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Astrocytes in the somatosensory ventrobasal (VB) thalamus of rats respond to glutamatergic synaptic input with metabotropic glutamate receptor (mGluR) mediated intracellular calcium ([Ca2+]i) elevations. Astrocytes in the VB thalamus also release the gliotransmitter (GT) glutamate in a Ca2+-dependent manner. The tripartite synapse hypothesis posits that astrocytic [Ca2+]i elevations resulting from synaptic input releases gliotransmitters that then feedback to modify the synapse. Understanding the dynamics of this process and the conditions under which it occurs are therefore important steps in elucidating the potential roles and impact of GT release in particular brain activities. In this study, we investigated the relationship between VB thalamus afferent synaptic input and astrocytic glutamate release by recording N-methyl-d-aspartate (NMDA) receptor-mediated slow inward currents (SICs) elicited in neighboring neurons. We found that Lemniscal or cortical afferent stimulation, which can elicit astrocytic [Ca2+]i elevations, do not typically result in the generation of SICs in thalamocortical (TC) neurons. Rather, we find that the spontaneous emergence of SICs is largely resistant to acute afferent input. The frequency of SICs, however, is correlated to long-lasting afferent activity. In contrast to short-term stimulus-evoked GT release effects reported in other brain areas, astrocytes in the VB thalamus do not express a straightforward input–output relationship for SIC generation but exhibit integrative characteristics., Highlights ▶VB thalamus afferents were stimulated at a range of frequencies and durations to investigate the interaction of afferent input and astrocytic glutamate output. ▶Acute afferent activity does not result in the evoking of astrocyte glutamate-mediated slow inward currents. ▶Prolonged afferent activity, however, increases SIC frequency in a time-dependent manner. ▶VB thalamus astrocytes therefore exhibit integrative properties that modulate the rate of spontaneous glutamate release.

Calumenin is a Ca2+-binding protein that belongs to the CREC superfamily. It contains six EF-hand domains that exhibit a low affinity for Ca2+ as well as an endoplasmic reticulum retention signal. Calumenin exhibits a broad and relatively high expression in various brain regions during development as demonstrated by in situ hybridization. Signal intensity of calumenin is highest during the early development and then declines over time to reach a relatively low expression in adult animals. Immunohistochemistry indicates that at the P0 stage, calumenin expression is most abundant in migrating neurons in the zones around the lateral ventricle. In the brain of adult animals, it is expressed in various glial and neuronal cell types, including immature neurons in subgranular zone of hippocampal dentate gyrus. At the subcellular level, calumenin is identified in punctuate and diffuse distribution mostly in somatic regions where it co-localizes with endoplasmic reticulum (ER) and partially Golgi apparatus. Upon subcellular fractionation, calumenin is enriched in fractions containing membranes and is only weakly present in soluble fractions. This study points to a possible important role of calumenin in migration and differentiation of neurons, and/or in Ca2+ signaling between glial cells and neurons., Highlights ▶We analyze the expression of the Ca2+-binding protein calumenin in the rodent brain. ▶Calumenin exhibits higher expression in early developmental stages. ▶Calumenin is expressed by neurons, glia, and progenitor cells. ▶Calumenin co-localizes with the ER and the Golgi complex but not with synaptic sites. ▶Calumenin may play a role in migration, differentiation, and Ca2+ signaling of neurons.

In a previous study the simple, naturally derived coumarin scopoletin (SCT) was identified as an inhibitor of acetylcholinesterase (AChE), using a pharmacophore-based virtual screening approach. In this study the potential of SCT as procholinergic and cognition-enhancing therapeutic was investigated in a more detailed way, using different experimental approaches like measuring newly synthesized acetylcholine (ACh) in synaptosomes, long-term potentiation (LTP) experiments in hippocampal slices, and behavior studies. SCT enhanced the K+-stimulated release of ACh from rat frontal cortex synaptosomes, showing a bell-shaped dose effect curve (Emax: 4 μM). This effect was blocked by the nicotinic ACh receptor (nAChR) antagonists mecamylamine (MEC) and dihydro-β-erythroidine (DHE). The nAChR agonist (and AChE inhibitor) galantamine induced a similar increase in ACh release (Emax: 1 μM). SCT potentiated LTP in hippocampal slices of rat brain. The high-frequency stimulation (HFS)-induced, N-methyl-D-aspartate (NMDA) receptor dependent LTP of field excitatory postsynaptic potentials at CA3-CA1 synapses was greatly enhanced by pre-HFS application of SCT (4 μM for 4 min). This effect was mimicked by nicotine (2 μM) and abolished by MEC, suggesting an effect on nAChRs. SCT did not restore the total inhibition of LTP by NMDA receptor antagonist d, l-2-amino-5-phosphonopentanoic acid (AP-5). SCT (2 μg, i.c.v.) increased T-maze alternation and ameliorated novel object recognition of mice with scopolamine-induced cholinergic deficit. It also reduced age-associated deficits in object memory of 15–18-month-old mice (2 mg/kg sc). Our findings suggest that SCT possesses memory-improving properties, which are based on its direct nAChR agonistic activity. Therefore, SCT might be able to rescue impaired cholinergic functions by enhancing nAChR-mediated release of neurotransmitters and promoting neural plasticity in hippocampus., Highlights ▶The coumarin scopoletin has been described as AChE inhibitor. ▶Now we show it exerts promising procognitive properties via nAChRs. ▶It enhances release of ACh and potentiates hippocampal LTP. ▶It improves novel object recognition and T-maze alternation in scopolamine-amnestic mice and ameliorates object memory in age-impaired mice.

The firing activity of dorsal raphe neurons is related to arousal state. However, it is unclear how this firing activity is precisely related to cortical activity, in particular oscillations occurring during sleep rhythms. Here we conducted single-cell extracellular recordings and juxtacellular labelling while monitoring electrocorticogram (ECoG) activity in urethane anaesthetised rats, to relate activity in neurochemically identified groups of neurons to cortical slow-wave activity (SWA). We observed that electrophysiological heterogeneity in dorsal raphe neurons revealed different neurochemical groups of DRN neurons and was mirrored by significant differences in the phase and strength of coupling to the cortical slow oscillations. Spike firing relationship of clock-like neurons, identified as 5-HT (5-hydroxytryptamine) or serotonin neurons, was higher during the inactive component of the oscillations. In contrast, half of the identified bursting 5-HT neurons did not exhibit strong cortical entrainment; those that did fired most during the inactive component of the SWA. Two groups of putatively non-5-HT neurons (irregular slow-firing and fast-firing) exhibited significant coherence and fired most during the active component of the SWA. These findings indicate that within the DRN electrophysiologically and neurochemically discrete neuronal groups exhibit distinct relations to cortical activity., Highlights ▶DRN neurons exhibit heterogeneous firing in relation to cortical oscillations. ▶Clock-like 5-HT neurons fire most during inactive component of the oscillation. ▶Half of bursting 5-HT neurons did not exhibit coupling to the oscillation. ▶Non-5-HT neurons fired most during the active component of the oscillation.

