bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of Sex and Menopausal Status on Episodic Memory Circuitry in Early Midlife
Authors: Jacobs Emily G. , Weiss Blair K. , Makris Nikos , Whitfield-Gabrieli Sue , Buka Stephen L. , Klibanski Anne , Goldstein Jill M. 
Published: September 2016

Cognitive neuroscience of aging studies traditionally target participants age 65 and older. However, epidemiological surveys show that many women report increased forgetfulness earlier in the aging process, as they transition to menopause. In this population-based fMRI study, we stepped back by over a decade to characterize the changes in memory circuitry that occur in early midlife, as a function of sex and women's reproductive stage. Participants (N= 200; age range, 45–55) performed a verbal encoding task during fMRI scanning. Reproductive histories and serologic evaluations were used to determine menopausal status. Results revealed a pronounced impact of reproductive stage on task-evoked hippocampal responses, despite minimal difference in chronological age. Next, we examined the impact of sex and reproductive stage on functional connectivity across task-related brain regions. Postmenopausal women showed enhanced bilateral hippocampal connectivity relative to premenopausal and perimenopausal women. Across women, lower 17β-estradiol concentrations were related to more pronounced alterations in hippocampal connectivity and poorer performance on a subsequent memory retrieval task, strongly implicating sex steroids in the regulation of this circuitry. Finally, subgroup analyses revealed that high-performing postmenopausal women (relative to low and middle performers) exhibited a pattern of brain activity akin to premenopausal women. Together, these findings underscore the importance of considering reproductive stage, not simply chronological age, to identify neuronal and cognitive changes that unfold in the middle decades of life. In keeping with preclinical studies, these human findings suggest that the decline in ovarian estradiol production during menopause plays a significant role in shaping memory circuitry.SIGNIFICANCE STATEMENTMaintaining intact memory function with age is one of the greatest public health challenges of our time, and women have an increased risk for memory disorders relative to men later in life. We studied adults early in the aging process, as women transition into menopause, to identify neuronal and cognitive changes that unfold in the middle decades of life. Results demonstrate regional and network-level differences in memory encoding-related activity as a function of women's reproductive stage, independent of chronological age. Analyzing data without regard to sex or menopausal status obscured group differences in circuit-level neural strategies associated with successful memory retrieval. These findings suggest that early changes in memory circuitry are evident decades before the age range traditionally targeted by cognitive neuroscience of aging studies.
Genetic Restoration of Plasma ApoE Improves Cognition and Partially Restores Synaptic Defects in ApoE-Deficient Mice
Authors: Lane-Donovan Courtney , Wong Wen Mai , Durakoglugil Murat S. , Wasser Catherine R. , Jiang Shan , Xian Xunde , Herz Joachim 
Published: September 2016

Alzheimer's disease (AD) is the most common form of dementia in individuals over the age of 65 years. The most prevalent genetic risk factor for AD is the ε4 allele of apolipoprotein E (ApoE4), and novel AD treatments that target ApoE are being considered. One unresolved question in ApoE biology is whether ApoE is necessary for healthy brain function. ApoE knock-out (KO) mice have synaptic loss and cognitive dysfunction; however, these findings are complicated by the fact that ApoE knock-out mice have highly elevated plasma lipid levels, which may independently affect brain function. To bypass the effect of ApoE loss on plasma lipids, we generated a novel mouse model that expresses ApoE normally in peripheral tissues, but has severely reduced ApoE in the brain, allowing us to study brain ApoE loss in the context of a normal plasma lipid profile. We found that these brain ApoE knock-out (bEKO) mice had synaptic loss and dysfunction similar to that of ApoE KO mice; however, the bEKO mice did not have the learning and memory impairment observed in ApoE KO mice. Moreover, we found that the memory deficit in the ApoE KO mice was specific to female mice and was fully rescued in female bEKO mice. Furthermore, while the AMPA/NMDA ratio was reduced in ApoE KO mice, it was unchanged in bEKO mice compared with controls. These findings suggest that plasma lipid levels can influence cognition and synaptic function independent of ApoE expression in the brain.SIGNIFICANCE STATEMENTOne proposed treatment strategy for Alzheimer's disease (AD) is the reduction of ApoE, whose ε4 isoform is the most common genetic risk factor for the disease. A major concern of this strategy is that an animal model of ApoE deficiency, the ApoE knock-out (KO) mouse, has reduced synapses and cognitive impairment; however, these mice also develop dyslipidemia and severe atherosclerosis. Here, we have shown that genetic restoration of plasma ApoE to wild-type levels normalizes plasma lipids in ApoE KO mice. While this does not rescue synaptic loss, it does completely restore learning and memory in the mice, suggesting that both CNS and plasma ApoE are independent parameters that affect brain health.
Genetically Encoded Voltage Indicators: Opportunities and Challenges
Authors: Yang Helen H. , St-Pierre François 
Published: September 2016

