Juvenile social isolation reduces sociability in adulthood, but the underlying neural circuit mechanisms are poorly understood. We found that, in male mice, 2 weeks of social isolation immediately following weaning leads to a failure to activate medial prefrontal cortex neurons projecting to the posterior paraventricular thalamus (mPFC→pPVT) during social exposure in adulthood. Chemogenetic or optogenetic suppression of mPFC→pPVT activity in adulthood was sufficient to induce sociability deficits without affecting anxiety-related behaviors or preference toward rewarding food. Juvenile isolation led to both reduced excitability of mPFC→pPVT neurons and increased inhibitory input drive from low-threshold-spiking somatostatin interneurons in adulthood, suggesting a circuit mechanism underlying sociability deficits. Chemogenetic or optogenetic stimulation of mPFC→pPVT neurons in adulthood could rescue the sociability deficits caused by juvenile isolation. Our study identifies a pair of specific medial prefrontal cortex excitatory and inhibitory neuron populations required for sociability that are profoundly affected by juvenile social experience.

Aquaporin-4 (AQP4) is the predominant water channel in brain and is selectively expressed in astrocytes. Astrocytic endfoot membranes exhibit tenfold higher densities of AQP4 than non-endfoot membranes, making AQP4 an excellent marker of astrocyte polarization. Loss of astrocyte polarization is known to compromise astrocytic function and to be associated with impaired water and K+ homeostasis. Here we investigate by a combination of light and electron microscopic immunocytochemistry whether amyloid deposition is associated with a loss of astrocyte polarization, using AQP4 as a marker. We used the tg-ArcSwe mouse model of Alzheimer's disease, as this model displays perivascular plaques as well as plaques confined to the neuropil. 3D reconstructions were done to establish the spatial relation between plaques and astrocytic endfeet, the latter known to contain the perivascular pool of AQP4. Changes in AQP4 expression emerge just after the appearance of the first plaques. Typically, there is a loss of AQP4 from endfoot membranes at sites of perivascular amyloid deposits, combined with an upregulation of AQP4 in the neuropil surrounding plaques. By electron microscopy it could be verified that the upregulation reflects an increased concentration of AQP4 in those delicate astrocytic processes that abound in synaptic regions. Thus, astrocytes exhibit a redistribution of AQP4 from endfoot membranes to non-endfoot membrane domains. The present data suggest that the development of amyloid deposits is associated with a loss of astrocyte polarization. The possible perturbation of water and K+ homeostasis could contribute to cognitive decline and seizure propensity in patients with Alzheimer's disease.

The overall aim of the present thesis is to clarify the control of intracellular chloride homeostasis in central neurons, because of the critical role of chloride ions (Cl^–) for neuronal function. Normal function of the central nervous system (CNS) depends on a delicate balance between neuronal excitation and inhibition. Inhibition is, in the adult brain, most often mediated by the neurotransmitter γ-aminobutyric acid (GABA). GABA may, however, in some cases cause excitation. GABA acts by activating GABA type A receptors (GABA_ARs), which are ion channels largely permeable to Cl^–. The effect of GABA_AR-mediated neuronal signaling - inhibitory or excitatory - is therefore mainly determined by the Cl^– gradient across the membrane. This gradient varies with neuronal activity and may be altered in pathological conditions. Thus, understanding Cl^– regulation is important to comprehend neuronal function. This thesis is an attempt to clarify several unknown aspects of neuronal Cl^– regulation. For such clarification, a sufficiently sensitive method for measuring the intracellular Cl^– concentration, [Cl^–]_i, is necessary. In the first study of this thesis, we examined two electrophysiological methods commonly used to estimate [Cl^–]_i. Both methods, here called the interpolation and the voltage-ramp method, depend on an estimate of the Cl^– equilibrium potential from the current-voltage relation of GABA- or glycine-evoked Cl^– currents. Both methods also provide an estimate of the membrane Cl^– conductance, g_Cl. With a combination of computational and electrophysiological techniques, we showed that the most common (interpolation) method failed to detect changes in [Cl^–]_i and g_Cl during prolonged GABA application, whereas the voltage-ramp method accurately detected such changes. Our analysis also provided an explanation as to why the two methods differ. In a second study, we clarified the role of the extracellular matrix (ECM) for the distribution of Cl^– across the cell membrane of neurons from rat brain. It was recently proposed that immobile charges located within the ECM, rather than as previously thought cation-chloride transporter proteins, determine the low [Cl^–]_i which is critical to GABA_AR-mediated inhibition. By using electrophysiological techniques to measure [Cl^–]_i, we showed that digestion of the ECM decreases the expression and function of the neuron-specific K⁺ Cl^– cotransporter 2 (KCC2), which normally extrudes Cl^- from the neuron, thus causing an increase in resting [Cl^–]_i. As a result of ECM degradation, the action of GABA may be transformed from inhibitory to excitatory. In a third study, we developed a method for quantifying the largely unknown resting Cl^– (leak) conductance, g_Cl, and examined the role of g_Cl for the neuronal Cl^– homeostasis. In isolated preoptic neurons from rat, resting g_Cl was about 6 % of total resting conductance, to a major part due to spontaneously open GABA_ARs and played an important role for recovery after a high Cl^– load. We also showed that spontaneous, impulse-independent GABA release can significantly enhance recovery when the GABA responses are potentiated by the neurosteroid allopregnanolone. In a final commentary, we formulated the mathematical relation between Cl^– conductance, KCC2-mediated Cl^– extrusion capacity and steady-state [Cl^–]_i. In summary, the present thesis (i) clarifies how well common electrophysiological methods describe [Cl^–]_i and g_Cl, (ii) provides a novel method for quantifying g_Cl in cell membranes and (iii) clarifies the roles of the ECM, ion channels and ion transporters in the control of [Cl^–]_i homeostasis and GABA_AR-mediated signaling in central neurons. 

The relation between current and voltage, I-V relation, is central to functional analysis of membrane ion channels. A commonly used method, since the introduction of the voltage-clamp technique, to establish the I-V relation depends on the interpolation of current amplitudes recorded at different steady voltages. By a theoretical computational approach as well as by experimental recordings from GABA(A) receptor mediated currents in mammalian central neurons, we here show that this interpolation method may give reversal potentials and conductances that do not reflect the properties of the channels studied under conditions when ion flux may give rise to concentration changes. Therefore, changes in ion concentrations may remain undetected and conclusions on changes in conductance, such as during desensitization, may be mistaken. In contrast, an alternative experimental approach, using rapid voltage ramps, enable I-V relations that much better reflect the properties of the studied ion channels.

