2024-03-28T22:12:19Zhttps://scholarworks.iu.edu/dspace-oai/requestoai:scholarworks.iu.edu:2022/142152021-10-18T12:39:36Zcom_2022_14205com_2022_19675com_2022_19673col_2022_14206
N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor
Bradshaw, Heather B.
Walker, J. Michael
Vogel, Zvi
Juknat, Ana
Rimmerman, Neta
Hu, Sherry SJ
McHugh, Douglas
Background: Microglia provide continuous immune surveillance of the CNS and upon activation rapidly change phenotype to express receptors that respond to chemoattractants during CNS damage or infection. These activated microglia undergo directed migration towards affected tissue. Importantly, the molecular species of chemoattractant encountered determines if microglia respond with pro- or anti-inflammatory behaviour, yet the signaling molecules that trigger migration remain poorly understood. The endogenous cannabinoid system regulates microglial migration via CB2 receptors and an as yet unidentified GPCR termed the 'abnormal cannabidiol' (Abn-CBD) receptor. Abn-CBD is a
synthetic isomer of the phytocannabinoid cannabidiol (CBD) and is inactive at CB1 or CB2 receptors, but functions as a selective agonist at this Gi/o-coupled GPCR. N-arachidonoyl glycine (NAGly) is an endogenous metabolite of the endocannabinoid anandamide and acts as an efficacious agonist at GPR18. Here, we investigate the relationship between NAGly, Abn-CBD, the unidentified 'Abn-CBD' receptor, GPR18, and BV-2 microglial migration.
Results: Using Boyden chamber migration experiments, yellow tetrazolium (MTT) conversion, In-cell Western, qPCR and immunocytochemistry we show that NAGly, at sub-nanomolar concentrations, and Abn-CBD potently drive cellular migration in both BV-2 microglia and HEK293-GPR18 transfected cells, but neither induce migration in HEKGPR55 or non-transfected HEK293 wildtype cells. Migration effects are blocked or attenuated in both systems by the 'Abn-CBD' receptor antagonist O-1918, and low efficacy agonists N-arachidonoyl-serine and cannabidiol. NAGly promotes proliferation and activation of MAP kinases in BV-2 microglia and HEK293-GPR18 cells at low nanomolar concentrations - cellular responses correlated with microglial migration. Additionally, BV-2 cells show GPR18 immunocytochemical staining and abundant GPR18 mRNA. qPCR demonstrates that primary microglia, likewise, express abundant amounts of GPR18 mRNA.
Conclusions: NAGly is the most effective lipid recruiter of BV-2 microglia currently reported and its effects mimic those of Abn-CBD. The data generated from this study supports the hypothesis that GPR18 is the previously unidentified 'Abn-CBD' receptor. The marked potency of NAGly acting on GPR18 to elicit directed migration, proliferation and perhaps other MAPK-dependent phenomena advances our understanding of the lipid-based signaling mechanisms employed by the CNS to actively recruit microglia to sites of interest. It offers a novel research avenue for developing
therapeutics to elicit a self-renewing population of neuroregenerative microglia, or alternatively, to prevent the accumulation of misdirected, pro-inflammatory microglia which contribute to and exacerbate neurodegenerative
disease.
2012-03-02
2012-03-02
2010-03-26
Article
McHugh D, Hu S S-J, Rimmerman N, Vogil Z., Walker JM, Bradshaw HB. N-arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neurosci. 2010 Mar 26;11:44
http://hdl.handle.net/2022/14215
en_US
http://www.biomedcentral.com/1471-2202/11/44
http://creativecommons.org/licenses/by/2.0
© 2010 McHugh et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
BioMed Central
oai:scholarworks.iu.edu:2022/142162021-10-18T12:39:40Zcom_2022_14205com_2022_19675com_2022_19673col_2022_14206
Uterine-specific p53 deficiency confers premature uterine senescence and promotes preterm birth in mice
Dey, Sudhansu K.
Bradshaw, Heather B.
