Transsynaptic tracing to dissect supraspinal serotonergic input regulating the bladder reflex in rats

Ahn, Jemin; Saltos, Tatiana M.; Tom, Veronica J.; Hou, Shaoping

doi:10.1002/nau.23762

Cited by 11 publications

(6 citation statements)

References 26 publications

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“…These mainly include the pontine micturition center/Barrington's nucleus, the periaqueductal gray, the hypothalamus, and the motor cortex (Andersson and Arner, 2004;Nadelhaft and Vera, 2001;Verstegen et al, 2019;Yao et al, 2019). The descending reticulospinal projections were severely affected by the SCI, resulting in a large decrease of spinal coverage below the level of the lesion including the CRF-positive fibers originating in the pontine micturition center, the main nucleus responsible for voiding initiation, as well as 5-HT-positive fibers from the raphe system (Ahn et al, 2018). 5-HT fibers regulate the level of excitation in different spinal circuits; they facilitate the urinary guarding reflex by inhibiting the parasympathetic pathway that causes detrusor contraction (Chang et al, 2007;Khaled and Elhilali, 2003).…”

Section: Discussionmentioning

confidence: 99%

Slow development of bladder malfunction parallels spinal cord fiber sprouting and interneurons' loss after spinal cord transection

Sartori

Hofer

Scheuber

et al. 2022

Experimental Neurology

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Section: Discussionmentioning

confidence: 99%

Slow development of bladder malfunction parallels spinal cord fiber sprouting and interneurons' loss after spinal cord transection

Sartori

Hofer

Scheuber

et al. 2022

Experimental Neurology

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“…Several reports also suggest GABAergic projections from RVM to spinal dorsal horn as direct input to postsynaptic neurons such as spinal interneurons and ascending projection neurons (Aicher et al., 2012; Hossaini et al., 2012; Kato et al., 2006; Reichling & Basbaum, 1990). PRV tracing from the bladder demonstrated that bladder‐specific serotonergic RVM neurons are mostly expressed in the caudal raphe with the highest number in the RMg (Ahn et al., 2018). Similarly, our PRV‐tracing experiments have demonstrated that about 14% of RVM neurons connected to the bladder are TpH2 positive with major expression in RMg, Gi, and LpGi nuclei.…”

Section: Discussionmentioning

confidence: 99%

Identification and characterization of rostral ventromedial medulla neurons synaptically connected to the urinary bladder afferents in female rats with or without neonatal cystitis

Talluri

Hoelzel

Medda

et al. 2021

J of Comparative Neurology

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The neurons in the rostral ventromedial medulla (RVM) play a major role in pain modulation. We have previously shown that early-life noxious bladder stimuli in rats resulted in an overall spinal GABAergic disinhibition and a long-lasting bladder/colon sensitization when tested in adulthood. However, the neuromolecular alterations within RVM neurons in the pathophysiology of early life bladder inflammation have not been elucidated. In this study, we have identified and characterized RVM neurons that are synaptically linked to the bladder and colon and examined the effect of neonatal bladder inflammation on molecular expressions of these neurons. A transient bladder inflammation was induced by intravesicular instillation of protamine sulfate and zymosan during postnatal days 14 through 16 (P14-16) followed by pseudorabies virus PRV-152 and PRV-614 injections into the bladder and colon, respectively, on postnatal day P60. Tissues were examined 96 h postinoculation for serotonergic, GABAergic, and enkephalinergic expressions using in situ hybridization and/or immunohistochemistry techniques. The results revealed that > 50% of RVM neurons that are synaptically connected to the bladder (i.e., PRV-152+) were GABAergic, 40% enkephalinergic, and about 14% expressing serotonergic marker tryptophan hydroxylase 2 (TpH2).Neonatal cystitis resulted in a significant increase in converging neurons in RVM receiving dual synaptic inputs from the bladder and colon. In addition, neonatal cystitis significantly downregulated vesicular GABA transporter (VGAT) with a concomitant increase in TpH2 expression in bladder-linked RVM neurons, suggesting an alteration in supraspinal signaling. These alterations of synaptic connectivity and GABAergic/serotonergic expressions in RVM neurons may contribute to bladder pain modulation and cross-organ visceral sensitivity.

