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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.

Nitric oxide produced by neuronal nitric oxide synthase (nNOS) in the spinal cord is required for development of hyperalgesia in inflammatory and neuropathic pain states. nNOS is expressed by some dorsal horn neurons, and an early study that used a histochemical method to identify these cells suggested that they were mainly inhibitory interneurons. We have carried out a quantitative analysis of nNOS-immunoreactivity in laminae I–III of the rat dorsal horn, to determine the proportion of inhibitory and excitatory neurons and axonal boutons that express the protein. nNOS was present in ∼5% of neurons in laminae I and III, and 18% of those in lamina II. Although most cells with strong nNOS immunostaining were GABA-immunoreactive, two-thirds of the nNOS-positive cells in lamina II and half of those in lamina III were not GABAergic, and some of these expressed protein kinase Cγ (PKCγ). We estimate that nNOS is present in 17–19% of the inhibitory interneurons in laminae I–II, and 6% of those in lamina III. However, our results suggest that nNOS is also expressed at a relatively low level by a significant proportion (∼17%) of excitatory interneurons in lamina II. nNOS was seldom seen in boutons that contained vesicular glutamate transporter 2, which is expressed by excitatory interneurons, but was co-localised with the vesicular GABA transporter (VGAT, a marker for GABAergic and glycinergic axons). nNOS was detected in 13% of VGAT boutons in lamina I and in 7–8% of those in laminae II–III. However, it was only found in 2–4% of the VGAT boutons that were presynaptic to PKCγ-expressing interneurons in this region. These results indicate that nNOS is more widely expressed than previously thought, being present in both inhibitory and excitatory neurons. They provide further evidence that axons of neurochemically defined populations of inhibitory interneuron are selective in their post-synaptic targets., Highlights ▶nNOS is expressed by nearly 20% of neurons in lamina II and 5% of those in laminae I and III. ▶The majority of nNOS neurons in laminae II and III are not GABAergic. ▶Between 7 and 13% of GABAergic boutons in laminae I–III are nNOS-immunoreactive. ▶nNOS axons form few synapses with PKCγ+ excitatory interneurons.

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.

Substance P by acting on its preferred receptor neurokinin 1 (NK1) in the amygdala appears to be critically involved in the modulation of fear and anxiety. The present study was undertaken to identify neurochemically specific subpopulations of neuron expressing NK1 receptors in the lateral amygdaloid nucleus (LA), a key site for regulating these behaviors. We also analyzed the sources of glutamatergic inputs to these neurons. Immunofluorescence analysis of the co-expression of NK1 with calcium binding proteins in LA revealed that ∼35% of NK1-containing neurons co-expressed parvalbumin (PV), whereas no co-localization was detected in the basal amygdaloid nucleus. We also show that neurons expressing NK1 receptors in LA did not contain detectable levels of calcium/calmodulin kinase IIα, thus suggesting that NK1 receptors are expressed by interneurons. By using a dual immunoperoxidase/immunogold-silver procedure at the ultrastructural level, we found that in LA ∼75% of glutamatergic synapses onto NK1-expressing neurons were labeled for the vesicular glutamate transporter 1 indicating that they most likely are of cortical, hippocampal, or intrinsic origin. The remaining ∼25% were immunoreactive for the vesicular glutamate transporter 2 (VGluT2), and may then originate from subcortical areas. On the other hand, we could not detect VGluT2-containing inputs onto NK1/PV immunopositive neurons. Our data add to previous localization studies by describing an unexpected variation between LA and basal nucleus of the amygdala (BA) in the neurochemical phenotype of NK1-expressing neurons and reveal the relative source of glutamatergic inputs that may activate these neurons, which in turn regulate fear and anxiety responses., Highlights ▶Subsets of LA neurons containing NK1 receptors co-express PV or CB, but not CR. ▶NK1- and CaMKIIα-like immunoreactivity do not co-localize in LA neurons. ▶In LA, ∼25% of glutamatergic inputs onto NK1-expressing neurons contain VGluT2. ▶NK1/PV labeled neurons do not seem to receive VGluT2-positive axon terminals.

Lamina I of the spinal cord contains many projection neurons that express the neurokinin 1 receptor (NK1r). It has been reported that these cells can undergo long-term potentiation (LTP), which may result from insertion of AMPA-type glutamate receptors (AMPArs) containing GluA1 or GluA4 subunits. We therefore investigated synaptic AMPAr expression on these cells with immunocytochemistry following antigen-retrieval. We also examined their density of glutamatergic input (by analysing AMPAr synaptic puncta and contacts from glutamatergic boutons), and phosphorylation of extracellular signal-regulated kinases (pERKs) following noxious stimulation. Our results indicate that there are two populations of NK1r-expressing projection neurons: large GluA4+/GluA1− cells with a high density of glutamatergic input and small GluA1+/GluA4− cells with a much lower input density. Results from pERK experiments suggested that the two groups may not differ in the types of noxious stimulus that activate them. Glutamatergic synapses on distal dendrites of the large cells were significantly longer than those on proximal dendrites, which presumably compensates for the greater attenuation of distally-generated excitatory postsynaptic currents (EPSCs). Both types of cell received contacts from peptidergic primary afferents, however, on the large cells these appeared to constitute over half of the glutamatergic synapses, and were often associated with elongated AMPAr puncta. This suggests that these afferents, which probably contain substance P, provide a powerful, secure synaptic input to large NK1r-expressing projection neurons. These results demonstrate the importance of GluA4-containing AMPArs in nociceptive transmission and raise the possibility that different forms of LTP in lamina I projection neurons may be related to differential expression of GluA1/GluA4.

