bluuebunny/crossref_metadata_2025_split huggingface dataset:
Modulation of Premotor and Primary Motor Cortical Activity during Volitional Adjustments of Speed-Accuracy Trade-Offs
Authors: Thura David , Cisek Paul 
Published: January 2016

Recent work suggests that while animals decide between reaching actions, neurons in dorsal premotor (PMd) and primary motor (M1) cortex reflect a dynamic competition between motor plans and determine when commitment to a choice is made. This competition is biased by at least two sources of information: the changing sensory evidence for one choice versus another, and an urgency signal that grows over time. Here, we test the hypothesis that the urgency signal adjusts the trade-off between speed and accuracy during both decision-making and movement execution. Two monkeys performed a reaching decision task in which sensory evidence continuously evolves over the course of each trial. In different blocks, task timing parameters encouraged monkeys to voluntarily adapt their behavior to be either hasty or conservative. Consistent with our hypothesis, during the deliberation process the baseline and gain of neural activity in decision-related PMd (29%) and M1 cells (45%) was higher when monkeys applied a hasty policy than when they behaved conservatively, but at the time of commitment the population activity was similar across blocks. Other cells (30% in PMd, 30% in M1) showed activity that increased or decreased with elapsing time until the moment of commitment. Movement-related neurons were also more active after longer decisions, as if they were influenced by the same urgency signal controlling the gain of decision-related activity. Together, these results suggest that the arm motor system receives an urgency/vigor signal that adjusts the speed-accuracy trade-off for decision-making and movement execution.SIGNIFICANCE STATEMENTThis work addresses the neural mechanisms that control the speed-accuracy trade-off in both decisions and movements, in the kinds of dynamic situations that are typical of natural animal behavior. We found that many “decision-related” premotor and motor neurons are modulated in a time-dependent manner compatible with an “urgency” signal that changes between hasty and conservative decision policies. We also found that such modulation influenced cells related to the speed of the reaching movements executed by the animals to report their decisions. These results suggest that a unified mechanism determines speed-accuracy trade-off adjustments during decision-making and movement execution, potentially influencing both the cognitive and motor aspects of reward-oriented behavior.
Intrinsic Functional Connectivity in the Adult Brain and Success in Second-Language Learning
Authors: Chai Xiaoqian J. , Berken Jonathan A. , Barbeau Elise B. , Soles Jennika , Callahan Megan , Chen Jen-Kai , Klein Denise 
Published: January 2016

There is considerable variability in an individual's ability to acquire a second language (L2) during adulthood. Using resting-state fMRI data acquired before training in English speakers who underwent a 12 week intensive French immersion training course, we investigated whether individual differences in intrinsic resting-state functional connectivity relate to a person's ability to acquire an L2. We focused on two key aspects of language processing—lexical retrieval in spontaneous speech and reading speed—and computed whole-brain functional connectivity from two regions of interest in the language network, namely the left anterior insula/frontal operculum (AI/FO) and the visual word form area (VWFA). Connectivity between the left AI/FO and left posterior superior temporal gyrus (STG) and between the left AI/FO and dorsal anterior cingulate cortex correlated positively with improvement in L2 lexical retrieval in spontaneous speech. Connectivity between the VWFA and left mid-STG correlated positively with improvement in L2 reading speed. These findings are consistent with the different language functions subserved by subcomponents of the language network and suggest that the human capacity to learn an L2 can be predicted by an individual's intrinsic functional connectivity within the language network.SIGNIFICANCE STATEMENTThere is considerable variability in second-language learning abilities during adulthood. We investigated whether individual differences in intrinsic functional connectivity in the adult brain relate to success in second-language learning, using resting-state functional magnetic resonance imaging in English speakers who underwent a 12 week intensive French immersion training course. We found that pretraining functional connectivity within two different language subnetworks correlated strongly with learning outcome in two different language skills: lexical retrieval in spontaneous speech and reading speed. Our results suggest that the human capacity to learn a second language can be predicted by an individual's intrinsic functional connectivity within the language network.
The First Alcohol Drink Triggers mTORC1-Dependent Synaptic Plasticity in Nucleus Accumbens Dopamine D1 Receptor Neurons
Authors: Beckley Jacob T. , Laguesse Sophie , Phamluong Khanhky , Morisot Nadege , Wegner Scott A. , Ron Dorit 
Published: January 2016

