Liana Merrill - Academia.edu (original) (raw)

Papers by Liana Merrill

Research paper thumbnail of Running Head: RVS induces bladder dysfunction and somatic sensitivity

Repeated variate stress (RVS) in male rats induces increased voiding frequency, somatic sensitivi... more Repeated variate stress (RVS) in male rats induces increased voiding frequency, somatic sensitivity and urinary bladder NGF expression

Research paper thumbnail of 4α-PDD 4alpha-phorbol 12,13-didecanoate AA acetic acid ATP adenosine triphosphate BOO bladder outlet obstruction BPS bladder pain syndrome Cap Capsaicin CGRP calcitonin gene-related peptide CYP cyclophosphamide DO detrusor overactivity DRG dorsal root ganglia EFS electrical field stimulation GSK GSK

Running head: Bladder sensory targets to improve function 17 18 19 20 21 22 23 24 25 26 27 28 29 ... more Running head: Bladder sensory targets to improve function 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 *Correspondence to: Margaret A. Vizzard, Ph.D. 33 University of Vermont College of Medicine 34 Department of Neurological Sciences 35 D405A Given Research Building 36 Burlington, VT 05405 37 Phone: 802-656-3209 38 Email: margaret.vizzard@uvm.edu 39 Articles in PresS. Am J Physiol Regul Integr Comp Physiol (April 23, 2014). doi:10.1152/ajpregu.00030.2014

The urothelium responds to changes in hydrostatic pressure by releasing factors, such as ATP, from its mucosal and serosal surfaces (50, 150). ATP released from the serosal surface may then interact with nerve terminals, interstitial cells, and/or basolateral urothelial P2 purinoceptors to transduce sensory information or regulate its release, respectively (150). In func- tional disorders of the urinary bladder, such as BPS/IC, how- ever, urothelial cells have been demonstrated to increase stretch-evoked ATP release relative to symptom-free controls (125). It has been suggested that the increased ATP release may, in part, underlie the development of lower urinary tract symptoms in micturition reflex dysfunction due to the capacity of intravesical purinergic agonist (ATP or «,8-meATP) instillation to increase the firing rate of urinary bladder afferent nerves and induce bladder overactivity (105, 109, 161). Taken together, these studies have begun to establish the influence of purinergic signal- ing in urinary bladder sensory transduction and demonstrate its possible role in micturition reflex dysfunction.

Research paper thumbnail of Anatomical Connections: Linking High Schools to the UVM College of Medicine with Anatomy

Anatomical Connections: Linking High Schools to the UVM College of Medicine with Anatomy

The FASEB Journal, 2017

Research paper thumbnail of Reduced marker of vascularization in the anterior hippocampus in a female monkey model of depression

Physiology & behavior, Jan 14, 2016

Depression is a common and debilitating mood disorder that impacts women more often than men. The... more Depression is a common and debilitating mood disorder that impacts women more often than men. The mechanisms that result in depressive behaviors are not fully understood; however, the hippocampus has been noted as a key structure in the pathophysiology of depression. In addition to neural implications of depression, the cardiovascular system is impacted. Although not as commonly considered, the cerebrovasculature is critical to brain function, impacted by environmental stimuli, and is capable of altering neural function and thereby behavior. In the current study, we assessed the relationship between depressive behavior and a marker of vascularization of the hippocampus in adult female cynomolgus macaques (Macaca fascicularis). Similar to previously noted impacts on neuropil and glia, the depressed phenotype predicts a reduction in a marker of vascular length in the anterior hippocampus. These data reinforce the growing recognition of the effects of depression on vasculature and supp...

