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Cytosolic phospholipase A2 alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment.

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Cytosolic phospholipase A2 alpha mediates electrophysiologic responses of hippocampal pyramidal neurons to neurotoxic NMDA treatment.

Proc Natl Acad Sci U S A. 2007 Mar 26;

Authors: Shen Y, Kishimoto K, Linden DJ, Sapirstein A

The arachidonic acid-generating enzyme cytosolic phospholipase A2 alpha (cPLA2alpha) has been implicated in the progression of excitotoxic neuronal injury. However, the mechanisms of cPLA2alpha toxicity have yet to be determined. Here, we used a model system exposing mouse hippocampal slices to NMDA as an excitotoxic injury, in combination with simultaneous patch-clamp recording and confocal Ca(2+) imaging of CA1 pyramidal neurons. NMDA treatment caused significantly greater injury in wild-type (WT) than in cPLA2alpha null CA1 neurons. Bath application of NMDA evoked a slow inward current in voltage-clamped neurons (composed of both NMDA receptor-mediated and other conductances) that was smaller in cPLA2alpha null than in WT slices. This was not due to down-regulation of NMDA receptor function because NMDA receptor-mediated currents were equivalent in each genotype following brief photolysis of caged glutamate. Current-clamp recordings were made during and following NMDA exposure by eliciting a single action potential with a brief current injection. After NMDA exposure, WT CA1 neurons developed a spike-evoked plateau potential and an increased spike-evoked dendritic Ca(2+) transient. These effects were absent in CA1 neurons from cPLA2alpha null mice and WT neurons treated with a cPLA2alpha inhibitor. The Ca-sensitive K-channel toxins, apamin and paxilline, caused spike broadening and Ca(2+) enhancement in WT and cPLA2alpha null slices. NMDA application in WT and arachidonate applied to cPLA2alpha null cells occluded the effects of apamin/paxilline. These results indicate that cPLA2alpha activity is required for development of aberrant electrophysiologic events triggered by NMDA receptor activation, in part through attenuation of K-channel function.

PMID: 17389392 [PubMed - as supplied by publisher]

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Feedforward Inhibition Contributes to the Control of Epileptiform Propagation Speed

It is still poorly understood how epileptiform events can recruit cortical circuits. Moreover, the speed of propagation of epileptiform discharges in vivo and in vitro can vary over several orders of magnitude (0.1–100 mm/s), a range difficult to explain by a single mechanism. We previously showed how epileptiform spread in neocortical slices is opposed by a powerful feedforward inhibition ahead of the ictal wave. When this feedforward inhibition is intact, epileptiform spreads very slowly (~100 µm/s). We now investigate whether changes in this inhibitory restraint can also explain much faster propagation velocities. We made use of a very characteristic pattern of evolution of ictal activity in the zero magnesium (0 Mg²⁺) model of epilepsy. With each successive ictal event, the number of preictal inhibitory barrages dropped, and in parallel with this change, the propagation velocity increased. There was a highly significant correlation (p < 0.001) between the two measures over a 1000-fold range of velocities, indicating that feedforward inhibition was the prime determinant of the speed of epileptiform propagation. We propose that the speed of propagation is set by the extent of the recruitment steps, which in turn is set by how successfully the feedforward inhibitory restraint contains the excitatory drive. Thus, a single mechanism could account for the wide range of propagation velocities of epileptiform events observed in vitro and in vivo.

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Differential effects of psychoactive drugs in adolescents and adults.

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Differential effects of psychoactive drugs in adolescents and adults.

Crit Rev Neurobiol. 2005;17(2):51-67

Authors: Izenwasser S

It is well known that most people who use psychoactive drugs started as teenagers. In spite of this, there has been little preclinical research on the effects of psychostimulants during adolescence. Recently, however, a number of laboratories have begun to focus on drug effects in adolescents as compared with adults. The data show that there are unique responses to drugs during this period of development. This review will focus on our current understanding of neurochemical and behavioral drug effects during adolescence.

PMID: 16808727 [PubMed - indexed for MEDLINE]

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The Role of Endocannabinoid System Blockade in the Treatment of the Metabolic Syndrome.

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The Role of Endocannabinoid System Blockade in the Treatment of the Metabolic Syndrome.

J Clin Pharmacol. 2007 Mar 28;

Authors: Kakafika AI, Mikhailidis DP, Karagiannis A, Athyros VG

This review considers the use of the first selective blocker of the cannabinoid receptor type 1, rimonabant, to reduce weight and improve cardiovascular disease risk factors in obese patients with metabolic syndrome or multiple cardiovascular disease risk factors. In 4 large trials--Rimonabant in Obesity (RIO)-Lipids, RIO-Europe, RIO-North America, and RIO-Diabetes--after 1 to 2 years of treatment, rimonabant (20 mg/day) led to a significantly greater weight loss and reduction in waist circumference compared with placebo. Treatment with rimonabant was also associated with other favorable changes, including better glycemic control in type 2 diabetes mellitus,improved lipid profile, reduced blood pressure, increased adiponectin levels, fall in high-sensitivity C-reactive protein concentrations, and an overall decrease in the prevalence of the metabolic syndrome. Initial experience with rimonabant shows that it is generally well tolerated with the most common side effect of mild nausea. Rimonabant may be a useful adjunct to lifestyle and behavior modification in the treatment of obese subjects with metabolic syndrome or multiple cardiometabolic risk factors.

