Heterogeneity and Parsimony in Intertemporal Choice

Behavioral theories of intertemporal choice involve many moving parts. Most descriptive theories model how time delays and rewards are perceived, compared, and/or combined into preferences or utilities. Most behavioral studies neglect to spell out how such constructs translate into heterogeneous observable choices. We consider several broad models of transitive intertemporal preference and combine these with several mathematically formal, yet very general, models of heterogeneity. We evaluate 20 probabilistic models of intertemporal choice using binary choice data from two large-scale experiments. Our analysis documents the interplay between heterogeneity and parsimony in accounting for empirical data: We find evidence for heterogeneity across individuals and across stimulus sets that can be accommodated with transitive models of varying complexity. We do not find systematic violations of transitivity in our data. Future work should continue to tackle the complex trade-off between parsimony and heterogeneity

Kynurenine 3-Monooxygenase Inhibition in Blood Ameliorates Neurodegeneration

SummaryMetabolites in the kynurenine pathway, generated by tryptophan degradation, are thought to play an important role in neurodegenerative disorders, including Alzheimer's and Huntington's diseases. In these disorders, glutamate receptor-mediated excitotoxicity and free radical formation have been correlated with decreased levels of the neuroprotective metabolite kynurenic acid. Here, we describe the synthesis and characterization of JM6, a small-molecule prodrug inhibitor of kynurenine 3-monooxygenase (KMO). Chronic oral administration of JM6 inhibits KMO in the blood, increasing kynurenic acid levels and reducing extracellular glutamate in the brain. In a transgenic mouse model of Alzheimer's disease, JM6 prevents spatial memory deficits, anxiety-related behavior, and synaptic loss. JM6 also extends life span, prevents synaptic loss, and decreases microglial activation in a mouse model of Huntington's disease. These findings support a critical link between tryptophan metabolism in the blood and neurodegeneration, and they provide a foundation for treatment of neurodegenerative diseases

Adaptive and Behavioral Changes in Kynurenine 3-Monooxygenase Knockout Mice:Relevance to Psychotic Disorders

BACKGROUND: Kynurenine 3-monooxygenase converts kynurenine to 3-hydroxykynurenine, and its inhibition shunts the kynurenine pathway-which is implicated as dysfunctional in various psychiatric disorders-toward enhanced synthesis of kynurenic acid, an antagonist of both α7 nicotinic acetylcholine and N-methyl-D-aspartate receptors. Possibly as a result of reduced kynurenine 3-monooxygenase activity, elevated central nervous system levels of kynurenic acid have been found in patients with psychotic disorders, including schizophrenia. METHODS: In the present study, we investigated adaptive-and possibly regulatory-changes in mice with a targeted deletion of Kmo (Kmo-/-) and characterized the kynurenine 3-monooxygenase-deficient mice using six behavioral assays relevant for the study of schizophrenia. RESULTS: Genome-wide differential gene expression analyses in the cerebral cortex and cerebellum of these mice identified a network of schizophrenia- and psychosis-related genes, with more pronounced alterations in cerebellar tissue. Kynurenic acid levels were also increased in these brain regions in Kmo-/- mice, with significantly higher levels in the cerebellum than in the cerebrum. Kmo-/- mice exhibited impairments in contextual memory and spent less time than did controls interacting with an unfamiliar mouse in a social interaction paradigm. The mutant animals displayed increased anxiety-like behavior in the elevated plus maze and in a light/dark box. After a D-amphetamine challenge (5 mg/kg, intraperitoneal), Kmo-/- mice showed potentiated horizontal activity in the open field paradigm. CONCLUSIONS: Taken together, these results demonstrate that the elimination of Kmo in mice is associated with multiple gene and functional alterations that appear to duplicate aspects of the psychopathology of several neuropsychiatric disorders

Essential control of the function of the striatopallidal neuron by pre-coupled complexes of adenosine A2A-dopamine D2 receptor heterotetramers and adenylyl cyclase