Research paper thumbnail of Sex Differences in Neuroanatomy and Neurophysiology

Sex Differences in Neuroanatomy and Neurophysiology

Sex Differences in Physiology, 2016

Sex differences in neurophysiology and behavior are crucial to the understanding of neurological ... more Sex differences in neurophysiology and behavior are crucial to the understanding of neurological diseases. Alzheimer’s disease, Parkinson’s disease, anxiety, and depression are just a few of the known sexually dimorphic neurological disorders in terms of prevalence, symptom presentation, disease progression, etc. Steroid hormones, particularly estrogen, are thought to play a protective role in some of these diseases. Thus, it is pertinent to understand how steroid hormones affect the central and peripheral nervous systems in order to uncover the underlying mechanisms involved in these diseases. Steroid hormones act on sexually dimorphic brain regions, including several nuclei of the hypothalamus, to influence neuronal signaling (eg, neurotransmitter systems), physiological functions of the body, and sexually dimorphic behaviors like mating and aggression. This chapter discusses the roles of steroid hormones including estrogen, progesterone, and testosterone in neuronal signaling, body functions, behavior, and neurological disease.

Research paper thumbnail of Brief anesthesia by isoflurane alters plasma corticosterone levels distinctly in male and female rats: Implications for tissue collection methods

Behavioural brain research, Jan 3, 2016

Euthanasia by anesthetic agents is commonly performed prior to tissue collection in order to mini... more Euthanasia by anesthetic agents is commonly performed prior to tissue collection in order to minimize pain and distress to the animal. However, depending on their mechanism of action as well as administration regimen, different methods of anesthesia may trigger an acute stress response through engaging the hypothalamic-pituitary-adrenal (HPA) axis, which can impact numerous other physiological processes that the researcher may wish to examine as endpoints. We investigated the effects of the commonly used anesthetic agent isoflurane on two different endpoints related to the stress response: plasma corticosterone levels and gene expression of the glucocorticoid receptor (GR) as well as several of its regulators including FK506-binding protein 51 (Fkbp5) in the hippocampus of male and female rats. Our results indicate that brief exposure to anesthesia by isoflurane prior to decapitation can alter plasma corticosterone levels differentially in male and female rats within minutes without...

Research paper thumbnail of Receptors, channels, and signalling in the urothelial sensory system in the bladder

Nature Reviews Urology, 2016

The storage and periodic elimination of urine, termed micturition, requires a complex neural cont... more The storage and periodic elimination of urine, termed micturition, requires a complex neural control system to coordinate the activities of the urinary bladder, urethra, and urethral sphincters. At the level of the lumbosacral spinal cord, lower urinary tract reflex mechanisms are modulated by supraspinal controls with mechanosensory input from the urothelium, resulting in regulation of bladder contractile activity. The specific identity of the mechanical sensor is not yet known, but considerable interest exists in the contribution of transient receptor potential (TRP) channels to the mechanosensory functions of the urothelium. The sensory, transduction, and signalling properties of the urothelium can influence adjacent urinary bladder tissues including the suburothelial nerve plexus, interstitial cells of Cajal, and detrusor smooth muscle cells. Diverse stimuli, including those that activate TRP channels expressed by the urothelium, can influence urothelial release of chemical mediators (such as ATP). Changes to the urothelium are associated with a number of bladder pathologies that underlie urinary bladder dysfunction. Urothelial receptor and/or ion channel expression and the release of signalling molecules (such as ATP and nitric oxide) can be altered with bladder disease, neural injury, target organ inflammation, or psychogenic stress. Urothelial receptors and channels represent novel targets for potential therapies that are intended to modulate micturition function or bladder sensation. Transient receptor potential (TRP) channels and purinergic receptors are expressed in neural and non-neural elements of the lower urinary tract (LUT) and are thought to contribute to physiological and pathological function. Targeting TRP channels and purinergic receptors in the LUT could affect mechanosensation, chemosensation, pain perception, and excitability of bladder sensory nerves to modulate the afferent limb of the micturition reflex and affect the overall function of the urinary bladder.

