Search

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.

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.

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)

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.

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.

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.

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.

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.

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.

This review covers the intrinsic organization and afferent and efferent connections of the midbrain dopaminergic complex, comprising the substantia nigra, ventral tegmental area and retrorubral field, which house, respectively, the A9, A10 and A8 groups of nigrostriatal, mesolimbic and mesocortical dopaminergic neurons. In addition, A10dc (dorsal, caudal) and A10rv (rostroventral) extensions into, respectively, the ventrolateral periaqueductal gray and supramammillary nucleus are discussed. Associated intrinsic and extrinsic connections of the midbrain dopaminergic complex that utilize gamma-aminobutyric acid (GABA), glutamate and neuropeptides and various co-expressed combinations of these compounds are considered in conjunction with the dopamine-containing systems. A framework is provided for understanding the organization of massive afferent systems descending and ascending to the midbrain dopaminergic complex from the telencephalon and brainstem, respectively. Within the context of this framework, the basal ganglia direct and indirect output pathways are treated in some detail. Findings from rodent brain are briefly compared with those from primates, including humans. Recent literature is emphasized, including traditional experimental neuroanatomical and modern gene transfer and optogenetic studies. An attempt was made to provide sufficient background and cite a representative sampling of earlier primary papers and reviews so that people new to the field may find this to be a relatively comprehensive treatment of the subject.

Experimental evidence has revealed the role of mitochondria in various aspects of neuronal physiology. Mitochondrial failure results in alterations that underlie the pathogeneses of many neurodegenerative disorders, such as Parkinson's disease, Alzheimer's disease, Huntington's disease (HD) and amyotrophic lateral sclerosis. The mitochondrial toxin 3-nitropropionic acid (3-NP) has been used to model failure; for example, systemic administration of 3-NP imitates the striatal degeneration that is exhibited in the postmortem tissue of patients afflicted with HD. We have demonstrated that low, sub-chronic doses of 3-NP are sufficient to initiate the damage to striatal neurons that is associated with changes in neurotrophin expression levels. However, the mechanisms underlying the alterations in neuronal activity and neurotransmission due to 3-NP-induced mitochondrial dysfunction remain to be elucidated. In this paper, we focus on how corticostriatal transmission and its modulation by neurotrophins are altered in vivo after 5 days of mitochondrial inhibition with 3-NP. Recordings of population spikes and a paired pulse (PP) stimulation protocol were used to document changes in corticostriatal synapses in 3-NP-treated brain slices. The corticostriatal synapses were modulated by neurotrophins but displayed differential amplitude increases in the presence of brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), or neurotrophin-4/5 (NT-4/5) under control conditions. Neurotrophin-mediated synaptic modulation was decreased in slices from 3-NP-treated mice. The protein and mRNA levels of neurotrophins and their receptors were also modified in the 3-NP-treated tissue. Neuronal structural evaluation demonstrated that synaptic length and density were reduced in the 3-NP-treated mice, which partially explained the changes in the amplitudes of the synaptic field responses. Our results demonstrate that corticostriatal synapses are differentially modulated by neurotrophins and that this modulation is altered by mitochondrial failure. Mitochondrial dysfunction also affects neurotransmitter release in corticostriatal synapses, neurotrophin availability, dendritic arborization and the lengths of the striatal medium spiny neurons (MSNs).

