Publications by authors named "Patrick Ronan"

27 Publications

  • Page 1 of 1

Interaction between CO2-consuming autotrophy and CO2-producing heterotrophy in non-axenic phototrophic biofilms.

PLoS One 2021 15;16(6):e0253224. Epub 2021 Jun 15.

Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.

As the effects of climate change become increasingly evident, the need for effective CO2 management is clear. Microalgae are well-suited for CO2 sequestration, given their ability to rapidly uptake and fix CO2. They also readily assimilate inorganic nutrients and produce a biomass with inherent commercial value, leading to a paradigm in which CO2-sequestration, enhanced wastewater treatment, and biomass generation could be effectively combined. Natural non-axenic phototrophic cultures comprising both autotrophic and heterotrophic fractions are particularly attractive in this endeavour, given their increased robustness and innate O2-CO2 exchange. In this study, the interplay between CO2-consuming autotrophy and CO2-producing heterotrophy in a non-axenic phototrophic biofilm was examined. When the biofilm was cultivated under autotrophic conditions (i.e. no organic carbon), it grew autotrophically and exhibited CO2 uptake. After amending its growth medium with organic carbon (0.25 g/L glucose and 0.28 g/L sodium acetate), the biofilm rapidly toggled from net-autotrophic to net-heterotrophic growth, reaching a CO2 production rate of 60 μmol/h after 31 hours. When the organic carbon sources were provided at a lower concentration (0.125 g/L glucose and 0.14 g/L sodium acetate), the biofilm exhibited distinct, longitudinally discrete regions of heterotrophic and autotrophic metabolism in the proximal and distal halves of the biofilm respectively, within 4 hours of carbon amendment. Interestingly, this upstream and downstream partitioning of heterotrophic and autotrophic metabolism appeared to be reversible, as the position of these regions began to flip once the direction of medium flow (and hence nutrient availability) was reversed. The insight generated here can inform new and important research questions and contribute to efforts aimed at scaling and industrializing algal growth systems, where the ability to understand, predict, and optimize biofilm growth and activity is critical.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0253224PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8205120PMC
June 2021

A 5-Minute Cognitive Assessment for Safe Remote Use in Patients With COVID-19: Clinical Case Series.

JMIR Form Res 2021 Jun 14;5(6):e26417. Epub 2021 Jun 14.

Laboratory for Clinical and Translational Research in Psychiatry, Rocky Mountain Regional VA Medical Center, Aurora, CO, United States.

Background: Early clinical experience during the COVID-19 pandemic has begun to elucidate that the disease can cause brain function changes that may result in compromised cognition both acutely and during variable recovery periods. Reports on cognitive assessment of patients with COVID-19 are often limited to orientation alone. Further assessment may seem to create an inappropriate burden for patients with acute COVID-19, which is characterized by fatigue and confusion, and may also compromise examiner safety.

Objective: The aims of this study were to assess cognition in patients with COVID-19 as comprehensively as possible in a brief format, while observing safety precautions, and to establish a clear face value of the external validity of the assessment.

Methods: We adapted a brief cognitive assessment, previously applied to liver transplant candidates and medical/surgical inpatients, for remote use in patients hospitalized for COVID-19 treatment. Collecting quality assurance data from telephone-administered assessments, this report presents a series of 6 COVID-19 case vignettes to illustrate the use of this 5-minute assessment in the diagnosis and treatment of brain effects. Primary medical teams referred the cases for neuropsychiatric consultation.

Results: The age of the patients varied over four decades, and none of them were able to engage meaningfully with their surroundings on admission. On follow-up examination 6 to 10 days later, 4 of the 6 patients had recovered working memory, and only 1 had recovered calculation ability. Of the 6 patients, 2 were capable of complex judgment responses, while none of the cases completed frontal executive function testing in the normal range.

Conclusions: Cognitive assessment in patients with COVID-19 using this remote examination reveals patterns of cognitive recovery that vary among cases and are far more complex than loss of orientation. In this series, testing of specific temporal, parietal, and frontal lobe functions suggests that calculation ability, judgment, and especially frontal executive functions may characterize the effects of COVID-19 on the brain. Used widely and serially, this examination method can potentially inform our understanding of the effects of COVID-19 on the brain and of healing from the virus.
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http://dx.doi.org/10.2196/26417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204938PMC
June 2021

A Novel System for Real-Time, In Situ Monitoring of CO Sequestration in Photoautotrophic Biofilms.

Microorganisms 2020 Jul 31;8(8). Epub 2020 Jul 31.

Department of Chemistry and Biology, Ryerson University, 350 Victoria St., Toronto, ON M5B 2K3, Canada.

Climate change brought about by anthropogenic CO emissions has created a critical need for effective CO management solutions. Microalgae are well suited to contribute to efforts aimed at addressing this challenge, given their ability to rapidly sequester CO coupled with the commercial value of their biomass. Recently, microalgal biofilms have garnered significant attention over the more conventional suspended algal growth systems, since they allow for easier and cheaper biomass harvesting, among other key benefits. However, the path to cost-effectiveness and scaling up is hindered by a need for new tools and methodologies which can help evaluate, and in turn optimize, algal biofilm growth. Presented here is a novel system which facilitates the real-time in situ monitoring of algal biofilm CO sequestration. Utilizing a CO-permeable membrane and a tube-within-a-tube design, the CO sequestration monitoring system (CSMS) was able to reliably detect slight changes in algal biofilm CO uptake brought about by light-dark cycling, light intensity shifts, and varying amounts of phototrophic biomass. This work presents an approach to advance our understanding of carbon flux in algal biofilms, and a base for potentially useful innovations to optimize, and eventually realize, algae biofilm-based CO sequestration.
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http://dx.doi.org/10.3390/microorganisms8081163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7464137PMC
July 2020

Calcineurin signaling as a target for the treatment of alcohol abuse and neuroinflammatory disorders.