A longstanding goal in neuroscience is to understand how spatiotemporal patterns of neuronal electrical activity underlie brain function, from sensory representations to decision making. An emerging technology for monitoring electrical dynamics, voltage imaging using genetically encoded voltage indicators (GEVIs), couples the power of genetics with the advantages of light. Here, we review the properties that determine indicator performance and applicability, discussing both recent progress and technical limitations. We then consider GEVI applications, highlighting studies that have already deployed GEVIs for biological discovery. We also examine which classes of biological questions GEVIs are primed to address and which ones are beyond their current capabilities. As GEVIs are further developed, we anticipate that they will become more broadly used by the neuroscience community to eavesdrop on brain activity with unprecedented spatiotemporal resolution.SIGNIFICANCE STATEMENTGenetically encoded voltage indicators are engineered light-emitting protein sensors that typically report neuronal voltage dynamics as changes in brightness. In this review, we systematically discuss the current state of this emerging method, considering both its advantages and limitations for imaging neural activity. We also present recent applications of this technology and discuss what is feasible now and what we anticipate will become possible with future indicator development. This review will inform neuroscientists of recent progress in the field and help potential users critically evaluate the suitability of genetically encoded voltage indicator imaging to answer their specific biological questions.
Age-Related Changes in Axonal and Mitochondrial Ultrastructure and Function in White Matter
Authors: Stahon Katharine E. , Bastian Chinthasagar , Griffith Shelby , Kidd Grahame J. , Brunet Sylvain , Baltan Selva 
Published: September 2016

The impact of aging on CNS white matter (WM) is of general interest because the global effects of aging on myelinated nerve fibers are more complex and profound than those in cortical gray matter. It is important to distinguish between axonal changes created by normal aging and those caused by neurodegenerative diseases, including multiple sclerosis, stroke, glaucoma, Alzheimer's disease, and traumatic brain injury. Using three-dimensional electron microscopy, we show that in mouse optic nerve, which is a pure and fully myelinated WM tract, aging axons are larger, have thicker myelin, and are characterized by longer and thicker mitochondria, which are associated with altered levels of mitochondrial shaping proteins. These structural alterations in aging mitochondria correlate with lower ATP levels and increased generation of nitric oxide, protein nitration, and lipid peroxidation. Moreover, mitochondria–smooth endoplasmic reticulum interactions are compromised due to decreased associations and decreased levels of calnexin and calreticulin, suggesting a disruption in Ca2+homeostasis and defective unfolded protein responses in aging axons. Despite these age-related modifications, axon function is sustained in aging WM, which suggests that age-dependent changes do not lead to irreversible functional decline under normal conditions, as is observed in neurodegenerative diseases.SIGNIFICANCE STATEMENTAging is a common risk factor for a number of neurodegenerative diseases, including stroke. Mitochondrial dysfunction and oxidative damage with age are hypothesized to increase risk for stroke. We compared axon–myelin–node–mitochondrion–smooth endoplasmic reticulum (SER) interactions in white matter obtained at 1 and 12 months. We show that aging axons have enlarged volume, thicker myelin, and elongated and thicker mitochondria. Furthermore, there are reduced SER connections to mitochondria that correlate with lower calnexin and calreticulin levels. Despite a prominent decrease in number, elongated aging mitochondria produce excessive stress markers with reduced ATP production. Because axons maintain function under these conditions, our study suggests that it is important to understand the process of normal brain aging to identify neurodegenerative changes.
Field Potential Oscillations in the Bed Nucleus of the Stria Terminalis Correlate with Compulsion in a Rat Model of Obsessive-Compulsive Disorder
Authors: Wu Hemmings , Tambuyzer Tim , Nica Ioana , Deprez Marjolijn , van Kuyck Kris , Aerts Jean-Marie , Van Huffel Sabine , Nuttin Bart 
Published: September 2016