Early binge-like alcohol drinking may promote the development of hazardous intake. However, the enduring cellular alterations following the first experience with alcohol consumption are not fully understood. We found that the first binge-drinking alcohol session produced enduring enhancement of excitatory synaptic transmission onto dopamine D1 receptor-expressing neurons (D1+ neurons) in the nucleus accumbens (NAc) shell but not the core in mice, which required D1 receptors (D1Rs) and mechanistic target of rapamycin complex 1 (mTORC1). Furthermore, inhibition of mTORC1 activity during the first alcohol drinking session reduced alcohol consumption and preference of a subsequent drinking session. mTORC1 is critically involved in RNA-to-protein translation, and we found that the first alcohol session rapidly activated mTORC1 in NAc shell D1+ neurons and increased synaptic expression of the AMPAR subunit GluA1 and the scaffolding protein Homer. Finally, D1R stimulation alone was sufficient to activate mTORC1 in the NAc to promote mTORC1-dependent translation of the synaptic proteins GluA1 and Homer. Together, our results indicate that the first alcohol drinking session induces synaptic plasticity in NAc D1+ neurons via enhanced mTORC1-dependent translation of proteins involved in excitatory synaptic transmission that in turn drives the reinforcement learning associated with the first alcohol experience. Thus, the alcohol-dependent D1R/mTORC1-mediated increase in synaptic function in the NAc may reflect a neural imprint of alcohol's reinforcing properties, which could promote subsequent alcohol intake.SIGNIFICANCE STATEMENTConsuming alcohol for the first time is a learning event that drives further drinking. Here, we identified a mechanism that may underlie the reinforcing learning associated with the initial alcohol experience. We show that the first alcohol experience induces a persistent enhancement of excitatory synaptic transmission on NAc shell D1+ neurons, which is dependent on D1R and mTORC1. We also find that mTORC1 is necessary for the sustained alcohol consumption and preference across the initial drinking sessions. The first alcohol binge activates mTORC1 in NAc D1+ neurons and increases levels of synaptic proteins involved in glutamatergic signaling. Thus, the D1R/mTORC1-dependent plasticity following the first alcohol exposure may be a critical cellular component of reinforcement learning.
Manipulating Decisiveness in Decision Making: Effects of Clonidine on Hippocampal Search Strategies
Authors: Amemiya Seiichiro , Redish A. David 
Published: January 2016

Decisiveness is the ability to commit to a decision quickly and efficiently; in contrast, indecision entails the repeated consideration of multiple alternative possibilities. In humans, the α2-adrenergic receptor agonist clonidine increases decisiveness in tasks that require planning through unknown neural mechanisms. In rats, indecision is manifested as reorienting behaviors at choice points (vicarious trial and error [VTE]), during which hippocampal representations alternate between prospective options. To determine whether the increase in decisiveness driven by clonidine also entails changes in hippocampal search processes, we compared the effect of clonidine on spatial representations in hippocampal neural ensembles as rats passed through a T-shaped decision point. Consistent with previous experiments, hippocampal representations reflected both chosen and unchosen paths during VTE events under saline control conditions. Also, consistent with previous experiments, hippocampal representations reflected the chosen path more than the unchosen path when the animal did not show VTE at the choice point. Injection of clonidine suppressed the spatial representation of the unchosen path at the choice point on VTE laps and hastened the differentiation of spatial representations of the chosen path from the unchosen path on non-VTE laps to appear before reaching the choice point. These results suggest that the decisiveness seen under clonidine is due to limited exploration of potential options in hippocampus, and suggest novel roles for noradrenaline as a modulator of the hippocampal search processes.SIGNIFICANCE STATEMENTClonidine, an α2-adrenergic receptor agonist, which decreases the level of noradrenalinein vivo, has an interesting effect in humans and other animals: it makes them more decisive. However, the mechanisms by which clonidine makes them more decisive remain unknown. Researchers have speculated that clonidine limits the amount of mental search that subjects do when planning options. We test this hypothesis by measuring the mental search strategy in rats through hippocampal recordings. We find that clonidine limits the options searched by rats, suggesting that noradrenaline also plays a role in balancing exploration and exploitation in internally simulated behaviors, similar to its role in balancing exploration and exploitation in external behaviors.
Local Control of Extracellular Dopamine Levels in the Medial Nucleus Accumbens by a Glutamatergic Projection from the Infralimbic Cortex
Authors: Quiroz César , Orrú Marco , Rea William , Ciudad-Roberts Andrés , Yepes Gabriel , Britt Jonathan P. , Ferré Sergi 
Published: January 2016