Prog Mol Biol Transl Sci 2019 12;167:125-142. Epub 2019 Aug 12.

Laboratory for Clinical and Translational Research in Psychiatry, Research Service and Psychiatry, Rocky Mountain Regional VA Medical Center (116), Aurora, CO, United States; Department of Psychiatry, University of Colorado Denver School of Medicine, Anschutz Medical Campus, Aurora, CO, United States.

Converging lines of evidence point to a significant role of neuroinflammation in a host of psychiatric conditions, including alcohol use disorder, TBI, and PTSD. A complex interaction of both peripheral and central signaling underlies processes involved in neuroinflammation. Calcineurin is a molecule that sits at the nexus of these processes and has been clearly linked to a number of psychiatric disorders including alcohol use disorder (AUD). Like its role in regulating peripheral immune cells, calcineurin (CN) plays an integral role in processes regulating neuroimmune function and neuroinflammatory processes. Targeting CN or elements of its signaling pathways at critical points may aid in the functional recovery from neuroinflammatory related disorders. In this review we will highlight the role of neuroinflammation and calcineurin signaling in AUD, TBI and stress-induced disorders and discuss recent findings demonstrating a therapeutic effect of immunosuppressant-induced calcineurin inhibition in a pre-clinical model of binge alcohol drinking.
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http://dx.doi.org/10.1016/bs.pmbts.2019.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286102PMC
May 2020

Central Administration of Cyclosporine A Decreases Ethanol Drinking.

Alcohol Alcohol 2018 Mar;53(2):193-199

Laboratory for Clinical and Translational Research in Psychiatry, Research Service and Psychiatry, Denver VA Medical Center, 1050 Clermont Street, Denver, CO 80220-0116, USA.

Aims: Abstinence among alcohol dependent liver graft recipients is remarkably high. The routine use of anti-immune agents in these patients led to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing alcohol consumption. It remained unclear, however, whether the decreased alcohol consumption in rodent models is mediated through peripheral suppression of immune response or centrally through direct inhibition of cyclophilin-CLN in the brain. We tested the hypothesis that direct brain inhibition of CLN with intracerebroventricular (ICV) injections of the immunosuppressant cyclosporine A (CsA) is sufficient to decrease ethanol consumption in a rodent model of binge-like drinking.

Methods: Male C57BL/6NHsd mice were put through a modified 'drinking in the dark' (DID) paradigm. Effects of both peripheral (IP) and central (ICV) injections of CsA on ethanol consumption were assessed.

Results: Here, as in earlier work, IP CsA administration significantly decreased alcohol consumption. Supporting our hypothesis, central administration of CsA was sufficient to decrease alcohol consumption in a dose-dependent manner. There was no significant effect of CsA on water or sucrose consumption.

Conclusions: These results clearly implicate a CLN-mediated mechanism in brain in the inhibitory effects of CsA on ethanol consumption and provide novel targets for investigation of treatment for Alcohol Use Disorders (AUD). These results also add to the growing body of literature implicating neuroimmune mechanisms in the etiology, pathophysiology and behaviors driving AUD.

Short Summary: The unusually high abstinence rate and routine use of immunosuppressants in AUD liver graft recipients led us to rodent studies showing that immunosuppressants acting through inhibition of calcineurin (CLN) are highly effective in decreasing drinking. Here we demonstrate that this effect is mediated by brain rather than peripheral immune mechanisms.
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http://dx.doi.org/10.1093/alcalc/agx102DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6246189PMC
March 2018

Late Reduction of Cocaine Cravings in a Randomized, Double-Blind Trial of Aripiprazole vs Perphenazine in Schizophrenia and Comorbid Cocaine Dependence.

J Clin Psychopharmacol 2017 Dec;37(6):657-663

From the *Laboratory for Clinical and Translational Research in Psychiatry, Department of Veterans Affairs, and †Denver Research Institute; and the ‡Colorado Biostatistics Consortium, University of Colorado Denver, Denver, CO.

Purpose: Co-occurring schizophrenia spectrum disorder and International Statistical Classification of Diseases, 10th Revision cocaine dependence present a particularly destructive constellation that is often difficult to treat. Both conditions raise dopamine transmission effects in the brain. Traditional neuroleptics block dopamine receptors, whereas aripiprazole modulates dopamine activity as an agonist/antagonist. We tested whether dopamine modulation is superior to dopamine blocking in dual-diagnosis patients.

Methods: In a randomized, double-blind, comparison design, cocaine-dependent schizophrenic subjects actively using cocaine received either aripiprazole or perphenazine in an 8-week trial. Primary outcome targeted cocaine-free urine sample proportions, whereas cocaine craving scores were a secondary variable.

Results: Subjects (N = 44) randomized (n = 22 per group) did not differ at baseline. The proportion of cocaine-free urine samples did not differ by medication group. Contrasting weeks 3 to 5 vs 6 to 8 revealed significant late reductions in craving with aripiprazole. On the respective 5-point subscales, craving intensity decreased by 1.53 ± 0.43 (P < 0.0005) points, craving frequency by 1.4 ± 0.40 (P > 0.0004) points, and craving duration by 1.76 ± 0.44 (P > 0.0001) points.

Conclusions: A drug effect of aripiprazole on craving items appeared at week 6 of treatment, on average, and was not seen before that length of drug exposure. The data suggest that dopamine modulation reduces cocaine cravings but requires an acclimation period. To understand the mechanism of action better, a trial of depot aripiprazole may be useful. Clinically, a reduction in craving potentially offers a clearer focus for ongoing behavioral treatment. It may also offer a longer-term treatment effect with respect to the severity of relapse.
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http://dx.doi.org/10.1097/JCP.0000000000000789DOI Listing
December 2017

Anxious behavior induces elevated hippocampal Cb receptor gene expression.

