Exposure to psychostimulants results in structural and synaptic plasticity in striatal medium spiny neurons (MSNs). These cellular adaptations arise from alterations in genes that are highly implicated in the rearrangement of the actin-cytoskeleton, such as T-lymphoma invasion and metastasis 1 (Tiam1). Previous studies have demonstrated a crucial role for dopamine receptor 1 (D1)-containing striatal MSNs in mediating psychostimulant induced plasticity changes. These D1-MSNs in the nucleus accumbens (NAc) positively regulate drug seeking, reward, and locomotor behavioral effects as well as the morphological adaptations of psychostimulant drugs. Here, we demonstrate that rats that actively self-administer cocaine display reduced levels of Tiam1 in the NAc. To further examine the cell type-specific contribution to these changes in Tiam1 we used optogenetics to selectively manipulate NAc D1-MSNs or dopamine receptor 2 (D2) expressing MSNs. We find that repeated channelrhodopsin-2 activation of D1-MSNs but not D2-MSNs caused a down-regulation of Tiam1 levels similar to the effects of cocaine. Further, activation of D2-MSNs, which caused a late blunted cocaine-mediated locomotor behavioral response, did not alter Tiam1 levels. We then examined the contribution of D1-MSNs to the cocaine-mediated decrease of Tiam1. Using the light activated chloride pump, eNpHR3.0 (enhanced Natronomonas pharaonis halorhodopsin 3.0), we selectively inhibited D1-MSNs during cocaine exposure, which resulted in a behavioral blockade of cocaine-induced locomotor sensitization. Moreover, inhibiting these NAc D1-MSNs during cocaine exposure reversed the down-regulation of Tiam1 gene expression and protein levels. These data demonstrate that altering activity in specific neural circuits with optogenetics can impact the underlying molecular substrates of psychostimulant-mediated behavior and function.
Abstract Isolation of cell populations is untangling complex biological interactions, but studies comparing methodologies lack in vivo complexity and draw limited conclusions about the types of transcripts identified by each technique. Furthermore, few studies compare FACS-based techniques to ribosomal affinity purification, and none do so genome-wide. We addressed this gap by systematically comparing nuclear-FACS, whole cell-FACS, and RiboTag affinity purification in the context of D1 or D2 dopamine receptor-expressing medium spiny neuron (MSN) subtypes of the nucleus accumbens (NAc), a key brain reward region. We find that nuclear-FACS-seq generates a substantially longer list of differentially expressed genes between these cell types, and a significantly larger number of neuropsychiatric GWAS hits than the other two methods. RiboTag-seq has much lower coverage of the transcriptome than the other methods, but very efficiently distinguishes D1- and D2-MSNs. We also demonstrate differences between D1- and D2-MSNs with respect to RNA localization, suggesting fundamental cell type differences in mechanisms of transcriptional regulation and subcellular transport of RNAs. Together, these findings guide the field in selecting the RNAseq method that best suits the scientific questions under investigation.
This paper examines the views of Adam Smith, Allyn Young and Amartya Sen on the role of the state. Smith has been widely interpreted as advocating non-interference in economic matters with the state confining itself to three basic tasks of defence, justice and public works. However, this traditional view gives a misleading impression that Smith was a champion of laissez faire. We examine and develop Young's contention that the main message from Wealth of Nations is not laissez faire but competition. Interpreted thus, a more active role for government is consistent with Smith. Young favoured neither laissez faire nor excessive intervention, but viewed the role of the state in the context of the stage of a society's development. Amartya Sen's stress on entitlements is also consistent with Smith's stress on distributive justice and the Smith-Young emphasis on the public interest (or communal welfare). The more recent approaches to development such as political entanglement and complexity economics view the dichotomy of state versus market as false as both have to join hands in the coevolution of appropriate institutions to solve communal problems of economic life.
Tao is a system that optimizes the execution of unit tests in large software programs and reduces the programmer wait time from minutes to seconds. Tao is based on two key ideas: First, Tao focuses on efficiency, unlike past work that focused on avoiding false negatives. Tao implements simple and fast function-level dependency tracking that identifies tests to run on a code change; any false negatives missed by this dependency tracking are caught by running the entire test suite on a test server once the code change is committed. Second, to make it easy for programmers to adopt Tao, it incorporates the dependency information into the source code repository. This paper describes an early prototype of Tao and demonstrates that Tao can reduce unit test execution time in two large Python software projects by over 96% while incurring few false negatives.
This chapter briefly discusses Young's life and times, his personality and the scheme of the book. Young emerges as the central figure of American economics in the early decades of the twentieth century. His fingerprints are everywhere—as an inspiring teacher, institution builder and a devoted public servant—but modern interest in him is more due to his contribution to economic thought than to the economics profession. Young was a profound thinker, had a wide range and had mastered the whole literature of economics. He appreciated opposed schools of thought for economic truth for him was not the monopoly of a single school. For him economics had an instrumental value which helped solve communal problems of economic life.