It is generally assumed that infralimbic cortex (ILC) and prelimbic cortex, two adjacent areas of the medial prefrontal cortex (mPFC) in rodents, provide selective excitatory glutamatergic inputs to the nucleus accumbens (NAc) shell and core, respectively. It is also generally believed that mPFC influences the extracellular levels of dopamine in the NAc primarily by an excitatory collateral to the ventral tegmental area (VTA). In the present study, we first established the existence of a selective functional connection between ILC and the posteromedial portions of the VTA (pmVTA) and the mNAc shell (pmNAc shell), by measuring striatal neuronal activation (immunohistochemical analysis of ERK1/2 phosphorylation) and glutamate release (in vivomicrodialysis) upon ILC electrical stimulation. A novel optogenetic-microdialysis approach allowed the measurement of extracellular concentrations of glutamate and dopamine in the pmNAc shell upon local light-induced stimulation of glutamatergic terminals from ILC. Cortical electrical and local optogenetic stimulation produced significant increases in the extracellular concentrations of glutamate and dopamine in the pmNAc shell. Local blockade of glutamate release by perfusion of an adenosine A2Areceptor antagonist in the pmNAc shell blocked the dopamine release induced by local optogenetic stimulation but only partially antagonized dopamine release induced by cortical electrical stimulation. The results demonstrate that ILC excitatory afferents directly modulate the extracellular concentration of dopamine in the pmNAc shell, but also support the involvement of an indirect mechanism of dopamine control, through a concomitant ILC-mediated activation of the pmVTA.SIGNIFICANCE STATEMENTWe established the existence of a functional connection between the infralimbic cortex (ILC) and the posteromedial portions of the ventral tegmental area (pmVTA) and the medial nucleus acumbens shell (pmNAc shell). A novel optogenetic-microdialysis approach allowed us to demonstrate that local glutamate release from glutamatergic terminals from the ILC exert a significant modulation of extracellular concentration of dopamine in the pmNAc shell. This mechanism provides the frame for a selective cortical-mediated tonic dopaminergic modulation of specific striatal compartments.
Mechanostimulation Promotes Nuclear and Epigenetic Changes in Oligodendrocytes
Authors: Hernandez Marylens , Patzig Julia , Mayoral Sonia R. , Costa Kevin D. , Chan Jonah R. , Casaccia Patrizia 
Published: January 2016

Oligodendrocyte progenitors respond to biophysical or mechanical signals, and it has been reported that mechanostimulation modulates cell proliferation, migration, and differentiation. Here we report the effect of three mechanical stimuli on mouse oligodendrocyte progenitor differentiation and identify the molecular components of the linker of nucleoskeleton and cytoskeleton (LINC) complex (i.e., SYNE1) as transducers of mechanical signals to the nucleus, where they modulate the deposition of repressive histone marks and heterochromatin formation. The expression levels of LINC components increased during progenitor differentiation and silencing theSyne1gene resulted in aberrant histone marks deposition, chromatin reorganization and impaired myelination. We conclude that spatial constraints, via the actin cytoskeleton and LINC complex, mediate nuclear changes in oligodendrocyte progenitors that favor a default pathway of differentiation.SIGNIFICANCE STATEMENTIt is recognized that oligodendrocyte progenitors are mechanosensitive cells. However, the molecular mechanisms translating mechanical stimuli into oligodendrocyte differentiation remain elusive. This study identifies components of the mechanotransduction pathway in the oligodendrocyte lineage.
Pathological Tau Promotes Neuronal Damage by Impairing Ribosomal Function and Decreasing Protein Synthesis
Authors: Meier Shelby , Bell Michelle , Lyons Danielle N. , Rodriguez-Rivera Jennifer , Ingram Alexandria , Fontaine Sarah N. , Mechas Elizabeth , Chen Jing , Wolozin Benjamin , LeVine Harry , Zhu Haining , Abisambra Jose F. 
Published: January 2016