Xie, Huirong
Tranguch, Susanne
Daikoku, Takiko
Hirota, Yasushi
Many signaling pathways that contribute to tumorigenesis are also functional in pregnancy, although they are dysregulated in the former and tightly regulated in the latter. Transformation-related protein 53 (Trp53), which encodes p53, is a tumor suppressor gene whose mutation is strongly associated with cancer. However, its
role in normal physiological processes, including female reproduction, is poorly understood. Mice that have a constitutive deletion of Trp53 exhibit widespread development of carcinogenesis at early reproductive ages,
compromised spermatogenesis, and fetal exencephaly, rendering them less amenable to studying the role of p53 in reproduction. To overcome this obstacle, we generated mice that harbor a conditional deletion of uterine Trp53 and examined pregnancy outcome in females with this genotype. These mice had normal ovulation,
fertilization, and implantation; however, postimplantation uterine decidual cells showed terminal differentiation and senescence-associated growth restriction with increased levels of phosphorylated Akt and p21, factors
that are both known to participate in these processes in other systems. Strikingly, uterine deletion of Trp53 increased the incidence of preterm birth, a condition that was corrected by oral administration of the selective COX2 inhibitor celecoxib. We further generated evidence to suggest that deletion of uterine Trp53 induces preterm birth through a COX2/PGF synthase/PGF2α pathway. Taken together, our observations underscore what we believe to be a new critical role of uterine p53 in parturition.
2012-03-02
2012-03-02
2010-03
Article
Hirota Y, Daikoku T, Tranguch S, Xie H, Bradshaw HB, Dey SK. p53 deficiency confers premature uterine senescence and promotes preterm birth. J Clin Invest. 2010 Mar 1;120(3):803-15
http://hdl.handle.net/2022/14216
en_US
http://www.jci.org/articles/view/40051
Copyright © 2010, American Society for Clinical Investigation
American Society for Clinical Investigation
oai:scholarworks.iu.edu:2022/142602021-10-18T14:59:05Zcom_2022_14205com_2022_19675com_2022_19673col_2022_14206
AA/12-lipoxygenase signaling contributes to inhibitory learning in Hermissenda Type B photoreceptors
Farley, Joseph
Cavallo, Joel S.
Campodonico, Joanna J.
Walker, Tony L.
K+ channels
HPETE
lipoxygenase
arachidonic acid
conditioned inhibition learning
Hermissenda crassicornis
Conditioned inhibition (CI) is a major category of associative learning that occurs when an
organism learns that one stimulus predicts the absence of another. In addition to being important in its own right, CI is interesting because its occurrence implies that the organism has formed an association between stimuli that are non-coincident. In contrast to other categories of associative learning that are dependent upon temporal contiguity (pairings) of stimuli, the neurobiology of CI is virtually unexplored. We have previously described a simple form of CI learning in Hermissenda, whereby animals’ phototactic behavior is increased by repeated exposures to explicitly unpaired (EU) presentations of light and rotation. EU conditioning also produces characteristic reductions in the excitability and light response, and increases several
somatic K+ currents in Type B photoreceptors. Type B photoreceptors are a major site of plasticity for classical conditioning in Hermissenda. Because arachidonic acid (AA) and/or its metabolites open diverse K+ channels in many cell types, we examined the potential contribution of AA to CI. Our results indicate that AA contributes to one of the major effects of EU-conditioning on Type B photoreceptors: decreases in light-evoked spike activity. We find that AA increases the transient (IA) somatic K+ current in Type B photoreceptors, further mimicking CI training. In addition, our results indicate that metabolism of AA by a 12-lipoxygenase enzyme is critical for these effects of AA, and further that 12-lipoxygenase metabolites are apparently generated during CI training.
2012-03-12
2012-03-12
2010-08-03
Article
Walker TL, Campodonico JJ, Cavallo JS and Farley J (2010) AA/12-lipoxygenase signaling contributes to inhibitory learning in Hermissenda Type B photoreceptors. Front. Behav. Neurosci. 4:50. doi: 10.3389/fnbeh.2010.00050
http://hdl.handle.net/2022/14260
en_US
http://www.frontiersin.org/Behavioral_Neuroscience/10.3389/fnbeh.2010.00050/abstract
Copyright: © 2010 Walker, Campodonico, Cavallo and Farley. This is an open-access article subject to an exclusive license agreement between the authors and the Frontiers Research Foundation, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are credited.