Neuroscience 2017 06 7;352:273-284. Epub 2017 Apr 7.

Department of Biology, University of South Dakota, Vermillion, SD 57069, USA; Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA; Veterans Affairs Research Service, Sioux Falls VA Health Care System, Sioux Falls, SD 57105, USA. Electronic address:

Anxiety is differentially expressed across a continuum of stressful/fearful intensity, influenced by endocannabinoid systems and receptors. The hippocampus plays important roles in the regulation of affective behavior, emotion, and anxiety, as well as memory. Location of Cb/Cb receptor action could be important in determining emotional valence, because while the dorsal hippocampus is involved in spatial memory and cognition, the ventral hippocampus has projections to the PFC, BNST, amygdala, and HPA axis, and is important for emotional responses to stress. During repeated social defeat in a Stress-Alternatives Model arena (SAM; an oval open field with escape portals only large enough for smaller mice), smaller C57BL6/N mice are subject to fear conditioning (tone=CS), and attacked by novel larger aggressive CD1 mice (US) over four daily (5min) trials. Each SAM trial presents an opportunity for escape or submission, with stable behavioral responses established by the second day of interaction. Additional groups had access to a running wheel. Social aggression plus fear conditioning stimulates enhanced Cb receptor gene expression in the dorsal CA, dorsal and ventral dentate gyrus subregions in animals displaying a submissive behavioral phenotype. Escape behavior is associated with reduced Cb expression in the dorsal CA region, with freezing and escape latency correlated with mRNA levels. Escaping and submitting animals with access to running wheels had increased Cb mRNA in dorsal DG/CA. These results suggest that the Cb receptor system is rapidly induced during anxiogenic social interactions plus fear conditioning or exercise; with responses potentially adaptive for coping mechanisms.
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http://dx.doi.org/10.1016/j.neuroscience.2017.03.061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482502PMC
June 2017

Molecular Mechanisms of Cannabis Signaling in the Brain.

Prog Mol Biol Transl Sci 2016 3;137:123-47. Epub 2015 Dec 3.

Department of Veterans Affairs Medical Center, Laboratory for Clinical and Translational Research in Psychiatry, Denver, Colorado, USA; Department of Psychiatry, School of Medicine, University of Colorado, Denver, Colorado, USA.

Cannabis has been cultivated and used by humans for thousands of years. Research for decades was focused on understanding the mechanisms of an illegal/addictive drug. This led to the discovery of the vast endocannabinoid system. Research has now shifted to understanding fundamental biological questions related to one of the most widespread signaling systems in both the brain and the body. Our understanding of cannabinoid signaling has advanced significantly in the last two decades. In this review, we discuss the state of knowledge on mechanisms of Cannabis signaling in the brain and the modulation of key brain neurotransmitter systems involved in both brain reward/addiction and psychiatric disorders. It is highly probable that various cannabinoids will be found to be efficacious in the treatment of a number of psychiatric disorders. However, while there is clearly much potential, marijuana has not been properly vetted by the medical-scientific evaluation process and there are clearly a range of potentially adverse side-effects-including addiction. We are at crossroads for research on endocannabinoid function and therapeutics (including the use of exogenous treatments such as Cannabis). With over 100 cannabinoid constituents, the majority of which have not been studied, there is much Cannabis research yet to be done. With more states legalizing both the medicinal and recreational use of marijuana the rigorous scientific investigation into cannabinoid signaling is imperative.
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http://dx.doi.org/10.1016/bs.pmbts.2015.10.002DOI Listing
December 2016

Intensity of anxiety is modified via complex integrative stress circuitries.

Psychoneuroendocrinology 2016 Jan 24;63:351-61. Epub 2015 Oct 24.

Department of Biology, University of South Dakota, Vermillion, SD 57069, USA; Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA. Electronic address:

Escalation of anxious behavior while environmentally and socially relevant contextual events amplify the intensity of emotional response produces a testable gradient of anxiety shaped by integrative circuitries. Apprehension of the Stress-Alternatives Model apparatus (SAM) oval open field (OF) is measured by the active latency to escape, and is delayed by unfamiliarity with the passageway. Familiar OF escape is the least anxious behavior along the continuum, which can be reduced by anxiolytics such as icv neuropeptide S (NPS). Social aggression increases anxiousness in the SAM, reducing the number of mice willing to escape by 50%. The apprehension accompanying escape during social aggression is diminished by anxiolytics, such as exercise and corticotropin releasing-factor receptor 1 (CRF1) antagonism, but exacerbated by anxiogenic treatment, like antagonism of α2-adrenoreceptors. What is more, the anxiolytic CRF1 and anxiogenic α2-adrenoreceptor antagonists also modify behavioral phenotypes, with CRF1 antagonism allowing escape by previously submissive animals, and α2-adrenoreceptor antagonism hindering escape in mice that previously engaged in it. Gene expression of NPS and brain-derived neurotrophic factor (BDNF) in the central amygdala (CeA), as well as corticosterone secretion, increased concomitantly with the escalating anxious content of the mouse-specific anxiety continuum. The general trend of CeA NPS and BDNF expression suggested that NPS production was promoted by increasing anxiousness, and that BDNF synthesis was associated with learning about ever-more anxious conditions. The intensity gradient for anxious behavior resulting from varying contextual conditions may yield an improved conceptualization of the complexity of mechanisms producing the natural continuum of human anxious conditions, and potential therapies that arise therefrom.
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http://dx.doi.org/10.1016/j.psyneuen.2015.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4838407PMC
January 2016

Recovering glycoside hydrolase genes from active tundra cellulolytic bacteria.

Can J Microbiol 2014 Jul 11;60(7):469-76. Epub 2014 Jun 11.

a Department of Biology, University of Waterloo, 200 University Avenue West, Waterloo, ON N2L 3G1, Canada.

