IU Indianapolis ScholarWorks :: Browsing by Subject "Rat"

Browsing by Subject "Rat"

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A-type FHFs mediate resurgent currents through TTX-resistant voltage-gated sodium channels
(eLife Sciences, 2022-04-20) Xiao, Yucheng; Theile, Jonathan W.; Zybura, Agnes; Pan, Yanling; Lin, Zhixin; Cummins, Theodore R.; Biology, School of Science
Resurgent currents (INaR) produced by voltage-gated sodium channels are required for many neurons to maintain high-frequency firing and contribute to neuronal hyperexcitability and disease pathophysiology. Here, we show, for the first time, that INaR can be reconstituted in a heterologous system by coexpression of sodium channel α-subunits and A-type fibroblast growth factor homologous factors (FHFs). Specifically, A-type FHFs induces INaR from Nav1.8, Nav1.9 tetrodotoxin (TTX)-resistant neuronal channels, and, to a lesser extent, neuronal Nav1.7 and cardiac Nav1.5 channels. Moreover, we identified the N-terminus of FHF as the critical molecule responsible for A-type FHFs-mediated INaR. Among the FHFs, FHF4A is the most important isoform for mediating Nav1.8 and Nav1.9 INaR. In nociceptive sensory neurons, FHF4A knockdown significantly reduces INaR amplitude and the percentage of neurons that generate INaR, substantially suppressing excitability. Thus, our work reveals a novel molecular mechanism underlying TTX-resistant INaR generation and provides important potential targets for pain treatment.
Alcohol Preferring P Rats Exhibit Elevated Motor Impulsivity Concomitant with Operant Responding and Self-Administration of Alcohol
(Wiley, 2016-05) Wesley Beckwith, Steven; Czachowski, Cristine Lynn; Psychology, School of Science
BACKGROUND: Increased levels of impulsivity are associated with increased illicit drug use and alcoholism. Previous research in our laboratory has shown that increased levels of delay discounting (a decision-making form of impulsivity) are related to appetitive processes governing alcohol self-administration as opposed to purely consummatory processes. Specifically, the high-seeking/high-drinking alcohol-preferring P rats showed increased delay discounting compared to nonselected Long Evans rats (LE) whereas the high-drinking/moderate-seeking HAD2 rats did not. The P rats also displayed a perseverative pattern of behavior such that during operant alcohol self-administration they exhibited greater resistance to extinction. METHODS: One explanation for the previous findings is that P rats have a deficit in response inhibition. This study followed up on this possibility by utilizing a countermanding paradigm (stop signal reaction time [SSRT] task) followed by operant self-administration of alcohol across increasing fixed ratio requirements (FR; 1, 2, 5, 10, and 15 responses). In separate animals, 24-hour access 2-bottle choice (10% EtOH vs. water) drinking was assessed. RESULTS: In the SSRT task, P rats exhibited an increased SSRT compared to both LE and HAD2 rats indicating a decrease in behavioral inhibition in the P rats. Also, P rats showed increased operant self-administration across all FRs and the greatest increase in responding with increasing FR requirements. Conversely, the HAD2 and LE had shorter SSRTs and lower levels of operant alcohol self-administration. However, for 2-bottle choice drinking HAD2s and P rats consumed more EtOH and had a greater preference for EtOH compared to LE. CONCLUSIONS: These data extend previous findings showing the P rats to have increased delay discounting (decision-making impulsivity) and suggest that P rats also have a lack of behavioral inhibition (motor impulsivity). This supports the notion that P rats are a highly impulsive as well as "high-seeking" model of alcoholism, and that the HAD2s' elevated levels of alcohol consumption are not mediated via appetitive processes or impulsivity.
Analysis of Heart Rate Variability During Focal Parasympathetic Drive of the Rat Baroreflex
(2020-05) Bustamante, David J.; Schild, John; Yoshida, Ken; Salama, Paul
Autonomic control of the heart results in variations in the intervals between heart beats, known as heart rate variability. One of the defining components of autonomic control is the baroreflex, a negative feedback controller that balances heart rate and blood pressure. The baroreflex is under constant command from the branches of the autonomic nervous system. To better understand how the autonomic nervous system commands the baroreflex, a baroreflex reflexogenic animal protocol was carried out. Heart rate variability analysis and baroreflex sensitivity were used to quantify the neural control of the heart. This thesis reconfirmed the existence of sexually dimorphic properties in the baroreflex through the use of heart rate variability analysis and baroreflex sensitivity. It was discovered that there are many caveats to utilizing heart rate variability analysis, which have to be addressed both in the experimental protocol and the signal processing technique. Furthermore, it was suggested that the slope method for quantifying baroreflex sensitivity also has many caveats, and that other baroreflex sensitivity methods are likely more optimal for quantifying sustained activation of the baroreflex. By utilizing various heart rate variability signal processing algorithms to assess autonomic tone in Sprague-Dawley rats during rest and sustained electrical activation of the baroreflex, the null hypothesis was rejected.