Frontiers Media SA
oai:scholarworks.iu.edu:2022/142652021-10-19T01:12:29Zcom_2022_14205com_2022_19675com_2022_19673col_2022_14206
Ceftriaxone-induced up-regulation of cortical and striatal GLT1 in the R6/2 model of Huntington’s disease
Rebec, George V.
Miller, Benjamin R.
Barton, Scott J.
Prieto, Anne L.
Sari, Youssef
Background: Huntington’s disease (HD) is an inherited neurodegenerative disorder characterized by cortico-striatal dysfunction and loss of glutamate uptake. At 7 weeks of age, R6/2 mice, which model an aggressive form of
juvenile HD, show a glutamate-uptake deficit in striatum that can be reversed by treatment with ceftriaxone, a b-lactam antibiotic that increases GLT1 expression. Only at advanced ages (> 11 weeks), however, do R6/2 mice show an actual loss of striatal GLT1. Here, we tested whether ceftriaxone can reverse the decline in GLT1 expression that occurs in older R6/2s.
Results: Western blots were used to assess GLT1 expression in both striatum and cerebral cortex in R6/2 and corresponding wild-type (WT) mice at 9 and 13 weeks of age. Mice were euthanized for immunoblotting 24 hr after five consecutive days of once daily injections (ip) of ceftriaxone (200 mg/kg) or saline vehicle. Despite a significant GLT1 reduction in saline-treated R6/2 mice relative to WT at 13, but not 9, weeks of age, ceftriaxone treatment increased cortical and striatal GLT1 expression relative to saline in all tested mice.
Conclusions: The ability of ceftriaxone to up-regulate GLT1 in R6/2 mice at an age when GLT1 expression is significantly reduced suggests that the mechanism for increasing GLT1 expression is still functional. Thus, ceftriaxone could be effective in modulating glutamate transmission even in late-stage HD.
2012-03-14
2012-03-14
2010-07-27
Article
Sari, Y., Prieto, A. L., Barton, S. J., Miller, B. M., Rebec, G. V. (2010). Ceftriaxone-induced up-regulation of GLT1 expression at multiple stages of Huntingtons disease in the R6/2 model. J. Biomed. Sci., 17:62 (1-5).
http://hdl.handle.net/2022/14265
en_US
http://www.jbiomedsci.com/content/17/1/62
http://creativecommons.org/licenses/by/2.0
© 2010 Sari et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.
BioMed Central Ltd
oai:scholarworks.iu.edu:2022/142662021-10-18T14:59:08Zcom_2022_14205com_2022_19675com_2022_19673col_2022_14206
Serotonin in the inferior colliculus fluctuates with behavioral state and environmental stimuli
Hurley, Laura M.
Rebec, George V.
Hall, Ian C.
stress
sensory
voltammetry
neuromodulation
auditory
inferior colliculus
serotonin
Neuromodulation by serotonin (5-HT) could link behavioral state and environmental events with sensory processing. Within the auditory system, the presence of 5-HT alters the activity of neurons in the inferior colliculus (IC), but the conditions that influence 5-HT neurotransmission in this region of the brain are unknown. We used in vivo voltammetry to measure extracellular 5-HT in the IC of behaving mice to address this issue. Extracellular 5-HT increased with the recovery from anesthesia, suggesting that the
neuromodulation of auditory processing is correlated with the level of behavioral arousal. Awake mice were further exposed to auditory (broadband noise), visual (light) or olfactory (2,5-dihydro-2,4,5-trimethylthiazoline, TMT) stimuli, presented with food or confined in a small arena. Only the auditory stimulus or restricted movement increased the concentration of extracellular 5-HT in the IC. Changes occurred within minutes of stimulus onset, with the auditory stimulus increasing extracellular 5-HT by an average of 5% and restricted movement increasing it by an average of 14%. These findings suggest that the neuromodulation of auditory processing by 5-HT is a dynamic process that is dependent on internal state and behavioral conditions.