Research paper thumbnail of Intravesical TRPV4 blockade reduces repeated variate stress-induced bladder dysfunction by increasing bladder capacity and decreasing voiding frequency in male rats

American journal of physiology. Regulatory, integrative and comparative physiology, Jan 15, 2014

Individuals with functional lower urinary tract disorders including interstitial cystitis (IC)/bl... more Individuals with functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) often report symptom (e.g., urinary frequency) worsening due to stress. One member of the transient receptor potential ion channel vanilloid family, TRPV4, has recently been implicated in urinary bladder dysfunction disorders including OAB and IC/BPS. These studies address the role of TRPV4 in stress-induced bladder dysfunction using an animal model of stress in male rats. To induce stress, rats were exposed to 7 days of repeated variate stress (RVS). Quantitative PCR data demonstrated significant (P ≤ 0.01) increases in TRPV4 transcript levels in urothelium but not detrusor smooth muscle. Western blot analyses of split urinary bladders (i.e., urothelium and detrusor) showed significant (P ≤ 0.01) increases in TRPV4 protein expression levels in urothelial tissues but not detrusor smooth muscle. We previously showed that RVS produces ...

Research paper thumbnail of Bladder sensory physiology: neuroactive compounds and receptors, sensory transducers, and target-derived growth factors as targets to improve function

American journal of physiology. Regulatory, integrative and comparative physiology, Jan 15, 2014

Urinary bladder dysfunction presents a major problem in the clinical management of patients suffe... more Urinary bladder dysfunction presents a major problem in the clinical management of patients suffering from pathological conditions and neurological injuries or disorders. Currently, the etiology underlying altered visceral sensations from the urinary bladder that accompany the chronic pain syndrome, bladder pain syndrome (BPS)/interstitial cystitis (IC), is not known. Bladder irritation and inflammation are histopathological features that may underlie BPS/IC that can change the properties of lower urinary tract sensory pathways (e.g., peripheral and central sensitization, neurochemical plasticity) and contribute to exaggerated responses of peripheral bladder sensory pathways. Among the potential mediators of peripheral nociceptor sensitization and urinary bladder dysfunction are neuroactive compounds (e.g., purinergic and neuropeptide and receptor pathways), sensory transducers (e.g., transient receptor potential channels) and target-derived growth factors (e.g., nerve growth factor...

Research paper thumbnail of Increased TRPV4 Expression in Urinary Bladder and Lumbosacral Dorsal Root Ganglia in Mice with Chronic Overexpression of NGF in Urothelium

Journal of Molecular Neuroscience, 2013

Transient receptor potential vanilloid (TRPV) family member 4 (TRPV4) expression has been demonst... more Transient receptor potential vanilloid (TRPV) family member 4 (TRPV4) expression has been demonstrated in urothelial cells and dorsal root ganglion (DRG) neurons and roles in normal micturition reflexes as well as micturition dysfunction have been suggested. TRP channel expression and function is dependent upon target tissue expression of growth factors. These studies expand upon the target tissue dependence of TRPV4 expression in the urinary bladder and lumbosacral DRG using a recently characterized transgenic mouse model with chronic overexpression of nerve growth factor (NGF-OE) in the urothelium. Immunohistochemistry with image analyses, real-time quantitative polymerase chain reaction (Q-PCR) and western blotting were used to determine TRPV4 protein and transcript expression in the urinary bladder (urothelium + suburothelium, detrusor) and lumbosacral DRG from littermate wildtype (WT) and NGF-OE mice. Antibody specificity controls were performed in TRPV4-/mice. TRPV4 transcript and protein expression was significantly (p ≤ 0.001) increased in the urothelium + suburothelium and suburothelial nerve plexus of the urinary bladder and in small-and medium-sized lumbosacral (L1, L2, L6-S1) DRG cells from NGF-OE mice compared to littermate WT mice. NGF-OE mice exhibit significant (p ≤ 0.001) increases in NGF transcript and protein in the urothelium + suburothelium and lumbosacral DRG. These studies demonstrate regulation of TRPV4 expression by NGF in lower urinary tract tissues. Ongoing studies are characterizing the functional roles of TRPV4 expression in the sensory limb (DRG, urothelium) of the micturition reflex.