Bacteria responsible for cellulose hydrolysis in situ are poorly understood, largely because of the relatively recent development of cultivation-independent methods for their detection and characterization. This study combined DNA stable-isotope probing (DNA-SIP) and metagenomics for identifying active bacterial communities that assimilated carbon from glucose and cellulose in Arctic tundra microcosms. Following DNA-SIP, bacterial fingerprint analysis of gradient fractions confirmed isotopic enrichment. Sequenced fingerprint bands and clone library analysis of 16S rRNA genes identified active bacterial taxa associated with cellulose-associated labelled DNA, including Bacteroidetes (Sphingobacteriales), Betaproteobacteria (Burkholderiales), Alphaproteobacteria (Caulobacteraceae), and Chloroflexi (Anaerolineaceae). We also compared glycoside hydrolase metagenomic profiles from bulk soil and heavy DNA recovered from DNA-SIP incubations. Active populations consuming [(13)C]glucose and [(13)C]cellulose were distinct, based on ordinations of light and heavy DNA. Metagenomic analysis demonstrated a ∼3-fold increase in the relative abundance of glycoside hydrolases in DNA-SIP libraries over bulk-soil libraries. The data also indicate that multiple displacement amplification introduced bias into the resulting metagenomic analysis. This research identified DNA-SIP incubation conditions for glucose and cellulose that were suitable for Arctic tundra soil and confirmed that DNA-SIP enrichment can increase target gene frequencies in metagenomic libraries.
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http://dx.doi.org/10.1139/cjm-2014-0193DOI Listing
July 2014

Neuropeptide S and BDNF gene expression in the amygdala are influenced by social decision-making under stress.

Front Behav Neurosci 2014 8;8:121. Epub 2014 Apr 8.

Department of Biology, University of South Dakota Vermillion, SD, USA ; Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota Vermillion, SD, USA.

In a newly developed conceptual model of stressful social decision-making, the Stress-Alternatives Model (SAM; used for the 1st time in mice) elicits two types of response: escape or remain submissively. Daily (4d) aggressive social interaction in a neutral arena between a C57BL6/N test mouse and a larger, novel aggressive CD1 mouse, begin after an audible tone (conditioned stimulus; CS). Although escape holes (only large enough for smaller test animals) are available, and the aggressor is unremittingly antagonistic, only half of the mice tested utilize the possibility of escape. During training, for mice that choose to leave the arena and social interaction, latency to escape dramatically decreases over time; this is also true for control C57BL6/N mice which experienced no aggression. Therefore, the open field of the SAM apparatus is intrinsically anxiogenic. It also means that submission to the aggressor is chosen despite this anxiety and the high intensity of the aggressive attacks and defeat. While both groups that received aggression displayed stress responsiveness, corticosterone levels were significantly higher in animals that chose submissive coexistence. Although both escaping and non-escaping groups of animals experienced aggression and defeat, submissive animals also exhibited classic fear conditioning, freezing in response to the CS alone, while escaping animals did not. In the basolateral amygdala (BLA), gene expression of brain-derived neurotrophic factor (BDNF) was diminished, at the same time neuropeptide S (NPS) expression was significantly elevated, but only in submissive animals. This increase in submission-evoked NPS mRNA expression was greatest in the central amygdala (CeA), which coincided with decreased BDNF expression. Reduced expression of BDNF was only found in submissive animals that also exhibit elevated NPS expression, despite elevated corticosterone in all socially interacting animals. The results suggest an interwoven relationship, linked by social context, between amygdalar BDNF, NPS and plasma corticosterone.
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http://dx.doi.org/10.3389/fnbeh.2014.00121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3986560PMC
April 2014

Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala.

Psychoneuroendocrinology 2014 Feb 30;40:17-26. Epub 2013 Oct 30.

Department of Biology, University of South Dakota, Vermillion, SD 57069, USA; Neuroscience Group, Division of Basic Biomedical Sciences, Sanford School of Medicine, University of South Dakota, Vermillion, SD 57069, USA. Electronic address:

The orexin/hypocretin system interacts with many of the same circuitries contributing to stress-associated disorders like depression and anxiety. These include potentially reciprocal connections with corticotropin releasing factor (CRF) neurons which drive the hypothalamic-pituitary-adrenal (HPA) endocrine response in addition to having an anxiogenic effect in the central amygdala (CeA). Antagonism of the orexin type 1 receptor (Orx1) in the hypothalamus has also been shown to block panic attacks. However, few studies have investigated the effect of orexinergic signaling in the basolateral amygdala (BLA) which is responsible for contextual fear, and modulates the activity of the CeA. To this end, we chronically stressed c57bl/6 mice with social defeat and examined the gene expression of the orexin receptors in the BLA. We found that the transcripts for the Orx1 and Orx2 receptors diverged in the BLA with Orx1 increasing and Orx2 decreasing in animals that were susceptible to the chronic defeat. These changes were not seen in the prelimbic cortex (PrL) which sends efferents to the BLA. We then tried to recapitulate these expression patterns in the BLA using short hairpin interfering sequences delivered by adeno-associated viruses to knock down the orexin receptors. While the Orx1 knockdown did reduce locomotor activity, it did not decrease depressive or anxious behaviors. Knocking down the Orx2 receptors in the BLA increased anxious behavior as measured by reduced social preference and reduced time spent in the center of an open field. Due to the divergent expression patterns of the two receptors in response to chronic stress, orexinergic activity in the BLA may be responsible for bidirectional modulation of anxious behavior. Furthermore, these data raise the possibility that an Orx2 agonist may serve as an effective means to treat anxiety disorders.
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http://dx.doi.org/10.1016/j.psyneuen.2013.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4361941PMC
February 2014

Inhibition of corticotropin releasing factor expression in the central nucleus of the amygdala attenuates stress-induced behavioral and endocrine responses.