Alzheimer's disease (AD) has traditionally been regarded as a disease of the gray matter (GM). However, the advent of diffusion tensor imaging (DTI) has contributed to new knowledge about how changes in white matter (WM) microstructure in vivo may be directly related to the pathophysiology of AD. It is now evident that WM is heavily affected in AD, even at early stages. Still, our knowledge about WM degeneration in AD is poor compared to what we know about GM atrophy. For instance, it has not been clear if WM can be directly affected in AD independently of GM degeneration, or whether WM changes mainly represent secondary effects of GM atrophy, e.g. through Wallerian degeneration. In this paper, we review recent studies using DTI to study WM alterations in AD. These studies suggest that microstructural WM affection at pre-AD stages cannot completely be accounted for by concomitant GM atrophy. Further, recent research has demonstrated relationships between increased cerebrospinal fluid levels of Tau proteins and changes in WM microstructure indexed by DTI, which could indicate that WM degeneration in pre-AD stages is related to ongoing axonal damage. We conclude that DTI is a promising biomarker for AD, with the potential also to identify subgroups of patients with especially high degree of WM affection, thereby contributing to more differentiated pre-AD diagnoses. However, more research and validation studies are needed before it is realistic to use this information in clinical practice with individual patients.

In rodents, many social behaviors are driven by the sense of smell. The vomeronasal organ (VNO), part of the accessory olfactory system mediates many of these chemically driven behaviors. The VNO is heavily vascularized, and is readily accessible to circulating peptide or steroid hormones. Potentially, this allows circulating hormones to alter behavior through modulating the output of the primary sensory neurons in the VNO, the vomeronasal sensory neurons (VSNs). Based on this, we hypothesized that steroid hormones, in particular 17β-estradiol, would modulate activity of VSNs. In this paper, we show that the estrogen receptors, GPR30 and ERα, were present in VSNs and that estradiol may be synthesized locally in the VNO. Our results also showed that 17β-estradiol decreased responses of isolated VSNs to dilute urine, a potent natural stimulus, with respect to current amplitudes and depolarization. Further, 17β-estradiol increased the latency of the first action potential (AP) and the AP amplitude. Additionally, calcium responses to sulfated steroids (present in the low molecular weight fraction of urine) that act as ligands for apical vomeronasal receptors were decreased by 17β-estradiol. In conclusion, we show that estradiol modulates odorant responses mediated by VSNs and hence paves the way for future studies to better understand the mechanisms by which odorant mediated behavior is altered by endocrine status of the animal.

The purpose of this paper is to study the effect of smilagenin (SMI) (PYM50028), a sapogenin compound originally identified from Chinese medicinal herb, on dopamine neurons and locomotor ability in aged rats. Experiments were carried out on young and aged Sprague-Dawley rats, which were daily administered with either SMI (18mg/kg/day) or vehicle (0.5% sodium carboxymethycellulose [CMCNa]). Open-field and rotarod performance tests revealed that behavioral ability was impaired in aged rats and was improved by oral administration of smilagenin. Immunohistochemical data showed that tyrosine hydroxylase (TH)-positive neuron numbers in the substantia nigra pars compacta (unbiased stereological counting) were altered with aging and were increased by smilagenin treatment. Likewise, the dopamine receptor density and the striatal dopamine transporter (DAT) density ((125)I-2β-carbomethoxy-3β-(4-iodophenyl)-N-(3-fluoropropyl) nortropane [(125)I-FP-CIT] autoradiography) were significantly lowered in aged rats as compared to young rats, and treatment with smilagenin significantly elevated the dopamine receptor and DAT density in aged rats. Furthermore, smilagenin enhances glial cell-derived neurotrophic factor (GDNF) release both in the striatum and midbrain. These results indicate a possible role of smilagenin in the treatment of age-related extrapyramidal disorders.