INTRODUCTION: Cognitive reserve might mitigate the risk of Alzheimer's dementia among memory clinic patients. No study has examined the potential modifying role of stress on this relation. METHODS: We examined cross-sectional associations of the cognitive reserve index (CRI; education, occupational complexity, physical and leisure activities, and social health) with cognitive performance and AD-related biomarkers among 113 memory clinic patients. The longitudinal association between CRI and cognition over a 3-year follow-up was assessed. We examined whether associations were influenced by perceived stress and five measures of diurnal salivary cortisol. RESULTS: Higher CRI scores were associated with better cognition. Adjusting for cortisol measures reduced the beneficial association of CRI on cognition. A higher CRI score was associated with better working memory in individuals with higher (favorable) cortisol AM/PM ratio, but not among individuals with low cortisol AM/PM ratio. No association was found between CRI and AD-related biomarkers. DISCUSSION: Physiological stress reduces the neurocognitive benefits of cognitive reserve among memory clinic patients. Highlights: Physiological stress may reduce the neurocognitive benefits accrued from cognitively stimulating and enriching life experiences (cognitive reserve [CR]) in memory clinic patients. Cortisol awakening response modified the relation between CR and P-tau181, a marker of Alzheimer's disease (AD). Effective stress management techniques for AD and related dementia prevention are warranted.

Oligodendrocytes wrap nerve fibres in the central nervous system with layers of specialized cell membrane to form myelin sheaths(1). Myelin is destroyed by the immune system in multiple sclerosis, but myelin is thought to regenerate and neurological function can be recovered. In animal models of demyelinating disease, myelin is regenerated by newly generated oligodendrocytes, and remaining mature oligodendrocytes do not seem to contribute to this process(2-4). Given the major differences in the dynamics of oligodendrocyte generation and adaptive myelination between rodents and humans(5-9), it is not clear how well experimental animal models reflect the situation in multiple sclerosis. Here, by measuring the integration of C-14 derived from nuclear testing in genomic DNA(10), we assess the dynamics of oligodendrocyte generation in patients with multiple sclerosis. The generation of new oligodendrocytes was increased several-fold in normal-appearing white matter in a subset of individuals with very aggressive multiple sclerosis, but not in most subjects with the disease, demonstrating an inherent potential to substantially increase oligodendrocyte generation that fails in most patients. Oligodendrocytes in shadow plaques-thinly myelinated lesions that are thought to represent remyelinated areas-were old in patients with multiple sclerosis. The absence of new oligodendrocytes in shadow plaques suggests that remyelination of lesions occurs transiently or not at all, or that myelin is regenerated by pre-existing, and not new, oligodendrocytes in multiple sclerosis. We report unexpected oligodendrocyte generation dynamics in multiple sclerosis, and this should guide the use of current, and the development of new, therapies.

Three human leucine-rich repeats and immunoglobulin-like domains (LRIG1-3) genes and proteins have recently been characterized. LRIG1 has been shown to be a suppressor of tumor growth by counteracting the signaling of epidermal growth factor receptor (EGFR) family members, including EGFR (ERBB1). Expression of LRIG proteins seems to be of importance in the pathogenesis of astrocytic tumors. In this study, the expression of LRIG1-3 was evaluated in 51 human ependymomas by immunohistochemistry. LRIG proteins were detected in all ependymomas analyzed, however, with a pronounced heterogeneity in expression and subcellular localization. Higher cytoplasmic immunoreactivity of LRIG1 correlated with older patient age and higher LRIG1 nuclear immunoreactivity with lower WHO Grade. LRIG1 displayed a stronger immunoreactivity in the cytoplasm and nuclei in spinal ependymomas than in the posterior fossa or supratentorial ependymomas, while perinuclear LRIG3 was more highly expressed in supratentorial than in infratentorial ependymomas. The indications that expression and subcellular localization of LRIG proteins could be pathogenetically associated with specific clinicopathological features of ependymoma tumors might be of importance in the carcinogeneses and tumor progression of human ependymomas.

BACKGROUND: Tumours involving the cavernous sinus may be challenging to neurosurgeons and neuro-oncologists to treat. Operation may be hazardous for lesions in this area, radical resection is seldom obtained, and other treatments are often needed. Different types of tumour occur at this location. Radiological examination may not be diagnostic so that a histopathological diagnosis is often needed before treatment can be recommended for the individual patient. If surgical resection is less feasible a biopsy will be necessary. CONCLUSION: We describe a technique for image-guided percutaneous biopsy through the oval foramen ovale and its use in two patients with a cavernous sinus tumour. We also describe and highlight the importance of pre- and intraoperative CT imaging in obtaining a safe and conclusive biopsy.

The search for an innovative and effective drug delivery system that can carry and release targeted drugs with enhanced activity to treat Alzheimer's disease has received much attention in the last decade. In this study, we first designed a boron-based drug delivery system for effective treatment of AD by integrating the folic acid (FA) functional group into hexagonal boron nitride (hBN) nanoparticles (NPs) through an esterification reaction. The hBN-FA drug carrier system was assembled with a new drug candidate and a novel boron-based hybrid containing an antioxidant as BLA, to constitute a self-assembled AD nano transport system. We performed molecular characterization analyses by using UV-vis spectroscopy, Fourier transform infrared spectrophotometer (FTIR), scanning electron microscope (SEM), Energy-dispersive X-ray spectroscopy (EDS) and Zeta potential investigations. Second, we tested the anti-Alzheimer properties of the carrier system on a differentiated neuroblastoma (SHSY5-Y) cell line, which was exposed to beta-amyloid (1-42) peptides to stimulate an experimental in vitro AD model. Next, we performed cytotoxicity analyses of synthesized molecules on the human dermal fibroblast cell line (HDFa) and the experimental AD model. Cytotoxicity analyses showed that even higher concentrations of the carrier system did not enhance the toxicological outcome in HDFa cells. Drug loading analyses reported that uncoated hBN nano conjugate could not load the BLA, whereas the memantine loading capacity of hBN was 84.3%. On the other hand, memantine and the BLA loading capacity of the hBN-FA construct was found to be 95% and 97.5%, respectively. Finally, we investigated the neuroprotective properties of the nano carrier systems in the experimental AD model. According to the results, 25 mu g/mL concentrations of hBN-FA+memantine (94% cell viability) and hBN-FA+BLA (99% cell viability) showed ameliorative properties against beta-amyloid (1-42) peptide toxicity (50% cell viability). These results were generated through the use of flow cytometry, acetylcholinesterase (AChE) and antioxidant assays. In conclusion, the developed drug carrier system for AD treatment showed promising potential for further investigations and enlightened neuroprotective capabilities of boron molecules to treat AD and other neurodegenerative diseases. On the other hand, enzyme activity, systematic toxicity analyses, and animal studies should be performed to understand neuroprotective properties of the designed carrier system comprehensively.

The identification of cerebral microinfarctions with magnetic resonance imaging (MRI) and histological methods remains challenging in aging and dementia. Here, we matched pathological changes in the microvasculature of cortical cerebral microinfarcts to MRI signals using single 100 μm-thick histological sections scanned with ultra-high-resolution 11.7 T MRI. Histologically, microinfarcts were located in superficial or deep cortical layers or transcortically, compatible with the pattern of layer-specific arteriolar blood supply of the cerebral cortex. Contrary to acute microinfarcts, at chronic stages the core region of microinfarcts showed pallor with extracellular accumulation of lipofuscin and depletion of neurons, a dense meshwork of collagen 4-positive microvessels with numerous string vessels, CD68-positive macrophages and glial fibrillary acidic protein (GFAP)-positive astrocytes. In MRI scans, cortical microinfarcts at chronic stages, called chronic cortical microinfarcts here, gave hypointense signals in T1-weighted and hyperintense signals in T2-weighted images when thinning of the tissue and cavitation and/or prominent iron accumulation were present. Iron accumulation in chronic microinfarcts, histologically verified with Prussian blue staining, also produced strong hypointense T2*-weighted signals. In summary, the microinfarct core was occupied by a dense microvascular meshwork with string vessels, which was invaded by macrophages and astroglia and contained various degrees of iron accumulation. While postmortem ultra-high-resolution single-section imaging improved MRI-histological matching and the structural characterization of chronic cortical cerebral microinfarcts, miniscule microinfarcts without thinning or iron accumulation could not be detected with certainty in the MRI scans. Moreover, string vessels at the infarct margin indicate disturbances in the microcirculation in and around microinfarcts, which might be exploitable in the diagnostics of cortical cerebral microinfarcts with MRI in vivo.