Many data suggest that alpha synuclein (α-syn) aggregation is involved in Parkinson's disease (PD) neurotoxicity and is accelerated by the pathogenetic point mutation A30P. The triplication of α-syn gene has been linked to early-onset familial PD, suggesting that the cellular dosage of α-syn is an important modulator of its toxicity. To verify this point, we developed an inducible model of α-syn expression (both wild type [WT] and mutated A30P) in rat PC12/TetOn cells. At low expression level, both α-syn(WT) and (A30P) did not aggregate, were not toxic, and displayed a protective action against oxidative stress triggered by hydrogen peroxide (H2O2). By increasing α-syn expression, its antioxidant function was no longer detectable as for the A30P form, but again no aggregation and cell death were present both for the WT and the mutated protein. To clarify why α-syn did not accumulate at high expression level, we inhibited macroautophagy by 3-methyladenine (3-MA) and the proteasome by MG132. In presence of 3-MA, α-syn(WT) accumulated, A11 anti-oligomer antibody-positive aggregates were detectable, and cell toxicity was evident, while proteasome inhibition did not increase α-syn(WT) accumulation. Macroautophagy or proteasome inhibition slightly increased α-syn(A30P) toxicity, with no detectable aggregation. This model can provide useful details about α-syn function, aggregation, and degradation pathways., Graphical abstract Graphical abstract summarizing the main findings of the article. The red flow chart describes the system when α-syn expression was induced at low level, while the green part splits the different scenario for α-syn(WT) and α-syn(A30P) at high expression level. The slot blot shows the appearance of A11 immunoreactivity. 3-MA, 3-methyladenine; doxy, doxycycline. For interpretation of the references to color in this figure legend, the reader is referred to the Web version of this article. Highlights ▶We developed a model of alpha-synuclein (wild type or A30P) expression in PC12 cells. ▶At low alpha-synuclein expression, we found no aggregation but neuroprotection. ▶At high alpha-synuclein expression macroautophagy was activated without aggregation. ▶Macroautophagy inhibition lead to alpha-synuclein wild type aggregation and toxicity. ▶The A30P form was not toxic and its removal involved also the proteasome.

The subiculum is the major output area of the hippocampus. It is closely interconnected with the entorhinal cortex and other parahippocampal areas. In animal models of temporal lobe epilepsy (TLE) and in TLE patients it exerts increased network excitability and may crucially contribute to the propagation of limbic seizures. Using immunohistochemistry and in situ-hybridization we now investigated neuropathological changes affecting parvalbumin and calretinin containing neurons in the subiculum and other parahippocampal areas after kainic acid-induced status epilepticus. We observed prominent losses in parvalbumin containing interneurons in the subiculum and entorhinal cortex, and in the principal cell layers of the pre- and parasubiculum. Degeneration of parvalbumin-positive neurons was associated with significant precipitation of parvalbumin-immunoreactive debris 24 h after kainic acid injection. In the subiculum the superficial portion of the pyramidal cell layer was more severely affected than its deep part. In the entorhinal cortex, the deep layers were more severely affected than the superficial ones. The decrease in number of parvalbumin-positive neurons in the subiculum and entorhinal cortex correlated with the number of spontaneous seizures subsequently experienced by the rats. The loss of parvalbumin neurons thus may contribute to the development of spontaneous seizures. On the other hand, surviving parvalbumin neurons revealed markedly increased expression of parvalbumin mRNA notably in the pyramidal cell layer of the subiculum and in all layers of the entorhinal cortex. This indicates increased activity of these neurons aiming to compensate for the partial loss of this functionally important neuron population. Furthermore, calretinin-positive fibers terminating in the molecular layer of the subiculum, in sector CA1 of the hippocampus proper and in the entorhinal cortex degenerated together with their presumed perikarya in the thalamic nucleus reuniens. In addition, a significant loss of calretinin containing interneurons was observed in the subiculum. Notably, the loss in parvalbumin positive neurons in the subiculum equaled that in human TLE. It may result in marked impairment of feed-forward inhibition of the temporo-ammonic pathway and may significantly contribute to epileptogenesis. Similarly, the loss of calretinin-positive fiber tracts originating from the nucleus reuniens thalami significantly contributes to the rearrangement of neuronal circuitries in the subiculum and entorhinal cortex during epileptogenesis., Graphical Abstract ••• Highlights ▶A subpopulation of PV neurons degenerates in subiculum and entorhinal cortex after KA seizures. ▶Surviving PV neurons exhibit increased PV mRNA expression. ▶The loss in PV neurons in subiculum and entorhinal cortex correlates to spontaneous seizures. ▶Degeneration of PV neurons in the subiculum may be related to seizure-induced loss of feed-forward inhibition. ▶CR-ir neurons in the N. reuniens thalami and their projections to the subiculum degenerate.

Low current cortex stimulation produces a sparse and distributed set of activated cells often with distances of several hundred micrometers between cell bodies and the microelectrode. A modeling study based on recently measured densities of high threshold sodium channels Nav1.2 in dendrites and soma and low threshold sodium channels Nav1.6 in the axon shall identify spike initiation sites including a discussion on dendritic spikes. Varying excitability along the neural axis has been observed while studying different electrode positions and configurations. Although the axon initial segment (AIS) and nodes of Ranvier are most excitable, many thin axons and dendrites which are likely to be close to the electrode in the densely packed cortical regions are also proper candidates for spike initiation sites. Cathodic threshold ratio for thin axons and dendrites is about 1:3, whereas 0.2 μm diameter axons passing the electrode tip in 10 μm distance can be activated by 100 μs pulses with 2.6 μA. Direct cathodic excitation of dendrites requires a minimum electrode-fiber distance, which increases with dendrite diameter. Therefore thin dendrites can profit from the stronger electrical field close to the electrode but low current stimulation cannot activate large diameter dendrites, contrary to the inverse recruitment order known from peripheral nerve stimulation. When local depolarization fails to generate a dendritic spike, stimulation is possible via intracellular current flow that initiates an action potential, for example 200 μm distant in the low threshold AIS or in certain cases at the distal dendrite ending. Beside these exceptions, spike initiation site for cathodic low current stimulation appears rather close to the electrode.

Glutamine plays multiple roles in the CNS, including metabolic functions and production of the neurotransmitters glutamate and GABA. It has been proposed to be taken up into neurons via a variety of membrane transport systems, including system A, which is a sodium-dependent electrogenic amino acid transporter system. In this study, we investigate glutamine transport by application of amino acids to individual principal neurons of the medial nucleus of the trapezoid body (MNTB) in acutely isolated rat brain slices. A glutamine transport current was studied in patch-clamped neurons, which had the electrical and pharmacological properties of system A: it was sodium-dependent, had a non-reversing current-voltage relationship, was activated by proline, occluded by N-(methylamino)isobutyric acid (MeAIB), and was unaffected by 2-aminobicyclo-[2.2.1]-heptane-2-carboxylic acid (BCH). Additionally, we examined the expression of different system A transporter isoforms using immunocytochemical staining with antibodies raised against system A transporter 1 and 2 (SAT1 and SAT2). Our results indicate that both isoforms are expressed in MNTB principal neurons, and demonstrate that functional system A transporters are present in the plasma membrane of neurons. Since system A transport is highly regulated by a number of cellular signaling mechanisms and glutamine then goes on to activate other pathways, the study of these transporters in situ gives an indication of the mechanisms of neuronal glutamine supply as well as points of regulation of neurotransmitter production, cellular signaling and metabolism in the native neuronal environment.

Lamina I of the spinal dorsal horn contains neurons that project to various brain regions, and approximately 80% of these projection cells express the neurokinin 1 receptor (NK1r), the main receptor for substance P. Two populations of NK1r-immunoreactive neurons have been identified in lamina I: small weakly immunoreactive cells and large cells with strong immunolabelling [Cheunsuang O and Morris R (2000) Neuroscience 97:335-345]. The main aim of this study was to test the hypothesis that the large cells are projection neurons and that the small cells are interneurons. Projection neurons were identified by injection of tracers into the caudal ventrolateral medulla and lateral parabrachial area, and this was combined with immunostaining for NK1r. We found a bimodal size distribution for NK1r-immunoreactive neurons. The small cells (with somatic cross-sectional areas200 microm(2)) showed weak immunoreactivity, while immunostaining intensity was variable among the large cells. Virtually all (99%) of the immunoreactive cells with soma areas200 microm(2) were retrogradely labelled, while only 10% of retrogradely labelled cells were smaller than this. Soma sizes of retrogradely labelled neurons that lacked NK1r did not differ from those of NK1r-expressing projection neurons. It has been suggested that a population of small pyramidal projection neurons that lack NK1r may correspond to cells activated by innocuous cooling, and we therefore assessed the morphology of retrogradely labelled cells that were not NK1r-immunoreactive. Fifteen percent of these were pyramidal, but these did not differ in size from pyramidal NK1r-immunoreactive projection neurons. These results confirm that large NK1r-immunoreactive lamina I neurons are projection cells, and suggest that the small cells are interneurons. Since almost all of the NK1r-immunoreactive cells with soma size200 microm(2) were retrogradely labelled, cells of this type can be identified as projection cells in anatomical studies.