Research paper thumbnail of Transcriptional and Translational Plasticity in Rodent Urinary Bladder TRP Channels with Urinary Bladder Inflammation, Bladder Dysfunction, or Postnatal Maturation

Journal of Molecular Neuroscience, 2012

These studies examined transcriptional and translational plasticity of three transient receptor p... more These studies examined transcriptional and translational plasticity of three transient receptor potential (TRP) channels (TRPA1, TRPV1, TRPV4) with established neuronal and non-neuronal expression and functional roles in the lower urinary tract. Mechanosensor and nociceptor roles in either physiological or pathological lower urinary tract states have been suggested for TRPA1, TRPV1 and TRPV4. We have previously demonstrated neurochemical, organizational and functional plasticity in micturition reflex pathways following induction of urinary bladder inflammation using the antineoplastic agent, cyclophosphamide (CYP). More recently, we have characterized similar plasticity in micturition reflex pathways in a transgenic mouse model with chronic urothelial overexpression (OE) of nerve growth factor (NGF) and in a transgenic mouse model with deletion of vasoactive intestinal polypeptide (VIP). In addition, the micturition reflex undergoes postnatal maturation that may also reflect plasticity in urinary bladder TRP channel expression. Thus, we examined plasticity in urinary bladder TRP channel expression in diverse contexts using a combination of quantitative, real-time PCR and western blotting approaches. We demonstrate transcriptional and translational plasticity of urinary bladder TRPA1, TRPV1 and TRVP4 expression. Although the functional significance of urinary bladder TRP channel plasticity awaits further investigation, these studies demonstrate context-(inflammation, postnatal development, NGF-OE, VIP deletion) and tissue-dependent (urothelium + suburothelium, detrusor) plasticity.

Research paper thumbnail of Neuropeptide/Receptor Expression and Plasticity in Micturition Pathways

Neuropeptide/Receptor Expression and Plasticity in Micturition Pathways

Current Pharmaceutical Design, 2013

Several motor behaviors such as locomotion, respiration, sexual function, and micturition are gen... more Several motor behaviors such as locomotion, respiration, sexual function, and micturition are generated by rhythmic and stereotyped motor patterns of activity. In most cases, these functions are primarily controlled by signals and neuronal commands that originate from the brainstem and spinal cord. Defined as the storage and periodic elimination of urine, micturition requires a complex neural control system that coordinates the activities of a variety of effector organs including the smooth muscle of the urinary bladder and the smooth and striated muscle of the urethral sphincters. The lower urinary tract (LUT) reflex mechanisms, organized at the level of the lumbosacral spinal cord, are modulated predominantly by supraspinal controls. These LUT mechanisms include: (1) storage reflexes organized at the spinal level; (2) elimination reflexes organized at a supraspinal site in the pons; and (3) spinal storage reflexes modulated by inputs from the rostral pons. Precise coordination of the reciprocal functions of the urinary bladder and urethra and complex neural organization are required for normal function. Numerous neuropeptide/receptor systems are expressed in central and peripheral nervous system pathways that regulate the LUT and expression can also be found in both neural and non-neural (e.g., urothelium) components. Neuropeptides have tissue-specific distributions and functions in the LUT and exhibit neuroplastic changes in expression and function with LUT dysfunction with neural injury, inflammation, stress and disease. LUT dysfunction with abnormal voiding including urinary urgency, increased voiding frequency, nocturia, urinary incontinence, urinary retention, continence, detrusor dysynergia and/or pain may reflect a change in the balance of neuropeptides in central and peripheral bladder reflex pathways. LUT neuropeptide/receptor systems in LUT pathways may thus represent potential targets for therapeutic intervention.

Research paper thumbnail of Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2013

Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cy... more Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) in humans, but mechanisms contributing to symptom worsening are unknown. These studies address stress-induced changes in the structure and function of the micturition reflex using an animal model of stress in male rats. Rats were exposed to 7 days of repeated variate stress (RVS). Target organ (urinary bladder, thymus, adrenal gland) tissues were collected and weighed following RVS. Evans blue (EB) concentration and histamine, myeloperoxidase (MPO), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), and CXCL12 protein content (ELISA) were measured in the urinary bladder, and somatic sensitivity of the hindpaw and pelvic regions was determined following RVS. Bladder function was evaluated using continuous, open outlet intravesical infusion of saline in conscious rats. Increases in body weight gain were s...

