ASU Scholarship Showcase

Illicit psychostimulant addiction remains a significant problem worldwide, despite decades of research into the neural underpinnings and various treatment approaches. The purpose of this review is to provide a succinct overview of the neurocircuitry involved in drug addiction, as well as the acute and chronic effects of cocaine and amphetamines within this circuitry in humans. Investigational pharmacological treatments for illicit psychostimulant addiction are also reviewed. Our current knowledge base clearly demonstrates that illicit psychostimulants produce lasting adaptive neural and behavioral changes that contribute to the progression and maintenance of addiction. However, attempts at generating pharmacological treatments for psychostimulant addiction have historically focused on intervening at the level of the acute effects of these drugs. The lack of approved pharmacological treatments for psychostimulant addiction highlights the need for new treatment strategies, especially those that prevent or ameliorate the adaptive neural, cognitive, and behavioral changes caused by chronic use of this class of illicit drugs.

Attention deficit/hyperactivity disorder (ADHD) is a risk factor for tobacco use and dependence. This study examines the responsiveness to nicotine of an adolescent model of ADHD, the spontaneously hypertensive rat (SHR). The conditioned place preference (CPP) procedure was used to assess nicotine-induced locomotion and conditioned reward in SHR and the Wistar Kyoto (WKY) control strain over a range of nicotine doses (0.0, 0.1, 0.3 and 0.6 mg/kg). Prior to conditioning, SHRs were more active and less biased toward one side of the CPP chamber than WKY rats. Following conditioning, SHRs developed CPP to the highest dose of nicotine (0.6 mg/kg), whereas WKYs did not develop CPP to any nicotine dose tested. During conditioning, SHRs displayed greater locomotor activity in the nicotine-paired compartment than in the saline-paired compartment across conditioning trials. SHRs that received nicotine (0.1, 0.3, 0.6 mg/kg) in the nicotine-paired compartment showed an increase in locomotor activity between conditioning trials. Nicotine did not significantly affect WKY locomotor activity. These findings suggest that the SHR strain is a suitable model for studying ADHD-related nicotine use and dependence, but highlights potential limitations of the WKY control strain and the CPP procedure for modeling ADHD-related nicotine reward.

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.

The probiotic effects of Lactobacillus reuteri have been speculated to partly depend on its capacity to produce the antimicrobial substance reuterin during the reduction of glycerol in the gut. In this study, the potential of this process to protect human intestinal epithelial cells against infection with Salmonella enterica serovar Typhimurium was investigated. We used a three-dimensional (3-D) organotypic model of human colonic epithelium that was previously validated and applied to study interactions between S. Typhimurium and the intestinal epithelium that lead to enteric salmonellosis. Using this model system, we show that L. reuteri protects the intestinal cells against the early stages of Salmonella infection and that this effect is significantly increased when L. reuteri is stimulated to produce reuterin from glycerol. More specifically, the reuterin-containing ferment of L. reuteri caused a reduction in Salmonella adherence and invasion (1 log unit), and intracellular survival (2 log units). In contrast, the L. reuteri ferment without reuterin stimulated growth of the intracellular Salmonella population with 1 log unit. The short-term exposure to reuterin or the reuterin-containing ferment had no observed negative impact on intestinal epithelial cell health. However, long-term exposure (24 h) induced a complete loss of cell-cell contact within the epithelial aggregates and compromised cell viability. Collectively, these results shed light on a potential role for reuterin in inhibiting Salmonella-induced intestinal infections and may support the combined application of glycerol and L. reuteri. While future in vitro and in vivo studies of reuterin on intestinal health should fine-tune our understanding of the mechanistic effects, in particular in the presence of a complex gut microbiota, this the first report of a reuterin effect on the enteric infection process in any mammalian cell type.

Extra-intestinal pathogenic E. coli (ExPEC), including avian pathogenic E. coli (APEC), pose a considerable threat to both human and animal health, with illness causing substantial economic loss. APEC strain χ7122 (O78∶K80∶H9), containing three large plasmids [pChi7122-1 (IncFIB/FIIA-FIC), pChi7122-2 (IncFII), and pChi7122-3 (IncI₂)]; and a small plasmid pChi7122-4 (ColE2-like), has been used for many years as a model strain to study the molecular mechanisms of ExPEC pathogenicity and zoonotic potential. We previously sequenced and characterized the plasmid pChi7122-1 and determined its importance in systemic APEC infection; however the roles of the other pChi7122 plasmids were still ambiguous. Herein we present the sequence of the remaining pChi7122 plasmids, confirming that pChi7122-2 and pChi7122-3 encode an ABC iron transport system (eitABCD) and a putative type IV fimbriae respectively, whereas pChi7122-4 is a cryptic plasmid. New features were also identified, including a gene cluster on pChi7122-2 that is not present in other E. coli strains but is found in Salmonella serovars and is predicted to encode the sugars catabolic pathways. In vitro evaluation of the APEC χ7122 derivative strains with the three large plasmids, either individually or in combinations, provided new insights into the role of plasmids in biofilm formation, bile and acid tolerance, and the interaction of E. coli strains with 3-D cultures of intestinal epithelial cells. In this study, we show that the nature and combinations of plasmids, as well as the background of the host strains, have an effect on these phenomena. Our data reveal new insights into the role of extra-chromosomal sequences in fitness and diversity of ExPEC in their phenotypes.

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.