The purpose of this study was to determine whether a decrease in cyclic AMP accumulation mediates the inhibition of norepinephrine release in response to alpha-2 adrenergic receptor activation in cultured rat superior cervical ganglion cells. Superior cervical ganglia from neonatal rats were dissociated and cultured on collagen-coated plastic strips. Neurotransmitter release was assessed by measuring the fractional overflow of tritium in superfused cells prelabeled with [ 3 H]norepinephrine. Intracellular cyclic AMP accumulation was measured using radioimmunoassay. Electrical field stimulation at 1 Hz, 30 pulses, 1 ms duration at 20 min intervals produced an increase in the fractional overflow of tritium that was composed predominantly of intact [ 3 H]norepinephrine. The alpha-2 adrenergic receptor agonist UK-14,304 dose-dependently attenuated the increase in fractional tritium overflow elicited by electrical field stimulation. The adenylyl cyclase activator, forskolin, increased cyclic AMP accumulation in superior cervical ganglion cells and UK-14,304 dose-dependently inhibited forskolin-stimulated cyclic AMP accumulation. UK-14,304 had no effect on basal cyclic AMP accumulation or cyclic AMP accumulation during electrical field stimulation. Forskolin (1–10 μM) or the non-hydrolysable cAMP analog, 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate (1–100 μM), slightly increased basal and dose-dependently potentiated the increase in fractional tritium overflow in response to electrical stimulation. Despite enhancement by forskolin and 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate of fractional tritium overflow caused by electrical field stimulation, UK-14304 (1–10 μM) reduced release to a similar degree as that observed in the absence of forskolin or 8-(4-chlorophenylthio)adenosine 3′,5′-cyclic monophosphate. These data suggest that in cultured rat superior cervical ganglion cells, stimulation of alpha-2 adrenergic receptors decreases cyclic AMP accumulation when adenyl cyclase is activated. A decrease in cyclic AMP does not mediate the inhibition of [ 3 H]norepinephrine release in response to alpha-2 adrenergic receptor activation, although elevations in cyclic AMP can enhance electrically-stimulated release of [ 3 H]norepinephrine.

International audience; Most of the literature on the brain impedance proposes a frequency independent resistive model. Recently, this conclusion was tackled by a series of papers (Bé-dard et al., 2006; Bédard and Destexhe, 2009; Gomes et al., 2016), based on microscopic scale modelling and measurements. Our paper aims to investigate the impedance issue using simultaneous in vivo depth and surface signals recorded during intracerebral electrical stimulation of epileptic patients, involving a pri-ori different tissues with different impedances. Our results confirm the conclusions from (Logothethis et al., 2007): there is no evidence of frequency dependence of the brain tissue impedance (more precisely, there is no difference, in terms of frequency filtering, between the brain and the skull bone), at least at a macroscopic scale. In order to conciliate findings from both microscopic and macroscopic scales, we recall different neural/synaptic current generators models from the literature and we propose an original computational model, based on fractional dynamics.

Gut microbiota represents a diverse and dynamic population of microorganisms harbouring the gastrointestinal tract, which influences host health and disease. Bacterial colonization of the gastrointestinal tract begins at birth and changes throughout life, with age being one of the conditioning factors for its vitality. Aging is also a primary risk factor for most neurodegenerative diseases. Among them, Alzheimeŕs disease (AD) is probably the one where its association with a state of dysbiosis of the gut microbiota has been most studied. In particular, intestinal microbial-derived metabolites have been associated with β-amyloid formation and brain amyloid deposition, tau phosphorylation, as well as neuroinflammation in AD patients. Moreover, it has been suggested that some oral bacteria increase the risk of developing AD. However, the causal connections among microbiome, amyloid-tau interaction, and neurodegeneration need to be addressed. This paper summarizes the emerging evidence in the literature regarding the link between the oral and gut microbiome and neurodegeneration with a focus on AD. Taxonomic features of bacteria as well as microbial functional alterations associated with AD biomarkers are the main points reviewed. Data from clinical studies as well as the link between microbiome and clinical determinants of AD are particularly emphasized. Further, relationships between gut microbiota and age-dependent epigenetic changes and other neurological disorders are also described. Together, all this evidence suggests that, in some sense, gut microbiota can be seen as an additional hallmark of human aging and neurodegeneration., Funding: Research in our labs is funded by Grants PID2019-108851RB-C21, PGC2018-096177-B-I00 & PID2021-123859OB-100 (Spanish Ministry of Science and Innovation), and ALIBIRD-CM 2020 P2018/BAA-4343 (Comunidad de Madrid, Spain). The authors would like to thank CSIC Interdisciplinary Thematic Platform (PTI + NEURO-AGING+) and Institutional grants from the Fundación Ramón Areces and Banco de Santander are also acknowledged.

Two major neurotrophic factors, nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) are involved in a number of physiological processes associated with neuronal growth, survival and plasticity. There are an increasing number of papers demonstrating their ability to serve as neuroprotective molecules under various pathological conditions. At the same time, it remains unclear whether both NGF and BDNF have similar roles under pathological conditions and their effects on the electrophysiological properties of neurons after acute pathogen exposure. In the present paper we investigated the neuroprotective role of these two neurotrophins in a well-characterized model of beta-amyloid peptide (Aβ)-dependent impairment of long-term potentiation (LTP). Using lentiviral gene delivery we performed long-term elevation of neurotrophin expression in the dentate gyrus (DG) of rats. One week after virus injection acute brain slices were incubated with beta-amyloid (25-35) for 1h and afterward in vitro LTP induction was performed in medial perforant path-DG synapses. We demonstrate that chronic elevation of NGF but not BDNF concentration protects LTP induction from beta-amyloid action. Further inhibitory analysis suggests that the effect of NGF is mediated by PI3K-signaling cascade.

Electroencephalography (EEG) signals are nonlinear and non-stationary sequences that carry much information. However, physiological signals from other body regions may readily interfere with EEG signal capture, having a significant unfavorable influence on subsequent analysis. Therefore, signal denoising is a crucial step in EEG signal processing. This paper proposes a bidirectional gated recurrent unit (GRU) network based on a self-attention mechanism (BG-Attention) for extracting pure EEG signals from noise-contaminated EEG signals. The bidirectional GRU network can simultaneously capture past and future information while processing continuous time sequence. And by paying different levels of attention to the content of varying importance, the model can learn more significant feature of EEG signal sequences, highlighting the contribution of essential samples to denoising. The proposed model is evaluated on the EEGdenoiseNet data set. We compared the proposed model with a fully connected network (FCNN), the one-dimensional residual convolutional neural network (1D-ResCNN), and a recurrent neural network (RNN). The experimental results show that the proposed model can reconstruct a clear EEG waveform with a decent signal-to-noise ratio (SNR) and the relative root mean squared error (RRMSE) value. This study demonstrates the potential of BG-Attention in the pre-processing phase of EEG experiments, which has significant implications for medical technology and brain-computer interface (BCI) applications.

Major depressive disorder (MDD) is a serious disease associated with abnormal brain regions, however, the interconnection between specific brain regions related to depression has not been fully explored. To solve this problem, the paper proposes a novel multiscale community detection method to compare the differences in brain regions between normal controls (NC) and MDD patients. This study adopted the Brainnetome Atlas to divide the brain into 246 regions and extract the time series of each region. The Pearson correlation was used to measure the similarity among different brain regions to conduct the brain functional network and to perform multiscale community detection. The optimal brain community structure of each group was further explored based on the modularized Qcut algorithm, normalized mutual information (NMI), and variation of information (VI). The Jaccard index was then applied to compare the abnormalities of each brain region from different community environments between the brain function networks of NC and MDD patients. The experiments revealed several abnormal brain regions between NC and MDD, including the superior frontal gyrus, middle frontal gyrus, inferior frontal gyrus, orbital gyrus, superior temporal gyrus, middle temporal gyrus, inferior temporal gyrus, posterior superior temporal sulcus, inferior parietal gyrus, precuneus, postcentral gyrus, insular gyrus, cingulate gyrus, hippocampus and basal ganglia. Finally, a new subnetwork related to cognitive function was discovered, which was composed of the island gyrus and inferior frontal gyrus. All experiments indicated that the proposed method is useful in detecting functional brain abnormalities in MDD, and it can provide valuable insights into the diagnosis and treatment of MDD.

