mGluR5 Mediates Dihydrotestosterone-Induced Nucleus Accumbens Structural Plasticity, but Not Conditioned Reward

Gonadal hormones play a vital role in driving motivated behavior. They not only modulate responses to naturally rewarding stimuli, but also influence responses to drugs of abuse. A commonality between gonadal hormones and drugs of abuse is that they both impact the neurocircuitry of reward, including the regulation of structural plasticity in the nucleus accumbens (NAc). Previous hormonal studies have focused on the mechanisms and behavioral correlates of estradiol-induced dendritic spine changes in the female NAc. Here we sought to determine the effects of androgens on medium spiny neuron (MSN) spine plasticity in the male NAc. Following treatment with the androgen receptor agonist dihydrotestosterone (DHT), MSNs in castrated male rats exhibited a significant decrease in dendritic spine density. This effect was isolated to the shell subregion of the NAc. The effect of DHT was dependent on mGluR5 activity, and local mGluR5 activation and subsequent endocannabinoid signaling produce an analogous NAc shell spine decrease. Somewhat surprisingly, DHT-induced conditioned place preference remained intact following systemic inhibition of mGluR5. These findings indicate that androgens can utilize mGluR signaling, similar to estrogens, to mediate changes in NAc dendritic structure. In addition, there are notable differences in the direction of spine changes, and site specificity of estrogen and androgen action, suggesting sex differences in the hormonal regulation of motivated behaviors

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

mGluR5 Structural Plasticity in the Nucleus Accumbens: Characterization, Mechanism, and Sex Differences

University of Minnesota Ph.D. dissertation. October 2017. Major: Neuroscience. Advisors: Paul G. Mermelstein, Robert L. Meisel. 1 computer file (PDF); viii, 105 pages.The group I metabotropic glutamate receptors, mGluR1 and mGluR5, are important modulators of neuronal signaling and plasticity. One specific way that group I mGluRs appear to influence excitatory neurotransmission is through the remodeling of neuronal structure by inducing changes to dendritic spines. However, group I mGluR spine remodeling has only been studied in an extremely limited number of regions and cell types, leaving the contribution of this mechanism to plasticity in many systems unknown. Group I mGluRs, especially mGluR5, have been associated with the synaptic plasticity in the reward circuitry of the brain that is believed to underlie addiction. Structural changes in this circuitry, particularly in the nucleus accumbens (NAc) are strongly correlated with the development and maintenance of addiction. Yet a potential relationship between mGluR5 signaling and spine plasticity in the NAc has not been directly studied. Here, the effects of mGluR5 signaling on spine plasticity in medium spiny neurons of the NAc are characterized, with particular attention on the sex differences and hormonal regulation of these effects. Activation of mGluR5 signaling is found to decrease spine density in the NAc with sex differences in subregion specificity. Additionally, primary gonadal hormones are found to trigger mGluR5 signaling to produce structural modulation in the NAc, with previous evidence implicating mGluR5 in estradiol-induced spine changes in this region in females, and research here finding a similar, novel role for androgen signaling in males. The mechanisms of mGluR5-mediated spine plasticity are also explored. Endocannabinoid signaling was found to be required for mGluR5-induced spine decreases in the male NAc, and spine changes were found to be correlated with a change in NAc F-actin content. Collectively, these results indicate that mGluR5 signaling results in structural plasticity in a region that is critical to reward in a sex-dependent manner, suggesting that the activity of this receptor might contribute differently to both natural and pathological motivated behavior in males and females

Opposite Effects of mGluR1a and mGluR5 Activation on Nucleus Accumbens Medium Spiny Neuron Dendritic Spine Density.