Strategies are needed to improve repopulation of decellularized lung scaffolds with stromal and functional epithelial cells. We demonstrate that decellularized mouse lungs recellularized in a dynamic low fluid shear suspension bioreactor, termed the rotating wall vessel (RWV), contained more cells with decreased apoptosis, increased proliferation and enhanced levels of total RNA compared to static recellularization conditions. These results were observed with two relevant mouse cell types: bone marrow-derived mesenchymal stromal (stem) cells (MSCs) and alveolar type II cells (C10). In addition, MSCs cultured in decellularized lungs under static but not bioreactor conditions formed multilayered aggregates. Gene expression and immunohistochemical analyses suggested differentiation of MSCs into collagen I-producing fibroblast-like cells in the bioreactor, indicating enhanced potential for remodeling of the decellularized scaffold matrix. In conclusion, dynamic suspension culture is promising for enhancing repopulation of decellularized lungs, and could contribute to remodeling the extracellular matrix of the scaffolds with subsequent effects on differentiation and functionality of inoculated cells.

We know very little about how soil-borne pollutants such as selenium (Se) can impact pollinators, even though Se has contaminated soils and plants in areas where insect pollination can be critical to the functioning of both agricultural and natural ecosystems. Se can be biotransferred throughout the food web, but few studies have examined its effects on the insects that feed on Se-accumulating plants, particularly pollinators. In laboratory bioassays, we used proboscis extension reflex (PER) and taste perception to determine if the presence of Se affected the gustatory response of honey bee (Apis mellifera L., Hymenoptera: Apidae) foragers. Antennae and proboscises were stimulated with both organic (selenomethionine) and inorganic (selenate) forms of Se that commonly occur in Se-accumulating plants. Methionine was also tested. Each compound was dissolved in 1 M sucrose at 5 concentrations, with sucrose alone as a control. Antennal stimulation with selenomethionine and methionine reduced PER at higher concentrations. Selenate did not reduce gustatory behaviors. Two hours after being fed the treatments, bees were tested for sucrose response threshold. Bees fed selenate responded less to sucrose stimulation. Mortality was higher in bees chronically dosed with selenate compared with a single dose. Selenomethionine did not increase mortality except at the highest concentration. Methionine did not significantly impact survival. Our study has shown that bees fed selenate were less responsive to sucrose, which may lead to a reduction in incoming floral resources needed to support coworkers and larvae in the field. If honey bees forage on nectar containing Se (particularly selenate), reductions in population numbers may occur due to direct toxicity. Given that honey bees are willing to consume food resources containing Se and may not avoid Se compounds in the plant tissues on which they are foraging, they may suffer similar adverse effects as seen in other insect guilds.

Octopamine plays an important role in many behaviors in invertebrates. It acts via binding to G protein coupled receptors located on the plasma membrane of responsive cells. Several distinct subtypes of octopamine receptors have been found in invertebrates, yet little is known about the expression pattern of these different receptor subtypes and how each subtype may contribute to different behaviors. One honey bee (Apis mellifera) octopamine receptor, AmOA1, was recently cloned and characterized. Here we continue to characterize the AmOA1 receptor by investigating its distribution in the honey bee brain. We used two independent antibodies produced against two distinct peptides in the carboxyl-terminus to study the distribution of the AmOA1 receptor in the honey bee brain. We found that both anti-AmOA1 antibodies revealed labeling of cell body clusters throughout the brain and within the following brain neuropils: the antennal lobes; the calyces, pedunculus, vertical (alpha, gamma) and medial (beta) lobes of the mushroom body; the optic lobes; the subesophageal ganglion; and the central complex. Double immunofluorescence staining using anti-GABA and anti-AmOA1 receptor antibodies revealed that a population of inhibitory GABAergic local interneurons in the antennal lobes express the AmOA1 receptor in the cell bodies, axons and their endings in the glomeruli. In the mushroom bodies, AmOA1 receptors are expressed in a subpopulation of inhibitory GABAergic feedback neurons that ends in the visual (outer half of basal ring and collar regions) and olfactory (lip and inner basal ring region) calyx neuropils, as well as in the collar and lip zones of the vertical and medial lobes. The data suggest that one effect of octopamine via AmOA1 in the antennal lobe and mushroom body is to modulate inhibitory neurons.

Neural representations of odors are subject to computations that involve sequentially convergent and divergent anatomical connections across different areas of the brains in both mammals and insects. Furthermore, in both mammals and insects higher order brain areas are connected via feedback connections. In order to understand the transformations and interactions that this connectivity make possible, an ideal experiment would compare neural responses across different, sequential processing levels. Here we present results of recordings from a first order olfactory neuropile – the antennal lobe (AL) – and a higher order multimodal integration and learning center – the mushroom body (MB) – in the honey bee brain. We recorded projection neurons (PN) of the AL and extrinsic neurons (EN) of the MB, which provide the outputs from the two neuropils. Recordings at each level were made in different animals in some experiments and simultaneously in the same animal in others. We presented two odors and their mixture to compare odor response dynamics as well as classification speed and accuracy at each neural processing level. Surprisingly, the EN ensemble significantly starts separating odor stimuli rapidly and before the PN ensemble has reached significant separation. Furthermore the EN ensemble at the MB output reaches a maximum separation of odors between 84–120 ms after odor onset, which is 26 to 133 ms faster than the maximum separation at the AL output ensemble two synapses earlier in processing. It is likely that a subset of very fast PNs, which respond before the ENs, may initiate the rapid EN ensemble response. We suggest therefore that the timing of the EN ensemble activity would allow retroactive integration of its signal into the ongoing computation of the AL via centrifugal feedback.