The central adenosine system and adenosine receptors play a fundamental role in the modulation of dopaminergic neurotransmission. This is mostly achieved by the strategic co-localization of different adenosine and dopamine receptor subtypes in the two populations of striatal efferent neurons, striatonigral and striatopallidal, that give rise to the direct and indirect striatal efferent pathways, respectively. With optogenetic techniques it has been possible to dissect a differential role of the direct and indirect pathways in mediating 'Go' responses upon exposure to reward-related stimuli and 'NoGo' responses upon exposure to non-rewarded or aversive-related stimuli, respectively, which depends on their different connecting output structures and their differential expression of dopamine and adenosine receptor subtypes. The striatopallidal neuron selectively expresses dopamine D2 receptors (D2R) and adenosine A2A receptors (A2AR), and numerous experiments using multiple genetic and pharmacological in vitro, in situ and in vivo approaches, demonstrate they can form A2AR-D2R heteromers. It was initially assumed that different pharmacological interactions between dopamine and adenosine receptor ligands indicated the existence of different subpopulations of A2AR and D2R in the striatopallidal neuron. However, as elaborated in the present essay, most evidence now indicates that all interactions can be explained with a predominant population of striatal A2AR-D2R heteromers forming complexes with adenylyl cyclase subtype 5 (AC5). The A2AR-D2R heteromer has a tetrameric structure, with two homodimers, which allows not only multiple allosteric interactions between different orthosteric ligands, agonists, and antagonists, but also the canonical Gs-Gi antagonistic interaction at the level of AC5. We present a model of the function of the A2AR-D2R heterotetramer-AC5 complex, which acts as an integrative device of adenosine and dopamine signals that determine the excitability and gene expression of the striatopallidal neurons. The model can explain most behavioral effects of A2AR and D2R ligands, including the psychostimulant effects of caffeine. The model is also discussed in the context of different functional striatal compartments, mainly the dorsal and the ventral striatum. The current accumulated knowledge of the biochemical properties of the A2AR-D2R heterotetramer-AC5 complex offers new therapeutic possibilities for Parkinson's disease, schizophrenia, SUD and other neuropsychiatric disorders with dysfunction of dorsal or ventral striatopallidal neurons

Charakterisierung des frühen endosomalen SNARE Komplexes

SNARE Proteine sind wichtige Faktoren in Membranfusion. Diese Proteine sitzen in gegenüberliegenden Lipid-doppelschichten und bilden vier-helix coiled-coil Komplexe, die je ein Qa-, Qb-, Qc- und ein R-SNARE enthalten. Die Ausbildung des SNARE Komplexes fusioniert die Membranen. Syntaxin 13, vti1a, syntaxin 6 and VAMP4 sind als die SNARE Proteine identifiziert worden, die die Fusion von frühen Endosomen vermitteln. Der Kern-Komplex wurde aufgereinigt und biochemisch und biophysikalisch charakterisiert. Die Kristallstruktur wurde mit einer Auflösung von 2.7Å gelöst. Der Komplex zeigt hohe Übereinstimmung mit dem neuronalen und späten endosomalen SNARE Komplex in Bezug auf die Thermostabilität, biochemisches Verhalten und Struktur. Proteoliposomen, die diese Proteine enthalten, fusionieren schneller als Liposomen mit den neuronalen SNAREs. Die Fusion kann mit löslichen Fragmenten der Proteine in einer konzentrationsabhängigen Weise inhibiert werden. Verwandte und auch nicht verwandte R-SNAREs inhibieren die Liposomenfusion. Liposomen die nicht-verwandte R-SNAREs enthalten fusionieren mit den frühen endosomalen Q-SNARE-liposomen und zeigen daher ein promiskes Verhalten. Dies wurde nicht gezeigt in einem zellfreien, mikroskopischen Assay mit PC12 frühen Endosomen, in dem die löslichen Fragmente nur der frühen endosomalen SNAREs starke und spezifische Inhibierung zeigten

Heterogeneity and Parsimony in Intertemporal Choice

Behavioral theories of intertemporal choice involve many moving parts. Most descriptive theories model how time delays and rewards are perceived, compared, and/or combined into preferences or utilities. Most behavioral studies neglect to spell out how such constructs translate into heterogeneous observable choices. We consider several broad models of transitive intertemporal preference and combine these with several mathematically formal, yet very general, models of heterogeneity. We evaluate 20 probabilistic models of intertemporal choice using binary choice data from two large-scale experiments. Our analysis documents the interplay between heterogeneity and parsimony in accounting for empirical data: We find evidence for heterogeneity across individuals and across stimulus sets that can be accommodated with transitive models of varying complexity. We do not find systematic violations of transitivity in our data. Future work should continue to tackle the complex trade-off between parsimony and heterogeneity