Front Neurosci 2013 29;7:195. Epub 2013 Oct 29.

Avera Research Institute, Avera McKennan Hospital and University Health Center Sioux Falls, SD, USA ; Neuroscience Group, Division of Basic Biomedical Sciences, University of South Dakota Sanford School of Medicine Vermillion, SD, USA ; Department of Psychiatry, University of South Dakota Sanford School of Medicine Sioux Falls, SD, USA ; Research Service, Sioux Falls VA Health Care System Sioux Falls, SD, USA.

Corticotropin releasing factor (CRF) is a primary mediator of endocrine, autonomic and behavioral stress responses. Studies in both humans and animal models have implicated CRF in a wide-variety of psychiatric conditions including anxiety disorders such as post-traumatic stress disorder (PTSD), depression, sleep disorders and addiction among others. The central nucleus of the amygdala (CeA), a key limbic structure with one of the highest concentrations of CRF-producing cells outside of the hypothalamus, has been implicated in anxiety-like behavior and a number of stress-induced disorders. This study investigated the specific role of CRF in the CeA on both endocrine and behavioral responses to stress. We used RNA Interference (RNAi) techniques to locally and specifically knockdown CRF expression in CeA. Behavior was assessed using the elevated plus maze (EPM) and open field test (OF). Knocking down CRF expression in the CeA had no significant effect on measures of anxiety-like behavior in these tests. However, it did have an effect on grooming behavior, a CRF-induced behavior. Prior exposure to a stressor sensitized an amygdalar CRF effect on stress-induced HPA activation. In these stress-challenged animals silencing CRF in the CeA significantly attenuated corticosterone responses to a subsequent behavioral stressor. Thus, it appears that while CRF projecting from the CeA does not play a significant role in the expression stress-induced anxiety-like behaviors on the EPM and OF it does play a critical role in stress-induced HPA activation.
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http://dx.doi.org/10.3389/fnins.2013.00195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3810776PMC
November 2013

Depressive behavior and activation of the orexin/hypocretin system.

Behav Neurosci 2013 Feb;127(1):86-94

Department of Biology, University of South Dakota, Vermillion, SD 57069-2390, USA.

The orexin/hypocretin peptide signaling system plays a neuromodulatory role in motivation and stress; two critical components of depression. Although work has been done to identify links between orexin and depression, few specific neuroanatomical associations have been made. These studies have not investigated the relationship between orexin and orexin receptor expression in specific brain regions associated with this disorder. To address this, we examined immobility during the forced swim test (FST) in mice, a commonly used measure of depressive behavior. We analyzed the variation in FST immobility with the distribution of orexin and its receptor mRNA. We found that animals that exhibited more robust depressive behavior had greater or lesser orexin system expression that depended on the limbic brain region analyzed. In the hippocampus there was a negative correlation between orexin expression and FST immobility. Animals that displayed relatively more depressive behavior had lower hippocampal expression of Orexin A (OrxA). In the amygdala, there was a curvilinear relationship between OrxA and FST performance. In addition there was a positive correlation with amygdalar Type I orexin receptor (Orx1) mRNA and depressive behavior. Despite the differences in limbic orexin expression, there was no correlation between immobility and hypothalamic orexin neuron activation as measured by c-Fos. Overall, more severe depressive behavior was associated with reduced hippocampal orexin expression, contrasted with increased orexin plus Orx1 receptor mRNA expression in the amygdala. This divergent pattern between the hippocampus and amygdala mirrors a neurobiological theme seen in depression resulting from reduced hippocampal, but increased amygdalar, size and function.
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http://dx.doi.org/10.1037/a0031442DOI Listing
February 2013

A versatile and robust aerotolerant microbial community capable of cellulosic ethanol production.

Bioresour Technol 2013 Feb 16;129:156-63. Epub 2012 Nov 16.

Department of Chemistry and Biology, Ryerson University, Toronto, ON, Canada.

The use of microbial communities in the conversion of cellulosic materials to bio-ethanol has the potential to improve the economic competitiveness of this biofuel and subsequently lessen our dependency on fossil fuel-based energy sources. Interactions between functionally different microbial groups within a community can expand habitat range, including the creation of anaerobic microenvironments. Currently, research focussing on exploring the nature of the interactions occurring during cellulose degradation and ethanol production within mixed microbial communities has been limited. The aim of this study was to enrich and characterize a cellulolytic bacterial community, and determine if ethanol is a major soluble end-product. Cellulolytic activity by the community was observed in both non-reduced and pre-reduced media, with ethanol and acetate being major fermentation products. Similar results were obtained when sterile wastewater extract was provided as nutrient. Several community members showed high similarity to Clostridium species with overlapping metabolic capabilities, suggesting clostridial functional redundancy.
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http://dx.doi.org/10.1016/j.biortech.2012.10.164DOI Listing
February 2013

Lipid-lowering effect of berberine in human subjects and rats.

Phytomedicine 2012 Jul 26;19(10):861-7. Epub 2012 Jun 26.

Avera Institute for Human Genetics, Sioux Falls, SD 57108, USA.