Although the exact etiology of Parkinson's disease (PD) is still unknown, there are a variety of treatments available to alleviate its symptoms according to the development stage of PD. Deep brain stimulation (DBS), the most common surgical treatment for advanced PD, accurately locates and implants stimulating electrodes at specific targets in the brain to deliver high-frequency electrical stimulation that alters the excitability of the corresponding nuclei. However, for different patients and stages of PD development, there exists a choice of the optimal DBS protocol. In this paper, we propose a quantitative method (multi-dimensional feature indexes) to determine the stimulation pattern, stimulation parameters, and target of DBS from the perspective of the network model. On the other hand, based on this method, the development of PD can be predicted so that timely treatment can be given to patients. Simulation results show that, first, different network states can be distinguished by extracting features of the firing activity of neuronal populations within the basal ganglia network system. Secondly, the optimal DBS treatment can be selected by comparing the feature indexes vectors of the pre- and post-state of the network after the action of different modes of DBS. Lastly, the evolution of the network state from normal to pathological is simulated. The critical point of network state transitions is determined. These results provide a quantitative and qualitative method for determining the optimal regimen for DBS for PD, which is helpful for clinical practice.

This special issue of Neuroscience, “From Cochlea to Cortex: Recent Advances in Auditory Neuroscience,” was organized as a tribute to the pioneering contributions to the field by Kirsten Kjelsberg Osen, Professor Emeritus, The University of Oslo. In this introduction, we summarize her professional career, highlighting her numerous scientific achievements, and provide references to all of her published papers. In addition, we briefly summarize the contents of the 35 papers that make up the issue.

Losses of working and long-term memory are hallmarks of human aging and may signal impending neurodegenerative disease. The maintenance of neural elements in brain systems that support memory, such as synapse formation in prefrontal cortex and hippocampus, are critical for cognitive health in aging. This paper reviews the biological basis for androgens as neuroprotectants or neuromodulators in aging and the importance of androgens on the brain systems important for memory. We relate biological effects to cognitive outcomes in elderly men under a variety of androgen conditions. In brief, androgen deprivation causes significant loss of synapses in the hippocampus in rodent and nonhuman primates, increases amyloid deposition in human and rodent models and causes changes in neurotransmission in prefrontal cortex in rodent models. Recent work suggests that these changes modify age-related cognitive loss, particularly to memory in men. In addition, the conversion of testosterone to its androgen metabolites or to estradiol may play a special role in the preservation of memory in aging. This paper reviews discrepancies between studies using animal models and studies of human cognition, and suggests new directions that are likely to be fruitful in the future for understanding the role of androgens in brain aging. This review suggests that studies of low androgen levels in older men may not index the same biological mechanisms and behavioral effects as the studies of gonadectomy in animal models.

The ideas of dynamical chaos have altered our understanding of the origin of random appearing behavior in many fields of physics and engineering. In the 1980s and 1990s these new viewpoints about apparent random oscillations arising in deterministic systems were investigated in neurophysiology and have led to quite successful reports of chaos in experimental and theoretical investigations. This paper is a "view" paper addressing the role of chaos in living systems, not just reviewing the evidence for its existence, and in particular we ask about the utility of chaotic behavior in nervous systems. From our point of view chaotic oscillations of individual neurons may not be essential for the observed activity of neuronal assemblies but may, instead, be responsible for the multitude of regular regimes of operation that can be accomplished by elements which are chaotic. The organization of chaotic elements in assemblies where their synchronization can result in organized adaptive and reliable activities may lead to general principles used by nature in accomplishing critical functional goals.

This paper examines the relation, or "synaptic coding", between the discharges of inhibitory fibres whose instantaneous firing rate is modulated periodically and pacemaker postsynaptic neurons using crayfish synapses and point process statistics. Several control parameters were varied individually, and the other maintained constant as far as possible: it extends the preceding publication that described the general features and varied only the modulation frequency [Segundo et al. (1995) Neuroscience 68, 657-692]. Statistics were mainly cycle histograms and Lissajous diagrams (with presynaptic and post-synaptic histograms on the abscissae and ordinate, respectively), complemented occasionally by displays of intervals along time and of interval differences along order ("basic graphs" and "recurrence plots", respectively). The postsynaptic influence of modulated inhibitory discharges is characteristically sensitive to all control parameters examined. (1) The frequency was reported in the companion paper [Segundo et al. (1995) Neuroscience 68, 657-692]. (2) The average slope per half-cycle, controlled via either frequency or depth, acts by way of its magnitude and sign in ways revealed by hysteretic loops. Hysteresis increases and varies as the modulation's steepness increases: it is minor and with a single clockwise loop at small slopes, but major and multi-looped at the larger ones. Slopes, because of their different postsynaptic consequences, were separated into the categories of "steep", "gentle" and "abrupt" if around, respectively, 1.0, 30.0 and 150.0 s-2. The influence of slopes in restricted portions of the cycle depends on their position on the inhibitory rate scale. (3) The modulation's range acts by way of its depth and of its position on the inhibitory rate scale. Deeper ranges, when compared with the shallower ones they contain, induce effects similar to those of shallower modulations with their central portion, plus effects peculiar to them at extreme rates. Changes in range position from the centre to the extremes of the inhibitory rate scale are influential (e.g., saturations appear). Changes within the centre can be highly influential, particularly when ranges are narrow and close to the postsynaptic natural rate, and modulation frequencies are low: relations between corresponding rates can be linear increasing, linear decreasing or piecewise linear. Changes around extreme rates are negligible, however, and saturations are present. (4) The usual modulations whose individual cycles did not differ from the cycle histogram were compared to others with the same cycle histograms but whose individual cycles had an unpredictable fast variability referred to as "noise".(ABSTRACT TRUNCATED AT 400 WORDS)

Neuroscientific research on pleasant touch has focused on the C-tactile pathway for gentle stroking and has successfully explained how these sensory fibers transmit information about affective social touch to the brain and induce sensations of pleasantness. The C-tactile social/affective touch hypothesis even proposes that C-tactile fibers form a privileged pathway underlying social touch. However, deep pressure is a type of touch commonly considered pleasant and calming, occurring in hugs, cuddling, and massage. In this paper we introduce a paradigm for studying pleasant deep pressure and propose that it constitutes another important form of social touch. We describe development of the oscillating compression sleeve (OCS) as one approach to administering deep pressure and demonstrate that this touch is perceived as pleasant and calming. Further, we show that deep pressure can be imaged with functional magnetic resonance imaging (MRI) using the air-pressure-driven OCS and that deep pressure activates brain regions highly similar to those that respond to C-tactile stroking, as well as regions not activated by stroking. We propose that deep pressure constitutes another social touch pathway of evolutionary importance signaling the close proximity of conspecifics.

