Faculty Bibliography

Elevated reactive oxygen species (ROS) production and ROS-dependent protein damage is a common observation in the pathogenesis of many muscle wasting disorders, including sarcopenia. However, the contribution of elevated ROS levels to -a breakdown in neuromuscular communication and muscle atrophy remains unknown. In this study, we examined a copper zinc superoxide dismutase [CuZnSOD (Sod1)] knockout mouse (Sod1-/-), a mouse model of elevated oxidative stress that exhibits accelerated loss of muscle mass, which recapitulates many phenotypes of sarcopenia as early as 5 months of age. We found that young adult Sod1-/- mice display a considerable reduction in hind limb skeletal muscle mass and strength when compared to age-matched wild-type mice. These changes are accompanied by gross alterations in neuromuscular junction (NMJ) morphology, including reduced occupancy of the motor endplates by axons, terminal sprouting and axon thinning and irregular swelling. Surprisingly however, the average density of acetylcholine receptors in endplates is preserved. Using in vivo electromyography and ex vivo electrophysiological studies of hind limb muscles in Sod1-/- mice, we found that motor axons innervating the extensor digitorum longus (EDL) and gastrocnemius muscles release fewer synaptic vesicles upon nerve stimulation. Recordings from individually identified EDL NMJs show that reductions in neurotransmitter release are apparent in the Sod1-/- mice even when endplates are close to fully innervated. However, electrophysiological properties, such as input resistance, resting membrane potential and spontaneous neurotransmitter release kinetics (but not frequency) are similar between EDL muscles of Sod1-/- and wild-type mice. Administration of the potassium channel blocker 3,4-diaminopyridine, which broadens the presynaptic action potential, improves both neurotransmitter release and muscle strength. Together, these results suggest that ROS-associated motor nerve terminal dysfunction is a contributor to the observed muscle changes in Sod1-/- mice.

Oral mucositis is a significant problem in cancer patients treated with radiation or chemotherapy, often hindering definitive cancer treatment. For patients with oral mucositis, pain is the most distressing symptom, leading to loss of orofacial function and poor quality of life. While oral mucositis has been well-described, its pathophysiology is poorly understood. Oral health professionals treating patients with mucositis have almost no effective therapies to treat or prevent oral mucositis. The purpose of this review is to (1) describe the current preclinical models of oral mucositis and their contribution to the understanding of mucositis pathophysiology, (2) explore preclinical studies on therapies targeting mucositis and discuss the clinical trials that have resulted from these preclinical studies, and (3) describe the proposed pathophysiology of oral mucositis pain and preclinical modeling of oral mucositis pain.

Cholinergic actions are critical for normal cortical cognitive functions. The release of acetylcholine (ACh) in neocortex and the impact of this neuromodulator on cortical computations exhibit remarkable spatiotemporal precision, as required for the regulation of behavioral processes underlying attention and learning. We discuss how the organization of the cholinergic projections to the cortex and their release properties might contribute to this specificity. We also review recent studies suggesting that the modulatory influences of ACh on the properties of cortical neurons can have the necessary temporal dynamic range, emphasizing evidence of powerful interneuron subtype-specific effects. We discuss areas that require further investigation and point to technical advances in molecular and genetic manipulations that promise to make headway in understanding the neural bases of cholinergic modulation of cortical cognitive operations.