The striatum is the main input station of the basal ganglia and is strongly associated with motor and cognitive functions. Anatomical evidence suggests that individual striatal neurons are unlikely to share their inputs from the cortex. Using a biologically realistic large-scale network model of striatum and cortico-striatal projections, we provide a functional interpretation of the special anatomical structure of these projections. Specifically, we show that weak pairwise correlation within the pool of inputs to individual striatal neurons enhances the saliency of signal representation in the striatum. By contrast, correlations among the input pools of different striatal neurons render the signal representation less distinct from background activity. We suggest that for the network architecture of the striatum, there is a preferred cortico-striatal input configuration for optimal signal representation. It is further enhanced by the low-rate asynchronous background activity in striatum, supported by the balance between feedforward and feedback inhibitions in the striatal network. Thus, an appropriate combination of rates and correlations in the striatal input sets the stage for action selection presumably implemented in the basal ganglia.

In vivo recordings in rat somatosensory cortex suggest that excitatory and inhibitory inputs are often correlated during spontaneous and sensory-evoked activity. Using a computational approach, we study how the interplay of input correlations and timing observed in experiments controls the spiking probability of single neurons. Several correlation-based mechanisms are identified, which can effectively switch a neuron on and off. In addition, we investigate the transfer of input correlation to output correlation in pairs of neurons, at the spike train and the membrane potential levels, by considering spike-driving and non-spike-driving inputs separately. In particular, we propose a plausible explanation for the in vivo finding that membrane potentials in neighboring neurons are correlated, but the spike-triggered averages of membrane potentials preceding a spike are not: Neighboring neurons possibly receive an ongoing bombardment of correlated subthreshold background inputs, and occasionally uncorrelated spike-driving inputs.

Alzheimer's disease (AD) is a neurodegenerative disease that mainly occurs in old age and involves progressive cognitive impairment. AD has become a major global issue for public health, with approximately 24 million people currently affected by the disease. Estimates indicted that this number will quadruple by 2050. Because of the high incidence of AD, there is an urgent need to develop new strategies to diagnose and treat AD. Many recent studies have indicated the multiple, yet somewhat controversial, roles of exosomes in AD. Although the underlying mechanisms by which exosomes play a role in AD are still unknown, current evidence suggests that exosomes can carry and spread toxic amyloid-beta, and hyperphosphorylated tau, between cells, and then induce apoptosis, thus contributing to the loss of neurons. In addition, exosomes appear to possess the ability to reduce brain amyloid-beta, and tau hyperphosphorylation, and transfer neuroprotective substances between neural cells. The accumulating data brings hope that the application of exosomes may be helpful for early diagnostics and the identification of new therapeutic targets for AD. Here, we summarized the various roles of exosomes, and how they might relate to the pathogenesis of AD. We also highlight the potential application of exosomes as a therapeutic option in AD therapy.

Background: Ayahuasca is a South American psychoactive brew that contains Dimethyltryptamine (DMT) and monoamine oxidase inhibitors (MAOIs). Research has experienced a resurgence of interest in exploring the potential of these substances in the last decade. Thus, the aim of this review was to systematically review studies that used a placebo-controlled design to explore the neural correlates and psychedelic experience induced by DMT and ayahuasca.

Method: The search was conducted using the Web of Science and Scopus databases to select studies published between January 2000 and February 2022 that used neuroimaging techniques and recruited healthy participants. Thus, 7 papers were selected.

Results: Ayahuasca alters electrical activity in the brain by decreasing spectralpower in all EEG frequency bands, predominantly in the alpha band. DMT caused a spatially widespread decrease in alpha bands and a more modest decrease in beta bands. Ayahuasca caused an increase in the flow of information in the brain from posterior regions to more frontal regions and an increase in scores in all the Hallucinogen Rating Scale (HRS) subscales. Ayahuasca decreased connectivity in the Default Mode Network (DMN) and increases connectivity between DMN and the salience network.

Conclusion: Ayahuasca and DMT can reliably produce profound changes in perception, emotions, and sense of self. Moreover, the decrease in the alpha band, the alteration of information flow between posterior and frontal regions, and the decrease in connectivity in the DMN could be the keystone understanding the neural correlates and the psychedelic experience induced by DMT andayahuasca. 

Alzheimer’s disease (AD) results in progressive cognitive decline owing to the accumulation of amyloid plaques and hyperphosphorylated tau. MicroRNAs (miRNAs) have attracted attention as a putative diagnostic and therapeutic target for neurodegenerative diseases. However, existing meta-analyses on AD and its association with miRNAs have produced inconsistent results. The primary objective of this study is to evaluate the magnitude and consistency of differences in miRNA levels between AD patients, mild cognitive impairment (MCI) patients and healthy controls (HC). Articles investigating miRNA levels in blood, brain tissue, or cerebrospinal fluid (CSF) of AD and MCI patients versus HC were systematically searched in PubMed/Medline from inception to February 16th, 2021. Fixed- and random-effects meta-analyses were complemented with the I2 statistic to measure the heterogeneity, assessment of publication bias, sensitivity subgroup analyses (AD severity, brain region, post-mortem versus ante-mortem specimen for CSF and type of analysis used to quantify miRNA) and functional enrichment pathway analysis. Of the 1512 miRNAs included in 61 articles, 425 meta-analyses were performed on 334 miRNAs. Fifty-six miRNAs were significantly upregulated (n = 40) or downregulated (n = 16) in AD versus HC and all five miRNAs were significantly upregulated in MCI versus HC. Functional enrichment analysis confirmed that pathways related to apoptosis, immune response and inflammation were statistically enriched with upregulated pathways in participants with AD relative to HC. This study confirms that miRNAs’ expression is altered in AD and MCI compared to HC. These findings open new diagnostic and therapeutic perspectives for this disorder.

