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.

Hydrophobic platinum(II)-5,10,15,20-tetrakis-(2,3,4,5,6-pentafluorophenyl)-porphyrin (PtTFPP) was physically incorporated into micelles formed from poly(ε-caprolactone)-block-poly(ethylene glycol) to enable the application of PtTFPP in aqueous solution. Micelles were characterized using dynamic light scattering (DLS) and atomic force microscopy (AFM) to show an average diameter of about 140 nm. PtTFPP showed higher quantum efficiency in micellar solution than in tetrahydrofuran (THF) and dichloromethane (CH₂Cl₂). PtTFPP in micelles also exhibited higher photostability than that of PtTFPP suspended in water. PtTFPP in micelles exhibited good oxygen sensitivity and response time. This study provided an efficient approach to enable the application of hydrophobic oxygen sensors in a biological environment.

Positive allosteric modulators (PAMs) of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors are a diverse class of compounds that increase fast excitatory transmission in the brain. AMPA PAMs have been shown to facilitate long-term potentiation, strengthen communication between various cortical and subcortical regions, and some of these compounds increase the production and release of brain-derived neurotrophic factor (BDNF) in an activity-dependent manner. Through these mechanisms, AMPA PAMs have shown promise as broad spectrum pharmacotherapeutics in preclinical and clinical studies for various neurodegenerative and psychiatric disorders. In recent years, a small collection of preclinical animal studies has also shown that AMPA PAMs may have potential as pharmacotherapeutic adjuncts to extinction-based or cue-exposure therapies for the treatment of drug addiction. The present paper will review this preclinical literature, discuss novel data collected in our laboratory, and recommend future research directions for the possible development of AMPA PAMs as anti-addiction medications.

Single-cell studies of phenotypic heterogeneity reveal more information about pathogenic processes than conventional bulk-cell analysis methods. By enabling high-resolution structural and functional imaging, a single-cell three-dimensional (3D) imaging system can be used to study basic biological processes and to diagnose diseases such as cancer at an early stage. One mechanism that such systems apply to accomplish 3D imaging is rotation of a single cell about a fixed axis. However, many cell rotation mechanisms require intricate and tedious microfabrication, or fail to provide a suitable environment for living cells. To address these and related challenges, we applied numerical simulation methods to design new microfluidic chambers capable of generating fluidic microvortices to rotate suspended cells. We then compared several microfluidic chip designs experimentally in terms of: (1) their ability to rotate biological cells in a stable and precise manner; and (2) their suitability, from a geometric standpoint, for microscopic cell imaging. We selected a design that incorporates a trapezoidal side chamber connected to a main flow channel because it provided well-controlled circulation and met imaging requirements. Micro particle-image velocimetry (micro-PIV) was used to provide a detailed characterization of flows in the new design. Simulated and experimental results demonstrate that a trapezoidal side chamber represents a viable option for accomplishing controlled single cell rotation. Further, agreement between experimental and simulated results confirms that numerical simulation is an effective method for chamber design.

Studies utilizing selective pharmacological antagonists or targeted gene deletion have demonstrated thattype 5 metabotropic glutamate receptors (mGluR5) are critical mediators and potential therapeutic targets for the treatment of numerous disorders of the central nervous system (CNS), including depression, anxiety, drug addiction, chronic pain, Fragile X syndrome, Parkinson’s disease, and gastroesophageal reflux disease. However, in recent years, the development of positive allosteric modulators (PAMs) of the mGluR5 receptor have revealed that allosteric activation of this receptor may also be of potential therapeutic benefit for the treatment of other CNS disorders, including schizophrenia, cognitive deficits associated with chronic drug use, and deficits in extinction learning. Here we summarize the discovery and characterization of various mGluR5 PAMs, with an emphasis on those that are systemically active. We will also review animal studies showing that these molecules have potential efficacy as novel antipsychotic agents. Finally, we will summarize findings that suggest that mGluR5 PAMs have pro-cognitive effects such as the ability toenhance synaptic plasticity, improve performance in various learning and memory tasks, including extinction of drug-seeking behavior, and reverse cognitive deficits produced by chronic drug use.

Glutamate plays a pivotal role in drug addiction, and the N-methyl-D-aspartate (NMDA) glutamate receptor subtype serves as a molecular target for several drugs of abuse. In this review, we will provide an overview of NMDA receptor structure and function, followed by a review of the mechanism of action, clinical efficacy, and side effect profile of NMDA receptor ligands that are currently in use or being explored for the treatment of drug addiction. These ligands include the NMDA receptor modulators memantine and acamprosate, as well as the partial NMDA agonist D-cycloserine. Data collected to date suggest that direct NMDA receptor modulators have relatively limited efficacy in the treatment of drug addiction, and that partial agonism of NMDA receptors may have some efficacy with regards to extinction learning during cue exposure therapy. However, the lack of consistency in results to date clearly indicates that additional studies are needed, as are studies examining novel ligands with indirect mechanisms for altering NMDA receptor function.

Investigating local-scale interactions within a network makes it possible to test hypotheses about the mechanisms of global network connectivity and to ask whether there are general rules underlying network function across systems. Here we use motif analysis to determine whether the interactions within social insect colonies resemble the patterns exhibited by other animal associations or if they exhibit characteristics of biological regulatory systems. Colonies exhibit a predominance of feed-forward interaction motifs, in contrast to the densely interconnected clique patterns that characterize human interaction and animal social networks. The regulatory motif signature supports the hypothesis that social insect colonies are shaped by selection for network patterns that integrate colony functionality at the group rather than individual level, and demonstrates the utility of this approach for analysis of selection effects on complex systems across biological levels of organization.

We asked how team dynamics can be captured in relation to function by considering games in the first round of the NBA 2010 play-offs as networks. Defining players as nodes and ball movements as links, we analyzed the network properties of degree centrality, clustering, entropy and flow centrality across teams and positions, to characterize the game from a network perspective and to determine whether we can assess differences in team offensive strategy by their network properties. The compiled network structure across teams reflected a fundamental attribute of basketball strategy. They primarily showed a centralized ball distribution pattern with the point guard in a leadership role.

However, individual play-off teams showed variation in their relative involvement of other players/positions in ball distribution, reflected quantitatively by differences in clustering and degree centrality. We also characterized two potential alternate offensive strategies by associated variation in network structure: (1) whether teams consistently moved the ball towards their shooting specialists, measured as “uphill/downhill” flux, and (2) whether they distributed the ball in a way that reduced predictability, measured as team entropy.

These network metrics quantified different aspects of team strategy, with no single metric wholly predictive of success. However, in the context of the 2010 play-offs, the values of clustering (connectedness across players) and network entropy (unpredictability of ball movement) had the most consistent association with team advancement. Our analyses demonstrate the utility of network approaches in quantifying team strategy and show that testable hypotheses can be evaluated using this approach. These analyses also highlight the richness of basketball networks as a dataset for exploring the relationships between network structure and dynamics with team organization and effectiveness.