Biology subjects

Harrington, A. M.

Publications and source records attributed to Harrington, A. M..

4 recordsLinked to original sources

bioRxiv2026

A Neuroendocrine Circuit That Suppresses Excretion and Pelvic Pain During Activity

Mate-seeking during peak sexual receptivity is tightly coupled with exploratory movement, a process made more efficient by transient suppression of excretion. Here, we define a functional hypothalamic-hindbrain circuit in mice that promotes locomotion while eliminating urination and defecation for hours. Chemogenetic stimulation of excitatory estrogen-melanocortin-responsive MC4R+ neurons in the ventrolateral ventromedial hypothalamus (VMHvl) effectively silences bladder and colonic visceral reflexes, even at noxious distension pressures, underscoring the potency of this anti-excretion circuit. Pelvic sensations and excretion are restored only after ablating inhibitory GABAergic neurons in the Barringtons nucleus/locus coeruleus (BAR/LC) hindbrain region or after antagonizing endogenous endorphin signaling. Our study illustrates how a hormone-responsive brain node prioritizes movement over excretion and blunts pelvic discomfort, thereby optimizing an essential voluntary behavior for evolutionary fitness.

physiology↗

bioRxiv2025

Bladder mucosal afferents detect UTI and aid pathogen clearance

The bladder is innervated by a complex network of sensory neurons that detect and transmit mechanical and chemical signals to the central nervous system, regulating both urine storage and voiding, as well as mediating sensations of bladder fullness and pain. While stretch-sensitive afferents within the bladder wall are known to monitor filling, the contribution of stretch-insensitive afferents that reside within the bladder mucosa to bladder sensation and function remains unclear. Here, we establish a novel mouse model of selective bladder mucosal afferent denervation using intravesical instillation of resiniferatoxin (RTX) to define the functional roles of these fibres in health and disease. We assessed the impact of mucosal denervation on sensory nerve activity and bladder function in healthy mice and in a model of urinary tract infection (UTI) induced by acute bacterial challenge with uropathogenic E. coli. We show that mucosa-innervating afferents do not influence bladder distension responses or voiding function under healthy conditions. In contrast, during UTI, these afferents become hypersensitive and serve as critical drivers of infection-induced pelvic pain and urinary frequency, responses that contribute to enhanced bacterial clearance. Together, these findings identify bladder mucosal afferents as key sensors of pathogenic challenge and reveal a previously unrecognised mechanism that drives behavioural responses to reduce the burden and extent of UTI.

neuroscience↗

bioRxiv2025

Splanchnic and pelvic spinal afferent pathways relay sensory information from the mouse colorectum into distinct brainstem circuits.

This study aimed to identify where the sensory information relayed by the two spinal afferent pathways innervating the distal colon and rectum (colorectum), the splanchnic and pelvic spinal afferent pathways, integrates within the brainstem. Localised injections of transneuronal viral tracer (herpes simplex virus H129 strain expressing EGFP (H129-EGFP)) into the distal colon was used to assess the brainstem structures receiving ascending input from the colorectum. H129-EGFP+ cells were distributed in structures involved in ascending sensory relay, descending pain modulation and autonomic regulation in the medulla from 96 hours and in pontine and caudal midbrain 120 hours after inoculation. In a separate cohort of mice, in vivo noxious colorectal distension (CRD) followed by brainstem immunolabelling for phosphorylated MAP kinase ERK 1/2 (pERK) showed that many of the structures in which H129-EGFP+ labelling was observed were relevant to colorectal sensory processing. Surgical removal of dorsal root ganglia (DRG) containing cell bodies of splanchnic colorectal afferent neurons, significantly reduced CRD evoked neuronal activation within the caudal ventrolateral medulla, rostral ventromedial medulla and the lateral parabrachial nuclei. Whilst, removal of DRG containing cell bodies of pelvic colorectal afferent neurons significantly reduced CRD evoked neuronal activation within the rostral ventromedial medulla, lateral parabrachial nuclei, the locus coeruleus, Barringtons nucleus and periaqueductal gray. Collectively, this study showed that the two spinal afferent pathways innervating the colorectum differentially shape colorectal processing within the brainstem and provides new insight into their unique roles to mediating visceromotor responses and defecation associated with colorectal nociception.

neuroscience↗

bioRxiv2020

Activation of MrgprA3 and MrgprC11 on bladder-innervating afferents induces peripheral and central hypersensitivity to bladder distension

Understanding the sensory mechanisms innervating the bladder is paramount to developing efficacious treatments for chronic bladder hypersensitivity conditions. The contribution of Mas-gene-related G protein-coupled receptors (Mrgpr) to bladder signalling is currently unknown. Here we show in mice with single-cell RT-PCR that sub-populations of dorsal root ganglion (DRG) neurons innervating the mouse bladder express MrgprA3 (14%) and MrgprC11 (38%), either individually or in combination, with high levels of co-expression with Trpv1 (81-89%). Calcium imaging studies demonstrated MrgprA3 and MrgprC11 agonists (chloroquine, BAM8-22 and neuropeptide FF) activated sub-populations of bladder-innervating DRG neurons, showing functional evidence of co-expression between MrgprA3, MrgprC11 and TRPV1. In ex vivo bladder-nerve preparations chloroquine, BAM8-22 and neuropeptide FF all evoked mechanical hypersensitivity in sub-populations (20-41%) of bladder afferents. These effects were absent in recordings from Mrgpr-cluster{Delta}-/- mice. In vitro whole-cell patch clamp recordings showed that application of an MrgprA3/C11 agonist cocktail induced neuronal hyper-excitability in 44% of bladder-innervating DRG neurons. Finally, in vivo instillation of an MrgprA3/C11 agonist cocktail into the bladder of wild-type mice induced a significant activation of dorsal horn neurons within the lumbosacral spinal cord, as quantified by pERK-immunoreactivity. This MrgprA3/C11 agonist-induced activation was particularly apparent within the superficial dorsal horn and the sacral parasympathetic nuclei of wild-type, but not Mrgpr-cluster{Delta}-/- mice. This study demonstrates, for the first time, functional expression of MrgprA3 and MrgprC11 in bladder afferents. Activation of these receptors is not required for normal bladder function but does trigger hypersensitivity to distension, a critically valuable factor for therapeutic target development. Significance statementDetermining how bladder afferents become sensitized is the first step in finding effective treatments for common urological disorders such as overactive bladder and interstitial cystitis/bladder pain syndrome. Here we show that two of the key receptors, MrgprA3 and MrgprC11, that mediate itch from the skin are also expressed on afferents innervating the bladder. Activation of these receptors results in sensitization of bladder afferents, resulting in sensory signals being sent into the spinal cord that prematurely indicate bladder fullness. Targeting bladder afferents expressing MrgprA3 or MrgprC11 and preventing their sensitisation may provide a novel approach for treating overactive bladder and interstitial cystitis/bladder pain syndrome.

neuroscience↗