BACKGROUND AND PURPOSE: Cerebrovascular oxygenation changes during respiratory challenges have clinically important implications for brain function, including cerebral autoregulation and the rate of brain metabolism. SWI is sensitive to venous oxygenation level by exploitation of the magnetic susceptibility of deoxygenated blood. We assessed cerebral venous blood oxygenation changes during simple voluntary breath-holding (apnea) and hyperventilation by use of SWI at 3T. MATERIALS AND METHODS: We performed SWI scans (3T; acquisition time of 1 minute, 28 seconds; centered on the anterior commissure and the posterior commissure) on 10 healthy male volunteers during baseline breathing as well as during simple voluntary hyperventilation and apnea challenges. The hyperventilation and apnea tasks were separated by a 5-minute resting period. SWI venograms were generated, and the signal changes on SWI before and after the respiratory stress tasks were compared by means of a paired Student t test. RESULTS: Changes in venous vasculature visibility caused by the respiratory challenges were directly visualized on the SWI venograms. The venogram segmentation results showed that voluntary apnea decreased the mean venous blood voxel number by 1.6% (P < .0001), and hyperventilation increased the mean venous blood voxel number by 2.7% (P < .0001). These results can be explained by blood CO2 changes secondary to the respiratory challenges, which can alter cerebrovascular tone and cerebral blood flow and ultimately affect venous oxygen levels. CONCLUSIONS: These results highlight the sensitivity of SWI to simple and noninvasive respiratory challenges and its potential utility in assessing cerebral hemodynamics and vasomotor responses.

Insulin signaling in the CNS modulates satiety and glucose metabolism, but insulin target neurons are poorly defined. We have previously shown that ablation of insulin receptors (InsR) in Glut4-expressing tissues results in systemic abnormalities of insulin action. We propose that Glut4 neurons constitute an insulin-sensitive neuronal subset. We determined their gene expression profiles using flow-sorted hypothalamic Glut4 neurons. Gene ontology analyses demonstrated that Glut4 neurons are enriched in olfacto-sensory receptors, M2 acetylcholine receptors, and pathways required for the acquisition of insulin sensitivity. Following genetic ablation of InsR, transcriptome profiling of Glut4 neurons demonstrated impairment of the insulin, peptide hormone, and cAMP signaling pathways, with a striking upregulation of anion homeostasis pathway. Accordingly, hypothalamic InsR-deficient Glut4 neurons showed reduced firing activity. The molecular signature of Glut4 neurons is consistent with a role for this neural population in the integration of olfacto-sensory cues with hormone signaling to regulate peripheral metabolism.

The associative processes that support free-operant instrumental avoidance behavior are still unknown. We used a revaluation procedure to determine whether the performance of an avoidance response is sensitive to the current value of the aversive, negative reinforcer. Rats were trained on an unsignaled, free-operant lever press avoidance paradigm in which each response avoided or escaped shock and produced a 5 s feedback stimulus. The revaluation procedure consisted of noncontingent presentations of the shock in the absence of the lever either paired or unpaired with systemic morphine and in a different cohort with systemic d-amphetamine. Rats were then tested drug free during an extinction test. In both the d-amphetamine and morphine groups, pairing of the drug and shock decreased subsequent avoidance responding during the extinction test, suggesting that avoidance behavior was sensitive to the current incentive value of the aversive negative reinforcer. Experiment 2 used central infusions of D-Ala(2), NMe-Phe(4), Gly-ol(5)]-enkephalin (DAMGO), a mu-opioid receptor agonist, in the periacqueductal gray and nucleus accumbens shell to revalue the shock. Infusions of DAMGO in both regions replicated the effects seen with systemic morphine. These results are the first to demonstrate the impact of revaluation of an aversive reinforcer on avoidance behavior using pharmacological agents, thereby providing potential therapeutic targets for the treatment of avoidance behavior symptomatic of anxiety disorders.