Persistent firing is believed to be a crucial mechanism for memory function including working memory. Recent in vivo and in vitro findings suggest an involvement of metabotropic glutamate receptors (mGluRs) in persistent firing. Using whole-cell patch-recording techniques in a rat entorhinal cortex (EC) slice preparation, we tested whether EC layer III neurons display persistent firing due to mGluR activation, independently of cholinergic activation. Stimulation of the angular bundle drove persistent firing in 90% of the cells in the absence of a cholinergic agonist. The persistent firing was typically stable for > 4.5 min at which point persistent firing was terminated by the experimenter. The average frequency of the persistent firing was 2.1 Hz, ranging from 0.4 to 5.5 Hz. This persistent firing was observed even in the presence of atropine (2 mu M), suggesting that the persistent firing can occur independent of cholinergic activation. Furthermore, ionotropic glutamate and GABAergic synaptic blockers (2 mm kynurenic acid, 100 mu M picrotoxin and 1 mu M CGP55845) did not block the persistent firing. On the other hand, blockers of group I mGluRs (100 mu M LY367385 and 20 mu M MPEP) completely blocked or suppressed the persistent firing. An agonist of group I mGluRs (20 mu M DHPG) greatly enhanced the persistent firing induced by current injection. These results indicate that persistent firing can be driven through group I mGluRs in entorhinal layer III neurons, suggesting that glutamatergic synaptic input alone could enable postsynaptic neurons to hold input signals in the form of persistent firing.

Objective: To examine the perceived impact of stroke between 1 and 6 years after stroke using the Stroke Impact Scale 3.0 (SIS). Design: A prospective longitudinal study.

Methods: A total of 100 individuals were assessed using the SIS 3.0 at 1 and 6 years after onset of stroke and clinically meaningful changes were explored. Changes in domain scores were calculated over time in relation to age, sex and stroke severity.

Results: The most impacted SIS domains after 6 years were Participation, Strength, Hand function, and Stroke recovery. Participants with moderate/severe stroke experienced a higher impact in all domains except Hand function and Stroke recovery, indicating more problems in everyday life, compared with those with mild stroke. Almost half of the participants had a clinically meaningful change in the domain Participation between 1 and 6 years. Those with moderate/severe stroke and the older age group experienced more negative clinically meaningful changes in several domains in comparison with those with mild stroke and the younger age group.

Conclusion: The long-term perceived impact of stroke highlights the importance of appropriate rehabilitation interventions within several areas to reduce the long-term negative impact in everyday life.

The versatility of somatosensation arises from heterogeneous dorsal root ganglion (DRG) neurons. However, soma transcriptomes of individual human (h)DRG neurons-critical information to decipher their functions-are lacking due to technical difficulties. In this study, we isolated somata from individual hDRG neurons and conducted deep RNA sequencing (RNA-seq) to detect, on average, over 9,000 unique genes per neuron, and we identified 16 neuronal types. These results were corroborated and validated by spatial transcriptomics and RNAscope in situ hybridization. Cross-species analyses revealed divergence among potential pain-sensing neurons and the likely existence of human-specific neuronal types. Molecular-profile-informed microneurography recordings revealed temperature-sensing properties across human sensory afferent types. In summary, by employing single-soma deep RNA-seq and spatial transcriptomics, we generated an hDRG neuron atlas, which provides insights into human somatosensory physiology and serves as a foundation for translational work. Dorsal root ganglia (DRGs) contain a plethora of neuron types. The authors show that the existence of human-specific DRG neuronal types and microneurography recordings reveal distinct temperature-sensing properties across human sensory afferent types.

XIAP (X chromosome-linked inhibitor of apoptosis protein) has been shown to inhibit cell death in a variety of cells. XIAP binds to active caspases, but XIAP also has a carboxy-terminal RING domain that can regulate cell death via protein degradation. Here we have studied the function of full-length and RING-deleted XIAP in mouse sympathetic neurons microinjected with expression plasmids and in neuroblastoma cells stably overexpressing these proteins. Both full-length and RING-deleted XIAP-protected sympathetic neurons against death induced by nerve growth factor (NGF) withdrawal to about the same extent. However, the two proteins were differentially localized in transfected neurons, with RING-deleted XIAP present in the cytoplasm and full-length XIAP found mostly in cytoplasmic protein aggregates, as revealed by transmission electron microscopy. The occurrence of these aggregates was blocked by lactacystin, a proteasome inhibitor. In neuroblastoma cells, RING-deleted XIAP protected against death induced by staurosporine, thapsigargin, or serum withdrawal, whereas full-length XIAP was without effect. Full-length, but not RING-deleted, XIAP was degraded and ubiquitinated in the neuroblastoma cells. The results show that the presence of the RING domain differentially affected the neuroprotective ability of XIAP in sensory neurons and neuroblastoma cells. The RING domain was essentially required for the proteasomal association of XIAP and for its ubiquitination. (C) 2003 Elsevier Science (USA). All rights reserved.

Purpose: 1) To estimate the threshold dose and the time evolution for cataract induction by near infrared radiation (IRR) in seconds exposure time domain; 2) to determine the ocular temperature development during the threshold exposure; 3) to investigate if near IRR induces cumulative lens damage considering irradiance exposure time reciprocity; 4) to experimentally estimate the temperature in the lens indirectly from the measurement of temperature-induced light scattering increase.

Methods: Before exposure, 6-weeks-old albino rats were anesthetized and the pupils of both eyes were dilated. Then the animals were unilaterally exposed to 1090 nm IRR within the pupil area. Temperature was recorded with thermocouples placed in the selected positions of the eye. At the planned post-exposure time, the animal was sacrificed and the lenses were extracted for measurements of forward light scattering and macroscopic imaging (Paper I-III). In Paper IV, the lens was extracted from six-weeks-old albino Sprague-Dawley female rats and put into a temperature-controlled cuvette filled with balanced salt solution. Altogether, 80 lenses were equally divided on four temperature groups, 37, 40, 43 and 46 ºC. Each lens was exposed for 5 minutes to temperature depending on group belonging while the intensity of forward light scattering was recorded.

Results: The in vivo exposure to 197 W/cm² 1090 nm IRR required a minimum 8 s for cataract induction. There was approximately 16 h delay between exposure and light scattering development in the lens. The same radiant exposure was found to cause a temperature increase of 10 °C at the limbus and 26 °C close to the retina. The in vivo exposure to 96 W/cm² 1090 nm IRR with exposure time up to 1 h resulted in an average temperature elevation of 7 °C at the limbus with the cornea humidified and no significant light scattering was induced one week after exposure. Arrhenius equation implies that the natural logarithm of the inclination coefficient for light scattering increase is linearly dependent on the inverse of the temperature. The proportionality constant and the intercept, estimated as CI(0.95)s, were 9.6±2.4 x10³ K and 22.8±7.7. Further, it implies that if averaging 20 measurements of inclination coefficients in a new experiment at constant heat load, the confidence limits for prediction of temperature correspond to ±1.9 °C.

Conclusions: It is indicated that IRR at 1090 nm produces thermal but not cumulatively photochemical cataract, probably by indirect heat conduction from absorption in tissues surrounding the lens. Applying the Arrhenius equation the in vivo temperature in the lens can be determined retrospectively with sufficient resolution.