There is strong evidence that vascular risk factors play a role in the development of Alzheimer's disease (AD) or vascular dementia (vaD). Ethanol (EtOH) and cholesterol are such vascular risk factors, and we recently showed that hypercholesterolemia causes pathologies similar to AD [Ullrich et al. (2010) Mol Cell Neurosci 45, 408–417]. The aim of this study was to investigate the effects of long-term (12 months) EtOH treatment (20% v/v in drinking water) alone or long-term 5% cholesterol diet alone or a combination (mix) in adult Sprague–Dawley rats. Long-term EtOH treatment (plasma EtOH levels 58±23 mg/dl) caused significant impairment of spatial memory, reduced the number of choline acetyltransferase- and p75 neurotrophin receptor-positive nucleus basalis of Meynert neurons, decreased cortical acetylcholine, elevated cortical monocyte chemoattractant protein-1 and tissue-type plasminogen activator, enhanced microglia, and markedly induced anti-rat immunoglobulin G-positive blood–brain barrier leakage. The effect of long-term hypercholesterolemia was similar. Combined long-term treatment of rats with 20% EtOH and 5% cholesterol (mix) did not potentiate treatment with EtOH alone, but instead counteracted some of the EtOH-associated effects. In conclusion, our data show that vascular risk factors EtOH and cholesterol play a role in cognitive impairment and possibly vaD., Highlights ▶Long-term chronic ethanol causes cognitive impairment in rats in vivo. ▶Chronic ethanol causes cholinergic neurodegeneration. ▶Chronic ethanol induces cortical rat IgG-influx and MCP-1 upregulation. ▶Chronic mild hypercholesterolemia causes similar impairments. ▶Hypercholesterolemia partly counteracts some of the ethanol-induced effects.

Our previous finding, that the capsaicin- and KCl-induced Ca(2+)-dependent production of the intra- and intercellular signaling molecule N-arachidonoyl ethanolamine (anandamide) in cultured primary sensory neurons could be abolished and reduced by approximately 2/3 by capsaicin-induced degeneration of capsaicin-sensitive neurons, respectively suggests that a major sub-population of capsaicin-sensitive cells together with a group of non-capsaicin-sensitive cells should express enzymes involved in Ca(2+)-dependent anandamide synthesis. N-acyl phosphotidylethanolamine phospholipase D (NAPE-PLD) is known to be involved in Ca(2+)-dependent anandamide production. Hence, here, we used reverse transcriptase and quantitative real time polymerase chain reaction to study NAPE-PLD expression in dorsal root ganglia and to clarify the sub-population of cells expressing this enzyme. Cultures prepared from mouse dorsal root ganglia were grown either in the absence or presence of the neurotoxin, capsaicin (10 muM) overnight. We report, that NAPE-PLD is expressed both in dorsal root ganglia and cultures prepared from dorsal root ganglia and grown in the absence of capsaicin. Furthermore, we also report that capsaicin application downregulates the expression of NAPE-PLD as well as the capsaicin receptor, transient receptor potential vanilloid type 1 ion channel, by about 70% in the cultures prepared from dorsal root ganglia. These findings indicate that a major sub-population of capsaicin-sensitive primary sensory neurons expresses NAPE-PLD, and suggest that NAPE-PLD is expressed predominantly by capsaicin-sensitive neurons in dorsal root ganglia. These data also suggest that NAPE-PLD might be a target to control the activity and excitability of a major sub-population of nociceptive primary sensory neurons.