One of the most common symptoms of Alzheimer's disease (AD) and related tauopathies is memory loss. The exact mechanisms leading to memory loss in tauopathies are not yet known; however, decreased translation due to ribosomal dysfunction has been implicated as a part of this process. Here we use a proteomics approach that incorporates subcellular fractionation and coimmunoprecipitation of tau from human AD and non-demented control brains to identify novel interactions between tau and the endoplasmic reticulum (ER). We show that ribosomes associate more closely with tau in AD than with tau in control brains, and that this abnormal association leads to a decrease in RNA translation. The aberrant tau–ribosome association also impaired synthesis of the synaptic protein PSD-95, suggesting that this phenomenon contributes to synaptic dysfunction. These findings provide novel information about tau-protein interactions in human brains, and they describe, for the first time, a dysfunctional consequence of tau–ribosome associations that directly alters protein synthesis.SIGNIFICANCE STATEMENTDespite the identification of abnormal tau–ribosomal interactions in tauopathies >25 years ago, the consequences of this association remained elusive until now. Here, we show that pathological tau associates closely with ribosomes in AD brains, and that this interaction impairs protein synthesis. The overall result is a stark reduction of nascent proteins, including those that participate in synaptic plasticity, which is crucial for learning and memory. These data mechanistically link a common pathologic sign, such as the appearance of pathological tau inside brain cells, with cognitive impairments evident in virtually all tauopathies.
Estrogen Restores Multisynaptic Boutons in the Dorsolateral Prefrontal Cortex while Promoting Working Memory in Aged Rhesus Monkeys
Authors: Hara Yuko , Yuk Frank , Puri Rishi , Janssen William G. M. , Rapp Peter R. , Morrison John H. 
Published: January 2016

Humans and nonhuman primates are vulnerable to age- and menopause- related decline in working memory, a cognitive function reliant on area 46 of the dorsolateral prefrontal cortex (dlPFC). We showed previously that presynaptic mitochondrial number and morphology in monkey dlPFC neurons correlate with working memory performance. The current study tested the hypothesis that the types of synaptic connections these boutons form are altered with aging and menopause in rhesus monkeys and that these metrics may be coupled with mitochondrial measures and working memory. Using serial section electron microscopy, we examined the frequencies and characteristics of nonsynaptic, single-synaptic, and multisynaptic boutons (MSBs) in the dlPFC. In contrast to our previous observations in the monkey hippocampal dentate gyrus, where MSBs comprised ∼40% of boutons, the vast majority of dlPFC boutons were single-synaptic, whereas MSBs constituted a mere 10%. The frequency of MSBs was not altered by normal aging, but decreased by over 50% with surgical menopause induced by ovariectomy in aged monkeys. Cyclic estradiol treatment in aged ovariectomized animals restored MSB frequencies to levels comparable to young and aged premenopausal monkeys. Notably, the frequency of MSBs positively correlated with working memory scores, as measured by the average accuracy on the delayed response (DR) test. Furthermore, MSB incidence positively correlated with the number of healthy straight mitochondria in dlPFC boutons and inversely correlated with the number of pathological donut-shaped mitochondria. Together, our data suggest that MSBs are coupled to cognitive function and mitochondrial health and are sensitive to estrogen.SIGNIFICANCE STATEMENTMany aged menopausal individuals experience deficits in working memory, an executive function reliant on recurrent firing of prefrontal cortex (PFC) neurons. However, little is known about the organization of presynaptic inputs to these neurons and how they may be altered with aging and menopause. Multisynaptic boutons (MSBs) were of particular interest, because they form multiple synapses and can enhance coupling between presynaptic and postsynaptic neurons. We found that higher MSB frequency correlated with better working memory performance in rhesus monkeys. Additionally, aged surgically menopausal monkeys experienced a 50% loss of MSBs that was restored with cyclic estradiol treatment. Together, our findings suggest that hormone replacement therapy benefits cognitive aging, in part by retaining complex synaptic organizations in the PFC.
Rescue of Impaired mGluR5-Driven Endocannabinoid Signaling Restores Prefrontal Cortical Output to Inhibit Pain in Arthritic Rats
Authors: Kiritoshi Takaki , Ji Guangchen , Neugebauer Volker 
Published: January 2016