This study aimed to verify nonexistence of clinically important pathological effects to the visual system after exposure to 532 nm green laser light close to the exposure limit. The present medical surveillance of vision and visual health reported in this paper is the conjunction with a study of driver performance in the presence of 532 nm laser induced glare. The driving time varied between 25 and 55 s, depending on background luminance. The laser was on during the complete test drive. The peak corneal irradiance typically was 3.5Wm2 in one test drive. Considering a typical test drive, the typical time integrated corneal radiant exposure for one test drive was estimated to be 53 J/m². The number of test drives varied among drivers but was typically 50, thus resulting in a cumulative corneal exposure dose of approximately 2.7 kJ/m². Altogether, ten subjects were recruited according to inclusion and exclusion criteria. All ten subjects were examined for visual acuity, intraocular pressure, contrast sensitivity, color vision, monocular reading speed, and eye structure with clinical slit-lamp microscopy examination and indirect retinoscopy. All subjects were examined before exposure, immediately after exposure, and finally within an interval between 1 week and 4 weeks after exposure. There was no significant change of visual acuity, intraocular pressure, contrast sensitivity, color vision, or monocular reading speed between before and after exposure. No abnormal ocular structure was detected after exposure. This study demonstrates that close to exposure limit, exposure to 532 nm green laser light during a vehicle driving task does not induce structural or functional damage to the human visual system as observed in the interval minutes to weeks after exposure.

An in vivo exposure to 197 W/cm² 1090 nm infrared radiation (IRR) requires a minimum 8 s for cataract induction. The present study aims to determine the ocular temperature evolution and the associated heat flow at the same exposure conditions. Two groups of 12 rats were unilaterally exposed within the dilated pupil with a close to collimated beam between lens and retina. Temperature was recorded with thermocouples. Within 5 min after exposure, the lens light scattering was measured. In one group, the temperature rise in the exposed eye, expressed as CI(0.95), was 11±3 ºC at the limbus, 16±6 ºC in the vitreous behind lens and 16±7 ºC on the sclera next to the optic nerve, respectively. In the other group, the temperature rise in the exposed eye was 9±1 ºC at the limbus and 26±11 ºC on the sclera next to the optic nerve, respectively. The difference of forward light scattering between exposed and contralateral not exposed eye was 0.01±0.09 tEDC. An exposure to 197 W/cm² 1090 nm IRR for 8 s induces a temperature increase of 10 °C at the limbus and 26 °C close to the retina. IRR cataract is probably of thermal origin.

The current study aims to experimentally estimate the temperature in the lens due to heat load indirectly from the measurement of increase rate of temperature-induced light scattering. The lens was extracted from Sprague-Dawley rats and put into a temperature-controlled cuvette filled with balanced salt solution. Altogether, 80 lenses were equally divided on four temperature groups. Each lens was exposed for 5 minutes to temperature depending on group belonging while the intensity of forward light scattering was recorded. The inclination coefficient of light scattering increase at the temperature 37, 40, 43, and 46 ºC was estimated as a CI(0.95), 3.1±0.8, 4.4±0.8, 5.5±0.9 and 7.0±0.8 x10^-4 tEDC/s, respectively. The Arrhenius equation implies that the natural logarithm of the inclination coefficient is linearly dependent on the inverse of the temperature. The proportionality constant and the intercept were 9.6±2.4 x10³ K and 22.8±7.7. The activation energy was 8.0±2.0 x10¹ kJ·mol^-1. The current experiment implies that if averaging 20 measurements of inclination coefficients in a new experiment at constant heat load, the confidence limits for predicted temperature correspond to ±1.9 °C. With the proportionality constant and the intercept estimated in the current experiment, the in vivo temperature in the lens can be determined retrospectively with sufficient resolution.

Meditation has shown to benefit a wide range of conditions and symptoms, but the neural mechanisms underlying the practice remain unclear. Magnetic resonance imaging (MRI) studies have investigated the structural brain changes due to the practice by examining volume, density, or cortical thickness changes. However, these studies have focused on adults; meditation's structural effects on the adolescent brain remain understudied. In this study, we investigated how meditation training affects the structure of the adolescent brain by scanning a group of 38 adolescents (16.48 +/- 1.29 years) before and after participating in a 12-week meditation training. Subjects underwent Training for Awareness, Resilience, and Action (TARA), a program that mainly incorporates elements from mindfulness meditation and yoga-based practices. A subset of the adolescents also received an additional control scan 12 weeks before TARA. We conducted voxel-based morphometry (VBM) to assess gray matter volume changes pre- to post-training and during the control period. Subjects showed significant gray matter (GM) volume decreases in the left posterior insula and to a lesser extent in the left thalamus and left putamen after meditation training. There were no significant changes during the control period. Our results support previous findings that meditation affects regions associated with physical and emotional awareness. However, our results are different from previous morphometric studies in which meditation was associated with structural increases. We posit that this discrepancy may be due to the differences between the adolescent brain and the adult brain.

Graph theory analysis of structural brain networks derived from diffusion tensor imaging (DTI) has become a popular analytical method in neuroscience, enabling advanced investigations of neurological and psychiatric disorders. The purpose of this study was to investigate: 1) the effects of edge weighting schemes, and 2) the effects of varying interscan periods on graph metrics' test-retest reliability within the adolescent brain. We compared a binary (B) network definition with three weighting schemes: fractional anisotropy (FA), streamline count (SC), and streamline count with density and length correction (SDL). Two commonly used global and two local graph metrics were examined. The analysis was conducted with two groups of adolescent volunteers who received DTI scans either 12 weeks apart (16.62±1.10yrs) or within the same scanning session (30 minutes apart) (16.65±1.14yrs). The intraclass correlation coefficient (ICC) was used to assess test-retest reliability and the coefficient of variation (CV) was used to assess precision. On average, each edge scheme produced reliable results at both time intervals. Weighted measures outperformed binary measures, with SDL-weights producing the most reliable metrics. All edge schemes except FA displayed high CV values, leaving FA as the only edge scheme that consistently showed high precision while also producing reliable results. Overall findings suggest that FA-weights are more suited for DTI connectome studies in adolescents.

Although no longer considered a public health threat, post-COVID cognitive syndrome continues to impact on a considerable proportion of individuals who were infected with COVID-19. Recent studies have also suggested that COVID may be represent a critical risk factor for the development of Alzheimer's disease (AD). We compared 17 COVID patients with 20 controls and evaluated the effects of COVID-19 on general cognitive performance, hippocampal volume, and connections using structural and seed-based connectivity analysis. We showed that COVID patients exhibited considerably worse cognitive functioning and increased hippocampal connectivity supported by the strong correlation between hippocampal connectivity and cognitive scores. Our findings of higher hippocampal connectivity with no observable hippocampal morphological changes even in mild COVID cases may be represent evidence of a prestructural compensatory mechanism for stimulating additional neuronal resources to combat cognitive dysfunction as recently shown for the prodromal stages of degenerative cognitive disorders. Our findings may be also important in light of recent data showing that other viral infections as well as COVID may constitute a critical risk factor for the development of AD. To our knowledge, this is the first study that investigated network differences in COVID patients, with a particular focus on compensatory hippocampal connectivity.

