanatomical tracing studies using transsynaptic tracers are consistent with these electrophysiological findings. For example, pseudorabies virus transfection studies (using two histologically distinguished modified types of pseudorabies virus) show double labelling of many MRF neurons following injection of the UB and external urethral sphincter (Nadelhaft & Vera, 2001). Only a very small number of double-labelled neurons are found, however, in the pontine micturition centre (Nadelhaft & Vera, 2001), which is known to be involved in the control of urine voiding and storage through its facilitatory and inhibitory projections, respectively, to lumbosacral spinal neurons that contribute to the functioning of the UB and the external urethral sphincter (Holstege et al. 1986; Noto et al. 1989; Kruse et al. 1990; Yoshimura, 1999; Griffiths, 2002).
A few studies have demonstrated the ability of MRF neurons to modulate the function of the pelvic organs involved in micturition. In one study using cats, MRF neurons were shown to be activated during voiding (Sugaya et al. 2003). In the same study, MRF neurons were shown to have reciprocal connections with the pontine micturition centre and to project axons to the spinal cord, suggesting that two descending spinal pathways from the pontine micturition centre play important roles in micturition, one of which projects by way of the MRF (Sugaya et al. 2003). In another study using cats, electrical stimulation of the MRF inhibited UB contractions (McMahon & Spillane, 1982).
In the present study, most of the inhibitory neurons in the MRF region examined were located in ventral areas (GiA and raphe magnus), which is consistent with previous results (Hubscher & Johnson, 1996). This segregation of the inhibitory and excitatory neurons coincides with segregation between the areas that have inhibitory versus excitatory descending influences on spinal reflexes, as shown in a study examining the effect of electrical stimulation of MRF subregions on the nociceptive tail-flick reflex (Zhuo & Gebhart, 1990).
Convergence of UB and colon inputs in the MRF
Most of the UB-responsive neurons responded to colon distension. Other electrophysiological studies also demonstrate the convergence of UB and colon inputs to single neurons in the brainstem, including studies of neurons within Barrington's nucleus (Rouzade-Dominguez et al. 2003b), the lateral medulla (Robbins et al. 2005) and rostral medulla (Baez et al. 2005), although the latter study tested UB voiding and not distension. Neurons in Barrington's nucleus that have been implicated to play a functional role in the micturition process are double labelled following pseudorabies virus transfection of the UB and colon (Rouzade-Dominguez et al. 2003a),
MRF neurons are likely to be part of the neural circuitry involved in coordinating eliminative processes, including micturition and defaecation. The underlying mechanisms for this control are not known. Lumbosacral spinal neurons have recently been shown in the rat to receive viscero-visceral convergent inputs from the bladder and colon (Qin & Foreman, 2004). These spinal neurons are obvious targets for brainstem modulation of the cross talk that is likely to be occurring between the various visceral organs.
The responses of the MRF neurons to UB and colon distension were in the noxious range (70 mmHg pressure). These results may indicate a role of MRF neurons in visceral nociception as well. It has been shown that the MRF can modulate nociceptive processing by its descending (excitatory and inhibitory) inputs (McCreery et al. 1979; Haber et al. 1980; Gebhart et al. 1983; Zhuo & Gebhart, 1990, 2002a,b), and work as relay nuclei to higher centres for nociceptive processing and ultimately pain perception (Foreman et al. 1984).
Convergence of UB and colon with genital inputs in the MRF
All the PN-responsive MRF neurons (thus all UB and colon-responsive MRF neurons) were responsive to electrical stimulation of dorsal nerve of the penis and mechanical stimulation of penis. These results indicate a role of the MRF neurons in the coordination of urogenital functions. For example, a subpopulation of MRF neurons may inhibit both voiding and defaecation circuitries during ejaculation. The brainstem neurons may also facilitate other aspects that are necessary for normal ejaculation, such as excitation of neurons important for closure of the internal urethral sphincter, which is important in order to avoid retrograde ejaculation.