Reactive gliosis has been implicated in injury and recovery patterns associated with hydrocephalus. The roles that these mechanisms play in the pathophysiology of hydrocephalus are still not clear in terms of cytopathology and gene expression. In this paper, we investigated the relationship between reactive gliosis and neuroinflammation of hydrocephalic rats of different severity at both cellular and molecular levels. Therefore 35 adult SD (standard deviation) rats were randomly divided into the normal group (n=5), the sham operation group (n=5) and the model group (n=25). Hydrocephalic rat models were induced by intraventricular injections of 3% kaolin, and the ventricular dilatation was examined by MRI (magnetic resonance imaging) at 2-week postoperation. Then the model group was subdivided into the mild group (n=5), the moderate group (n=7) and the severe group (n=9) according to the degree of ventricular dilatation. While IL-18 (interlukin 18), GFAP (glial fibrillary acidic protein), and Iba-1 (ionized calcium binding adaptor molecule-1) were detected by ELISA (enzyme-linked immunosorbent assay), RT-PCR, immunohistochemistry, Western blot and correlation analysis were conducted at the same time. According to the result comparison between the normal group and the sham operation group, the ventricle of model group was obviously enlarged (P0.01). The expression of GFAP and Iba-1 was increased (P0.05) in brain tissue of the model group and IL-18 was also increased in CSF (cerebrosinal fluid) sample of model group. It was revealed by correlation analysis that the increase was positively correlated with the severity of ventricular dilatation.These results indicate that gliosis and inflammation continue to rise dramatically in experimental hydrocephalus and can be regarded as the main factors of hydrocephalus. Regulating the level of gliosis and alleviating inflammation may provide new therapeutic methods of hydrocephalus.

Mutant huntingtin (mhtt) causes loss of synaptic plasticity and selective degeneration of striatal medium spiny neurons (MSNs), a core pathological feature of Huntington's disease (HD). However, projecting neurons become dysfunctional in the very early stages, long before death and this dysfunctional state may contribute to disease. Interneurons appear to be more resistant to the effects of mhtt and play important roles in supporting the activity of projecting neurons. Therefore, early modifications in the plasticity or in the pattern of cortical and striatal interneuronal activity may also be a factor in the alteration of the corticostriatal pathway in HD. While new models of HD provide information on the onset of complex behavioral changes, the mechanisms underlying alterations of the striatal microcircuit and their role in HD pathogenesis are still unclear. As a consequence, despite the development of new compounds, no adequate treatment is so far available to stop or reverse HD. Electrophysiological studies provide crucial information on neuronal dysfunction and circuit changes that underlie or precede symptoms. Here we review recent papers in which HD models have been used to study various aspects of neuronal physiology of corticostriatal pathway. We will also discuss advantages and limitations of rodent models compared to primate models and current challenges of therapies aimed at rescuing striatal function in HD. This article is part of a Special Issue entitled: Neuroscience Disease Models.

This paper puts together and links some classic and recent molecular data and hypothesis from different authors and laboratories related to learning and memory consolidation. Mainly addressed to non-specialists, it describes how the glutamatergic activation of plastic synapses in the hippocampus can give rise to new or enlarged dendritic spines which may constitute the main structural basis of some kind of memories. To establish learning and memory, the nervous system can use part of the same mechanisms which make the basic structure of neurons during the ontogenetic development of the brain. Through different families of kinases, phosphatases and other proteins, the activated N-methyl-d-aspartate (NMDA) receptors and different intracellular signals originated in the post-synaptic membranes can promote the synthesis of new proteins and the dynamic of actin. The consecutive morphological changes in the cytoskeleton of the neuron, later stabilized by new receptors inserted in the post-synaptic membranes, make possible memory consolidation. Short and long-term, as well as persistence, of memory mechanisms are related to these molecular processes. Recent research on system consolidation and memory allocation in neural circuits is also explained.

The amygdala is enriched with histochemically reactive zinc, which is dynamically coupled with neuronal activity and co-released with glutamate. The dynamics of the zinc in the amygdala was analyzed in rats, which were subjected to inescapable stress, to understand the role of the zinc in emotional behavior. In the communication box, two rats were subjected to foot shock stress and anxiety stress experiencing emotional responses of foot-shocked rat under amygdalar perfusion. Extracellular zinc was increased by foot shock stress, while decreased by anxiety stress, suggesting that the differential changes in extracellular zinc are associated with emotional behavior. In rats conditioned with foot shock, furthermore, extracellular zinc was increased again in the recall of fear (foot shock) in the same box without foot shock. When this recall was performed under perfusion with CaEDTA, a membrane-impermeable zinc chelator, to examine the role of the increase in extracellular zinc, the time of freezing behavior was more increased, suggesting that zinc released in the lateral amygdala during the recall of fear participates in freezing behavior. To examine the role of the increase in extracellular zinc during fear conditioning, fear conditioning was also performed under perfusion with CaEDTA. The time of freezing behavior was more increased in the contextual recall, suggesting that zinc released in the lateral nucleus during fear conditioning also participates in freezing behavior in the recall. In brain slice experiment, CaEDTA enhanced presynaptic activity (exocytosis) in the lateral nucleus after activation of the entorhinal cortex. The present paper demonstrates that zinc released in the lateral amygdala may participate in emotional behavior in response to fear.