Mitragyna speciosa is reported to be beneficial for the management of chronic pain and opioid withdrawal in the evolving opioid epidemic. Data on the blood-brain barrier (BBB) transport of mitragynine and 7-hydroxymitragynine, the active compounds of the plant, are still lacking and inconclusive. Here, we present for the first time the rate and the extent of mitragynine and 7-hydroxymitragynine transport across the BBB, with an investigation of their post-BBB intra-brain distribution. We utilized an in vitro BBB model to study the rate of BBB permeation of the compounds and their interaction with efflux transporter P-glycoprotein (P-gp). Mitragynine showed higher apical-to-basolateral (A-B, i.e. blood-to-brain side) permeability than 7-hydroxymitragynine. 7-Hydroxymitragynine showed a tendency to efflux, with efflux ratio (B-A/A-B) of 1.39. Both were found to inhibit the P-gp and are also subject to efflux by the P-gp. Assessment of the extent of BBB transport in vivo in rats from unbound brain to plasma concentration ratios (K_p,uu,brain ) revealed extensive efflux of both compounds, with less than 10 percent of unbound mitragynine and 7-hydroxymitragynine in plasma crossing the BBB. By contrast, the extent of intra-brain distribution was significantly different, with mitragynine having 18-fold higher brain tissue uptake in brain slice assay compared with 7-hydroxymitragynine. Mitragynine showed a moderate capacity to accumulate inside brain parenchymal cells, while 7-hydroxymitragynine showed restricted cellular barrier transport. The presented findings from this systematic investigation of brain pharmacokinetics of mitragynine and 7-hydroxymitragynine are essential for design and interpretation of in vivo experiments aiming to establish exposure-response relationship.

BACKGROUND: Prolonged lowering of blood pressure after a stroke reduces the risk of recurrent stroke. In addition, inhibition of the renin-angiotensin system in high-risk patients reduces the rate of subsequent cardiovascular events, including stroke. However, the effect of lowering of blood pressure with a renin-angiotensin system inhibitor soon after a stroke has not been clearly established. We evaluated the effects of therapy with an angiotensin-receptor blocker, telmisartan, initiated early after a stroke.

METHODS: In a multicenter trial involving 20,332 patients who recently had an ischemic stroke, we randomly assigned 10,146 to receive telmisartan (80 mg daily) and 10,186 to receive placebo. The primary outcome was recurrent stroke. Secondary outcomes were major cardiovascular events (death from cardiovascular causes, recurrent stroke, myocardial infarction, or new or worsening heart failure) and new-onset diabetes.

RESULTS: The median interval from stroke to randomization was 15 days. During a mean follow-up of 2.5 years, the mean blood pressure was 3.8/2.0 mm Hg lower in the telmisartan group than in the placebo group. A total of 880 patients (8.7%) in the telmisartan group and 934 patients (9.2%) in the placebo group had a subsequent stroke (hazard ratio in the telmisartan group, 0.95; 95% confidence interval [CI], 0.86 to 1.04; P=0.23). Major cardiovascular events occurred in 1367 patients (13.5%) in the telmisartan group and 1463 patients (14.4%) in the placebo group (hazard ratio, 0.94; 95% CI, 0.87 to 1.01; P=0.11). New-onset diabetes occurred in 1.7% of the telmisartan group and 2.1% of the placebo group (hazard ratio, 0.82; 95% CI, 0.65 to 1.04; P=0.10).

CONCLUSIONS: Therapy with telmisartan initiated soon after an ischemic stroke and continued for 2.5 years did not significantly lower the rate of recurrent stroke, major cardiovascular events, or diabetes. (ClinicalTrials.gov number, NCT00153062.)

Dopamine replacement therapy is the main method of treating Parkinson’s Disease (PD), however over time this treatment causes increasingly abnormal, involuntary movements. This symptom, known as Levodopa-Induced-Dyskinesia (LID) is associated with aberrant, high frequency oscillations (HFOs) in the motor cortex and basal ganglia, as demonstrated with implanted electrodes in human Parkinson’s patients as well as in a rat model of Parkinson’s Disease. However, despite efforts to determine if the same high frequency oscillations are also present during dyskinesia in the widespread 6-OHDA mouse model of Parkinson’s Disease, studies have been unable to do so. By building and implanting a 64-channel multi-electrode array into a unilateral 6-OHDA lesioned mouse, we were able to record HFOs at 80Hz and >100Hz in the motor cortex, basal ganglia and thalamus in the lesioned hemisphere during LID. We also recorded bilateral HFOs at >100Hz in the intact hemisphere. With this work we show that the same HFOs that are present in the motor cortex and basal ganglia of rats and humans are also present in mice during dyskinesia. This work will act to further validate the 6-OHDA PD-model in mice and provide opportunities to investigate new treatments for Parkinson’s Disease, dyskinesia and other neurological conditions. It will also serve as a model to study a purposed mechanism underlying the information processing in populations of neurons.

Parkinson’s Disease affects 10 million people worldwide, with 40% of patients developing an associated psychosis which has been identified by studies as the number one source of caretaker distress and is related to increased mortality. This is further complicated by the fact that typical antipsychotic drugs worsen many of the motor symptoms implicated in Parkinson’s Disease, with only one commercially available drug able to ameliorate both symptoms. This problem ushers the development of novel drugs to treat these symptoms, as first tested on research animals. Complicating matters, drug effectiveness on the degree of psychosis is hard to obtain in animals without a reliable biomarker. However, a hallmark of psychotic states is thought to be the reduced coordination between brain structures, through neuronal synchronization, as demonstrated by steady-state responses and is suggested to be a potential biomarker of psychosis. By building a MATLAB software we were able to analyze the degree of neural synchronization between structures, during an auditory steady-state response, in rats that had been unilaterally lesioned by the 6-Hydroxydopamine model of Parkinson’s Disease, before and after administration of the psychotomimetic drug MK801. These rats had been chronically implanted with 128-channel multi electrode array, enabling us to measure the strength of coherence between several limbic structures, associated with auditory processing, from the sampled local field potential, identifying the degree of synchronization in the animal brain. As our data demonstrate that coherence levels dropped in the psychotic drug state, for structures in both the healthy and the Parkinsonian hemisphere, we are able to further demonstrate the validity of coherence measures as a biomarker for psychosis. These results demonstrate that our software can be used as a tool to assess the therapeutic response of drugs developed, aimed at treating Parkinson’s associated psychosis.

Zebrafish is a frequently used model organism with an array of transgenic lines that have been used indevelopmental and physiological studies.

We aim to generate novel transgenic zebrafish reporter lines to study subpopulations of spinal neurons in vivo.

The gene editing system called CRISPR/Cas9 system was used to knock in reporter genes such as green fluorescent protein (GFP) or Gal4 transcription factor, to generate transgenic fish lines. Zebrafish embryos were injected with gRNAs targeting gabrb1 or nr4a2a and GFP or Gal4 plasmid, respectively. F0 larvae were screened, positive fish were raised until sexual maturity, and founders characterized to verify germline insertion. Three founders were found for gabrb1 and the location and the direction of the insert verified. The GFP expression was studied during development and differential expression patterns were identified whereas all founders had expression in brain and spinal cord. In parallel, positive fish from the Gal4 injections were raised and will be screened. Immunohistochemistry was performed to check if nr4a2a is expressed in the same cells as known neuronal markers. However, no co-localization was detected.

The three gabrb1 founders identified in this study highlight the challenges into creating stable transgenic lines recapitulating true expression of the gene of interest. Sequencing, in-situ hybridization and immunohistochemistry should be performed to verify the line. A possible reason for the varying expression may be that through the knock-in we may interfere with regions regulating gene. The nr4a2a-Gal4 line will be used to perform functional studies. Those experiments will be performed using reporter genes, such as opsins or GCaMP, controlled by Upstream Activation Sequence (UAS). These transgenic lines will provide important insights regarding neuronal subpopulations that express gabrb1 and nr4a2a to unravelhow the locomotor network is formed. 