Anxiety disorders are the most prevalent central nervous system diseases imposing a high social burden to our society. Emotional processing is particularly controlled by GABA-ergic transmission in the amygdala. Using in situ hybridization and immunohistochemistry we now investigated changes in the expression of GABA synthesizing enzymes (GAD65 and GAD67), GABAA (α1–5, β1–3, γ1–2) and GABAB receptor subunits (GBBR1, GBBR2) in amygdaloid nuclei of high anxiety-related behavior (HAB) mice in comparison to mice selected for normal anxiety-related behavior (NAB). Levels of GAD65 and GAD67 mRNAs and protein, as well as those of GABA were increased in the amygdala of HAB mice. Relative to NAB controls, mRNA expression of the GABAA receptor subunits β1, β2 and γ2 was specifically increased in the basolateral amygdala of HAB mice while transcription of α5 and γ1 subunits was reduced in the central and medial amygdala. On the protein level, increases in β2 and γ2 subunit immunoreactivities were evident in the basolateral amygdala of HAB mice. No change in GABAB receptor expression was observed. These findings point towards an imbalanced GABA-ergic neurotransmission in the amygdala of HAB mice. On the other hand, FosB, a marker for neuronal activity, was increased in principal neurons of the basolateral amygdala in HAB mice, reflecting activation of excitatory neurons, possibly as a consequence of reduced GABA-ergic tonic inhibition through α5 and γ1 containing receptors. Ultimately these mechanisms may lead to the compensatory activation of GABA transmission, as indicated by the increased expression of GAD65/67 in HAB mice., Graphical Abstract Highlights ▶Mice with increased trait anxiety revealed: ▶Increased activity of principal neurons of the basolateral amygdala. ▶A compensatory increase of glutamate decarboxylase expression. ▶Differential alterations of GABAA receptor subunit expression in the amygdala.

Neuronal networks generating rhythmic activity as an emergent property are common throughout the nervous system. Some are responsible for rhythmic behaviours, as is the case for the spinal cord locomotor networks; however, for others the function is more subtle and usually involves information processing and/or transfer. An example of the latter is sympathetic nerve activity, which is synchronized into rhythmic bursts in vivo. This arrangement is postulated to offer improved control of target organ responses compared to tonic nerve activity. Traditionally, oscillogenic circuits in the brainstem are credited with generating these rhythms, despite evidence for the persistence of some frequencies in spinalized preparations. Here, we show that rhythmic population activity can be recorded from the intermediolateral cell column (IML) of thoracic spinal cord slices. Recorded in slices from 10- to 12-day-old rats, this activity was manifest as 8–22 Hz oscillations in the field potential and was spatially restricted to the IML. Oscillations often occurred spontaneously, but could also be induced by application of 5-HT, α-methyl 5-HT or MK212. These agents also significantly increased the strength of spontaneous oscillations. Rhythmic activity was abolished by TTX and attenuated by application of gap junction blockers or by antagonists of GABAA receptors. Together these data indicate that this rhythm is an emergent feature of a population of spinal neurons coupled by gap junctions. This work questions the assumption that sympathetic rhythms are dependent on supraspinal pacemaker circuits, by highlighting a surprisingly strong rhythmogenic capability of the reduced sympathetic networks of the spinal cord slice.

Although most anti-epileptic drugs are considered to have a primary molecular target, it is clear that their actions are unlikely to be limited to effects on a single aspect of inhibitory synaptic transmission, excitatory transmission or voltage-gated ion channels. Systemically administered drugs can obviously simultaneously access all possible targets, so we have attempted to determine the overall effect of diverse agents on the balance between GABAergic inhibition, glutamatergic excitation and cellular excitability in neurones of the rat entorhinal cortex in vitro. We used an approach developed for estimating global background synaptic excitation and inhibition from fluctuations in membrane potential obtained by intracellular recordings. We have previously validated this approach in entorhinal cortical neurones [Greenhill and Jones (2007a) Neuroscience 147:884–892]. Using this approach, we found that, despite their differing pharmacology, the drugs tested (phenytoin, lamotrigine, valproate, gabapentin, felbamate, tiagabine) were unified in their ability to increase the ratio of background GABAergic inhibition to glutamatergic excitation. This could occur as a result of decreased excitation concurrent with increased inhibition (phenytoin, lamotrigine, valproate), a decrease in excitation alone (gabapentin, felbamate), or even with a differential increase in both (tiagabine). Additionally, we found that the effects on global synaptic conductances agreed well with whole cell patch recordings of spontaneous glutamate and GABA release (our previous studies and further data presented here). The consistency with which the synaptic inhibition:excitation ratio was increased by the antiepileptic drugs tested was matched by an ability of all drugs to concurrently reduce intrinsic neuronal excitability. Thus, it seems possible that specific molecular targets among antiepileptic drugs are less important than the ability to increase the inhibition:excitation ratio and reduce overall neuronal and network excitability.

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.