RATIONALE: Serotonin-1A (5-HT1A) receptors modulate the stress response and have been implicated in the etiology and treatment of depression and anxiety disorders. A reduction in postsynaptic 5-HT1A receptor function in limbic areas has consistently been observed following exposure to chronic stress. OBJECTIVES: To investigate the hypothesis that increased activation of 5-HT1A receptors in rats having reduced 5-HT function may improve stress adaptation and the behavioral sequelae commonly associated with chronic stress. METHODS: One hundred forty-four Sprague-Dawley rats received injections of para-chlorophenylalanine to partially deplete 5-HT then were given daily systemic pretreatment with the 5-HT1A receptor agonist, 8-hydroxy-2- (di-n-propylamino) tetralin (8-OH-DPAT), the antagonist, WAY 100635, or vehicle prior to either restraint stress (6 h/day for 10 daily sessions) or control conditions. Anxiety- and depressive-like behaviors were then assessed using the open field and sucrose preference tests. Protein level of hippocampal glucocorticoid receptors (GR) and mineralocorticoid receptors was detected by immunohistochemistry and brain-derived neurotrophic factor (BDNF) was determined by in situ hybridization. RESULTS: 8-OH-DPAT pretreatment prior to stress exposure attenuated later stress-induced anxiety- and depression-like behaviors and increased GR and BDNF mRNA expression in the hippocampus relative to vehicle- and WAY 100635-pretreated, stressed animals. CONCLUSION: The stress-related impairments associated with 5-HT deficiency can be improved by 8-OH-DPAT pretreatment prior to stress exposure and are associated with an augmentation of GR-like immunoreactivity and BDNF mRNA expression in the hippocampus. It suggested that selective activation of 5-HT1A receptors may be a potential treatment strategy for stress-related disorders such as anxiety and depression.

Excessive checking is a common, debilitating symptom of obsessive-compulsive disorder (OCD). In an established rodent model of OCD checking behaviour, quinpirole (dopamine D2/3-receptor agonist) increased checking in open-field tests, indicating dopaminergic modulation of checking-like behaviours. We designed a novel operant paradigm for rats (observing response task (ORT)) to further examine cognitive processes underpinning checking behaviour and clarify how and why checking develops. We investigated i) how quinpirole increases checking, ii) dependence of these effects on D2/3 receptor function (following treatment with D2/3 receptor antagonist sulpiride) and iii) effects of reward uncertainty. In the ORT, rats pressed an 'observing' lever for information about the location of an 'active' lever that provided food reinforcement. High- and low-checkers (defined from baseline observing) received quinpirole (0.5mg/kg, 10 treatments) or vehicle. Parametric task manipulations assessed observing/checking under increasing task demands relating to reinforcement uncertainty (variable response requirement and active-lever location switching). Treatment with sulpiride further probed the pharmacological basis of long-term behavioural changes. Quinpirole selectively increased checking, both functional observing lever presses (OLPs) and non-functional extra OLPs (EOLPs). The increase in OLPs and EOLPs was long-lasting, without further quinpirole administration. Quinpirole did not affect the immediate ability to use information from checking. Vehicle and quinpirole-treated rats (VEH and QNP respectively) were selectively sensitive to different forms of uncertainty. Sulpiride reduced non-functional EOLPs in QNP rats but had no effect on functional OLPs. These data have implications for treatment of compulsive checking in OCD, particularly for serotonin-reuptake-inhibitor treatment-refractory cases, where supplementation with dopamine receptor antagonists may be beneficial.

Abstract Preoperative breast pain in women with breast cancer may result from a number of causes. Previous work from our team found that breast pain occurred in 28.2% of women (n = 398) who were about to undergo breast cancer surgery. The occurrence of preoperative breast pain was associated with a number of demographic and clinical characteristics, as well as variation in two cytokine genes. Given that ion channels regulate excitability of sensory neurons, we hypothesized that variations in potassium channel genes would be associated with preoperative breast pain in these patients. Therefore, in this study, we evaluated for associations between single-nucleotide polymorphisms and inferred haplotypes among 10 potassium channel genes and the occurrence of preoperative breast pain in patients scheduled to undergo breast cancer surgery. Multivariable logistic regression analyses were used to identify those genetic variations that were associated with the occurrence of preoperative breast pain while controlling for age and genomic estimates of and self-reported race/ethnicity. Variations in four potassium channel genes: (1) potassium voltage-gated channel, delayed rectifier, subfamily S, member 1 (KCNS1); (2) potassium inwardly rectifying channel, subfamily J, member 3 (KCNJ3); (3) KCNJ6; and (4) potassium channel, subfamily K, member 9 (KCNK9) were associated with the occurrence of breast pain. Findings from this study warrant replication in an independent sample of women who report breast pain following one or more breast biopsies.