Loss of Striatonigral GABAergic Presynaptic Inhibition Enables Motor Sensitization in Parkinsonian Mice

SummaryDegeneration of dopamine (DA) neurons in Parkinson’s disease (PD) causes hypokinesia, but DA replacement therapy can elicit exaggerated voluntary and involuntary behaviors that have been attributed to enhanced DA receptor sensitivity in striatal projection neurons. Here we reveal that in hemiparkinsonian mice, striatal D1 receptor-expressing medium spiny neurons (MSNs) directly projecting to the substantia nigra reticulata (SNr) lose tonic presynaptic inhibition by GABAB receptors. The absence of presynaptic GABAB response potentiates evoked GABA release from MSN efferents to the SNr and drives motor sensitization. This alternative mechanism of sensitization suggests a synaptic target for PD pharmacotherapy

Annotated Bibliography of Research in the Teaching of English

Since 2003, RTE has published the annual “Annotated Bibliography of Research in the Teaching of English,” and we are proud to share these curated and annotated citations once again. The goal of the annual bibliography is to offer a synthesis of the research published in the area of English language arts within the past year that may be of interest to RTE readers. Abstracted citations and those featured in the “Other Related Research” sections were published, either in print or online, between June 2019 and June 2020. The bibliography is divided into nine subject area sections. A three-person team of scholars with diverse research interests and background experiences in preK–16 educational settings reviewed and selected the manuscripts for each section using library databases and leading empirical journals. Each team abstracted significant contributions to the body of peer-reviewed studies that addressed the current research questions and concerns in their topic area

Mechanisms of amphetamine action illuminated through optical monitoring of dopamine synaptic vesicles in Drosophila brain

Amphetamines elevate extracellular dopamine, but the underlying mechanisms remain uncertain. Here we show in rodents that acute pharmacological inhibition of the vesicular monoamine transporter (VMAT) blocks amphetamine-induced locomotion and self-administration without impacting cocaine-induced behaviours. To study VMAT’s role in mediating amphetamine action in dopamine neurons, we have used novel genetic, pharmacological and optical approaches in Drosophila melanogaster. In an ex vivo whole-brain preparation, fluorescent reporters of vesicular cargo and of vesicular pH reveal that amphetamine redistributes vesicle contents and diminishes the vesicle pH-gradient responsible for dopamine uptake and retention. This amphetamine-induced deacidification requires VMAT function and results from net H+ antiport by VMAT out of the vesicle lumen coupled to inward amphetamine transport. Amphetamine-induced vesicle deacidification also requires functional dopamine transporter (DAT) at the plasma membrane. Thus, we find that at pharmacologically relevant concentrations, amphetamines must be actively transported by DAT and VMAT in tandem to produce psychostimulant effects

The Mechanistic Classification of Addictive Drugs

The authors review recent research on the molecular mechanisms of addiction and propose a new classification for addictive drugs

Transcriptomic Analysis of Toxoplasma Development Reveals Many Novel Functions and Structures Specific to Sporozoites and Oocysts

Sexual reproduction of Toxoplasma gondii occurs exclusively within enterocytes of the definitive felid host. The resulting immature oocysts are excreted into the environment during defecation, where in the days following, they undergo a complex developmental process. Within each oocyst, this culminates in the generation of two sporocysts, each containing 4 sporozoites. A single felid host is capable of shedding millions of oocysts, which can survive for years in the environment, are resistant to most methods of microbial inactivation during water-treatment and are capable of producing infection in warm-blooded hosts at doses as low as 1–10 ingested oocysts. Despite its extremely interesting developmental biology and crucial role in initiating an infection, almost nothing is known about the oocyst stage beyond morphological descriptions. Here, we present a complete transcriptomic analysis of the oocyst from beginning to end of its development. In addition, and to identify genes whose expression is unique to this developmental form, we compared the transcriptomes of developing oocysts with those of in vitro-derived tachyzoites and in vivo-derived bradyzoites. Our results reveal many genes whose expression is specifically up- or down-regulated in different developmental stages, including many genes that are likely critical to oocyst development, wall formation, resistance to environmental destruction and sporozoite infectivity. Of special note is the up-regulation of genes that appear “off” in tachyzoites and bradyzoites but that encode homologues of proteins known to serve key functions in those asexual stages, including a novel pairing of sporozoite-specific paralogues of AMA1 and RON2, two proteins that have recently been shown to form a crucial bridge during tachyzoite invasion of host cells. This work provides the first in-depth insight into the development and functioning of one of the most important but least studied stages in the Toxoplasma life cycle