The group I metabotropic glutamate receptors (mGluR1a and mGluR5) are important modulators of neuronal structure and function. Although these receptors share common signaling pathways, they are capable of having distinct effects on cellular plasticity. We investigated the individual effects of mGluR1a or mGluR5 activation on dendritic spine density in medium spiny neurons in the nucleus accumbens (NAc), which has become relevant with the potential use of group I mGluR based therapeutics in the treatment of drug addiction. We found that systemic administration of mGluR subtype-specific positive allosteric modulators had opposite effects on dendritic spine densities. Specifically, mGluR5 positive modulation decreased dendritic spine densities in the NAc shell and core, but was without effect in the dorsal striatum, whereas increased spine densities in the NAc were observed with mGluR1a positive modulation. Additionally, direct activation of mGluR5 via CHPG administration into the NAc also decreased the density of dendritic spines. These data provide insight on the ability of group I mGluRs to induce structural plasticity in the NAc and demonstrate that the group I mGluRs are capable of producing not just distinct, but opposing, effects on dendritic spine density

AmphibiaWeb and HerpNET: On the Cutting Edge of Herpetological Biodiversity Informatics

<p>Poster presentation at:</p> <p><strong>6th World Congress of Herpetology</strong>, Manaus, Brazil, August 2008.<br><strong>Latin American Congress of Herpetology</strong>, Cuba, November 2008.<br><strong>Sackler Colloquia of the National Academy of Sciences: Biogeography, Changing Climates and Niche Evolution</strong>, Irvine, California, December 2008.</p

Positive modulation of mGluR1a increases spine density in the nucleus accumbens but not in the dorsal striatum.

<p>(A) Twenty-four hours after systemic administration, SYN119 (10 mg/kg, <i>n</i> = 10 animals) increased dendritic spine density compared to vehicle control (<i>n</i> = 9) in the nucleus accumbens core but had no effect on spine length or head diameter. (B) SYN119 also decreased spine density in the nucleus accumbens shell and did not affect spine length or head diameter. *<i>p</i> < 0.05.</p

Activation of mGluR5 site-specifically decreases spine density in the nucleus accumbens.

<p>(A) Schematic representation of injection sites of either vehicle (open circles) or CHPG (filled circles). Numbers represent distance from bregma, based on the atlas of Paxinos and Watson [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0162755#pone.0162755.ref016" target="_blank">16</a>]. (B)Twenty-four hours after local microinfusion to the nucleus accumbens, CHPG (10 μg/side, <i>n</i> = 7 animals) decreased dendritic spine density compared to vehicle control (<i>n</i> = 7) in the nucleus accumbens core but had no effect on spine length or head diameter. (B) CHPG also decreased spine density in the nucleus accumbens shell and did not affect spine length or head diameter. *<i>p</i> < 0.05.</p

Representative images of DiI-labeled neuron and dendritic segment.

<p>(A) Low power magnification of a DiI-labeled medium spiny neuron, <i>scale bar</i> 50 μm. (B) High power magnification of a reconstructed dendritic segment from a medium spiny neuron, <i>scale bar</i> 5 μm.</p

AmphibiaWeb tracks the paradox: New species discovery in an era of declines

<p>Presented at the 7th World Congress of Herpetology, <br>Vancouver, BC, Canada, September 2-7, 2012.</p> <p> </p

A Simple and Efficient Synthesis of an Acid-Labile Polyphosphoramidate by Organobase-Catalyzed Ring-Opening Polymerization and Transformation to Polyphosphoester Ionomers by Acid Treatment

The direct synthesis of an acid-labile polyphosphoramidate by organobase-catalyzed ring-opening polymerization and an overall two-step preparation of polyphosphodiester ionomers (PPEI) by acid-assisted cleavage of the phosphoramidate bonds along the backbone of the polyphosphoramidate were developed in this study. The ultrafast organobase-catalyzed ring-opening polymerization of a cyclic phospholane methoxyethyl amidate monomer initiated by benzyl alcohol allowed for the preparation of well-defined polyphosphoramidates (PPA) with predictable molecular weights, narrow molecular weight distributions (PDI<1.10), and well-defined chain ends. Cleavage of the acid-labile phosphoramidate bonds on the polyphosphoramidate repeat units was evaluated under acidic conditions over a pH range of 1–5, and the complete hydrolysis produced polyphosphodiesters. The thermal properties of the resulting polyphosphoester ionomer acid and polyphosphoester ionomer sodium salt exhibited significant thermal stability. The parent PPA and both forms of the PPEIs showed low cytotoxicities toward HeLa cells and RAW 264.7 mouse macrophage cells. The synthetic methodology developed here has enriched the family of water-soluble polymers prepared by rapid and convenient organobase-catalyzed ring-opening polymerizations and straightforward chemical medication reactions, which are designed to be hydrolytically degradable and have promise for numerous biomedical and other applications