Unlike other mammalian AQPs, multiple tetramers of AQP4 associate in the plasma membrane to form peculiar structures called Orthogonal Arrays of Particles (OAPs), that are observable by freeze-fracture electron microscopy (FFEM). However, FFEM cannot give information about the composition of OAPs of different sizes, and due to its technical complexity is not easily applicable as a routine technique. Recently, we employed the 2D gel electrophoresis BN-SDS/PAGE that for the first time enabled the biochemical isolation of AQP4-OAPs from several tissues. We found that AQP4 protein is present in several higher-order complexes (membrane pools of supra-structures) which contain different ratios of M1/M23 isoforms corresponding to AQP4-OAPs of different size. In this paper, we illustrate in detail the potentiality of 2D BN/SDS-PAGE for analyzing AQP4 supra-structures, their relationship with the dystrophin glycoprotein complex and other membrane proteins, and their role as a specific target of Neuromyelitis Optica autoantibodies.

In adult neostriatal projection neurons, the intracellular Ca 2+ supplied by Ca V 2.1 (P/Q) Ca 2+ channels is in charge of both the generation of the afterhyperpolarizing potential (AHP) and the release of GABA from their synaptic terminals, thus being a major target for firing pattern and transmitter release modulations. We have shown that activation of muscarinic M 1 -class receptors modulates Ca V 2.1 channels in these neurons in rats. This modulation is reversible, is not membrane delimited, is blocked by the specific M 1 -class muscarinic antagonist muscarine toxin 7 (MT-7), and is neither mediated by protein kinase C (PKC) nor by protein phosphatase 2B (PP-2B). Hence, the signaling mechanism of muscarinic Ca V 2.1 channel modulation has remained elusive. The present paper shows that inactivation of phospholipase C (PLC) abolishes this modulation while inhibition of phosphoinositide kinases, PI-3K and PI-4K, prevents its reversibility, suggesting that the reconstitution of muscarinic modulation depends on phosphoinositide rephosphorylation. In support of this hypothesis, the supply of intracellular phosphatidylinositol (4,5) bisphosphate [PI(4,5)P 2 ] blocked all muscarinic modulation of this channel. The results indicate that muscarinic M 1 modulation of Ca V 2.1 Ca 2+ channels in these neurons involves phosphoinositide hydrolysis.

Ferulic acid (4-hydroxy-3-methoxycinnamic acid; FA) is a plant constituent and is contained in several medicinal plants for clinical use. In this paper, we investigated the effects of FA on the proliferation of neural stem/progenitor cells (NSC/NPCs) in vitro and in vivo. FA significantly increased the proliferation of NSC/NPCs cultured from the telencephalon of embryonic day-14 rats, and increased the number and size of secondary formed neurospheres. An in vitro differentiation assay showed that FA did not affect the percentage of either neuron-specific class III beta-tubulin (Tuj-1)-positive cells or glial fibrillary acidic protein (GFAP)-positive cells in the total cell population. Oral administration of FA increased the number of newly generated cells in the dentate gyrus (DG) of the hippocampus of corticosterone (CORT)-treated mice, indicating that FA enhances the proliferation of adult NSC/NPCs in vivo. We also found that oral administration of FA increased cAMP response element binding protein (CREB) phosphorylation and brain-derived neurotrophic factor (BDNF) mRNA level in the hippocampus of CORT-treated mice, and ameliorated the stress-induced depression-like behavior of mice. These novel pharmacological effects of FA may be useful for the treatment of mood disorders such as depression.