Is sentence structure processed by the same neural and cognitive resources that are recruited for processing word meanings, or do structure and meaning rely on distinct resources? Linguistic theorizing and much behavioral evidence suggest tight integration between lexico-semantic and syntactic representations and processing. However, most current proposals of the neural architecture of language continue to postulate a distinction between the two. One of the earlier and most cited pieces of neuroimaging evidence in favor of this dissociation comes from a paper by Dapretto and Bookheimer (1999) . Using a sentence-meaning judgment task, Dapretto & Bookheimer observed two distinct peaks within the left inferior frontal gyrus (LIFG): one was more active during a lexico-semantic manipulation, and the other during a syntactic manipulation. Although the paper is highly cited, no attempt has been made, to our knowledge, to replicate the original finding. We report an fMRI study that attempts to do so. Using a combination of whole-brain, group-level ROI, and participant-specific functional ROI approaches, we fail to replicate the original dissociation. In particular, whereas parts of LIFG respond reliably more strongly during lexico-semantic than syntactic processing, no part of LIFG (including in the region defined around the peak reported by Dapretto & Bookheimer) shows the opposite pattern. We speculate that the original result was a false positive, possibly driven by a small subset of participants or items that biased a fixed-effects analysis with low power.

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.

International audience; In their recent paper, Alkoby et al. (2017) provide the readership with an extensive and very insightful review of the factors influencing NeuroFeedback (NF) performance. These factors are drawn from both the NF literature and the Brain-Computer Interface (BCI) literature. Our short review aims to complement Alkoby et al.'s review by reporting recent additions to the BCI literature. The object of this paper is to highlight this literature and discuss its potential relevance and usefulness to better understand the processes underlying NF and further improve the design of clinical trials assessing NF efficacy. Indeed, we are convinced that while NF and BCI are fundamentally different in many ways, both the BCI and NF communities could reach compelling achievements by building upon one another. By reviewing the recent BCI literature, we identified three types of factors that influence BCI performance: task-specific, cognitive/motivational and technology-acceptance-related factors. Since BCIs and NF share a common goal (i.e., learning to modulate specific neurophysiological patterns), similar cognitive and neurophysiological processes are likely to be involved during the training process. Thus, the literature on BCI training may help (1) to deepen our understanding of neurofeedback training processes and (2) to understand the variables that influence the clinical efficacy of NF. This may help to properly assess and/or control the influence of these variables during randomized controlled trials.

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.

Preprint - bioRxiv posts many COVID19-related papers. A reminder: they have not been formally peer-reviewed and should not guide health-related behavior or be reported in the press as conclusive. Maintaining balance typically occurs sub-consciously. Occasionally, however, individuals will direct conscious attention towards balance, e.g., in response to a postural threat. Such conscious movement processing (CMP) increases the reliance on attentional resources and may disrupt control of balance, but the underlying changes in neuromuscular control remain poorly understood. We investigated the effects of CMP (manipulated using verbal instructions) on neural control of posture in twenty-five adults (11 females, mean age = 23.9, range = 18–33). Participants performed 90-second, narrow-stance balance trials in high- and low-CMP conditions, and in stable (solid surface) and unstable (foam) task conditions. Postural sway amplitude, frequency and complexity were used to assess postural control. Surface EMG was recorded bilaterally from lower leg muscles (Soleus, Tibialis Anterior, Gastrocnemius Medialis, Peroneus Longus) and intermuscular coherence (IMC) was assessed for 12 muscle pairs across four frequency bands. We found significantly increased sway amplitude, and decreased sway frequency and complexity in the high- compared to the low-CMP condition. All sway variables (frequency, amplitude and complexity) increased in the unstable compared to the stable condition. Results suggested reduced beta band IMC between several muscles pairs during high- compared to low-CMP, but these findings did not remain significant after controlling for multiple comparisons. Finally, IMC significantly increased in the unstable conditions for most muscle combinations and frequency bands. In all, results tentatively suggest that CMP-induced changes in sway outcomes may be underpinned by reduced beta-band IMC, but these findings need to be replicated before they can be interpreted more conclusively. Funding: LJ was funded by the Kootstra Talent Fellowship awarded by Maastricht UMC+

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?

BrainScaleS-2 is an accelerated and highly configurable neuromorphic system with physical models of neurons and synapses. Beyond networks of spiking point neurons, it allows for the implementation of user-defined neuron morphologies. Both passive propagation of electric signals between compartments as well as dendritic spikes and plateau potentials can be emulated. In this paper, three multi-compartment neuron morphologies are chosen to demonstrate passive propagation of postsynaptic potentials, spatio-temporal coincidence detection of synaptic inputs in a dendritic branch, and the replication of the BAC burst firing mechanism found in layer 5 pyramidal neurons of the neocortex.

The cerebellum is a brain structure that is highly interconnected with other brain regions. There are many contributing factors to cerebellar-related brain disease, such as altered afferent input, local connectivity, and/or cerebellar output. Purkinje cells (PC) are the principle cells of the cerebellar cortex, and fire intrinsically; that is, they fire spontaneous action potentials at high frequencies. This review paper focuses on PC intrinsic firing activity, which is altered in multiple neurological diseases, including ataxia, Huntington Disease (HD) and autism spectrum disorder (ASD). Notably, there are several cases where interventions that restore or rescue PC intrinsic activity also improve impaired behavior in these mouse models of disease. These findings suggest that rescuing PC firing deficits themselves may be sufficient to improve impairment in cerebellar-related behavior in disease. We propose that restoring PC intrinsic firing represents a good target for drug development that might be of therapeutic use for several disorders.