Due to serious adverse effects and the limited effectiveness of currently available pharmacological therapies for obesity, many research efforts have focused on the development of drugs from natural products. Our previous studies demonstrated that berberine, an alkaloid originally isolated from traditional Chinese herbs, prevented fat accumulation in vitro and in vivo. In this pilot study, obese human subjects (Caucasian) were given 500 mg berberine orally three times a day for twelve weeks. The efficacy and safety of berberine treatment was determined by measurements of body weight, comprehensive metabolic panel, blood lipid and hormone levels, expression levels of inflammatory factors, complete blood count, and electrocardiograph. A Sprague-Dawley rat experiment was also performed to identify the anti-obesity effects of berberine treatment. The results demonstrate that berberine treatment produced a mild weight loss (average 5 lb/subject) in obese human subjects. But more interestingly, the treatment significantly reduced blood lipid levels (23% decrease of triglyceride and 12.2% decrease of cholesterol levels) in human subjects. The lipid-lowering effect of berberine treatment has also been replicated in the rat experiment (34.7% decrease of triglyceride and 9% decrease of cholesterol level). Cortisol, calcitriol, ACTH, TSH, FT4, and SHBG levels were not significantly changed following 12 weeks of berberine treatment. However, there was interestingly, an increase in calcitriol levels seen in all human subjects following berberine treatment (mean 59.5% increase, p=0.11). Blood inflammatory factors (CRP, IL-6, TNFα, COX-2) and erythrocyte sedimentation rate (ESR) were not significantly affected by treatment with berberine. Tests of hematological, cardiovascular, liver, and kidney function following berberine treatment showed no detrimental side effects to this natural compound. Collectively, this study demonstrates that berberine is a potent lipid-lowering compound with a moderate weight loss effect, and may have a possible potential role in osteoporosis treatment/prevention.
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http://dx.doi.org/10.1016/j.phymed.2012.05.009DOI Listing
July 2012

Molecular signaling and translational significance of the corticotropin releasing factor system.

Prog Mol Biol Transl Sci 2011 ;98:235-92

Avera Research Institute, Sioux Falls, South Dakota, USA.

The corticotropin releasing factor (CRF) system coordinates a wide range of stress responses and has been implicated in the etiology of a number of clinical disorders. It is made up of a complex array of interactive peptides that interact with many other neurotransmitter and neuromodulatory systems. Dysregulation of CRF system signaling may be a common molecular pathway for the myriad "stress-related" disorders. Understanding the signaling and circuitry affected by this system is essential to understanding these psychiatric disorders. The extremely wide range of behaviors and physiological processes mediated by this system and the complexity of its signaling make this a difficult task-especially to successfully target it for pharmacotherapy. In this review, we describe the molecular signaling of the CRF system and its interaction with other key neurotransmitter systems. Its role in a range of psychiatric disorders and potential as a target for therapeutic intervention will also be discussed.
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http://dx.doi.org/10.1016/B978-0-12-385506-0.00006-5DOI Listing
July 2011

Critical role of 7,8-didemethyl-8-hydroxy-5-deazariboflavin for photoreactivation in Chlamydomonas reinhardtii.

J Biol Chem 2010 Oct 9;285(42):32467-75. Epub 2010 Aug 9.

Basic Research Division, Avera Research Institute, Sioux Falls, South Dakota 57105, USA.

DNA photolyases use two noncovalently bound chromophores to catalyze photoreactivation, the blue light-dependent repair of DNA that has been damaged by ultraviolet light. FAD is the catalytic chromophore for all photolyases and is essential for photoreactivation. The identity of the second chromophore is often 7,8-didemethyl-8-hydroxy-5-deazariboflavin (FO). Under standard light conditions, the second chromophore is considered nonessential for photoreactivation because DNA photolyase bound to only FAD is sufficient to catalyze the repair of UV-damaged DNA. phr1 is a photoreactivation-deficient strain of Chlamydomonas. In this work, the PHR1 gene of Chlamydomonas was cloned through molecular mapping and shown to encode a protein similar to known FO synthases. Additional results revealed that the phr1 strain was deficient in an FO-like molecule and that this deficiency, as well as the phr1 photoreactivation deficiency, could be rescued by transformation with DNA constructs containing the PHR1 gene. Furthermore, expression of a PHR1 cDNA in Escherichia coli produced a protein that generated a molecule with characteristics similar to FO. Together, these results indicate that the Chlamydomonas PHR1 gene encodes an FO synthase and that optimal photoreactivation in Chlamydomonas requires FO, a molecule known to serve as a second chromophore for DNA photolyases.
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http://dx.doi.org/10.1074/jbc.M110.146050DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2952248PMC
October 2010

Ammonia causes decreased brain monoamines in fathead minnows (Pimephales promelas).

Brain Res 2007 May 17;1147:184-91. Epub 2007 Feb 17.

Avera Research Institute, Sioux Falls, SD 57105, USA.

Hyperammonemia, arising from variety of disorders, leads to severe neurological dysfunction. The mechanisms of ammonia toxicity in brain are not completely understood. This study investigated the effects of ammonia on monoaminergic systems in brains of fathead minnows (Pimephales promelas). Fish serve as a good model system to investigate hyperammonemic effects on brain function since no liver manipulations are necessary to increase endogenous ammonia concentrations. Using high performance liquid chromatography with electrochemical detection, monoamines and some associated metabolites were measured from whole brain homogenate. Adult males were exposed for 48 h to six different concentrations of ammonia (0.01-2.36 mg/l unionized) which bracketed the 96-h LC(50) for this species. Ammonia concentration-dependent decreases were found for the catecholamines (norepinephrine and dopamine) and the indoleamine serotonin (5-HT). After an initial increase in the 5-HT precursor 5-hydroxytryptophan it too decreased with increasing ammonia concentrations. There were also significant increases in the 5-HIAA/5-HT and DOPAC/DA ratios, often used as measures of turnover. There were no changes in epinephrine (Epi) or monoamine catabolites (DOPAC, 5-HIAA) at any ammonia concentrations tested. Results suggest that ammonia causes decreased synthesis while also causing increased release and degradation. Increased release may underlie behavioral reactions to ammonia exposure in fish. This study adds weight to a growing body of evidence demonstrating that ammonia leads to dysfunctional monoaminergic systems in brain which may underlie neurological symptoms associated with human disorders such as hepatic encephalopathy.
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http://dx.doi.org/10.1016/j.brainres.2007.02.015DOI Listing
May 2007

Effects of labor contractions on catecholamine release and breathing frequency in newborn rats.