Homotypic fusion of early endosomes: SNAREs do not determine fusion specificity

Membrane fusion in the secretory pathway is mediated by soluble N-ethylmaleimide-sensitive factor attachment receptor (SNARE) proteins. Different fusion steps are thought to be effected by independent sets of SNAREs, but it is unclear whether specificity is determined by an intrinsic specificity of SNARE pairing or by upstream factors. Using a newly developed microscopy-based assay, we have investigated the SNARE specificity of homotypic early endosomal fusion. We show that early endosomes contain multiple sets of SNAREs, including, in addition to the putative early endosomal SNAREs, those involved in exocytosis and in fusion of late endosomes. We demonstrate that fusion is largely mediated by a complex formed by syntaxin 13, syntaxin 6, vti1a, and VAMP4, whereas the exocytic and late endosomal SNAREs play little or no role in the reaction. In contrast, proteoliposomes reconstituted with early endosomal SNAREs promiscuously fuse with liposomes containing exocytotic or late endosomal SNAREs. We conclude that the specificity of SNARE pairing does not suffice to determine the specificity of organelle fusion

Structure and physicochemistry of anodic oxide films on titanium and TA6V alloy

International audienceAnodization of titanium and its alloys is an important surface treatment, especially for adhesion applications, but is not as well studied as for aluminium alloys. This paper deals with the morphological, structural and physicochemical characterization of anodic oxide films grown on titanium and Ti-6Al-4V (TA6V) in chromic acid solution without (CA) or with (CA/HF) hydrofluoric acid addition, Several investigations methods are used: high-resolution scanning electron microscopy (HR-SEM), reflection high-energy electron diffraction (RHEED), x-ray photoelectron spectroscopy (XPS), secondary ion mass spectrometry (SIMS), nuclear reaction analysis (NRA) and wetting angle measurements. The occurrence and morphology of the nanoporous structure for CA/HF anodization are described. The compact films grown in CA solution are amorphous and the porous films grown in the CA/HF solution are partially crystalline. The thickness and morphology of the films are described and discussed as a function of the anodizing conditions and of the composition of the underlying substrate. The composition of the film appears to be TiO2 + Al2O3 (with Ti/Al atomic ratio similar to 5), with incorporation of fluorine from the solution in the porous films and of small quantities of vanadium in the films that are grown. The specific role played by the Cr(VI) and F species on the film growth-and-dissolution formation process is discussed and a growth mechanism is proposed

Hilar GABAergic interneuron activity controls spatial learning and memory retrieval.

Although extensive research has demonstrated the importance of excitatory granule neurons in the dentate gyrus of the hippocampus in normal learning and memory and in the pathogenesis of amnesia in Alzheimer's disease (AD), the role of hilar GABAergic inhibitory interneurons, which control the granule neuron activity, remains unclear.We explored the function of hilar GABAergic interneurons in spatial learning and memory by inhibiting their activity through Cre-dependent viral expression of enhanced halorhodopsin (eNpHR3.0)--a light-driven chloride pump. Hilar GABAergic interneuron-specific expression of eNpHR3.0 was achieved by bilaterally injecting adeno-associated virus containing a double-floxed inverted open-reading frame encoding eNpHR3.0 into the hilus of the dentate gyrus of mice expressing Cre recombinase under the control of an enhancer specific for GABAergic interneurons. In vitro and in vivo illumination with a yellow laser elicited inhibition of hilar GABAergic interneurons and consequent activation of dentate granule neurons, without affecting pyramidal neurons in the CA3 and CA1 regions of the hippocampus. We found that optogenetic inhibition of hilar GABAergic interneuron activity impaired spatial learning and memory retrieval, without affecting memory retention, as determined in the Morris water maze test. Importantly, optogenetic inhibition of hilar GABAergic interneuron activity did not alter short-term working memory, motor coordination, or exploratory activity.Our findings establish a critical role for hilar GABAergic interneuron activity in controlling spatial learning and memory retrieval and provide evidence for the potential contribution of GABAergic interneuron impairment to the pathogenesis of amnesia in AD