Research paper thumbnail of Running Head: RVS induces bladder dysfunction and somatic sensitivity

Repeated variate stress (RVS) in male rats induces increased voiding frequency, somatic sensitivi... more Repeated variate stress (RVS) in male rats induces increased voiding frequency, somatic sensitivity and urinary bladder NGF expression

Research paper thumbnail of 4α-PDD 4alpha-phorbol 12,13-didecanoate AA acetic acid ATP adenosine triphosphate BOO bladder outlet obstruction BPS bladder pain syndrome Cap Capsaicin CGRP calcitonin gene-related peptide CYP cyclophosphamide DO detrusor overactivity DRG dorsal root ganglia EFS electrical field stimulation GSK GSK

Running head: Bladder sensory targets to improve function 17 18 19 20 21 22 23 24 25 26 27 28 29 ... more Running head: Bladder sensory targets to improve function 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 *Correspondence to: Margaret A. Vizzard, Ph.D. 33 University of Vermont College of Medicine 34 Department of Neurological Sciences 35 D405A Given Research Building 36 Burlington, VT 05405 37 Phone: 802-656-3209 38 Email: margaret.vizzard@uvm.edu 39 Articles in PresS. Am J Physiol Regul Integr Comp Physiol (April 23, 2014). doi:10.1152/ajpregu.00030.2014

The urothelium responds to changes in hydrostatic pressure by releasing factors, such as ATP, from its mucosal and serosal surfaces (50, 150). ATP released from the serosal surface may then interact with nerve terminals, interstitial cells, and/or basolateral urothelial P2 purinoceptors to transduce sensory information or regulate its release, respectively (150). In func- tional disorders of the urinary bladder, such as BPS/IC, how- ever, urothelial cells have been demonstrated to increase stretch-evoked ATP release relative to symptom-free controls (125). It has been suggested that the increased ATP release may, in part, underlie the development of lower urinary tract symptoms in micturition reflex dysfunction due to the capacity of intravesical purinergic agonist (ATP or «,8-meATP) instillation to increase the firing rate of urinary bladder afferent nerves and induce bladder overactivity (105, 109, 161). Taken together, these studies have begun to establish the influence of purinergic signal- ing in urinary bladder sensory transduction and demonstrate its possible role in micturition reflex dysfunction.

Research paper thumbnail of Anatomical Connections: Linking High Schools to the UVM College of Medicine with Anatomy

Anatomical Connections: Linking High Schools to the UVM College of Medicine with Anatomy

The FASEB Journal, 2017

Research paper thumbnail of Reduced marker of vascularization in the anterior hippocampus in a female monkey model of depression

Physiology & behavior, Jan 14, 2016

Depression is a common and debilitating mood disorder that impacts women more often than men. The... more Depression is a common and debilitating mood disorder that impacts women more often than men. The mechanisms that result in depressive behaviors are not fully understood; however, the hippocampus has been noted as a key structure in the pathophysiology of depression. In addition to neural implications of depression, the cardiovascular system is impacted. Although not as commonly considered, the cerebrovasculature is critical to brain function, impacted by environmental stimuli, and is capable of altering neural function and thereby behavior. In the current study, we assessed the relationship between depressive behavior and a marker of vascularization of the hippocampus in adult female cynomolgus macaques (Macaca fascicularis). Similar to previously noted impacts on neuropil and glia, the depressed phenotype predicts a reduction in a marker of vascular length in the anterior hippocampus. These data reinforce the growing recognition of the effects of depression on vasculature and supp...

Research paper thumbnail of Sex Differences in Neuroanatomy and Neurophysiology

Sex Differences in Neuroanatomy and Neurophysiology

Sex Differences in Physiology, 2016

Sex differences in neurophysiology and behavior are crucial to the understanding of neurological ... more Sex differences in neurophysiology and behavior are crucial to the understanding of neurological diseases. Alzheimer’s disease, Parkinson’s disease, anxiety, and depression are just a few of the known sexually dimorphic neurological disorders in terms of prevalence, symptom presentation, disease progression, etc. Steroid hormones, particularly estrogen, are thought to play a protective role in some of these diseases. Thus, it is pertinent to understand how steroid hormones affect the central and peripheral nervous systems in order to uncover the underlying mechanisms involved in these diseases. Steroid hormones act on sexually dimorphic brain regions, including several nuclei of the hypothalamus, to influence neuronal signaling (eg, neurotransmitter systems), physiological functions of the body, and sexually dimorphic behaviors like mating and aggression. This chapter discusses the roles of steroid hormones including estrogen, progesterone, and testosterone in neuronal signaling, body functions, behavior, and neurological disease.