Behav Neurosci 2006 Dec;120(6):1308-14

Department of Obstetrics and Gynecology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA.

Plasma catecholamines in newborn rats (0-2 hr old) were analyzed following vaginal birth, cesarean section with simulated labor contractions, or cesarean section without labor contractions. Upon delivery, pups were exposed to key elements of the rat's natural birth process, that is, umbilical cord occlusion, tactile stimulation, and cooling. Only pups exposed to actual or simulated labor showed an immediate rise in norepinephrine and epinephrine. Initial postpartum respiratory frequencies were higher in vaginal than in cesarean delivered pups and, in all groups, inversely correlated with catecholamine titers, suggesting respiratory distress or transient tachypnea at lower catecholamine levels. These findings establish a rat model for analyzing effects of labor on neonatal adaptive response during the transition from prenatal to postnatal life.
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http://dx.doi.org/10.1037/0735-7044.120.6.1308DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2749474PMC
December 2006

Does serotonin influence aggression? comparing regional activity before and during social interaction.

Physiol Biochem Zool 2005 Sep-Oct;78(5):679-94. Epub 2005 Jul 29.

Biology and Neuroscience, University of South Dakota, Vermillion, SD 57069, USA.

Serotonin is widely believed to exert inhibitory control over aggressive behavior and intent. In addition, a number of studies of fish, reptiles, and mammals, including the lizard Anolis carolinensis, have demonstrated that serotonergic activity is stimulated by aggressive social interaction in both dominant and subordinate males. As serotonergic activity does not appear to inhibit agonistic behavior during combative social interaction, we investigated the possibility that the negative correlation between serotonergic activity and aggression exists before aggressive behavior begins. To do this, putatively dominant and more aggressive males were determined by their speed overcoming stress (latency to feeding after capture) and their celerity to court females. Serotonergic activities before aggression are differentiated by social rank in a region-specific manner. Among aggressive males baseline serotonergic activity is lower in the septum, nucleus accumbens, striatum, medial amygdala, anterior hypothalamus, raphe, and locus ceruleus but not in the hippocampus, lateral amygdala, preoptic area, substantia nigra, or ventral tegmental area. However, in regions such as the nucleus accumbens, where low serotonergic activity may help promote aggression, agonistic behavior also stimulates the greatest rise in serotonergic activity among the most aggressive males, most likely as a result of the stress associated with social interaction.
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http://dx.doi.org/10.1086/432139DOI Listing
May 2006

Serotonin metabolism in directly developing frog embryos during paternal care.

Neurosci Lett 2005 Nov;388(2):100-5

Department of Psychology, Biopsychology Area, The University of Michigan, Ann Arbor, MI 48109, USA.

Central serotonin (5-HT) metabolism during embryogenesis and a 3-day post-hatching period was analyzed using high performance liquid chromatography in the directly developing frog, Eleutherodactylus coqui. This anuran bypasses the free-swimming larval stage and embryos hatch as miniature frogs in the adult phenotype. During embryogenesis and for a short time immediately after hatching, male E. coqui provide paternal care by brooding and guarding eggs/embryos to prevent desiccation and predation. Serotonin and its catabolite, 5-HIAA, were measured from whole brain during embryogenesis and at 3 days post-hatch to identify critical periods in 5-HT development and to determine the relationship between 5-HT and life history events such as hatching and frog dispersal from the nest site. Serotonergic activity was highest during the early-mid embryonic stages as indicated by the ratio of 5-HIAA/5-HT, a general indicator of turnover and metabolism. There were significant increases in tissue concentrations of 5-HT during the latest or terminal embryonic stage, just prior to hatching, and also at 3 days post-hatch, shortly before neonates disperse into the rainforest. These two increases probably represent different functional requirements during development. The first may occur as a result of the surge of development in the 5-HT system during late embryogenesis that occurs in E. coqui and the second may be from the increase demand in sensory and motor neural development required before dispersal from the nest site.
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http://dx.doi.org/10.1016/j.neulet.2005.06.039DOI Listing
November 2005

Dynamics and mechanics of social rank reversal.

J Comp Physiol A Neuroethol Sens Neural Behav Physiol 2005 Mar 11;191(3):241-52. Epub 2004 Sep 11.

Biology and Neuroscience, University of South Dakota, 414 East Clark Street, Vermillion, SD 57069-2390, USA.

Stable social relationships are rearranged over time as resources such as favored territorial positions change. We test the hypotheses that social rank relationships are relatively stable, and although social signals influence aggression and rank, they are not as important as memory of an opponent. In addition, we hypothesize that eyespots, aggression and corticosterone influence serotonin and N-methyl-D: -aspartate (NMDA) systems in limbic structures involved in learning and memory. In stable adult dominant-subordinate relationships in the lizard Anolis carolinensis, social rank can be reversed by pharmacological elevation of limbic serotonergic activity. Any pair of specific experiences: behaving aggressively, viewing aggression or perceiving sign stimuli indicative of dominant rank also elevate serotonergic activity. Differences in the extent of serotonergic activation may be a discriminating and consolidating factor in attaining superior rank. For instance, socially aggressive encounters lead to increases in plasma corticosterone that stimulate both serotonergic activity and expression of the NMDA receptor subunit 2B (NR(2B)) within the CA(3) region of the lizard hippocampus. Integration of these systems will regulate opponent recognition and memory, motivation to attack or retreat, and behavioral and physiological reactions to stressful social interactions. Contextually appropriate social responses provide a modifiable basis for coping with the flexibility of social relationships.
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http://dx.doi.org/10.1007/s00359-004-0554-zDOI Listing
March 2005

Focal deletion of the adenosine A1 receptor in adult mice using an adeno-associated viral vector.

J Neurosci 2003 Jul;23(13):5762-70

Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.