When an area of the adult rat CNS is depleted of neurons by an in situ excitotoxic injection, afferent axons to the area exhibit morphological alterations reminiscent of growth cones. These morphological changes are likely to be related to the deprivation of target cells. In addition, however, the area of neuronal loss is itself the site of profound changes in glial cell content, and altered axon-glial interactions may play a role in the axonal changes. In an attempt to define these interactions, we have undertaken a systemic study of glial populations in excitotoxically lesioned CNS over time. The microglial/macrophagic response is analysed in this paper; the astrocytic response is described in the companion paper [Dusart et al . (1991) Neuroscience 45 , 541–549]. The microglial/macrophagic response was studied following kainic acid-induced neuronal loss in the thalamus of the adult rat. These microglial/macrophagic cells were labeled with the B4 isolectin from Griffonia simplicifolia , and the time-course of their response was studied between one day and one year post-lesion. This time-course study revealed different stages in the evolution of the response. At one day post-lesion, cell counts indicated that there was no increase in the number of non-neuronal cells in the neuron-depleted area. However, activated labeled cells were present in the entire thalamus on the side of the lesion, neuron-depleted or not. They were characterized by both increased lectin-binding and altered morphology when compared to quiescent microglia. In the absence of recruitment and/or proliferation, this result indicates that the early response consisted solely of the activation of resident microglia. By contrast, we observed a progressive increase in the number of non-neuronal cells in the lesion from four to 15 days post-lesion. A recruitment of blood-borne monocytes was apparent, and the observation of mitotic labeled cells indicated a proliferation of microglial/macrophagic cells in situ . There was a progressive decrease in the microglial/macrophagic reaction that began one month after lesion. In a thin band of parenchyma surrounding the neuron-depleted area, activated microglial/macrophagic cells were seen contacting neurons, and clusters of glial cells were observed around neurons up to one year post-lesion. These results suggest that neurons around the lesion site itself may be injured, secondarily, from a long term deleterious effect of the inflammatory process. This study allows us to conclude that activated microglia/macrophages are the predominant glial cell type in the excitotoxically lesioned CNS over the first weeks. It is known that, in their activated stage, these cells are able to release numerous factors acting on other cell types. It is proposed, therefore, that microglia/macrophages may play a key role in the evolution of cellular populations observed in the area of neuronal loss.

Choline acetyltransferase (ChAT) synthesizes the neurotransmitter acetylcholine (Ach). Exogenous supplementation with ChAT can functionally compensate for decreased Ach levels and ameliorate memory and cognitive deficits. In this paper, the treatment efficacy of recombinant ChAT (peptide transduction domain (PTD)-ChAT) and donepezil were compared in aged dementia mice, and their mechanisms were explored by performing the gene function annotation and enrichment analysis of differentially expressed genes. The Morris water maze test showed that the swimming times of PTD-ChAT-treated (4 mg/kg) and donepezil-treated (0.5 mg/kg) mice with mild and moderate dementia were significantly shortened (P 0.01 vs aged dementia mice), and no significant changes were observed between the PTD-ChAT- and donepezil-treated groups. In contrast, the swimming times of PTD-ChAT-treated mice with severe dementia were noticeably shorter than those of donepezil-treated mice with severe dementia (P 0.01), indicating that the treatment efficacy of PTD-ChAT is superior to that of donepezil. The effect of PTD-ChAT was further confirmed in transgenic dementia mice (C57BL/6J-TgN (APP/PS1) ZLFILAS). Gene function annotation and enrichment analysis showed that PTD-ChAT improved cognitive deficits through Ach and was implicated in neuroprotection, synaptic plasticity, neuronal survival, and cerebrovascular remodeling through ACh and vascular endothelial growth factor (VEGF) pathway activation. Donepezil was significantly correlated with the immune inflammatory response and the insulin and IGF-1 signaling pathways. Therefore, although PTD-ChAT and donepezil were both effective in the treatment of aged dementia mice, their mechanisms were significantly different. Our research indicated that PTD-ChAT has potential promise for research on new drugs for AD treatment.

The fact that neurobiological research is reliant upon laboratory-reared rodents is well known. The following paper discusses this topic broadly, but also aims to highlight other species used in the study of the nervous system and the evolution of animal species usage from the end of World War II through recent investigations. Attention is drawn to the dramatic reduction in the diversity of species used in neuroscience, with a significant shift toward two species, the mouse (Mus musculus) and rat (Rattus norvegicus). Such a limitation in animal species causes many difficulties in the development of new therapies for various neuropsychiatric diseases. Based on numerous scientific publications, the advantages of using a greater diversity of species in neuroscience and the disadvantages of focusing on mice and rats are presented.

Fetal alcohol spectrum disorders (FASD) constitute a prevalent, yet preventable, developmental disorder worldwide. While a wealth of research demonstrates that altered function of hippocampus and prefrontal cortex may underlie behavioral impairments in FASD, only one published paper to date has examined the impact of developmental alcohol exposure on the region responsible for coordinated prefrontal-hippocampal activity: thalamic nucleus reuniens (Re). In the current study, we used a rodent model of human third trimester alcohol exposure to examine both the acute and lasting impact of a single-day alcohol exposure on Re. We administered 5.25 g/kg of ethanol to male and female Long Evans rat pups on postnatal day (PD) 7. We used unbiased stereological estimation to evaluate cell death or cell loss at three time points: 12 hours after alcohol administration; 4 days after alcohol administration (i.e., PD11); in adulthood (i.e.,postnatal day 72). Alcohol exposure on PD7 increased apoptotic cell death in Re on PD7, and caused short-term cell loss on PD11. This relationship between short-term cell death versus cell number suggests that alcohol-related cell loss is driven by induction of apoptosis. In adulthood, alcohol-exposed animals displayed permanent cell loss (mediating volume loss in the Re), which included a reduction in neuron number (relative to procedural controls). Both procedural controls and alcohol exposed animals displayed a deficit in non-neuronal cell number relative to typically-developing controls, suggesting that Re cell populations may be vulnerable to early life stress as well as alcohol exposure in an insult- and cell type-dependent manner.

As the Neuroscience Peer Review Consortium (NPRC) ends its first year, it is worth looking back to see how the experiment has worked. NPRC was conceived in the summer of 2007 at a meeting of editors and publishers of neuroscience journals. One of the working groups addressed whether it was possible to construct a system for permitting authors whose manuscript received supportive reviews at one journal but was not accepted (perhaps because it was not within the scope of the first journal, or not sufficiently novel to merit publication in a general journal and therefore better for a speciality journal) to send a revised manuscript together with its first round of reviews to a new journal for the second round. This would speed up the review process and reduce the work for reviewers and editors. The working group not only designed a framework for transferring reviews among journals, but also implemented it as the NPRC. By the autumn of 2007, more than a dozen major journals had signed onto the NPRC, sufficient to launch the experiment in January, 2008. As of the autumn of 2008, 33 journals belong to the Consortium (Table 1). For details about the NPRC, you can go to its website at http://nprc.incf.org. You will find information for Authors, Reviewers, Editors, and Publishers there, as well as the information on how journals can join the Consortium. Table 1 The NPRC as of November 19, 2008 The editors of Consortium journals were recently polled to determine how the NPRC has been working. They responded that during the first 9 months about 1–2% of manuscripts that they received had been forwarded from another Consortium journal. A similar number had been sent out from each journal to other participants. In most cases, the papers had been expedited, because the editors at the second journal felt the previous reviews, and the authors’ response to them, were sufficiently positive to permit re-review by one or both of the original referees. In those cases when the editor at the second journal felt that they needed to get new reviews, the review time at the second journal was about what it would have been if the paper had been submitted there by ordinary means. So, the savings in time and labor are considerable for most of the papers that are transferred between journals via the NPRC. Why then are so few authors using this option?

Humans are more vulnerable to addiction in comparison to all other mammals, including nonhuman primates, yet there is a lack of research addressing this. This paper reviews the field of comparative addiction neuroscience, highlighting the significant inter-species variation in the mesocortical dopaminergic and other neuromodulatory systems involved in addiction. Artificial selection gives rise to significant changes in neuroanatomy, neurophysiology and behaviour as shown in certain rodent strains and other domesticated animals. These changes occur over a few generations, relatively short periods of time in evolutionary terms, and demonstrate how dynamic these neuromodulatory systems are in response to the environment. During the course of human evolution, traits crucial to our survival, expansion and domination (traits such as the ability to innovate, adapt to different environments and thrive in a civilization) have been positively selected for, yet also predispose humans to addiction. This is evident in our unique neurochemistry and receptor-drug activation potencies. Examples of these are provided as possible targets for precision medicine.