The bed nucleus of the stria terminalis (BNST) is implicated in anxiety and reward processing, both of which are associated with obsessive-compulsive disorder (OCD). Specific neuronal groups in the BNST related to anxiety and reward have been identified, but quantitative data about the information carried by local field potential (LFP) signals in this area during obsession/compulsion are lacking. Here we investigate the BNST LFP in the schedule-induced polydipsia, an animal model of OCD. We implanted electrodes bilaterally in the BNST and random control brain regions in 32 male Wistar rats, and recorded corresponding LFP during compulsive and noncompulsive behavior. We first applied high-frequency (100 Hz) electrical stimulation through the implanted electrodes and analyzed its effects on compulsive behavior. We then performed time-frequency analysis of LFPs and statistically compared the normalized power of δ (1–4 Hz), θ (4–8 Hz), α (8–12 Hz), β (12–30 Hz), and lower γ (30–45 Hz) bands between different groups. Our data showed that the normalized δ, β, and γ powers in the right BNST were specifically correlated with compulsive behaviors. δ and γ oscillations increased and decreased during the initiation phase of compulsion, respectively, whereas β increased after compulsion stopped. Moreover, the effect of BNST electrical stimulation, in terms of suppression of compulsion, was significantly correlated with the percentage change of these bands during compulsion. Our research reveals potential biomarkers and underlying neurophysiological mechanisms of compulsion and warrants further assessment of the use of LFP for closed-loop neuromodulation in OCD.SIGNIFICANCE STATEMENTAlthough specific neuronal groups in the bed nucleus of the stria terminalis (BNST) related to anxiety and reward circuitries have been identified, psychopathological information carried by local field potentials in the BNST has not yet been described. We discovered that normalized powers of the right BNST δ, β, and γ oscillations were highly correlated with compulsion. Specifically, δ and γ oscillations increased and decreased during the initiation phase of compulsion, respectively, whereas β increased after compulsion stopped. Such correlations were not found in other parts of the brain during compulsion, or in the BNST during noncompulsive behavior. Current findings reveal real-time neurophysiological biomarkers of compulsion and warrant further assessment of the use of local field potentials for closed-loop neuromodulation for OCD.
Transfer after Dualn-Back Training Depends on Striatal Activation Change
Authors: Salminen Tiina , Kühn Simone , Frensch Peter A. , Schubert Torsten 
Published: September 2016