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“…A recent study has also shown that bladder-projecting neurons in the caudal raphe nucleus, the area of the brainstem which exhibits supraspinal control of the bladder, also express serotonin (Ahn et al 2018), suggesting that serotonergic control of the bladder could have both peripheral and central components which involve the 5-HT 3 receptor.…”

Section: -Ht Has a Direct Effect On Afferent Firing Via The 5-ht 3 Re...mentioning

confidence: 99%

Serotonin exerts a direct modulatory role on bladder afferent firing in mice

Konthapakdee

Grundy

O’Donnell

et al. 2019

The Journal of Physiology

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Key points Functional disorders (i.e. interstitial cystitis/painful bladder syndrome and irritable bowel syndrome) are associated with hyperexcitability of afferent nerves innervating the urinary tract and the bowel, respectively. Various non‐5‐HT3 receptor mRNA transcripts are expressed in mouse urothelium and exert functional responses to 5‐HT. Whilst 5‐HT3 receptors were not detected in mouse urothelium, 5‐HT3 receptors expressed on bladder sensory neurons plays a role in bladder afferent excitability both under normal conditions and in a mouse model of chronic visceral hypersensitivity. These data suggest that the role 5‐HT3 receptors play in bladder afferent signalling warrants further study as a potential therapeutic target for functional bladder disorders. Abstract Serotonin (5‐HT) is an excitatory mediator that in the gastrointestinal (GI) tract plays a physiological role in gut–brain signalling and is dysregulated in functional GI disorders such as irritable bowel syndrome (IBS). Patients suffering from IBS frequently suffer from urological symptoms characteristic of interstitial cystitis/painful bladder syndrome, which manifests due to cross‐sensitization of shared innervation pathways between the bladder and colon. However, a direct modulatory role of 5‐HT in bladder afferent signalling and its role in colon–bladder neuronal crosstalk remain elusive. The aim of this study was to investigate the action of 5‐HT on bladder afferent signalling in normal mice and mice with chronic visceral hypersensitivity (CVH) following trinitrobenzenesulfonic acid‐induced colitis. Bladder afferent activity was recorded directly using ex vivo afferent nerve recordings. Expression of 14 5‐HT receptor subtypes, the serotonin transporter (SERT) and 5‐HT‐producing enzymes was determined in the urothelium using RT‐PCR. Retrograde labelling of bladder‐projecting dorsal root ganglion neurons was used to investigate expression of 5‐HT3 receptors using single cell RT‐PCR, while sensory neuronal and urothelial responses to 5‐HT were determined by live cell calcium imaging. 5‐HT elicited bladder afferent firing predominantly via 5‐HT3 receptors expressed on afferent terminals. CVH animals showed a downregulation of SERT mRNA expression in urothelium, suggesting increased 5‐HT bioavailability. Granisetron, a 5‐HT3 antagonist, reversed bladder afferent hypersensitivity in CVH mice. These data suggest 5‐HT exerts a direct effect on bladder afferents to enhance signalling. 5‐HT3 antagonists could therefore be a potential therapeutic target to treat functional bladder and bowel disorders.

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Transsynaptic tracing to dissect supraspinal serotonergic input regulating the bladder reflex in rats

Abstract: The caudal subsets of RN, especially the raphe magnus, are the main sources of serotonergic input to the lower spinal cord controlling bladder activity.

Cited by 11 publications

References 26 publications

Slow development of bladder malfunction parallels spinal cord fiber sprouting and interneurons' loss after spinal cord transection

Slow development of bladder malfunction parallels spinal cord fiber sprouting and interneurons' loss after spinal cord transection

Identification and characterization of rostral ventromedial medulla neurons synaptically connected to the urinary bladder afferents in female rats with or without neonatal cystitis

Serotonin exerts a direct modulatory role on bladder afferent firing in mice

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