2012-03-14
2012-03-14
2010-04-01
Article
Hall, I. C., Rebec, G. V., Hurley, L. M. (2010). Serotonin in the inferior colliculus fluctuates with behavioral state and environmental stimuli.Journal of Experimental Biology, 213:1009-1017.
http://hdl.handle.net/2022/14266
en_US
http://jeb.biologists.org/content/213/7/1009.full
© 2010. Published by The Company of Biologists Ltd
The Company of Biologists Ltd
oai:scholarworks.iu.edu:2022/228692021-10-19T02:44:12Zcom_2022_20283com_2022_19675com_2022_19673com_2022_14205col_2022_22675col_2022_14206
Editorial: Phonology in the Bilingual and Bidialectal Lexicon
Darcy, Isabelle
Tremblay, Annie
Simonet, Miquel
One critical step when trying to comprehend a spoken message is to identify the words that the speaker intended. To recognize spoken words, listeners continuously attempt to map the incoming speech signal onto lexical representations stored in memory (McClelland and Elman, 1986; Norris, 1994): Words that partially overlap with the signal are activated until the lexical candidate that best matches the input wins over its competitors, a process known as lexical competition. Models of spoken-word recognition, most of which are based on native listener behavior, assume that lexical representations are stable, and contain at least the phonological form of words in citation. While lexical representations likely also contain other forms, for example the reduced forms found in conversational speech, it is a matter of debate whether native listeners encode spoken words exclusively as phonetically detailed exemplars (Johnson, 1997; Goldinger, 1998) or whether phonological abstraction also takes place (McQueen et al., 2006). Another assumption of models of native spoken-word recognition is that, under normal circumstances, listeners’ perception of the input is optimal and faithful to the signal: Accurate lexical representations are easily contacted, and an optimal set of candidates is activated for quick lexical selection.
2019-03-26
2019-03-26
2017-04
Article
Darcy, I., Tremblay, A., & Simonet, M. (2017). Editorial: Phonology in the Bilingual and Bidialectal Lexicon. Frontiers in Psychology, 8(507). doi:10.3389/fpsyg.2017.00507
http://hdl.handle.net/2022/22869
10.3389/fpsyg.2017.00507
en
https://www.frontiersin.org/articles/10.3389/fpsyg.2017.00507/full
Frontiers in Psychology
oai:scholarworks.iu.edu:2022/228712021-10-19T02:44:11Zcom_2022_14205com_2022_19675com_2022_19673com_2022_20283col_2022_14206col_2022_22675
Second Language Working Memory Deficits and Plasticity in Hearing Bimodal Learners of Sign Language
Williams, Joshua
Darcy, Isabelle
Newman, Sharlene
American sign language
working memory
second language acquisition
bimodal bilingualism
Little is known about the acquisition of another language modality on second language (L2) working memory (WM) capacity. Differential indexing within the WM system based on language modality may explain differences in performance on WM tasks in sign and spoken language. We investigated the effect of language modality (sign versus spoken) on L2 WM capacity. Results indicated reduced L2 WM span relative to first language span for both L2 learners of Spanish and American Sign Language (ASL). Importantly, ASL learners had lower L2 WM spans than Spanish learners. Additionally, ASL learners increased their L2 WM spans as a function of proficiency, whereas Spanish learners did not. This pattern of results demonstrated that acquiring another language modality disadvantages ASL learners. We posited that this disadvantage arises out of an inability to correctly and efficiently allocate linguistic information to the visuospatial sketchpad due to L1-related indexing bias.
2019-03-26
2019-03-26
2015-10
Article
Williams, J.T., & Darcy, I., & Newman, S.D. (2015). Second language working memory deficits and plasticity in hearing bimodal learners of sign language. Psychology of Language & Communication, 19, 128-148. doi: 10.1515/plc-2015-0008.
http://hdl.handle.net/2022/22871
10.1515/plc-2015-0008
en
https://content.sciendo.com/view/journals/plc/19/2/article-p128.xml
Psychology of Language and Communication