The dualn-back working memory (WM) training paradigm (comprising auditory and visual stimuli) has gained much attention since studies have shown widespread transfer effects. By including a multimodal dual-task component, the task is demanding to the human cognitive system. We investigated whether dualn-back training improves general cognitive resources or a task-specific WM updating process in participants. We expected: (1) widespread transfer effects and the recruitment of a common neuronal network by the training and the transfer tasks and (2) narrower transfer results and that a common activation network alone would not produce transfer, but instead an activation focus on the striatum, which is associated with WM updating processes. The training group showed transfer to an untrained dual-modality WM updating task, but not to single-task versions of the training or the transfer task. They also showed diminished neuronal overlap between the training and the transfer task from pretest to posttest and an increase in striatal activation in both tasks. Furthermore, we found an association between the striatal activation increase and behavioral improvement. The control groups showed no transfer and no change in the amount of activation overlap or in striatal activation from pretest to posttest. We conclude that, instead of improving general cognitive resources (which would have required a transfer effect to all transfer tasks and that a frontal activation overlap between the tasks produced transfer), dualn-back training improved a task-specific process: WM updating of stimuli from two modalities.SIGNIFICANCE STATEMENTThe current study allows for a better understanding of the cognitive and neural effects of working memory (WM) training and transfer. It shows that dualn-back training mainly improves specific processes of WM updating, and this improvement leads to narrow transfer effects to tasks involving the same processes. On a neuronal level this is accompanied by increased neural activation in the striatum that is related to WM updating. The current findings challenge the view that dualn-back training provokes a general boosting of the WM system and of its neural underpinnings located in frontoparietal brain regions. Instead, the findings imply the relevance of task-specific brain regions which are involved in important cognitive processes during training and transfer tasks.
The Neurotrophic Factor Receptor p75 in the Rat Dorsolateral Striatum Drives Excessive Alcohol Drinking
Authors: Darcq Emmanuel , Morisot Nadege , Phamluong Khanhky , Warnault Vincent , Jeanblanc Jerome , Longo Frank M. , Massa Stephen M. , Ron Dorit 
Published: September 2016

Brain-derived neurotrophic factor (BDNF) signaling in the dorsolateral striatum (DLS) keeps alcohol intake in moderation. For example, activation of the BDNF receptor tropomyosin receptor kinase B (TrkB) in the DLS reduces intake in rats that consume moderate amounts of alcohol. Here, we tested whether long-term excessive consumption of alcohol produces neuroadaptations in BDNF signaling in the rat DLS. We found that BDNF was no longer able to gate alcohol self-administration after a history of repeated cycles of binge alcohol drinking and withdrawal. We then elucidated the possible neuroadaptations that could block the ability of BDNF to keep consumption of alcohol in moderation. We report that intermittent access to 20% alcohol in a two-bottle choice paradigm that models excessive alcohol drinking produces a mobilization of DLS p75 neurotrophin receptor (p75NTR), whose activities oppose those of the Trk receptors, including TrkB. These neuroadaptations were not observed in the DLS of rats exposed to continuous access to 10% alcohol or in rats consuming sucrose. Furthermore, short hairpin RNA (shRNA)-mediated knockdown of thep75NTRgene in the DLS, as well as intra-DLS infusion or systemic administration of the p75NTR modulator, LM11A-31, significantly reduced binge drinking of alcohol. Together, our results suggest that excessive alcohol consumption produces a change in BDNF signaling in the DLS, which is mediated by the recruitment of p75NTR. Our data also imply that modulators of p75NTR signaling could be developed as medications for alcohol abuse disorders.SIGNIFICANCE STATEMENTNeuroadaptations gate or drive excessive, compulsive alcohol drinking. We previously showed that brain-derived neurotrophic factor and its receptor, TrkB, in the dorsolateral striatum (DLS), are part of an endogenous system that keeps alcohol drinking in moderation. Here, we show that a history of excessive alcohol intake produces neuroadaptations in the DLS that preclude BDNF's ability to gate alcohol self-administration in rats by the recruitment of the low-affinity neurotrophin receptor, p75NTR, whose activities opposes those of the Trk receptors. Finally, we show that the administration of the p75NTR modulator, LM11A-31, significantly reduces excessive alcohol intake suggesting that the drug may be developed as a new treatment for alcohol abuse disorders.
KAIP KALBĖTI APIE MAŽAS VALSTYBES? MAŽUMO REIKŠMIŲ ANALIZĖ
Authors: Lingevičius Justinas 
Published: September 2016