In 2013, Thomas Jessell published a paper with Andrew Miri and Eiman Azim that took on the task of examining corticospinal neuron function during movement ( Miri et al., 2013 ). They took the view that a combination of approaches would be able to shed light on corticospinal function, and that this function must be considered in the context of corticospinal connectivity with spinal circuits. In this review, we will highlight recent developments in this area, along with new information regarding inputs and cross-connectivity of the corticospinal circuit with other circuits across the rodent central nervous system. The genetic and viral manipulations available in these animals have led to new insights into descending circuit interaction and function. As species differences exist in the circuitry profile that contributes to dexterous forelimb movements ( Lemon, 2008 , Yoshida and Isa, 2018 ), highlighting important advances in one model could help to compare and contrast with what is known about other models. We will focus on the circuitry underpinning dexterous forelimb movements, including some recent developments from systems besides the corticospinal tract, to build a more holistic understanding of sensorimotor circuits and their control of voluntary movement. The rodent corticospinal system is thus a central point of reference in this review, but not the only focus.

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.

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.

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 main goal of this paper is to introduce the concept of iso-perceptual manifold for perception of body configuration and related variables (kinesthetic perception) and to discuss its relation to the equilibrium-point hypothesis and the concepts of reference coordinate and uncontrolled manifold. Hierarchical control of action is postulated with abundant transformations between sets of spatial reference coordinates for salient effectors at different levels. Iso-perceptual manifold is defined in the combined space of afferent and efferent variables as the subspace corresponding to a stable percept. Examples of motion along an iso-perceptual manifold (perceptually equivalent motion) are considered during various natural actions. Some combinations of afferent and efferent signals, in particular those implying a violation of body's integrity, give rise to variable percepts by artificial projection onto iso-perceptual manifolds. This framework is used to interpret unusual features of vibration-induced kinesthetic illusions and to predict new illusions not yet reported in the literature.

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.

Our previous studies on healthy individuals and stroke patients led us to propose that the dominant and nondominant arms are specialized for distinct motor control processes. We hypothesize that the dominant arm is specialized for predictive control of limb dynamics, and the nondominant arm is specialized for impedance control. We previously introduced a hybrid control scheme to explain lateralization of single-joint elbow movements. In this paper we apply a similar computational framework to explore interlimb differences in multi-joint reaching movements: the movements of both arms are initiated using predictive control mechanisms, and terminated using impedance mechanisms. Four parameters characterize predictive mechanisms, four parameters characterize impedance mechanisms, and the ninth parameter describes the instant of switch between the two modes of control. Based on our hypothesis of motor lateralization, we predict an early switch to impedance control for the nondominant arm, but a late switch, near the end of motion, for the dominant arm. We fit our model to multi-joint reaching movements of each arm, made in the horizontal plane. Our results reveal that the more curved trajectories of the nondominant arm are characterized by an early switch to impedance mechanisms, in the initial phase of motion near peak velocity. In contrast, the trajectories of the dominant arm were best fit, when the switch to impedance mechanisms occurred late in the deceleration phase of motion. These results support a model of motor lateralization in which the dominant controller is specialized for predictive control of task dynamics, while the nondominant arm is specialized for impedance control mechanisms. For the first time, we are able to operationally define handedness expressed during multi-joint movements by applying a computational control model.

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.

There has been a dramatic rise in geneenvironment studies of human behavior over the past decade that have moved the field beyond simple nature versus nurture de- bates. These studies offer promise in accounting for more variability in behavioral and biological phenotypes than stud- ies that focus on genetic or experiential factors alone. They also provide clues into mechanisms of modifying genetic risk or resilience in neurodevelopmental disorders. Yet, it is rare that these studies consider how these interactions change over the course of development. In this paper, we describe research that focuses on the impact of a polymorphism in a brain-derived neurotrophic factor (BDNF) gene, known to be involved in learning and development. Specifically we present findings that assess the effects of genotypic and environmental loadings on neuroanatomic and behavioral phenotypes across development. The findings illustrate the use of a genetic mouse model that mimics the human poly- morphism, to constrain the interpretation of gene-environ- ment interactions across development in humans. © 2009

Attention influences many aspects of cognitive development. Variations in the catechol-O-methyltransferase (COMT) gene, known to affect dopamine neurotransmission, have frequently been found to influence attention in adults and older children. In this paper we examined 2 year old children and found that variation in the COMT gene influenced attention in a task involving looking to a sequence of visual stimuli. Because the influence of another dopamine-related gene (DRD4) has been shown to interact with parenting quality at this age, we explored parenting in relation to variations in the COMT gene. Variations in COMT interacted with parenting quality to influence our attention measure. The Val108/158Met polymorphism of COMT is commonly used to determine allelic groups, but recently haplotypes of several polymorphisms within this gene have been shown to be more strongly associated with perceived pain. Since attention and pain both involve the activation of the anterior cingulate gyrus in imaging studies, we compared the Val108/158Met influence with the COMT haplotypes and found the latter to be more predictive of attention. Our results confirm that important aspects of cognitive development including attention depend on the interaction of genes and early environment.