A dominant approach to brain mapping is to define functional regions in the brain by analyzing brain activation images obtained by PET or fMRI. In [1], it has been shown that the scale-space primal sketch provides a useful tool for such analysis. Some attractive properties of this method are that it only makes few assumptions about the data and the process for extracting activations is fully automatic.

In the present version of the scale-space primal sketch, however, there is no method for determining p-values. The purpose here is to present a new methodology for addressing this question, by introducing a descriptor referred to as the -curve, which serves as a first step towards determining the probability of false positives, i.e. alpha.

Introduction

Primary brain tumors are a common cause of morbidity and mortality in children and young people (CYP) globally. Impaired neurocognitive function is a potential severe consequence in primary brain tumor (PBT) survivors. There are no in-depth studies from low- and middle-income countries (LMICs) to inform management and follow-up. The research questions of this study were as follows: Are the sociodemographic factors (lower age of CYP, female gender, low socioeconomic status, low parental education), disease-related factors (high grade of tumor, presence of seizures, presence of hydrocephalous), and treatment-related factors (adjuvant therapy, no surgical intervention, post-treatment seizures, placement of shunts) associated with decline in neurcognition outcomes 12 months post-treatment in CYP with PBTs?

Methods

A prospective cohort study was conducted from November 2020 to July 2023 at the Aga Khan University Hospital and Jinnah Postgraduate Medical Centre, tertiary care hospitals in Karachi, Pakistan. All CYP aged 5 to 21 years with a newly diagnosed PBTs were eligible. The neurocognition assessment was undertaken by a psychologist at two points, i.e., pre-treatment and at 12 months post-treatment using validated tools. The verbal intelligence was assessed by Slosson Intelligence tool, revised 3rd edition (SIT-R3), perceptual reasoning by Raven’s Progressive Matrices (RPM), and the Processing Speed Index by Wechsler Intelligence Scale (WISC V) and Wechsler Adult Intelligence Scale (WAIS-IV). The data were analyzed by STATA version 12 software. Generalized estimating equation (GEE) was used to determine the factors associated with the mean change in 12 months post-treatment verbal and non-verbal neurocognition scores. Unadjusted and adjusted beta coefficients with their 95% confidence intervals were reported.

Results

A total of 48 CYPs with PBTs were enrolled, 23 (48%) of them were lost to follow-up and 10 (21%) died. The remaining 25 (52%) were reassessed 12 months after treatment. On multivariable analysis, a significant decline in verbal intelligence scores at 12 months was predicted by post-treatment seizures beta =  − 20.8 (95% CI, − 38.2, − 3.4), mothers having no formal educational status and lower household monthly income. Similarly, a significant decline in perceptual reasoning scores was also predicted by post-treatment seizures beta =  − 10.7 (95% CI, − 20.6, − 0.8), mothers having no formal education and having lower household monthly income. Worsening of processing speed scores at 12 months post-treatment were predicted by tumor histology, post-treatment seizures beta =  − 33.9 (95% CI, − 47.7, − 20.0), lower educational status of the mother, and having lower household monthly. However, an improvement was seen in processing speed scores after surgical tumor resection.

Conclusion

In this novel study, the post-treatment mean change in verbal and non-verbal neurocognition scores was associated with sociodemographic, tumor, and treatment factors. These findings may have potential implications for targeted early psychological screening of higher risk CYP with PBTs. Identification of these predictors may serve as a foundation for developing more cost-effective treatment thereby alleviating the burden of neurocognitive morbidity. However to establish generalizability, future research should prioritize larger-scale, multicountry studies. (Trial registration: ClinicalTrials.gov Identifier: NCT05709522)

Reciprocal interactions between the nervous and immune systems have gained a lot of attention in the last two decades, especially after demonstrating that cytokine immunotherapies can induce depression and after describing the inflammatory reflex. A lot of effort has been dedicated to understanding how the signals from the immune system reach the brain and vice versa, and on their role in health and disease. However, it is not well-known which of the brain circuits, receptors and signalling molecules give rise to behavioural and affective changes induced by inflammation, such as reduced food intake and induction of negative mood. Moreover, although it is well established that early life stress leads to an increased risk of developing inflammatory diseases in adulthood, the acute effects of stress on the inflammatory response in childhood are not well described. Using mouse models of systemic and local inflammation, I studied (1) how inflammatory pain elicits negative affect, (2) if CGRPα is necessary for parabrachial-amygdaloid pathway-mediated behaviours associated with pain and inflammation, and finally, (3) what are the effects of stress on the inflammatory process during early life. The results indicate that (1) the negative affect of inflammatory pain is triggered by inhibition of serotonergic neurons of the dorsal raphe nucleus, as a result of prostaglandin E2 binding to EP3 receptors; (2) CGRPα is dispensable for most pain- and inflammation-related protective behaviours; (3) acute stress potentiates the pro-inflammatory cytokine expression after an inflammatory challenge in mouse pups. The phenomena studied here can contribute to understanding how immune system activation induces changes in mood and behaviour common for inflammation and depression.

Calcitonin gene related peptide (CGRP) expressing neurons in the parabrachial nucleus have been shown to encode danger. Through projections to the amygdala and other forebrain structures, they regulate food intake and trigger adaptive behaviors in response to threats like inflammation, intoxication, tumors and pain. Despite the fact that this danger-encoding neuronal population has been defined based on its CGRP expression, it is not clear if CGRP is critical for its function. It is also not clear if CGRP in other neuronal structures is involved in danger-encoding. To examine the role of CGRP in danger-related motivational responses, we used male and female mice lacking alpha CGRP, which is the main form of CGRP in the brain. These mice had no, or only very weak, CGRP expression. Despite this, they did not behave differently compared to wildtype mice when they were tested for a battery of danger-related responses known to be mediated by CGRP neurons in the parabrachial nucleus. Mice lacking alpha CGRP and wildtype mice showed similar inflammation-induced anorexia, conditioned taste aversion, aversion to thermal pain and pain-induced escape behavior, although it should be pointed out that the study was not powered to detect any possible differences that were minor or sex-specific. Collectively, our findings suggest that alpha CGRP is not necessary for many threat-related responses, including some that are known to be mediated by CGRP neurons in the parabrachial nucleus.

Little is known about needs of grandparents of young children with autism in family and community settings. This study investigated perceived needs of grandparents of preschool-aged children diagnosed with ASD in the cultural context of Sweden. Participants were 120 grandparents of children enrolled into autism intervention programs provided by the public disability services in Stockholm. The Grandparents’ Needs Survey and the SDQ Impact supplement were used to collect data. Grandparents expressed most needs in topic areas of information and childcare. No significant relations were found between grandparents’ demographics and perceptions of needs; grandparents’ needs were predicted by their perceived burden. The findings provide insight into understanding of grandparents’ needs essential for planning and provision of quality family-centered early intervention services.

Identification of the key components in the physical and chemical milieu directing donor cells into a desired phenotype is a requirement in the investigation of bioscaffolds for the advancement of cell-based therapies for retinal neurodegeneration.