Automatic Detection and Characterization of Autonomic Dysreflexia Using Multi-Modal Non-Invasive Sensing and Neural Networks
(Mary Ann Liebert, 2022-11-10) Suresh, Shruthi; Everett, Thomas H., IV; Shi, Riyi; Duerstock, Bradley S.; Medicine, School of Medicine
Autonomic dysreflexia (AD) frequently occurs in persons with spinal cord injuries (SCIs) above the T6 level triggered by different stimuli below the level of injury. If improperly managed, AD can have severe clinical consequences, even possibly leading to death. Existing techniques for AD detection are time-consuming, obtrusive, lack automated detection capabilities, and have low temporal resolution. Therefore, a non-invasive, multi-modal wearable diagnostic tool was developed to quantitatively characterize and distinguish unique signatures of AD. Electrocardiography and novel skin nerve activity (skNA) sensors with neural networks were used to detect temporal changes in the sympathetic and vagal systems in rats with SCI. Clinically established metrics of AD were used to verify the onset of AD. Five physiological features reflecting different metrics of sympathetic and vagal activity were used to characterize signatures of AD. An increase in sympathetic activity, followed by a lagged increase in vagal activity during the onset of AD, was observed after inducing AD. This unique signature response was used to train a neural network to detect the onset of AD with an accuracy of 93.4%. The model also had a 79% accuracy in distinguishing between sympathetic hyperactivity reactions attributable to different sympathetic stressors above and below the level of injury. These neural networks have not been used in previous work to detect the onset of AD. The system could serve as a complementary non-invasive tool to the clinically accepted gold standard, allowing an improved management of AD in persons with SCI.
Characterization of the relationship between spontaneous locomotor activity and cardiovascular parameters in conscious freely moving rats
(Elsevier, 2016-02) Zaretsky, Dmitry V.; Zaretskaia, Maria V.; DiMicco, Joseph A.; Department of Emergency Medicine, IU School of Medicine
In freely behaving rats, variations in heart rate (HR) and blood pressure (BP) are coupled closely with changes in locomotor activity (Act). We have attempted to characterize this relationship mathematically. In 10- and 16-week-old rats, HR, BP and Act were recorded telemetrically every minute for 2 days under 12h:12h light-dark cycling. After examining data for individual rats, we found that the relationship between Act and HR could be approximated by the negative exponential function HR(Act)=HRmax-(HRmax-HRmin)∗exp(-Act/Acte), where HRmax, HRmin, and Acte are constants. These constants were calculated separately for light and dark periods by non-linear curve fitting. HR corresponding to maximal locomotion was similar during the light and dark phases, while HR at rest during the dark phase was higher than during the light phase. The range of HR variability associated with Act during the dark phase was similar in young and older animals, but minimal HR was significantly lower in older rats. The relationship between Act and BP was approximated with a similar function. We have found no differences between BP at rest and at maximal locomotion between light and dark and between 10-week and 16-week-old rats. Our results indicate that in rats, cardiovascular parameters are coupled to locomotion to a high degree; however both the HR and the BP reach maximal values when locomotor activity is relatively low. We also found that the phase of daily cycle affects HR in conscious rats independent of locomotor activity.