The MRF has been shown to have a modulatory effect over sexual functions through its descending projections (Marson & McKenna, 1990; Johnson & Hubscher, 1998, 2000). For example, recordings from the motor branch of the pudendal nerve to MRF stimulation demonstrate that MRF neurons (mainly within the LPGi) have an inhibitory effect on the pudendal reflex (Johnson & Hubscher, 1998) and an excitatory effect on sympathetic fibres in the pudendal nerve (Johnson & Hubscher, 2000). Also, injection of an anterograde neuronal tracer (Fluoro-Ruby) into Gi and LPGi (Hermann et al. 2003) and raphe obscurus nucleus (Hermann et al. 1998) shows direct projections from these nuclei to motor neurons labelled with a retrograde neuronal tracer (Fluoro-Gold) injected into the external urethral sphincter, ischiocavernosus and bulbospongiosus muscles. On the other hand, other studies indicate that there are descending inputs from MRF to the spinal cord motor neurons that innervate different pelvic organs. For example, transneuronal-tracing studies with pseudorabies virus injected into UB (Marson, 1997; Sugaya et al. 1997; Zermann, 2002), prostate (Zermann, 2002), penis (Marson et al. 1993) and ischiocavernosus and bulbospongiosus muscles (Marson & McKenna, 1996) labels neurons in different brainstem nuclei (including the MRF nuclei under investigation in this study).
Convergence of vagal inputs into MRF
The PN-responsive MRF neurons that responded to UB distension have significantly higher convergent inputs from abdominal branches of vagus than neurons that did not respond to UB distension. The high convergence of pelvic/visceral inputs with the input resulting from vagus nerve stimulation could indicate a dual innervation of the pelvic/visceral organs. Other studies have demonstrated vagal innervation to pelvic/visceral organs. For example, bilateral vagotomy, in female rats, eliminates the responses of solitary nucleus neurons to uterine horn distension, and affects the response to cervical and vaginal stimuli (Hubscher & Berkley, 1995). Neurons in the dorsal motor nucleus of the vagus and the solitary nucleus have been labelled with neuroanatomical tracers from all areas of the colon, with the exception of rectum (Altschuler et al. 1993). In addition, tracers injected into the urinary bladder labels some nodose ganglion neurons. Capsaicin treatment doesn't affect this pattern of labelling in the nodose ganglion (Jancso & Maggi, 1987), indicating that the UB may be innervated by myelinated fibres in the vagus nerve.
Somato-visceral convergence in the MRF
All the PN-responsive MRF neurons have convergent inputs from cutaneous regions all over the body. The convergence of somatic inputs from all over the body to the same neurons that are responsive to the pelvic/visceral organs may indicate a role of MRF in controlling the body posture during micturition and/or preventing unwanted reflexes that may interrupt micturition (Baez et al. 2005). The significance for an increase in the amount of low-threshold sensory inputs to the MRF for neurons responding to urinary bladder distension (as indicated in Fig. 8) is not known, but perhaps relates to the maintenance of body posture during micturition.
The high degree of pelvic/visceral and somatic convergence onto single MRF neurons could also explain the diffuse and overlapping perception of pelvic visceral pain in some pelvic/visceral pathologies (Whorwell et al. 1986b; Longstreth, 1994; Cervero & Laird, 1999). In the present study, some of the PN-responsive MRF neurons had complex response properties, having opposite responses from stimulation of different areas (usually stimulation of the face evoked an inhibitory response with the remaining convergent responsive territories evoking excitatory responses). This may indicate the ability of MRF neurons to modulate cutaneous and/or visceral pain through somatic stimulation of other areas (see Fig. 3 in Hubscher & Johnson, 2004).
Viscero-visceral convergence in the MRF
The high degree of convergence of afferent inputs from multiple visceral organs into various regions of the CNS (including the MRF) provides a way for the CNS to control and coordinate functions between various pelvic/visceral organs, and may also explain how a pathology associated with one organ can affect the physiology/functioning of another organ (Qin et al. 2005; Berkley, 2005). The importance of regions located supraspinally in viscero-visceral interactions is apparent from the interruption of the physiological functions of the pelvic/visceral organs after spinal cord injury (Heruti et al. 2001). The MRF is one of the supraspinal regions that can play a key role in modulating these pelvic/visceral functions.
The ability of MRF neurons to modulate and/or coordinate multiple pelvic/visceral functions, as discussed in the present paper, necessitates the convergence of sensory inputs from different internal organs onto the same neurons. The results of this study indicate that the PN-responsive MRF neurons that respond to UB distension show a high degree of viscero-visceral convergence, which may indicate a role for a subset of neurons at this level of the neural axis in the modulation of spinal reflexes for the coordination of functions associated with these organs, such as elimination (urination, defaecation, ejaculation).
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