It is acknowledged that neurotransmission in the mouse vas deferens is predominantly mediated by ATP and noradrenaline (NA) released from sympathetic nerves while cholinergic transmission in the rodent vas deferens is often overlooked despite early literature. Recently we have characterized a cholinergic component of neurogenic contraction of mouse isolated vas deferens. In the present paper, by confocal imaging of Ca(2+) dynamics we detected acetylcholine (ACh) action at muscarinic cholinergic neuroeffector junctions at high-resolution. Experiments were carried out in the presence of prazosin (100 nM) and alpha,beta methylene ATP (alpha,beta-MeATP) (1 microM) to inhibit responses to NA and ATP respectively. Exogenous ACh (10 microM) elicited Ca(2+) transients, an effect blocked by the muscarinic receptor antagonist, cyclopentolate (1 microM). Ca(2+) transients were evoked by electrical stimulation of intrinsic nerves in the presence of the cholinesterase inhibitor neostigmine (10 microM). Stimulation produced a marked increase in the frequency and number of Ca(2+) transients. Cyclopentolate reduced the frequency of occurrence of spontaneous and evoked events to control levels. The alpha(2)-adrenoceptor antagonist yohimbine (300 nM) did not affect the spontaneous Ca(2+) transients, but increased the frequency of occurrence of evoked transients, an effect inhibited by cyclopentolate. The postjunctional effects of neuronally-released ACh are limited by the action of cholinesterase. Release of ACh appears to be tonically inhibited by NA released from sympathetic nerve terminals through action at prejunctional alpha(2)-adrenoceptors. Tetrodotoxin (TTX, 300 nM) abolished the nerve-evoked Ca(2+) events, with no effect on Ca(2+) transients elicited by exogenous ACh. In conclusion, the presence of spontaneous and evoked cholinergic Ca(2+) transients in smooth muscle cells of the mouse isolated vas deferens has been revealed. These events are mediated by ACh acting at M(3) muscarinic receptors. This action stands in marked contrast to the lack of effect of neuronally-released NA on smooth muscle Ca(2+) dynamics in this tissue.

This paper will outline the history of study of the cerebellum from its beginnings to relatively recent times. Although there is no unanimous agreement about what the cerebellum does or how it does it, some principles of its structure and function are well understood. The historical approach can help to identify remaining questions and point the way to future progress. We make no effort to separate anatomical, physiological and clinical studies; rather, we hope to emphasize their interrelation. The cerebellum has always been seen as a distinct subdivision of the brain. Over the years there was an increasingly accurate description of its gross appearance and major subdivisions. By the beginning of the 19th century, the classical descriptive anatomical work was completed, and experimental study of the functions of the cerebellum began. Lesions were made in the cerebellum of experimental animals, and the behavioral deficits that were caused by the lesion were studied and described. These early animal studies powerfully influenced clinical interpretation of the symptoms seen in patients with cerebellar disease. Several questions are implicit in the anatomical and clinical studies of the nineteenth and early twentieth centuries, some of which remain incompletely answered. Many of these are addressed in other chapters in this volume. 1. Do different parts of the cerebellum do different things? The uniformity of the neuronal architecture of the cerebellar cortex suggests that each small region must operate in a similar way, but it is also clear that different regions control different functions. Is there a systematic sensory and/or body representation? 2. What are the functions of the cerebellar hemispheres? Massive in humans and very large in primates, their functions remain in dispute. Because the size of the cerebellar hemispheres parallels the development of the cerebral cortex, some have suggested that the hemispheres in humans and the higher primates may play a role in cognitive functions. 3. If one part of the cerebellum is damaged, can another part take over? A related question is whether normal motor function is possible in cases of complete or near-complete agenesis of the cerebellum. 4. What are the functions of the two distinctly different afferent systems to the cerebellum; the climbing and mossy fibers?