The development and maintenance of paclitaxel-induced neuropathic pain require activation of the sphingosine 1-phosphate receptor subtype 1
(ASBMB, 2014-07-25) Janes, Kali; Little, Joshua W.; Li, Chao; Bryant, Leesa; Chen, Collin; Chen, Zhoumou; Kamocki, Krzysztof; Doyle, Timothy; Snider, Ashley; Esposito, Emanuela; Cuzzocrea, Salvatore; Bieberich, Erhard; Obedi, Lina; Petrache, Irina; Nicol, Grant; Neumann, William L.; Salvemini, Daniela; Department of Pharmacology and Toxicology, IU School of Medicine
The ceramide-sphingosine 1-phosphate (S1P) rheostat is important in regulating cell fate. Several chemotherapeutic agents, including paclitaxel (Taxol), involve pro-apoptotic ceramide in their anticancer effects. The ceramide-to-S1P pathway is also implicated in the development of pain, raising the intriguing possibility that these sphingolipids may contribute to chemotherapy- induced painful peripheral neuropathy, which can be a critical dose-limiting side effect of many widely used chemotherapeutic agents.We demonstrate that the development of paclitaxel-induced neuropathic pain was associated with ceramide and S1P formation in the spinal dorsal horn that corresponded with the engagement of S1P receptor subtype 1 (S1PR(1))- dependent neuroinflammatory processes as follows: activation of redox-sensitive transcription factors (NFκB) and MAPKs (ERK and p38) as well as enhanced formation of pro-inflammatory and neuroexcitatory cytokines (TNF-α and IL-1β). Intrathecal delivery of the S1PR1 antagonist W146 reduced these neuroinflammatory processes but increased IL-10 and IL-4, potent anti-inflammatory/ neuroprotective cytokines. Additionally, spinal W146 reversed established neuropathic pain. Noteworthy, systemic administration of the S1PR1 modulator FTY720 (Food and Drug Administration- approved for multiple sclerosis) attenuated the activation of these neuroinflammatory processes and abrogated neuropathic pain without altering anticancer properties of paclitaxel and with beneficial effects extended to oxaliplatin. Similar effects were observed with other structurally and chemically unrelated S1PR1 modulators (ponesimod and CYM-5442) and S1PR1 antagonists (NIBR-14/15) but not S1PR1 agonists (SEW2871). Our findings identify for the first time the S1P/S1PR1 axis as a promising molecular and therapeutic target in chemotherapy-induced painful peripheral neuropathy, establish a mechanistic insight into the biomolecular signaling pathways, and provide the rationale for the clinical evaluation of FTY720 in chronic pain patients.
Ethanol pre-exposure does not increase delay discounting in P rats, but does impair the ability to dynamically adapt behavioral allocation to changing reinforcer contingencies
(Elsevier, 2019-12) Beckwith, Steven Wesley; Czachowski, Cristine Lynn; Psychology, School of Science
Increased subjective discounting of delayed rewards is associated with substance abuse, and individuals tend to discount their drug of choice at a greater rate compared to monetary rewards. While there is evidence indicating that increased delay discounting (DD) is a risk factor for substance abuse, some results suggest that exposure to drugs of abuse also increases DD, but effects are mixed. The current study examined whether ethanol pre-exposure increases DD and if an ethanol reinforcer would be discounted at a greater rate than sucrose. Alcohol preferring (P) rats were pre-exposed to either ethanol or sucrose using an intermittent access protocol (IAP) for 8 weeks. Then animals completed an operant fixed choice procedure where each pre-exposure group was split into either an ethanol or sucrose reinforcer group. Afterwards, animals completed an adjusting delay DD task using the same groups as the fixed choice task. Animals that received access to ethanol in the IAP showed increased delayed reward preference in a delay and session dependent manner. Specifically, ethanol pre-exposed animals took more sessions to decrease their preference for the delayed reward at longer delays. In the adjusting delay task, no differences in mean adjusting delays were seen, but ethanol pre-exposure impaired animals' ability to reach stability criteria. The observed results are not consistent with ethanol pre-exposure causing a change in DD. Rather they indicate ethanol pre-exposure impaired animals' ability to reallocate their behavior in response to a change in reinforcer contingencies. The current findings extend prior results showing alcohol naïve P rats exhibit both increased DD and decreased response inhibition (Beckwith and Czachowski 2014, 2016) by demonstrating that after alcohol exposure they exhibit a form of behavioral inflexibility. Hence, a "two-hit" genetic vulnerability/environmental acceleration of addictive behavior is supported.