Motor neuroplasticity: A MEG-fMRI study of motor imagery and execution in healthy ageing

Age-related decline in motor function is associated with over-activation of the sensorimotor circuitry. Using a multimodal MEG-fMRI paradigm, we investigated whether this neural over-recruitment in old age would be related to changes in movement-related beta desynchronization (MRBD), a correlate of the inhibitory neurotransmitter γ-aminobutyric acid (GABA), and whether it would characterize compensatory recruitment or a reduction in neural specialization (dedifferentiation). We used MEG to assess age-related changes in beta band oscillations in primary motor cortices, fMRI to localize age-related changes in brain activity, and the Finger Configuration Task to measure task performance during overt and covert motor processing: motor execution (ME) and motor imagery (MI). The results are threefold: first, showing age-related neuroplasticity during ME of older adults, compared to young adults, as evidenced by increased MRBD in motor cortices and over-recruitment of sensorimotor areas; second, showing similar age-related neuroplastic changes during MI; and finally, showing signs of dedifferentiation during ME in older adults whose performance negatively correlated with connectivity to bilateral primary motor cortex. Together, these findings demonstrate that elevated MRBD levels, reflecting greater GABAergic inhibitory activity, and over-activation of the sensorimotor network during ME may not be compensatory, but rather might reflect an age-related decline of the quality of the underlying neural signal

Guidelines for the use and interpretation of assays for monitoring autophagy (3rd edition)

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. For example, a key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process versus those that measure fl ux through the autophagy pathway (i.e., the complete process including the amount and rate of cargo sequestered and degraded). In particular, a block in macroautophagy that results in autophagosome accumulation must be differentiated from stimuli that increase autophagic activity, defi ned as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (inmost higher eukaryotes and some protists such as Dictyostelium ) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the fi eld understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. It is worth emphasizing here that lysosomal digestion is a stage of autophagy and evaluating its competence is a crucial part of the evaluation of autophagic flux, or complete autophagy. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. Along these lines, because of the potential for pleiotropic effects due to blocking autophagy through genetic manipulation it is imperative to delete or knock down more than one autophagy-related gene. In addition, some individual Atg proteins, or groups of proteins, are involved in other cellular pathways so not all Atg proteins can be used as a specific marker for an autophagic process. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field

Probing trinitrotoluene (TNT) by low-energy electrons: Strong fragmentation following attachment of electrons near 0 eV

Electron attachmentto gas phase trinitrotoluene (TNT) is studiedbymeansof a crossedelectron-molecular beam experiment at high-energy resolution. TNT shows unique features in the way that electrons right at threshold (near 0 eV) generate both the non-decomposed anion and a variety of anions arising from dissociative electron attachment (DEA). While the parent anion is formed within a very narrowresonance near 0 eV, the DEA reactions extend to higher energies and are operative via several resonant features in the energy range 0–10 eV. They involve remarkably complex reaction sequences associated with multiple bond cleavages and formation of new bonds. By far the dominant DEA reaction generates an ion formed by the loss of a neutral OH radical from the precursor ion. Further strong ion signals arise from the loss of up to three neutral NO units. The remarkable instability of TNT following attachment of electrons with virtually no energy underlines the explosive nature of this compound

Creating a portable data-collection system with Microsoft Embedded Visual Tools for the Pocket PC.

This paper describes an overview and illustrative example for creating a portable data-collection system using Microsoft Embedded Visual Tools for the Pocket PC. A description of the Visual Basic programming language is given, along with examples of computer code procedures for developing data-collection software. Program specifications, strategies for customizing the collection system, and troubleshooting tips are also provided