Exploring sexual dimorphisms in the brain morphology is important for their impact and therapeutic implications for several neurological diseases. The hypothesis that sex could influence the transcriptome of brain cells could be the basis regarding the different response to cognitive decline identified in men and women. In this paper, we analyzed several prefrontal cortices (PFC) microarrays datasets of young/middle-aged healthy subjects and then Alzheimer's disease (AD) patients, according to the sex. The significant transcriptomes were overlapped with the main genes characterizing cells of the central nervous system (CNS) in order to determine the respective weighted percentages of significantly expression gene modulation (WPSEG). We identified differences in brain transcriptional activity between young and middle-aged. In middle-aged women, the WPSEG were higher for the Astrocytes, the Endotheliocytes, and the Microglia. In addition, the sex-matched analysis of transcriptome identified a convergent molecular signature in men and women AD patients. Furthermore, the WPSEG belonging to CNS cells in PFC of healthy middle-aged subjects was correlated to AD profiles according to the sex. Since our results, it is possible to conclude that during the aging the PFC' cells adopt transcriptional strategies sex-dependent that could potentially control the development of neurodegenerative diseases.

Directing differentiation of neural stem/progenitor cells (NSCs/NPCs) to produce functional neurons is one of the greatest challenges in regenerative medicine. Our previous paper has confirmed that electrical stimulation has a high efficiency of triggering neuronal differentiation by using isolated filum terminale (FT)-derived NPCs. To further clarify the intrinsic molecular mechanisms, protein–protein interaction (PPI) network analysis was applied to pinpoints novel hubs in electric field (EF)-induced neuronal differentiation. In this study, siRNA transfection of Achaete-scute homolog 1 (Ascl1) in NPCs or NPCs was followed by direct current stimulation at 150 mV/mm. Neuronal differentiation rate and protein expression level were analyzed after 7 or 14 days of electrical stimulation. The data showed that the expression level of Ascl1 was enhanced by electrical stimulation and positively correlated to EF strength. Moreover, we identified that the expression of Ascl1 positively regulated neuronal differentiation of NPCs and can be up-regulated by EF-stimulation through the activation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway. Therefore, this study provides new insights into the role of Ascl1 and its relevant PI3K/Akt pathway in regulating of EF-induced neuronal differentiation and pointed out that continuous expression of Ascl1 in NPCs is required for EF-induced neuronal differentiation.

This article has been retracted at the request of the editors and authors. Please see Elsevier Policy on Article Withdrawal ( http://www.elsevier.com/locate/withdrawalpolicy ). After publication the authors found significant errors in the data, for which they apologize, and asked to retract the paper. In the paper, the TORC1 staining in Figure 5B and Figure 5C may derive from different optical slices of the same retinal section. In Figure 7C and 7D, BDNF mRNA in situ hybridization was detected by probes toward another gene by mistake.

Being able to inhibit an impending movement in response to a contextual change is a distinctive feature of action control. Such inhibitory control relies on a complex cortical–subcortical network, including posterior prefrontal regions such as caudal inferior frontal gyrus and pre-supplementary motor area. According to hierarchical models of action control, both areas represent the intermediate level between prefronto-dependent and motor-related cortices. Going at a lower level, accumulating evidence speaks for an involvement of the primary motor cortex (M1) to dorsal premotor cortex (PMCd) or supplementary motor area proper (SMA-proper) pathways in producing inhibitory control. However, the clear-cut evidence for this conjecture is still missing. The aim of the present paper was to start filling this gap, investigating this lowest level of inhibitory control. We stimulated PMCd in a group of healthy volunteers with transcranial magnetic stimulation (TMS) or sham TMS during the response phase of a STOP-signal task performed with the lips. In a separate experimental group, we applied effective TMS/sham TMS to SMA-proper during the same task. We found that effective TMS over PMCd increased false-start errors in STOP trials (p = 0.0005), but had no effect on GO trial performance (p = 0.85). Effective TMS on SMA-proper produced no effect on STOP trials’ performance (p = 0.31) nor in the GO trial performance (p = 0.56). Our data show that there is at least a portion of PMCd playing a distinctive role in the control of mouth-related M1 during instructed visuomotor inhibitory behavior. This region could therefore represent a low-level hierarchical node for externally cued action inhibition.

Neurodegenerative disorders, including Amyotrophic Lateral Sclerosis (ALS), have been associated to alterations in chromatin structure resulting in long-lasting changes in gene expression. ALS is predominantly a sporadic disease and environmental triggers may be involved in its onset. In this respect, alterations in the epigenome can provide the key to transform the genetic information into phenotype. In this paper, we demonstrate that two modifications associated with transcriptional activation, namely dimethylation of lysine 4 on H3 tail (H3K4me2) and phospho-acetylation of serine 10 and lysine 14 on H3 tail (H3K14ac-S10ph), and two modifications associated to transcriptional repression, namely trimethylation of lysine 9 on H3 tail (H3K9me3) and DNA methylation are selectively altered in cellular and animal model of ALS. These results reinforce the idea that epigenetic therapy may represent a potential and attractive approach for ALS treatment.

Neurofeedback training is a form of brain training in which information about a neural measure is fed back to the trainee who is instructed to increase or decrease the value of that particular measure. This paper focuses on electroencephalography (EEG) neurofeedback in which the neural measures of interest are the brain oscillations. To date, the neural mechanisms that underlie successful neurofeedback training are still unexplained. Such an understanding would benefit researchers, funding agencies, clinicians, regulatory bodies, and insurance firms. Based on recent empirical work, an emerging theory couched firmly within computational neuroscience is proposed that advocates a critical role of the striatum in modulating EEG frequencies. The theory is implemented as a computer simulation of peak alpha upregulation, but in principle any frequency band at one or more electrode sites could be addressed. The simulation successfully learns to increase its peak alpha frequency and demonstrates the influence of threshold setting - the threshold that determines whether positive or negative feedback is provided. Analyses of the model suggest that neurofeedback can be likened to a search process that uses importance sampling to estimate the posterior probability distribution over striatal representational space, with each representation being associated with a distribution of values of the target EEG band. The model provides an important proof of concept to address pertinent methodological questions about how to understand and improve EEG neurofeedback success.

The close anatomical and functional relationship between neuronal circuits and the astroglial network in the neocortex has been demonstrated at several organization levels supporting the idea that neuron-astroglial crosstalk can play a key role in information processing. In addition to chemical and electrical neurotransmission, other non-synaptic mechanisms called ephaptic interactions seem to be important to understand neuronal coupling and cognitive functions. Recent interest in this issue comes from the fact that extra-cranial electric and magnetic field stimulations have shown therapeutic actions in the clinical practice. The present paper reviews the current knowledge regarding the ephaptic effects in mammalian neocortex and proposes that astroglial bio-magnetic fields associated with Ca2+ transients could be implicated in the ephaptic coupling of neurons by a direct magnetic modulation of the intercellular local field potentials.

The thalamus is one of the most commonly affected brain regions in preterm infants, particularly in infants with white matter lesions (WML). The aim of this paper is to explore the development and alterations of the functional thalamocortical connectivity in preterm infants with and without punctate white matter lesions (PWMLs) during the period before term equivalent age (TEA). In this study, twenty-two normal preterm infants (NP), twenty-two preterm infants with PWMLs and thirty-one full-term control infants (FT) were enrolled. Thalamus parcellation was performed based on partial correlation between the thalamus and seven well-recognized infant networks obtained from independent component analysis (ICA), and thalamocortical connectivity was further reconstructed between the defined thalamus clusters and the whole brain. Thalamo-salience (SA) and thalamo-sensorimotor (SM) connectivity were predominantly identified, while other types of thalamocortical connectivity remained largely limited during the neonatal period. Both preterm groups exhibited prominent development in thalamo-SA and thalamo-SM connectivity during this period. Compared with NP infants, PWML infants demonstrated increased connectivity in the parietal area in thalamo-SA connectivity but no significant differences in thalamo-SM connectivity. Our results reveal that compared with NP infants, PWML infants exhibit slightly altered thalamo-SA connectivity, and this alteration is deduced to be functional compensations for inefficient thalamocortical processing due to PWMLs.