Glutathione S-transferase 8-8 expression is lower in alcohol-preferring than in alcohol-nonpreferring rats
(Wiley Online Library, 2004-11) Liang, Tiebing; Spence, John P.; Foroud, Tatiana; Ellison, Julie A.; Lumeng, Lawrence; Li, Ting-Kai; Carr, Lucinda G.; Department of Medical and Molecular Genetics, IU School of Medicine
OBJECTIVE: A primary focus of alcohol research is to provide novel targets for alcohol treatment by identifying genes that predispose individuals to drink alcohol. Animal models of alcoholism developed by selective breeding are invaluable tools to elucidate both the genetic nature and the underlying biological mechanisms that contribute to alcohol dependence. These selected lines (high alcohol preferring and low alcohol preferring) display phenotypic and genetic differences that can be studied to further our understanding of alcohol preference and related genetic traits. By combining molecular techniques, genetic and physiological factors that underlie the cause of alcoholism can be identified. METHODS: Total gene expression analysis was used to identify genes that are differentially expressed in specific brain regions between alcohol-naive, inbred alcohol-preferring (iP) and -nonpreferring (iNP) rats. Quantitative reverse transcriptase-polymerase chain reaction, in situ hybridization, Western blot, and sequence analysis were used to further characterize rat glutathione S-transferase 8-8 (rGST 8-8). RESULTS: Lower expression of rGST 8-8 mRNA was observed in discrete brain regions of iP compared with iNP animals, and these expression differences were confirmed. To determine additional expression patterns of rGST 8-8, we used in situ hybridization. Rat GST 8-8 was highly expressed in hippocampus, the choroid plexus of the dorsal third ventricle and the lateral ventricle, and ependymal cells along the dorsal third ventricle and the third ventricle. Western blot analysis showed that rGST 8-8 protein levels were lower in the hippocampus and the amygdala of iP compared with iNP. A silent single-nucleotide polymorphism in the coding region and three single-nucleotide polymorphisms in the 3'-UTR were identified in the rGST 8-8 cDNA. CONCLUSION: There is regional variation of rGST 8-8 expression in the brain, at both the mRNA and protein level, and the iP strain has lower innate rGST 8-8 levels than the iNP strain in discrete brain regions.
An In Vivo Duo-color Method for Imaging Vascular Dynamics Following Contusive Spinal Cord Injury
(Journal of Visualized Experiments, 2017-12-31) Chen, Chen; Zhang, Yi Ping; Sun, Yan; Xiong, Wenhui; Shields, Lisa B. E.; Shields, Christopher B.; Jin, Xiaoming; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
Spinal cord injury (SCI) causes significant vascular disruption at the site of injury. Vascular pathology occurs immediately after SCI and continues throughout the acute injury phase. In fact, endothelial cells appear to be the first to die after a contusive SCI. The early vascular events, including increased permeability of the blood-spinal cord barrier (BSCB), induce vasogenic edema and contribute to detrimental secondary injury events caused by complex injury mechanisms. Targeting the vascular disruption, therefore, could be a key strategy to reduce secondary injury cascades that contribute to histological and functional impairments after SCI. Previous studies were mostly performed on postmortem samples and were unable to capture the dynamic changes of the vascular network. In this study, we have developed an in vivo duo-color two-photon imaging method to monitor acute vascular dynamic changes following contusive SCI. This approach allows detecting blood flow, vessel diameter, and other vascular pathologies at various sites of the same rat pre- and post-injury. Overall, this method provides an excellent venue for investigating vascular dynamics.
Increased delay discounting tracks with a high ethanol-seeking phenotype and subsequent ethanol seeking but not consumption
(Wiley Online Library, 2014-10) Beckwkith, Steven Wesley; Czachowski, Cristine Lynn; Department of Psychology, School of Science
BACKGROUND: Increased levels of delay discounting have been associated with alcoholism and problematic levels of drinking. Attempts to assess the directionality of this relationship by studying individuals with a family history of alcoholism as well as rodent lines selectively bred for high home cage alcohol preference have yielded discordant results. One possible reason for this discordance is that increased levels of delay discounting may only track with specific processes that lead to addiction vulnerability. This study investigated this possibility by assessing 3 strains of rats previously identified to exhibit heritable differences in ethanol (EtOH) seeking and consumption. METHODS: In an adjusting amount delay discounting task, alcohol-preferring (P) rats who display high levels of both EtOH seeking and consumption were compared to high alcohol-drinking (HAD2) rats who only exhibit moderate EtOH seeking despite high levels of consumption, and Long Evans (LE) rats who display moderate seeking and consumption. EtOH-seeking and consumption phenotypes were subsequently confirmed in an operant self-administration task with a procedural separation between EtOH seeking and drinking. RESULTS: P rats discounted delayed rewards to a greater extent than both HAD2s and LE who did not show differences in discounting. Moreover, the EtOH-seeking and drinking phenotypes were replicated with P rats displaying greater EtOH seeking compared to both the HAD2s and LE, and both the HAD2s and P rats consuming more EtOH than LEs. CONCLUSIONS: Only the high-seeking strain, the P rats, exhibited increased levels of delay discounting. This suggests that this measure of behavioral under-control is specifically associated with alcohol-related appetitive, but not consummatory, processes as the moderate seeking/high drinking line did not show increased levels of impulsivity. This finding supports the hypothesis that delay discounting is specifically associated with only certain processes which are sufficient but not necessary to confer addiction vulnerability and therefore also supports increased levels of delay discounting as a predisposing risk factor for alcoholism.

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