The medial prefrontal cortex (mPFC) serves executive functions that are impaired in neuropsychiatric disorders and pain. Underlying mechanisms remain to be determined. Here we advance the novel concept that metabotropic glutamate receptor 5 (mGluR5) fails to engage endocannabinoid (2-AG) signaling to overcome abnormal synaptic inhibition in pain, but restoring endocannabinoid signaling allows mGluR5 to increase mPFC output hence inhibit pain behaviors and mitigate cognitive deficits. Whole-cell patch-clamp recordings were made from layer V pyramidal cells in the infralimbic mPFC in rat brain slices. Electrical and optogenetic stimulations were used to analyze amygdala-driven mPFC activity. A selective mGluR5 activator (VU0360172) increased pyramidal output through an endocannabinoid-dependent mechanism because intracellular inhibition of the major 2-AG synthesizing enzyme diacylglycerol lipase or blockade of CB1 receptors abolished the facilitatory effect of VU0360172. In an arthritis pain model mGluR5 activation failed to overcome abnormal synaptic inhibition and increase pyramidal output. mGluR5 function was rescued by restoring 2-AG-CB1 signaling with a CB1 agonist (ACEA) or inhibitors of postsynaptic 2-AG hydrolyzing enzyme ABHD6 (intracellular WWL70) and monoacylglycerol lipase MGL (JZL184) or by blocking GABAergic inhibition with intracellular picrotoxin. CB1-mediated depolarization-induced suppression of synaptic inhibition (DSI) was also impaired in the pain model but could be restored by coapplication of VU0360172 and ACEA. Stereotaxic coadministration of VU0360172 and ACEA into the infralimbic, but not anterior cingulate, cortex mitigated decision-making deficits and pain behaviors of arthritic animals. The results suggest that rescue of impaired endocannabinoid-dependent mGluR5 function in the mPFC can restore mPFC output and cognitive functions and inhibit pain.SIGNIFICANCE STATEMENTDysfunctions in prefrontal cortical interactions with subcortical brain regions, such as the amygdala, are emerging as important players in neuropsychiatric disorders and pain. This study identifies a novel mechanism and rescue strategy for impaired medial prefrontal cortical function in an animal model of arthritis pain. Specifically, an integrative approach of optogenetics, pharmacology, electrophysiology, and behavior is used to advance the novel concept that a breakdown of metabotropic glutamate receptor subtype mGluR5 and endocannabinoid signaling in infralimbic pyramidal cells fails to control abnormal amygdala-driven synaptic inhibition in the arthritis pain model. Restoring endocannabinoid signaling allows mGluR5 activation to increase infralimbic output hence inhibit pain behaviors and mitigate pain-related cognitive deficits.
INDONESIA NEGARA HUKUM DEMOKRATIS BUKAN NEGARA KEKUASAAN OTORITER
Authors: Maggalatung A Salman 
Published: January 2016

Istilah negara hukum selain dikenal dengan istilah rechtsstaat dan rule of law, juga dikenal istilah monocracy yang artinya sama dengan negara hukum. Intinya bahwa, hukum yang berlaku dalam suatu negara hukum haruslah yang terumus secara demokratis, yakni yang dikehendaki oleh rakyat. Sejalan dengan perkembangan kehidupan kebangsaan dan ketatanegaraan Indonesia, maka dengan melalui amandemen UUD 1945, istilah negra hukum (rechtsstaat) secara jelas dan tegas disebutkan dalam Batang Tubuh UUD NRI tahun 1945 yang sebelum amandemen hanya ditemukan dalam Penjelasan UUD 1945. Hal itu mempertegas komitmen bahwa Indonesia adalah negara hukum yang demokratis bukan negara kekuasaan yang otoriter. Indonesia sebagai negara hukum yang demokratis, maka kekuasaan manapun harus berlandaskan konstitusi. Konstitusi itu diadakan supaya para penyelenggara negara mempunyai arah serta tujuan yang jelas dalam menjalankan tugas dan kewenangannya, konstitusi itu merupakan hukum dasar tertinggi dan dinobatkan sebagai negara hukum yang demokratis. Dalam konteks itu, negara menempatkan hukum sebagai dasar kekuasaan negara dan penyelenggaraan kekuasaan tersebut dalam segala bentuknya dilakukan di bawah kekuasaan hukum. Hukum sebagai urat nadi dalam segala aspek kehidupan. Negara hukum, konstitusi, dan demokrasi merupakan satu kesatuan yang tak terpisahkan menuju sebuah bangunan negara yang menjunjung tinggi supremasi konstitusi dan demokrasi yang berdasarakan kepada hukum. Kata Kunci: Negara Hukum, Konstitusi, dan DemokrasiDOI: 10.15408/sjsbs.v2i2.2379