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.

When given in a warm environment MDMA (3,4-methylenedioxymethamphetamine, ecstasy) causes hyperthermia by increasing interscapular brown adipose tissue (iBAT) heat production and decreasing heat loss via cutaneous vasoconstriction. When given in a cold environment, however, MDMA causes hypothermia by an unknown mechanism. This paper addresses these mechanisms and in addition examines whether antagonists at 5-HT(1A) and D(2) receptors reduce the hypothermic action of MDMA. Male Sprague-Dawley rats instrumented with a Doppler probe for measuring tail blood flow, and probes for measuring core and iBAT temperatures, were placed in a temperature-controlled chamber. The chamber temperature was reduced to 10 degrees C and vehicle (0.5 ml Ringer), the 5-HT(1A) antagonist WAY 100635 (0.5 mg/kg), the D(2) antagonist spiperone (20 mug/kg), or the combination of Way 100635 and spiperone were injected s.c. Thirty minutes later the antagonists were injected again along with MDMA (10 mg/kg) or vehicle. MDMA reduced core body temperature by preventing cold-elicited iBAT thermogenesis and by transiently reversing cold-elicited cutaneous vasoconstriction. Pretreatment with WAY 100635 prevented MDMA induced increases in tail blood flow, and briefly attenuated MDMA's effects on iBAT and core temperature. While spiperone alone failed to affect any of the parameters, the combination of spiperone and WAY 100635 decreased MDMA-mediated hypothermia by attenuating both the effects on tail blood flow and iBAT thermogenesis. MDMA's prevention of cold-induced iBAT thermogenesis appears to have a central origin as it rapidly reverses cold-induced increases in iBAT sympathetic nerve discharge in anesthetized rats. Our results demonstrate that MDMA in a cold environment reduces core body temperature by inhibiting iBAT thermogenesis and tail artery vasoconstriction and suggest that mechanisms by which this occurs include the activation of 5-HT1A and dopamine D2 receptors.

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.

The neurotransmitter serotonin (5-HT) plays a central role in brain development, regulation of mood, stress reactivity and risk of psychiatric disorders, and thus alterations in 5-HT signaling early in life have critical implications for behavior and mental health across the life span. Drawing on preclinical and emerging human evidence this narrative review paper will examine three key aspects when considering the consequences of early life changes in 5-HT: (1) developmental origins of variations of 5-HT signaling; (2) influence of genetic and epigenetic factors; and (3) preclinical and clinical consequences of 5-HT-related changes associated with antidepressant exposure (SSRIs). The developmental consequences of altered prenatal 5-HT signaling varies greatly and outcomes depend on an ongoing interplay between biological (genetic/epigenetic variations) and environmental factors, both pre and postnatally. Emerging evidence suggests that variations in 5-HT signaling may increase sensitivity to risky home environments, but may also amplify a positive response to a nurturing environment. In this sense, factors that change central 5-HT levels may act as ‘plasticity’ rather than ‘risk’ factors associated with developmental vulnerability. Understanding the impact of early changes in 5-HT levels offers critical insights that might explain the variations in early typical brain development that underlies behavioral risk.

The prefrontal cortex has long been thought to subserve both working memory and "executive" function, but the mechanistic basis of their integrated function has remained poorly understood, often amounting to a homunculus. This paper reviews the progress in our laboratory and others pursuing a long-term research agenda to deconstruct this homunculus by elucidating the precise computational and neural mechanisms underlying these phenomena. We outline six key functional demands underlying working memory, and then describe the current state of our computational model of the prefrontal cortex and associated systems in the basal ganglia (BG). The model, called PBWM (prefrontal cortex, basal ganglia working memory model), relies on actively maintained representations in the prefrontal cortex, which are dynamically updated/gated by the basal ganglia. It is capable of developing human-like performance largely on its own by taking advantage of powerful reinforcement learning mechanisms, based on the midbrain dopaminergic system and its activation via the basal ganglia and amygdala. These learning mechanisms enable the model to learn to control both itself and other brain areas in a strategic, task-appropriate manner. The model can learn challenging working memory tasks, and has been corroborated by several important empirical studies.