Research paper thumbnail of Brief anesthesia by isoflurane alters plasma corticosterone levels distinctly in male and female rats: Implications for tissue collection methods

Behavioural brain research, Jan 3, 2016

Euthanasia by anesthetic agents is commonly performed prior to tissue collection in order to mini... more Euthanasia by anesthetic agents is commonly performed prior to tissue collection in order to minimize pain and distress to the animal. However, depending on their mechanism of action as well as administration regimen, different methods of anesthesia may trigger an acute stress response through engaging the hypothalamic-pituitary-adrenal (HPA) axis, which can impact numerous other physiological processes that the researcher may wish to examine as endpoints. We investigated the effects of the commonly used anesthetic agent isoflurane on two different endpoints related to the stress response: plasma corticosterone levels and gene expression of the glucocorticoid receptor (GR) as well as several of its regulators including FK506-binding protein 51 (Fkbp5) in the hippocampus of male and female rats. Our results indicate that brief exposure to anesthesia by isoflurane prior to decapitation can alter plasma corticosterone levels differentially in male and female rats within minutes without...

Research paper thumbnail of Receptors, channels, and signalling in the urothelial sensory system in the bladder

Nature Reviews Urology, 2016

The storage and periodic elimination of urine, termed micturition, requires a complex neural cont... more The storage and periodic elimination of urine, termed micturition, requires a complex neural control system to coordinate the activities of the urinary bladder, urethra, and urethral sphincters. At the level of the lumbosacral spinal cord, lower urinary tract reflex mechanisms are modulated by supraspinal controls with mechanosensory input from the urothelium, resulting in regulation of bladder contractile activity. The specific identity of the mechanical sensor is not yet known, but considerable interest exists in the contribution of transient receptor potential (TRP) channels to the mechanosensory functions of the urothelium. The sensory, transduction, and signalling properties of the urothelium can influence adjacent urinary bladder tissues including the suburothelial nerve plexus, interstitial cells of Cajal, and detrusor smooth muscle cells. Diverse stimuli, including those that activate TRP channels expressed by the urothelium, can influence urothelial release of chemical mediators (such as ATP). Changes to the urothelium are associated with a number of bladder pathologies that underlie urinary bladder dysfunction. Urothelial receptor and/or ion channel expression and the release of signalling molecules (such as ATP and nitric oxide) can be altered with bladder disease, neural injury, target organ inflammation, or psychogenic stress. Urothelial receptors and channels represent novel targets for potential therapies that are intended to modulate micturition function or bladder sensation. Transient receptor potential (TRP) channels and purinergic receptors are expressed in neural and non-neural elements of the lower urinary tract (LUT) and are thought to contribute to physiological and pathological function. Targeting TRP channels and purinergic receptors in the LUT could affect mechanosensation, chemosensation, pain perception, and excitability of bladder sensory nerves to modulate the afferent limb of the micturition reflex and affect the overall function of the urinary bladder.

Research paper thumbnail of Intravesical TRPV4 blockade reduces repeated variate stress-induced bladder dysfunction by increasing bladder capacity and decreasing voiding frequency in male rats

American journal of physiology. Regulatory, integrative and comparative physiology, Jan 15, 2014

Individuals with functional lower urinary tract disorders including interstitial cystitis (IC)/bl... more Individuals with functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) often report symptom (e.g., urinary frequency) worsening due to stress. One member of the transient receptor potential ion channel vanilloid family, TRPV4, has recently been implicated in urinary bladder dysfunction disorders including OAB and IC/BPS. These studies address the role of TRPV4 in stress-induced bladder dysfunction using an animal model of stress in male rats. To induce stress, rats were exposed to 7 days of repeated variate stress (RVS). Quantitative PCR data demonstrated significant (P ≤ 0.01) increases in TRPV4 transcript levels in urothelium but not detrusor smooth muscle. Western blot analyses of split urinary bladders (i.e., urothelium and detrusor) showed significant (P ≤ 0.01) increases in TRPV4 protein expression levels in urothelial tissues but not detrusor smooth muscle. We previously showed that RVS produces ...