Quality control applications sometimes require one to obtain tolerance intervals for Poisson or binomial variables. Situations of this type are described and the construction of the desired interval is shown. This involves the combination of probability intervals and confidence intervals.
Summary Opioid discontinuation generates a withdrawal syndrome marked by a negative emotional state. Increased anxiety and dysphoria during opioid discontinuation are a significant barrier to achieving long-term abstinence in opioid-dependent individuals. Adaptations in brain-reward circuitry are implicated in the opioid abstinence syndrome, but current knowledge is limited to changes following natural and semi-synthetic opioids. Here we report abstinence from the synthetic opioid fentanyl engenders structural, functional, and molecular plasticity in nucleus accumbens neuron subtypes (MSNs) that mediate negative emotional behaviors. We show fentanyl abstinence causes dendritic atrophy and increased excitatory drive exclusive to D1-receptor containing MSNs. Using subtype specific RNAseq and Weighted Gene Co-Expression Network Analysis, we identified molecular signatures of fentanyl abstinence in MSN subtypes. We found a network of co-expressed genes downregulated selectively in D1-MSNs, and transcriptionally co-regulated by E2F1. We show targeting abstinence-induced molecular changes protects D1-MSNs from maladaptive plasticity and alleviates negative emotional behaviors after fentanyl abstinence.
Click to increase image sizeClick to decrease image size Notes 1In a letter to his PhD student Frank Knight, Young expressed the view that ‘increasing returns do not exhibit themselves adequately when approached from the point of equilibrium price theory.’ He further stated that he was abandoning equilibrium analysis for increasing returns. See Blitch (Citation1995, p. 170). 2‘Most of the advantages of increasing returns can be had in an industry that is not consolidated—such, in fact, is the typical modern industry. Take the cotton industry. It depends on industries manufacturing machinery, dye-stuffs, etc, railways. The advantages of consolidation are not, generally speaking, those of increasing returns’ (Young, Citation1990, p. 54). 3‘The commercial revolution preceded the industrial revolution, for with the growth of trade industrial specialisation became advantageous. The new industrial and economic situation led to inventions, not vice versa’ (Young, Citation1990, p. 18). 4In Young, the long-run supply and demand curves are downward-sloping, nearly approximating each other. Smith argued, analogously, that ‘The increase in demand … though in the beginning may sometimes raise the price of goods, never fails to lower it in the long run’ (Smith Citation1776, pp. 271–272). 5Young (Citation1928, p. 531) emphasized that ‘the principal economies which manifest themselves in increasing returns are the economies of capitalistic or roundabout methods.’ Naturally, therefore, a growing economy accumulates a larger and larger stock of fixed capital. But Grieve misses the point that if this capital is introduced by a larger and larger number of increasingly specialized enterprises (when it pays to do so) the average size of the firms' fixed capital does not necessarily increase. Young himself drew two implications. First, we may miss these economies ‘if we try to make of large-scale production (in the sense of production by large firms and industries), as contrasted with large production, any more than an incident in the general process by which increasing returns are secured and if accordingly we look too much at the individual firm or even … at the individual industry’ (Young's italics). Secondly, ‘the economies of roundabout methods, even more than the economies of other forms of the division of labour, depend upon the extent of the market…’ (italics added). 6Grieve strangely attributes to us the term ‘external economies of scale’ as an explanation for increasing returns. We never used the term in our 2006 paper. Wherever we use the term ‘external economies’ we largely mean pecuniary external economies, which are the most relevant for development. 7See, for example, Viner Citation(1928) for a long list of functions that the state could legitimately perform in the Smithean system.
A spotlight was directed by Laidler and Sandilands (2002) on the neglected 1932 Harvard memorandum (by Lauchlin Currie, Paul Theodore Ellsworth and Harry Dexter White). They interpret the memorandum as advocating fiscal inflationism as opposed to Keynesian fiscalism in tackling the Great Depression. While the former involves the creation of new money, the latter can operate independently of new money. This paper goes beyond this interpretation of the memorandum and argues the following: (i) the memorandum emphasises recovery in a manner which does not lose sight of secular growth; (ii) it does not take an isolationist position on the US depression but views it as a part of the broader international calamity; (iii) the memorandum appears at odds with the post-1936 notion of the liquidity trap and the consequent ineffectiveness of monetary policy and (iv) is aware of the various intricacies involved in expanding the money supply. In brief, the memorandum is an elegant piece of writing which displays a good understanding of the nuts and bolts of the money-supply process.