The avian hippocampal formation (HF) is reported to have a role equivalent to that of the mammalian hippocampus, which may involve the glutamatergic system as well. In the present paper we offer evidence of the occurrence and distribution of the subunits composing AMPA-type glutamate receptors on neurons in the hippocampus region of the pigeon brain. The experiment analyzed the immunolabeling of glutamate receptor (GluR)(1)(,) GluR(4,) and GluR(2/3) receptor subunits in adult pigeons and found consistent evidence that neurons located in the five main areas of the avian HF have these AMPA-type subunits, but their incidence varies according to position and neuro-type. About 20%-35% of the irregular and 35%-70% of the triangular neurons on the lateral and medial "V" arms contain GluR(1) and GluR(2/3), while GluR(4) was found only at rounded neurons. The majority of the triangular neurons (over 90%) and about half of the irregular neurons in the medial area contain GluR(1) and GluR(2/3,) whereas the rounded neurons contain primarily GluR(4) (95%). Labeling revealed GluR(1) (40%-60%) and GluR(2/3) (30%) in the dorsomedial and lateral areas but only in irregular neurons, while 60%-80% of the rounded neurons synthesize GluR(4). While triangular and irregular neurons appear to match the description of projecting neurons, rounded ones seem to participate in local circuits. A discussion of the functional significance of the avian HF concentrates on a postulation of the "V" arms as equivalent to the dentate gyrus and the dorsomedial area being similar to the Ammon's horn.

Experimental data demonstrate that the nervous system is widely influenced by sex hormones and the brain is continuously shaped by the changing hormone milieu throughout the whole life. Earlier we demonstrated that on the effect of estradiol there is a cyclic synaptic remodeling, i.e. a transient decrease in the number of GABAergic axo-somatic synapses in the arcuate nucleus. By using preembedding estrogen receptor and postembedding GABA immunostaining, in the present paper we studied the specificity of this effect and we found that in the anteroventral periventricular nucleus (AvPv) of adult female rats 17beta-estradiol treatment does not affect all synapses and neurons. In contrast to the arcuate nucleus, hormonal treatment induces a significant increase of inhibitory axo-somatic synapses in the AvPv and we found selectivity at the level of the postsynaptic neurons, as well. We analyzed the hormone-induced synaptic remodeling in estrogen receptor alpha and beta immunoreactive and non-labeled cells and the change in synapse number was observed only in neurons which express estrogen beta receptor.

Consolidation theory assumes that memories are labile during a limited time window after acquisition, but as time passes, memories become stable and resistant to amnesic agents. However, the vision of immutable memories after consolidation has been challenged. Thus, after the presentation of a reminder, the reactivated old memories become labile and again susceptible to amnesic treatments. This process implies a re-stabilization phase, usually referred to as reconsolidation. Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter both in the Central nervous system (CNS) and in the periphery. A considerable amount of evidence has arisen from different studies regarding the role of the GABA(A) receptor in diverse behavioral paradigms and tasks. Here, we investigate the role of the GABAergic system on both memory consolidation and reconsolidation phases by using the memory paradigm of the crab Chasmagnathus. In order to achieve such a goal, we design pharmacological-behavioral experiments, which include the administration of classic agonist (muscimol) and antagonist (bicuculline) of the mammals GABA(A) receptors. The current results show that the systemic administration of muscimol impairs the consolidation and reconsolidation processes. In contrast, the administration of bicuculline improves the consolidation and reconsolidation processes. Furthermore, the co-administration of both drugs blocks the agonist amnesic effect on the consolidation phase. The ubiquity of the neurotransmitter and its receptors in the animal taxa allows us to use the classic agonist-and-antagonist administration procedure in this invertebrate. Thus, all the results reported in this paper can be judged as a result of the modulation exerted by the functional state of the GABAergic system in the CNS. To conclude, the results obtained in this report with an invertebrate model represent additional evidences supporting the view that some molecular mechanisms subserving different memory phases could be the basic tools employed by phylogenetically disparate animals.