Adenosine is a ubiquitous neuromodulator that increases sleep, inhibits seizures, and promotes neuroprotection. Many of these effects are mediated by A1 receptors, but A1 receptors are expressed in most brain regions, and distinguishing the precise site of action of adenosine is challenging. To test the role of adenosine in different hippocampal regions, we have used the Cre-loxP system and an adeno-associated viral (AAV) vector to focally delete endogenous adenosine A1 receptors in the hippocampus. Microinjection of an AAV vector containing the gene for Cre recombinase induced intense, focal, neuron-specific recombination in reporter mice. In a separate line of mice with loxP sites flanking the major coding exon for the adenosine A1 receptor, this AAV-Cre markedly reduced A1 receptor mRNA and focally abolished the postsynaptic response to adenosine without any change in basic electrophysiologic properties. Adenosine inhibits signaling between CA3 and CA1 neurons, but it is unclear from pharmacologic studies whether this response is caused by presynaptic or postsynaptic effects. Deletion of A1 receptors from CA3 neurons abolished this response to adenosine, but deletion of A1 receptors from CA1 neurons had no effect, demonstrating a presynaptic site of action. This transduction knock-out technique holds enormous potential for dissecting the functions of different CNS pathways.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6741251PMC
July 2003

Rapid glucocorticoid stimulation and GABAergic inhibition of hippocampal serotonergic response: in vivo dialysis in the lizard anolis carolinensis.

Horm Behav 2003 Jan;43(1):245-53

Biology and Neuroscience, University of South Dakota, Vermillion, SD 57069, USA.

Central serotonin (5-HT) is activated during stressful situations and aggressive interactions in a number of species. Glucocorticoids secreted peripherally during stressful events feed back on central systems and may affect 5-HT mediation of stress-induced behavioral events. To test the neuromodulatory effect of stress hormone secretion, serotonin overflow was measured from the hippocampus of the lizard Anolis carolinensis. Microdialysis was used to collect repeated samples from anesthetized lizards, with perfusate measured by HPLC with electrochemical analysis. Following initially high levels of 5-HT, concentrations stabilized to basal levels after approximately 2 h. Intracortical infusion of 200 ng/ml corticosterone evoked transient increases in 5-HT release of approximately 400%. The effect of corticosterone on 5-HT overflow appears to be dose dependent as 20 ng/ml stimulated an increase of 200%, whereas 2 ng/ml stimulated a 50% increase. Administration of 0.1 and 1 ng/ml GABA via the dialysis probe significantly inhibited 5-HT overflow by 20 and 40%, respectively. The duration of GABA inhibition is greater than the stimulatory response for glucocorticoids. Short-lived glucocorticoid stimulation of 5-HT release suggests a possible mechanism for endocrine mediation of continuously changing social behavioral events.
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http://dx.doi.org/10.1016/s0018-506x(02)00014-4DOI Listing
January 2003

Dopamine receptors and learned helplessness in the rat: an autoradiographic study.

Prog Neuropsychopharmacol Biol Psychiatry 2002 May;26(4):639-45

Dallas Veterans Affairs Medical Center, University of Texas Southwestern Medical Center at Dallas, 75216, USA.

(1) Disturbances of mesolimbic and mesocortical dopamine (DA) function have been implicated in the pathophysiology of several psychiatric disorders, including major depressive disorder. (2) Utilizing the learned helplessness (LH) animal model of clinical depression and quantitative autoradiography, the authors studied the densities of D1 and dopamine-2-like receptors (D2-like receptors) in medial prefrontal cortex, septum, nucleus accumbens and caudate nucleus in rats that received inescapable stress and were subsequently tested for LH behavior. (3) Dopamine-1 receptor (D1 receptor) densities were significantly higher in the core and shell of the nucleus accumbens and in the medial caudate nucleus of rats that did not become helpless after stress, compared to rats that developed LH. (4) Densities of D2-like receptors were significantly lower in the core of the nucleus accumbens in both the LH and the nonhelpless (NH) rats compared to controls. Densities of D2-like receptors were also lower in the medial and lateral caudate nuclei in LH rats compared to the other groups. (5) Increased D1 receptor densities in NH rats in the nucleus accumbens may be associated with an adaptive or protective role of this brain region in the prevention of escape deficits after exposure to inescapable stress. (6) Decreased D2-like receptor densities in the caudate nucleus in helpless rats may reflect a motor deficit associated with LH behavior, while decreases of D2-like receptor densities in the core of the nucleus accumbens may reflect a generalized effect of exposure to inescapable stress. (7) This study highlights the importance of the mesolimbic/nigrostriatal dopaminergic systems in mediating behavioral responses to inescapable stress.
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http://dx.doi.org/10.1016/s0278-5846(01)00222-6DOI Listing
May 2002

Brain Monoamine Concentrations as Predictors of Growth Inhibition in Channel Catfish Exposed to Ammonia.

J Aquat Anim Health 2000 Mar;12(1):69-73

b Department of Biology , University of South Dakota , Vermillion , South Dakota , 57069 , USA.

Fingerlings of channel catfish Ictalurus punctatus exhibited a significant exposure-dependent decrease in growth (measured by weight gain and increase in total length) and condition factor after 9 weeks of exposure to environmental ammonia. Concentrations of 5-hydroxytryptamine (5-HT) and dopamine in the brain decreased significantly whereas the ratio of 5-hydroxyindoleacetic acid (5-HIAA) to 5-HT increased significantly in exposure-dependent manners. The brain dopamine concentrations and the 5-HIAA : 5-HT ratio collectively explained 88% of the variation in growth due to ammonia exposure. This study demonstrates the potential to predict ammonia-induced inhibition of growth in channel catfish with physiological changes.
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http://dx.doi.org/10.1577/1548-8667(2000)012<0069:BMCAPO>2.0.CO;2DOI Listing
March 2000
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