Research paper thumbnail of Bladder sensory physiology: neuroactive compounds and receptors, sensory transducers, and target-derived growth factors as targets to improve function

American journal of physiology. Regulatory, integrative and comparative physiology, Jan 15, 2014

Urinary bladder dysfunction presents a major problem in the clinical management of patients suffe... more Urinary bladder dysfunction presents a major problem in the clinical management of patients suffering from pathological conditions and neurological injuries or disorders. Currently, the etiology underlying altered visceral sensations from the urinary bladder that accompany the chronic pain syndrome, bladder pain syndrome (BPS)/interstitial cystitis (IC), is not known. Bladder irritation and inflammation are histopathological features that may underlie BPS/IC that can change the properties of lower urinary tract sensory pathways (e.g., peripheral and central sensitization, neurochemical plasticity) and contribute to exaggerated responses of peripheral bladder sensory pathways. Among the potential mediators of peripheral nociceptor sensitization and urinary bladder dysfunction are neuroactive compounds (e.g., purinergic and neuropeptide and receptor pathways), sensory transducers (e.g., transient receptor potential channels) and target-derived growth factors (e.g., nerve growth factor...

Research paper thumbnail of Increased TRPV4 Expression in Urinary Bladder and Lumbosacral Dorsal Root Ganglia in Mice with Chronic Overexpression of NGF in Urothelium

Journal of Molecular Neuroscience, 2013

Transient receptor potential vanilloid (TRPV) family member 4 (TRPV4) expression has been demonst... more Transient receptor potential vanilloid (TRPV) family member 4 (TRPV4) expression has been demonstrated in urothelial cells and dorsal root ganglion (DRG) neurons and roles in normal micturition reflexes as well as micturition dysfunction have been suggested. TRP channel expression and function is dependent upon target tissue expression of growth factors. These studies expand upon the target tissue dependence of TRPV4 expression in the urinary bladder and lumbosacral DRG using a recently characterized transgenic mouse model with chronic overexpression of nerve growth factor (NGF-OE) in the urothelium. Immunohistochemistry with image analyses, real-time quantitative polymerase chain reaction (Q-PCR) and western blotting were used to determine TRPV4 protein and transcript expression in the urinary bladder (urothelium + suburothelium, detrusor) and lumbosacral DRG from littermate wildtype (WT) and NGF-OE mice. Antibody specificity controls were performed in TRPV4-/mice. TRPV4 transcript and protein expression was significantly (p ≤ 0.001) increased in the urothelium + suburothelium and suburothelial nerve plexus of the urinary bladder and in small-and medium-sized lumbosacral (L1, L2, L6-S1) DRG cells from NGF-OE mice compared to littermate WT mice. NGF-OE mice exhibit significant (p ≤ 0.001) increases in NGF transcript and protein in the urothelium + suburothelium and lumbosacral DRG. These studies demonstrate regulation of TRPV4 expression by NGF in lower urinary tract tissues. Ongoing studies are characterizing the functional roles of TRPV4 expression in the sensory limb (DRG, urothelium) of the micturition reflex.

Research paper thumbnail of Transcriptional and Translational Plasticity in Rodent Urinary Bladder TRP Channels with Urinary Bladder Inflammation, Bladder Dysfunction, or Postnatal Maturation