Prolyl oligopeptidase (POP) is an endopeptidase which cleaves short proline-containing neuropeptides, and it is involved in memory and learning. POP also has an intercellular function mediated through the inositol pathway, and has been involved in cell death. POP has been early considered as a housekeeping enzyme, but the recent research indicates that POP expression is regulated across tissues and intracellularly. In the brain, POP is exclusively expressed in neurons and most abundantly in pyramidal neurons of cerebral cortex, in the CA1 field neurons of hippocampus and in cerebellar Purkinje's cells. Intracellularly, POP is mainly present in the cytoplasm and some in intracellular membranes, like rough endoplasmic reticulum and Golgi apparatus. In this paper, we systematically studied the levels of expression of POP along the life of cerebellar granule cells (CGC) in culture and the distribution of POP within different intracellular compartments. We used the tight-binding inhibitor JTP-4819 covalently coupled with fluorescein (FJTP) as a tool to study the changes on expression and localization of POP protein. Our results indicate that POP activity levels are regulated during the life of the neurons. POP was found mainly in cytoplasm and neuronal projections, but at an early developmental phase significant amounts were found also in nuclei. Along the life of the neurons, POP activity fluctuated in 7-day cycles. In young neurons, the cytosolic POP activity was low but increased by maturation so that the activity peak coincided with full differentiation. Over aging, cytoplasmic POP was concentrated around nucleus, but the activity decreased with time. POP was also present in vesicles across the neuron. No major changes were seen in the nuclear or membrane bound POP over aging until activity disappeared upon neuronal death. This is the first time when POP was found in the nuclei of human neuronal cells. (C) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.

In most mammals the cochlear nuclear complex (CN) contains a distributed system of granule cells (GCS), whose parallel fiber axons innervate the dorsal cochlear nucleus (DCN). Like their counterpart in cerebellum, CN granules are innervated by mossy fibers of various origins. The GCS is complemented by unipolar brush (UBCs) and Golgi cells, and by stellate and cartwheel cells of the DCN. This cerebellum-like microcircuit modulates the activity of the DCN's main projection neurons, the pyramidal, giant and tuberculoventral neurons, and is thought to improve auditory performance by integrating acoustic and proprioceptive information. In this paper, we focus on the rat UBCs, a chemically heterogeneous neuronal population, using antibodies to calretinin, metabotropic glutamate receptor 1alpha (mGluR1alpha), epidermal growth factor substrate 8 (Eps8) and the transcription factor T-box gene Tbr2 (Tbr2). Eps8 and Tbr2 labeled most of the CN's UBCs, if not the entire population, while calretinin and mGluR1alpha distinguished two largely separate subsets with overlapping distributions. By double labeling with antibodies to Tbr2 and the alpha6 GABA receptor A (GABAA) subunit, we found that UBCs populate all regions of the GCS and occur at remarkably high densities in the DCN and subpeduncular corner, but rarely in the lamina. Although GCS subregions likely share the same microcircuitry, their dissimilar UBC densities suggest they may be functionally distinct. UBCs and granules are also present in regions previously not included in the GCS, namely the rostrodorsal magnocellular portions of ventral cochlear nucleus, vestibular nerve root, trapezoid body, spinal tract and sensory and principal nuclei of the trigeminal nerve, and cerebellar peduncles. The UBC's dendritic brush receives AMPA- and NMDA-mediated input from an individual mossy fiber, favoring singularity of input, and its axon most likely forms several mossy fiber-like endings that target numerous granule cells and other UBCs, as in the cerebellum. The UBCs therefore, may amplify afferent signals temporally and spatially, synchronizing pools of target neurons.