5-Hydroxymethylcytosine (5hmC) is abundant in the brain, suggesting an important role in epigenetic control of neuronal functions. In this paper, we show that 5hmC and 5-methylcytosine (5mC) levels are coordinately distributed in gene promoters of the rhesus macaque prefrontal cortex. Although promoter hydroxymethylation and methylation are overall negatively correlated with expression, a subset of highly expressed genes involved in specific cerebral functions is associated with high levels of 5mC and 5hmC. These relationships were also observed in the mouse cortex. Furthermore, we found that early-life maternal deprivation is associated, in the adult monkey cortex, with DNA hydroxymethylation changes of promoters of genes related to neurological functions and psychological disorders. These results reveal that early social adversity triggers variations in brain DNA hydroxymethylation that could be detected in adulthood.

This paper investigates the vulnerability of astrocytes to oxidative injury as a function of age in culture in mice. Primary murine cortical astrocyte cultures of different ages were exposed to H2O2, combined oxygen-glucose deprivation or glucose deprivation. Astrocytes became more vulnerable to damage from each injury paradigm with age, showing transitions between 15 and 22 days. Both the antioxidant glutathione and superoxide dismutase activity increased after 30 days in culture, while catalase activity did not change up to 34 days. When the decrease in glutathione with injury was measured, young cells showed no change with H2O2 and decreases of20% after oxygen-glucose deprivation or glucose deprivation, while older cultures lost50% of their glutathione with the same insults. Since iron can be a catalyst for hydroxyl radical formation, we stained cultures and found both iron staining and ferritin immunoreactivity increased with age. Increased iron correlated with protection by deferoxamine against H2O2 injury. The three injury paradigms each had a unique pattern of protection by antioxidants. Dimethylthiourea, a hydrophilic antioxidant, protected from all three insults. Trolox, a lipophilic antioxidant, protected older astrocytes from oxygen-glucose deprivation and glucose deprivation. Deferoxamine provided near complete protection from H2O2, partial protection from oxygen-glucose deprivation and no protection from glucose deprivation. As evidence of increasing oxidative stress, lipid peroxidation resulting from oxygen-glucose deprivation increased with age, assessed with cis-parinaric acid. The increasing sensitivity of ageing astrocytes to oxidative injury occurs while antioxidant defenses are maintained. Increased sensitivity to H2O2 or oxygen-glucose deprivation correlates with iron accumulation.

The present paper reports a nanosecond time-resolved fluorescence derived from the cortex and the area of the periaqueductal gray including the nucleus raphe dorsalis (PAG-nRD) in unanaesthetized freely moving rats. The measurements were acquired through a single optic fibre transmitting a subnanosecond nitrogen laser pulse (337 nm, 15 Hz) and collecting the brain fluorescence occurring at 460 nm which might depend on mitochondrial NADH (reduced form of nicotinamide adenine dinucleotide). The fluorometric method was combined with polygraphic recordings, and this procedure allowed us to define, for the first time, variations of the 460 nm signal occurring throughout the sleep-wake cycle. In the PAG-nRD, the signal exhibited moderate heterogeneous variation in amplitude during slow-wave as compared to the waking state. Constant increases were observed during paradoxical sleep as compared to the waking state. For this state of sleep the magnitude of the variations depended on the optic fibre location. In the cortex and during either slow-wave sleep or paradoxical sleep, the signal presented moderate increases which were significant during paradoxical sleep. The magnitude of the redox variations observed either in the PAG-nRD or in the cortex might be ascribed to the oxidative energy balance which is related to sleep states.

During all stages of neural development-from the fate switches of neural precursor/progenitor cells to activity-dependent synapse maturation-chromatin-level modifications are important regulators of the gene expression that control developmental programs. Such modifications, including both alterations of histone tails and cytosine residues in the DNA, as well as changes in the chromatin structure, act dynamically throughout development and work together to determine the chromatin state at each time point. While many studies have shown localized action of chromatin modifiers at relevant gene loci, recent reports have also indicated that some chromatin modifications work on a more global scale, altering many loci throughout the genome. Here we review recent papers that describe the roles of chromatin-level regulation, at both the local and global scale, in the development of the mouse brain.

An in vitro system was established to analyse corticostriatal processing. Cortical and striatal slices taken at postnatal days 0–2 were co-cultured for three to six weeks. The anatomy of the organotypic co-cultures was determined using immunohistochemistry. In the cortex parvalbumin-positive and calbindin-positive cells, which resembled those seen in vivo , had laminar distributions. In the striatum, strongly stained parvalbumin-positive cells resembling striatal GABAergic interneurons and cholinergic interneurons were scattered throughout the tissue. The soma area of these iterneuron classes was larger than the average striatal soma area, thus enabling visual selections of cells by class before recording. Cortical neurons with projections to the striatum showed similar morphological features to corticostriatal projection neurons in vivo . No projections from the striatum to the cortex were found. Intracellular recordings were obtained from 94 neurons. These were first classified on the basis of electrophysiological characteristics and the morphologies of cells in each class were reconstructed. Two types of striatal secondary neurons with unique electrophysiological dynamics were identified: GABAergic interneurons ( n = 17) and large aspiny, probably cholinergic, interneurons ( n = 15). The electrophysiological and morphological characteristics of cortical pyramidal cells ( n = 27), cortical interneurons ( n = 1), as well as striatal principal neurons ( n = 34), were identical to those reported for similar ages in vivo . Organotypic cortex-striatum co-cultures are therefore suitable as an in vitro system in which to analyse corticostriatal processing. The network dynamics, which developed spontaneously in that system, are examined in the companion paper.