Journal of Molecular Neuroscience, 2012

These studies examined transcriptional and translational plasticity of three transient receptor p... more These studies examined transcriptional and translational plasticity of three transient receptor potential (TRP) channels (TRPA1, TRPV1, TRPV4) with established neuronal and non-neuronal expression and functional roles in the lower urinary tract. Mechanosensor and nociceptor roles in either physiological or pathological lower urinary tract states have been suggested for TRPA1, TRPV1 and TRPV4. We have previously demonstrated neurochemical, organizational and functional plasticity in micturition reflex pathways following induction of urinary bladder inflammation using the antineoplastic agent, cyclophosphamide (CYP). More recently, we have characterized similar plasticity in micturition reflex pathways in a transgenic mouse model with chronic urothelial overexpression (OE) of nerve growth factor (NGF) and in a transgenic mouse model with deletion of vasoactive intestinal polypeptide (VIP). In addition, the micturition reflex undergoes postnatal maturation that may also reflect plasticity in urinary bladder TRP channel expression. Thus, we examined plasticity in urinary bladder TRP channel expression in diverse contexts using a combination of quantitative, real-time PCR and western blotting approaches. We demonstrate transcriptional and translational plasticity of urinary bladder TRPA1, TRPV1 and TRVP4 expression. Although the functional significance of urinary bladder TRP channel plasticity awaits further investigation, these studies demonstrate context-(inflammation, postnatal development, NGF-OE, VIP deletion) and tissue-dependent (urothelium + suburothelium, detrusor) plasticity.

Research paper thumbnail of Neuropeptide/Receptor Expression and Plasticity in Micturition Pathways

Neuropeptide/Receptor Expression and Plasticity in Micturition Pathways

Current Pharmaceutical Design, 2013

Several motor behaviors such as locomotion, respiration, sexual function, and micturition are gen... more Several motor behaviors such as locomotion, respiration, sexual function, and micturition are generated by rhythmic and stereotyped motor patterns of activity. In most cases, these functions are primarily controlled by signals and neuronal commands that originate from the brainstem and spinal cord. Defined as the storage and periodic elimination of urine, micturition requires a complex neural control system that coordinates the activities of a variety of effector organs including the smooth muscle of the urinary bladder and the smooth and striated muscle of the urethral sphincters. The lower urinary tract (LUT) reflex mechanisms, organized at the level of the lumbosacral spinal cord, are modulated predominantly by supraspinal controls. These LUT mechanisms include: (1) storage reflexes organized at the spinal level; (2) elimination reflexes organized at a supraspinal site in the pons; and (3) spinal storage reflexes modulated by inputs from the rostral pons. Precise coordination of the reciprocal functions of the urinary bladder and urethra and complex neural organization are required for normal function. Numerous neuropeptide/receptor systems are expressed in central and peripheral nervous system pathways that regulate the LUT and expression can also be found in both neural and non-neural (e.g., urothelium) components. Neuropeptides have tissue-specific distributions and functions in the LUT and exhibit neuroplastic changes in expression and function with LUT dysfunction with neural injury, inflammation, stress and disease. LUT dysfunction with abnormal voiding including urinary urgency, increased voiding frequency, nocturia, urinary incontinence, urinary retention, continence, detrusor dysynergia and/or pain may reflect a change in the balance of neuropeptides in central and peripheral bladder reflex pathways. LUT neuropeptide/receptor systems in LUT pathways may thus represent potential targets for therapeutic intervention.

Research paper thumbnail of Repeated variate stress in male rats induces increased voiding frequency, somatic sensitivity, and urinary bladder nerve growth factor expression

American Journal of Physiology-Regulatory, Integrative and Comparative Physiology, 2013

Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cy... more Stress exacerbates symptoms of functional lower urinary tract disorders including interstitial cystitis (IC)/bladder pain syndrome (BPS) and overactive bladder (OAB) in humans, but mechanisms contributing to symptom worsening are unknown. These studies address stress-induced changes in the structure and function of the micturition reflex using an animal model of stress in male rats. Rats were exposed to 7 days of repeated variate stress (RVS). Target organ (urinary bladder, thymus, adrenal gland) tissues were collected and weighed following RVS. Evans blue (EB) concentration and histamine, myeloperoxidase (MPO), nerve growth factor (NGF), brain-derived neurotropic factor (BDNF), and CXCL12 protein content (ELISA) were measured in the urinary bladder, and somatic sensitivity of the hindpaw and pelvic regions was determined following RVS. Bladder function was evaluated using continuous, open outlet intravesical infusion of saline in conscious rats. Increases in body weight gain were s...