Pedunculopontine nucleus (PPN) has been considered a critically important region in the regulation of some of the physiological functions that fail during the progression of Parkinson's disease (PD). In this paper, the effects of unilateral neurotoxic lesion of the PPN [through the injection of N-methyl-d-aspartate (NMDA) solution (concentration: 0.1M; volume: 0.5µL)] in motor execution and gait disorders and the changes in cellular and molecular indicators in rat nigral tissue were evaluated. The motor execution was assessed using the beam test (BT) and the gait disorders by footprint test. Glutathione (GSH) concentrations, acetyl cholinesterase enzymatic activity (AChE EA), and brain-derived neurotrophic factor (BDNF) mRNA expression in nigral tissue were analyzed. NMDA-lesioned rats showed fine motor dysfunction with a significant increase in the slow (p≤0.01) and fast movement (p≤0.01) time and in path deviation (p≤0.01) on the smaller diameter beams. Moreover, NMDA-lesioned rats exhibited an imprecise path with moments of advances and setbacks, alternating with left and right deviations, suspensions, and inverted positions. Footprint test revealed slight gait disorders, which were manifested by a reduction in the left and right stride lengths, the intra-step distance, and the support area (p≤0.01). Biochemical studies showed that 48h after the PPN neurotoxic injury, the GSH concentrations and BDNF expression were significantly increased (p≤0.01). These variables returned to normal values 7days after the PPN lesion; the AChE EA showed a significant increase at this time. These functional changes in nigral tissue could be a plastic responses associated with early PD.

Working memory (WM) refers to the holding and manipulation of information during cognitive tasks. Its underlying neural mechanisms have been explored through both functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Trial-by-trial coupling of simultaneously collected EEG and fMRI signals has become an important and promising approach to study the spatio-temporal dynamics of such cognitive processes. Previous studies have demonstrated a modulation effect of the WM load on both the BOLD response in certain brain areas and the amplitude of P3. However, much remains to be explored regarding the WM load-dependent relationship between the amplitude of ERP components and cortical activities, and the low signal-to-noise ratio (SNR) of the EEG signal still poses a challenge to performing single-trial analyses. In this paper, we investigated the spatio-temporal activities of P3 during an n-back verbal WM task by introducing an adaptive wavelet denoiser into the extraction of single-trial P3 features and using general linear model (GLM) to integrate simultaneously collected EEG and fMRI data. Our results replicated the modulation effect of the WM load on the P3 amplitude. Additionally, the activation of single-trial P3 amplitudes was detected in multiple brain regions, including the insula, the cuneus, the lingual gyrus (LG), and the middle occipital gyrus (MOG). Moreover, we found significant correlations between P3 features and behavioral performance. These findings suggest that the single-trial integration of simultaneous EEG and fMRI signals may provide new insights into classical cognitive functions.

Highlights • Creatine is a compound that is critical for energy metabolism of nervous cells. • Creatine absence due to deficit of creatine transporter causes severe brain symptoms. • Creatine crosses BBB and neuronal membrane slowly, and only using its transporter. • Creatine derivatives may cross BBB and neuronal membrane without the transporter. • Creatine derivatives may be a useful strategy in creatine transporter deficiency., Creatine, a compound that is critical for energy metabolism of nervous cells, crosses the blood-brain barrier (BBB) and the neuronal plasma membrane with difficulty, and only using its specific transporter. In the hereditary condition where the creatine transporter is defective (creatine transporter deficiency) there is no creatine in the brain, and administration of creatine is useless lacking the transporter. The disease is severe and incurable. Creatine-derived molecules that could cross BBB and plasma membrane independently of the transporter might be useful to cure this condition. Moreover, such molecules could be useful also in stroke and other brain ischemic conditions. In this paper, we investigated three creatine salts, creatine ascorbate, creatine gluconate and creatine glucose. Of these, creatine glucose was ineffective after transporter block with guanidine acetic acid (GPA) administration. Creatine ascorbate was not superior to creatine in increasing tissue creatine and phosphocreatine content after transporter impairment, however even after such impairment it delayed synaptic failure during anoxia. Finally, creatine gluconate was superior to creatine in increasing tissue content of creatine after transporter block and slowed down PS disappearance during anoxia, an effect that creatine did not have. These findings suggest that coupling creatine to molecules having a specific transporter may be a useful strategy in creatine transporter deficiency. In particular, creatine ascorbate has effects comparable to those of creatine in normal conditions, while being superior to it under conditions of missing or impaired creatine transporter.

The noradrenergic neurons of the locus coeruleus in the albino rat have been mapped and characterized morphologically with the unlabeled peroxidase anti-peroxidase method employing an antiserum to rat dopamine β-hydroxylase. A comprehensive series of low-power photomicrographs of immunocytochemically stained sections is presented depicting the full extent of this nucleus in relationship to other structural landmarks. The paper provides the first detailed atlas of dopamine β-hydroxylase-immunoreactive cells in the pontine and mesencephalic tegmentum of the rat. In addition, this study provides for the first time (1) a description of dopamine β-hydroxylase-positive cells in the periaqueductal gray of the caudal midbrain, that have not previously been visualized, (2) illustrations of dopamine β-hydroxylase-positive cells in the roof of the IVth ventricle that extend their dendrites between ependymal cells to the ventricular surface, (3) a depiction of the extensively ramified dendrites that characterize noradrenergic cells in the ventral division of the locus coeruleus, and (4) morphological evidence that cells of the locus coeruleus group can be divided into four contiguous but cytologically distinct sets. The data presented in this paper provide a guide for planning and interpreting studies of the locus coeruleus, in particular, for the elucidation of its afferents and efferents, the electrophysiologic characteristics of its cells, and the behavioral effects of lesions.

The distribution of neuropeptide Y-like immunoreactivity in the rat brain was investigated by means of immunochemical techniques. In the first part of the study (present paper) neuropeptide Y radioimmunoassays were characterised and the chromatographic properties and regional distribution of neuropeptide Y-like immunoreactivity was investigated. The second part of the study (accompanying paper) involved immunohistochemical techniques. Extracts from several regions of rat brain were found to contain immunoreactivity that behaved like synthetic porcine neuropeptide Y in three test systems: dilution in the radioimmunoassay (test of antigenic properties), gel chromatography (molecular weight), reverse phase high performance liquid chromatography (solubility properties). Experiments were conducted to optimise the extraction of neuropeptide Y. Boiling 0.1 M sodium phosphate buffer, pH 7.4, extracted at least two times as much immunoreactivity from whole brain pieces as other buffers. The nature of the extracted immunoreactivity was confirmed using chromatography. Experiments (using added iodinated or unlabelled neuropeptide Y standards) demonstrated that the differences between extraction media could not be explained by differential recovery of the peptide, although differences in recovery between media existed. Tissue sample weight was found to influence neuropeptide Y recovery. Evidence that rat neuropeptide Y-like immunoreactivity was not identical to the porcine peptide was obtained from experiments which demonstrated an early eluting peak of immunoreactivity in addition to the main peak on high performance liquid chromatograms. This material could be generated by oxidation of extracted rat neuropeptide Y, suggesting the presence in the rat peptide of a methionine residue. Some evidence of high molecular weight neuropeptide Y precursors was obtained from chromatography of hypothalamus extracts. Bovine pancreatic polypeptide-like material represented less than 1% of the amounts of neuropeptide Y in the brain. The distribution of neuropeptide Y-like immunoreactivity was non-uniform in the rat brain with highest concentrations observed in the hypothalamus, amygdaloid complex and periaqueductal central gray matter. Other regions of forebrain contained moderate to high concentrations including olfactory tubercle, striatum, nucleus accumbens, neocortex and hippocampus. Negligible amounts were detected in the cerebellum. In spinal cord immunoreactivity was concentrated in the dorsal horn, although measurable amounts were found in the ventral horn. The neurointermediate but not anterior lobe of the pituitary contained neuropeptide Y.