Increases in plasma osmolality enhance nitric oxide (NO) levels in magnocellular neurosecretory cells (MNCs) of the supraoptic nucleus (SON) and modulate the secretion of both vasopressin (VP) and oxytocin (OT). In this paper, we describe the effects of hypertonicity on the electrical properties of MNCs by focusing on the nitrergic modulation of their activity in this condition. Membrane potentials were measured using the patch clamp technique, in the presence of both glutamatergic and GABAergic neurotransmission blockers, in coronal brain slices of male Wistar rats. The recordings were first made under a control condition (295 mosm/kg H2O), then in the presence of a hypertonic stimulus (330 mosm/kg H2O) and, finally, with a hypertonic stimulus plus 500 μM l -Arginine or 100 μM N-nitro- l -Arginine methyl ester hydrochloride ( l -NAME). Hypertonicity per se increased the firing frequency of the neurons. l -Arginine prevented the increase in fire frequency induced by hypertonic stimulus, and l -NAME (inhibitor of nitric oxide synthase) induced an additional increase in frequency when applied together with the hypertonic solution. Moreover, l -Arginine hyperpolarizes the resting potential and decreases the peak value of the after-hyperpolarization; both effects were blocked by l -NAME and hypertonicity and/or l -NAME reduced the time constant of the rising phase of the after-depolarization. These results demonstrate that an intrinsic nitrergic system is part of the mechanisms controlling the excitability of MNCs of the SON when the internal fluid homeostasis is disturbed.

During early embryonic development, the olfactory placode is the source of different cell types migrating toward the telencephalic vesicle. Among these cell types are the ensheathing cells, the luteinizing hormone-releasing hormone-producing cells and the olfactory marker protein-immunoreactive cells. We have identified a novel group of olfactory placode-derived migratory cells using an antibody against beta-tubulin to label neurons and acetylcholinesterase histochemistry to label postmitotic cells. In this paper we describe the morphology, migration and fate of this novel group of cells. The first neurons detected in the rostral prosencephalon with acetylcholinesterase and anti-beta-tubulin antibody are localized in the olfactory placodes at embryonic day 11 in the rat. At embryonic day 12, anti-beta-tubulin antibody-positive cells were observed in the mesenchymal tissue between the olfactory pit and the rostral pole of the telencephalic vesicle. Anti-beta-tubulin antibody-positive cells were seen running superficially over the pial (dorsal) side of the telencephalic vesicle at embryonic day 13. The majority of these cells have a bipolar profile with short leading and trailing processes, suggesting that they are migratory elements. However, some of these cells showed elaborate processes extending for quite long distances, overlying the pial surface of the telencephalic vesicle. A mass of cells extending over the telencephalic vesicle from the developing olfactory epithelium were observed at embryonic day 13 using acetylcholinesterase histochemistry. Some of these acetylcholinesterase-positive cells were identified as neurons with the specific neuronal marker anti-beta-tubulin antibody. On embryonic day 12, neurons from the olfactory epithelium send axonal fibers toward the telencephalic vesicles. Most of these fibers spread over the anteroventral pole of the vesicles but others entered deep into the telencephalon, reaching the germinal ventricular zone. We also show that fibers run rostrocaudally over the surface of the telencephalic vesicles. We suggest that these cells and fibers, apparently originating in the olfactory placode and migrating through non-conventional routes, might play a significant role in the earliest stages of telencephalic vesicle development.

The notion that stress plays a role in the etiology of psychotic disorders, especially schizophrenia, is longstanding. However, it is only in recent years that the potential neural mechanisms mediating this effect have come into sharper focus. The introduction of more sophisticated models of the interplay between psychosocial factors and brain function has expanded our opportunities for conceptualizing more detailed psychobiological models of stress in psychosis. Further, scientific advances in our understanding of adolescent brain development have shed light on a pivotal question that has challenged researchers; namely, why the first episode of psychosis typically occurs in late adolescence/young adulthood. In this paper, we begin by reviewing the evidence supporting associations between psychosocial stress and psychosis in diagnosed patients as well as individuals at clinical high risk for psychosis. We then discuss biological stress systems and examine changes that precede and follow psychosis onset. Next, research findings on structural and functional brain characteristics associated with psychosis are presented; these findings suggest that normal adolescent neuromaturational processes may go awry, thereby setting the stage for the emergence of psychotic syndromes. Finally, a model of neural mechanisms underlying the pathogenesis of psychosis is presented and directions for future research strategies are explored.