We explore the effect of electrospun poly-ε-caprolactone (PCL) fiber scaffold topography and functionalization and culture medium, on the behavior of mouse retinal cells. Dissociated mouse retinal post-natal cells were seeded on random or aligned oriented fibers, with or without laminin coating and cultured with either basic or neurotrophins enriched medium for 7 days.

Addition of laminin in combination with neurotrophins clearly promoted cell– morphology, fate, and neurite extension. Nanotopography per se significantly affected cell morphology, with mainly bipolar profiles on aligned fibers and more multipolar profiles on random fibers. Laminin induced a remarkable 90° switch of neurite orientation. Herewith, we demonstrate that the chemical cue is stronger than the physical cue for the orientation of retinal neurites and describe the requirement of both neurotrophins and extracellular matrix proteins for extended neurite outgrowth and formation of complex retinal neuronal networks. Therefore, tailor-made PCL fiber mats, which can be physically and chemically modified, indeed influence cell behavior and hence motivate further retinal restorative studies using this system.

Several factors present in the extracellular environment regulate epithelial cell adhesion and dynamics. Among them, growth factors such as EGF, upon binding to their receptors at the cell surface, get internalized and directly activate the acto-myosin machinery. In this study we present the effects of EGF on the contractility of epithelial cancer cell colonies in confined geometry of different sizes. We show that the extent to which EGF triggers contractility scales with the cluster size and thus the number of cells. Moreover, the collective contractility results in a radial distribution of traction forces, which are dependent on integrin beta 1 peripheral adhesions and trans-mitted to neighboring cells through adherens junctions. Taken together, EGF-induced contractility acts on the mechanical crosstalk and linkage between the cell-cell and cell-matrix compartments, regulating collective responses.

The insula contributes to the detection of salient events during goal-directed behavior and participates in the coordination of motor, multisensory, and cognitive systems. Recent task-fMRI studies with trained singers sug-gest that singing experience can enhance the access to these resources. However, the long-term effects of vocal training on insula-based networks are still unknown. In this study, we employed resting-state fMRI to assess experience-dependent differences in insula co-activation patterns between conservatory-trained singers and non-singers. Results indicate enhanced bilateral anterior insula connectivity in singers relative to non-singers with constituents of the speech sensorimotor network. Specifically, with the cerebellum (lobule V-VI) and the superior parietal lobes. The reversed comparison showed no effects. The amount of accumulated singing training pre-dicted enhanced bilateral insula co-activation with primary sensorimotor areas representing the diaphragm and the larynx/phonation area-crucial regions for cortico-motor control of complex vocalizations-as well as the bilateral thalamus and the left putamen. Together, these findings highlight the neuroplastic effect of expert singing training on insula-based networks, as evidenced by the association between enhanced insula co-activation profiles in singers and the brain's speech motor system components.

The insula contributes to the detection and integration of salient events during goaldirected behavior and facilitates the interaction between motor, multisensory, and cognitive networks. Task-fMRI studies have suggested that experience with singing can enhance access to these resources. However, the long-term effects of vocal motor training on insula-based networks are currently unknown. In thisstudy, we used restingstate fMRI to explore experience-dependent differences in insula co-activation patterns between conservatory-trained singers and non-singers. We found enhanced insula connectivity in singers compared to non-singers with constituents of the speech sensorimotor network, including the cerebellum (lobule VI, crus 2), primary somatosensory cortex, the parietal lobes, and the thalamus. Moreover, accumulated singing training correlated positively with increased co-activation in bilateral primary sensorimotor cortices in the somatotopic representations of the larynx (left dorsal anterior insula, dAI) and the diaphragm (bilateral dAI)—crucial regions for motorcortical control of complex vocalizations—together with the thalamus (bilateral posterior insula/left dAI) and the left putamen (left dAI). The results of this study support the view that the insula plays a central role in the experience-dependent modulation of sensory integration within the vocal motor system, possibly by optimizing conscious and non-conscious aspects of salience processing associated with singing-related bodily signals.

Intra- or extracellular aggregates of proteins are central pathogenic features in most neurodegenerative disorders. The accumulation of such proteins in diseased brains is believed to be the end-stage of a stepwise aggregation of misfolded monomers to insoluble cross-beta fibrils via a series of differently sized soluble oligomers/protofibrils. Several studies have shown how alpha-synuclein, amyloid-beta, tau and other amyloidogenic proteins can act as nucleating particles and thereby share properties with misfolded forms, or strains, of the prion protein. Although the roles of different protein assemblies in the respective aggregation cascades remain unclear, oligomers/protofibrils are considered key pathogenic species. Numerous observations have demonstrated their neurotoxic effects and a growing number of studies have indicated that they also possess seeding properties, enabling their propagation within cellular networks in the nervous system. The seeding behavior of oligomers differs between the proteins and is also affected by various factors, such as size, shape and epitope presentation. Here, we are providing an overview of the current state of knowledge with respect to the "prion-like" behavior of soluble oligomers for several of the amyloidogenic proteins involved in neurodegenerative diseases. In addition to providing new insight into pathogenic mechanisms, research in this field is leading to novel diagnostic and therapeutic opportunities for neurodegenerative diseases.

Space coding affects perception of stimuli associated to negative valence: threatening stimuli presented within the peripersonal space (PPS) speed up behavioral responses compared with nonthreatening events. However, it remains unclear whether the association between stimuli and their negative valence is acquired in a body part-centered reference system, a main feature of the PPS coding. Here we test the hypothesis that associative learning takes place in hand-centered coordinates and can therefore remap according to hand displacement. In two experiments, we used a Pavlovian fear-learning paradigm to associate a visual stimulus [light circle, the conditioned stimulus (CS)] with an aversive stimulus (electrocutaneous shock) applied on the right hand only when the CS was displayed close (CS+) but when not far from it (CS−). Measuring the skin conductance response (SCR), we observed successful fear conditioning, with increased anticipatory fear responses associated with CS+. Crucially, experiment I showed a remapping of these responses following hand displacement, with a generalization to both types of CS. Experiment II corroborated and further extended our findings by ruling out the novelty of the experimental context as a driving factor of such modulations. Indeed, fear responses were present only for stimuli within the PPS but not for new stimuli displayed outside the PPS. By revealing a hand-centered (re)mapping of the conditioning effect, these findings indicate that associative learning can arise in hand-centered coordinates. They further suggest that the threatening valence of an object also depends on its basic spatial relationship with our body.

Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4 Gy whole-brain radiation dose on postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed on PND 77, 91, and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors, but neuronal integration occurred only after it was discontinued. Also, the treatment ameliorated deficits in spatial learning and memory retention observed in irradiated mice. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with microtubule stabilization, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced loss of hippocampal neurogenesis and cognitive impairment even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.

Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4 Gy whole-brain radiation dose on postnatal day (PND) 21 and were randomized to 0.24% Li2CO(3) chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed on PND 77, 91, and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors, but neuronal integration occurred only after it was discontinued. Also, the treatment ameliorated deficits in spatial learning and memory retention observed in irradiated mice. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with microtubule stabilization, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced loss of hippocampal neurogenesis and cognitive impairment even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.