Straipsnyje nagrinėjama, kaip tarptautinių santykių disciplina apibrėžia ir aiškina mažų valstybių problematiką. Išskiriant pagrindinius klausimus, formuluojama iki šiol mažų valstybių studijų lauke plačiai netaikyta poststruktūralistinė teorinė ir metodologinė prieiga, kreipianti dėmesį į mažumą, kaip šalies identiteto dimensiją, ir reikšmes, kuriomis buvimas maža valstybe yra formuluojamas, siejamas arba sietinas su saugumo bei užsienio politika. Pateikiama Lietuvos ir Naujosios Zelandijos atvejų analizė ir jų palyginimas pristatant pagrindines mažumą apibrėžiančias reikšmes, jų santykį su saugumo bei užsienio politika. Remiantis atlikta analize, pasiūlomi į studijų lauko plėtojimą referuojantys principai, kurie gali būti svarbūs toliau tiriant ir aiškinant mažas valstybes.
Hegelio Dvasios fenomenologijos genezė ir reikšmė
Authors: Pagano Maurizio 
Published: September 2016

Straipsnyje gilinamasi į Georgo Wilhelmo Friedricho Hegelio mąstymo raidą pradedant ankstyvaisiais jo tekstais. Teigiama, kad Hegelio apmąstymai apie moderniosios visuomenės ir kultūros susiskaidymus ir įtampas paskatino jį kelti klausimą apie galimą jungimąsi ir ieškoti principo, galinčio šį jungimąsi pagrįsti. Taip gimsta Absoliuto teorija, taip pat šiuo pagrindu vėliau plėtojamas ir Dvasios fenomenologijos projektas. Šiame kūrinyje Hegelis kalba apie kelią, kurį, pereidama visus patirties laipsnius, privalo nueiti absoliutaus žinojimo siekianti sąmonė. Paskutinėje straipsnio dalyje susitelkiama prie dvasios sąvokos vėlyvajame Hegelio mąstyme ir jos reikšmės šiuolaikinei filosofijai.
Preterm Thrombocytopenia and Delay of Ductus Arteriosus Closure
Authors: Kulkarni Vinay Vamadev , Dutta Sourabh , Sundaram Venkataseshan , Saini Shiv Sajan 
Published: September 2016

OBJECTIVES:
To evaluate whether preterm thrombocytopenia within 24 hours of birth is associated with delayed closure of patent ductus arteriosus (PDA) and higher proportion of hemodynamically significant PDA (Hs-PDA).

METHODS:
Neonates (gestation 260/7–336/7 weeks, age &lt;24 hours) with known platelet count and PDA on echocardiogram were prospectively enrolled. Asphyxia, congenital infections, structural heart disease, major malformations and clinical sepsis were exclusions. Subjects were recruited in groups A (n = 35), B (n = 18), and C (n = 17) [platelet counts &gt;150,000, 100,000-150,000 and &lt;100,000 per μL respectively] and underwent daily echocardiography until first closure of PDA, death, or day 10.

RESULTS:
The primary outcome was time to first closure of PDA. Secondary outcomes included proportion with PDA at 72 hours and 7 days, Hs-PDA, and PDA needing treatment. In groups A, B, and C, median (first–third quartile) platelet counts (×100000/μL) were 2.28 (1.94–3.19), 1.25 (1.14–1.37), and 0.68 (0.54–0.83) and time to PDA closure was 2 (2–2), 2 (2–3), and 10 (6–10) days, respectively (log-rank test, P &lt; .001). On Cox proportional hazard regression, platelet count (in multiples of 10 000 /μL) independently predicted time to PDA closure (adjusted hazard ratio: 1.045; 95% confidence interval: 1.019–1.07). On day 7, 47.1% neonates in group C had PDA and none in groups A and B (P &lt; .001).

CONCLUSIONS:
Thrombocytopenia within 24 hours of birth independently predicts delayed PDA closure and PDA on day 7 in preterm neonates.