The bilateral, monosynaptic projection from the entorhinal cortex to the dentate gyrus provides a suitable system for studying long-term changes of synaptic strength. In particular, the synaptic response of the sparse contralateral projection can be increased or decreased depencling on the exact conditioning protocol. Since changes in either direction require high-frequency stimulation of the potent, converging ipsilateral system, these synaptic alterations are called associative potentiation/depression. In part, associative potentiation/depression is Anatogous to what others call long-term potentiation. Synaptic phenomena like associative potentiation/depression are central to several theories of associative brain function and neuronal models of cognition. In elaborating such theories, the conditions which alter synaptic physiology as well as the size and direction of the changes are expressed as an algebraic equation. This paper is the initial report attempting to quantify one part of one such ‘synaptic learning equation’. This paper quantifies the term in the equation which expresses the role of presynaptic activity. Through this term the equation can express both synaptic potentiation and depression as a function of the afferent frequency of the particular synapse under consideration. In this term there exists a critical frequency or a balance point. When there is sufficient co-activity among converging excitatory afferents, then the synapse under consideration will either potentiate or depress. If the afferent's frequency is above the balance point, potentiation occurs; if the frequency is below the critical value, depression occurs. For a constant amount of postsynaptic excitation, the amount of change is a nonnegative function of the frequency around this balance point. Prior theoretical proposals postulate that this balance point resides near the average frequency of the afferents. In fact, the value obtained, 100 ± 50 Hz for short duration trains, is orders of magnitude greater than the time-averaged frequency previously observed for these afferents. Other considerations indicate that although a balance point exists it is more likely a variable rather than a constant.

We have shown experimentally in theprevious paper that spontaneous epileptiform activity, as recorded by extracellular field potentials, propagates smoothly across the CA2-CA3 region of the convulsant-treated hippocampal slice of the guinea pig at velocities of about 0.1 m/s. In the present paper, we used computer simulations of either 500 or 1000 cell arrays of model neurons to examine possible mechanisms underlying this propagation. We show that propagation of epileptiform field potentials can be explained plausibly by slow conduction along axons interconnecting CA2-CA3 neurons, provided that there are sufficiently many interconnections. This propagation can take place even if the interconnections occur randomly. The number of interconnections required decreases as the number of synchronously activated cells initiating a population burst increases. Axonal propagation at 0.1 m/s appears to be a plausible assumption, since conduction velocities along Schaffer collaterals have been experimentally estimated to be as slow as 0.2 m/s, and small recurrent collaterals are likely to conduct more slowly than the main axonal branches. If spontaneous synchronized population bursts are initiated by activity in four or fewer cells, then our model requires, for smooth field potential propagation, more interconnections than are believed to occur on the basis of dual intracellular recording.

In a previous paper, a model was developed to study and contrast the relations between cell geometry and repetitive firing in large and small motorneurons. This model is extended and revised in the present paper and used to analyze certain experimental findings in normal and axotomized motorneurons. (1) For normal motorneurons, in order to reproduce the experimentally observed difference in interspike voltage trajectory (concave vs convex) in the primary and secondary ranges respectively of the current-firing rate curve, it is necessary to localize the major part of a slow potassium conductance on the motorneuron dendrites. This slow potassium conductance leads to the afterhyperpolarization following an action potential. (2) In order to activate the slow potassium conductance after an action potential, we have postulated a calcium conductance in the motorneuron membrane, as suggested by the work of Barrett and Barrett, and Krnjevid and Lisiewicz. In normal motorneurons, the proximal dendrites must display a certain amount of sodium conductance (g Na ) in order to activate the calcium conductance (g Ca ) sufficiently to ‘trigger’ the slow potassium channel. (3) With the above mechanism for calcium and slow potassium conductances, the model shows that the firing rate in the primary range is mainly determined by the decay of the slow potassium conductance which generates the long afterhyperpolarization. In the secondary range, this slow potassium conductance is essentially constant between spikes, so that the firing rate is determined by fast potassium recovery. (4) The model is further able to display several features of the partial responses seen in axotomized motorneurons: for example, their all-or-nothing character following different levels of synaptic excitation, and the hump on the trailing part of an action potential. The model achieves this when a patch of membrane with an increased sodium and fast potassium conductance (a ‘hot spot’) is localized on a dendritic branch about 0.4–0.5 or more space constants away from the soma. (5) For an axotomized motorneuron, we were able to obtain simultaneously the correct current-firing rate curve (a single, high-slope region), and also the experimentally observed convex interspike trajectories, by manipulating slow potassium and ‘hot spot’ g Na parameters; this could be done by moving the ‘hot spots’ distally (to 0.6–0.7 space constants from the somas With a ‘hot spot’ close to the soma, shifting the Hodgkin-Huxley rate functions α m and α h (which lowers the voltage threshold) tended to accentuate the amount of primary range present; this was not observed with ‘hot spots’ located more distally. (6) An important variable in determining the nature of repetitive firing in both normal and axotomized motorneurons is the height of the dendritic potential (in the region in which the afterhyperpolarization is developed) immediately following the soma action potential.

An earlier study has demonstrated that exogenous allopregnanolone (APα) can reverse the reduction of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc) of 3-month-old male triple transgenic Alzheimer's disease mouse (3xTgAD). This paper is focused on further clarifying the origin of these new-born TH-positive neurons induced by exogenous APα treatment. We performed a deeper research in another AD mouse model, 4-month-old male APPswe/PSEN1 double transgenic AD mouse (2xTgAD) by measuring APα concentration and counting immunopositive neurons using enzyme-linked immunosorbent assay (ELISA) and unbiased stereology. It was found that endogenous APα level and the number of TH-positive neurons were reduced in the 2xTgAD mice, and these reductions were present prior to the appearance of β-amyloid (Aβ)-positive plaques. Furthermore, a single 20mg/kg of exogenous APα treatment prevented the decline of total neurons, TH-positive neurons and TH/bromodeoxyuridine (BrdU) double-positive neurons in the SNpc of 2xTgAD mice although the decreased intensity of TH-positive fibers was not rescued in the striatum. It was also noted that exogenous APα administration had an apparent increase in the doublecortin (DCX)-positive neurons and DCX/BrdU double-positive neurons of subventricular zone (SVZ), as well as in the percentage of neuronal nuclear antigen (NeuN)/BrdU double-positive neurons of the SNpc in the 2xTgAD mice. These findings indicate that a lower level of endogenous APα is implicated in the loss of midbrain dopaminergic neurons in the 2xTgAD mice, and exogenous APα-induced a significant increase in the new-born dopaminergic neurons might be derived from the proliferating and differentiation of neural stem niche of SVZ.

Neuropathy target esterase (NTE) is a protein involved in the development of a polyneuropathy caused by exposure to certain organophosphorus compounds. In vivo and in vitro studies have also associated NTE with embryonic development since NTE null mice embryos are non-viable, and silencing the NTE-codifying gene (Pnpla6) in mouse embryonic stem cells strongly alters the differentiation of vascular and nervous systems. In this paper, human embryonal carcinoma stem cells human-derived NTera2/D1 (hNT2) are used as an in vitro neurodifferentiation model to determine whether PNPLA6 silencing is able to alter the differentiation process. In control cultures, PNPLA6 mRNA levels increased in parallel with other neuroectodermal markers during neurodifferentiation. PNPLA6 silencing with specific interference RNA reached a 97% decrease in gene expression 3days after transfection and with a maximum reduction in NTE enzymatic activity (50%), observed on day 4. Silencing PNPLA6 showed an 80% decrease in quantifiable neuronal cells after 13days in vitro (DIV) compared to controls and absence of different neuronal markers after 66DIV. Microarray data analysis of the PNPLA6-silenced cells showed alterations in several developmental processes, mainly neurogenesis and epithelium tube morphogenesis. PNPLA6 silencing also led to a reduction in electrical activity and an altered neuronal phenotype. This work is the first proof supporting the hypothesis that NTE plays a role in human early neurodevelopment using a human cell differentiation model.