PMID: 17392496 [PubMed - as supplied by publisher]

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Cannabis, feeding, SR141716A

A comparison of the effects of the CB(1) receptor antagonist SR141716A, pre-feeding and changed palatability on the microstructure of ingestive behaviour.

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A comparison of the effects of the CB(1) receptor antagonist SR141716A, pre-feeding and changed palatability on the microstructure of ingestive behaviour.

Psychopharmacology (Berl). 2007 Mar 20;

Authors: Thornton-Jones ZD, Kennett GA, Vickers SP, Clifton PG

RATIONALE: The cannabinoid CB(1) receptor inverse agonist SR141716A (rimonabant) is known to cause hypophagia and this study uses microstructural data to elucidate the relevant behavioural mechanisms. OBJECTIVES: The aim of these studies was to determine the behavioural changes induced by SR141716A in animals consuming either a fat or carbohydrate solution. These behavioural changes were directly compared with those induced by behavioural manipulations that modify motivational state and palatability. METHODS: Male hooded Lister rats drank a highly palatable fat emulsion (10% Intralipid) or a carbohydrate solution (10% sucrose) during 30-min test sessions. Microstructural analyses of licking patterns were made after either administration of SR141716A (0, 0.3, 1 and 3 mg/kg, ip) or one of the after behavioural manipulations: pre-feeding, addition of quinine to the fat solution or changes in sucrose concentration. RESULTS: Intake of the fat solution was decreased after both the drug treatment and the behavioural manipulations of pre-feeding and addition of quinine. Pre-feeding and SR141716A-induced reductions were mediated via changes in bout number whereas addition of quinine caused a decrease in bout size. Although sucrose drinking was also decreased by pre-feeding, reduced sucrose concentration and SR141716A, the drug did not significantly alter the microstructure of intake. CONCLUSIONS: The effects of SR141716A on consumption of Intralipid solutions are likely to reflect changes in motivational state rather than modified hedonic impact.

PMID: 17372721 [PubMed - as supplied by publisher]

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Cognition and cannabinoids

Increased sensitivity of adolescent spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder, to the locomotor stimulation induced by the cannabinoid receptor agonist WIN 55,212-2.

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Increased sensitivity of adolescent spontaneously hypertensive rats, an animal model of attention deficit hyperactivity disorder, to the locomotor stimulation induced by the cannabinoid receptor agonist WIN 55,212-2.

Eur J Pharmacol. 2007 Feb 17;

Authors: Pandolfo P, Pamplona FA, Prediger RD, Takahashi RN

Converging evidence points to adolescence as a critical period for the onset of a wide range of neuropsychiatric disorders, including attention deficit hyperactivity disorder (ADHD) and drug abuse. Spontaneously hypertensive rats (SHR) are generally considered to be a suitable genetic model for the study of ADHD, since they display hyperactivity, impulsivity, poorly sustained attention, cognitive deficits and increased novelty seeking. Despite the high prevalence of ADHD among adolescents, studies using SHR have mainly been performed on adult animals. The aim of the present study was to evaluate the effect of acute intraperitoneal (i.p.) administration of the cannabinoid receptor agonist WIN 55,212-2 (0.25-2.5 mg/kg) on locomotor activity and anxiety-like behavior in male adolescent and adult SHR and Wistar rats using the open field and elevated plus-maze tests. WIN 55,212-2 at doses of 0.25 and 1.25 mg/kg (i.p.) selectively promoted locomotor stimulation in adolescent SHR in the open field, but not in adult SHR or Wistar rats (regardless of age). The effect of WIN 55,212-2 (0.25 mg/kg, i.p.) on locomotion of adolescent SHR was reversed by pretreatment with the selective cannabinoid CB(1) receptor antagonist AM 251 (0.25 mg/kg, i.p.). Moreover, although the present doses of WIN 55,212-2 had no effect on anxiety-related behaviors in any of the animal groups evaluated in the open field (central locomotion) or elevated plus-maze (time and entries in open arms), the highest dose of WIN 55,212-2 tested (2.5 mg/kg, i.p.) significantly decreased the number of closed-arm entries (an index of locomotor activity) of adolescent rats of both the Wistar and SHR strains in the elevated plus-maze. The present results indicate strain- and age-related effects of cannabinoids on locomotor activity in rats, extending the notion that adolescence and ADHD represent risk factors for the increased sensitivity to the effects of drugs.

PMID: 17374533 [PubMed - as supplied by publisher]

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Cell attached patch

Cell-attached voltage-clamp and current-clamp recording and stimulation techniques in brain slicesKatherine L. PerkinsCorresponding Author Contact Information, a, E-mail The Corresponding AuthoraDepartment of Physiology and Pharmacology, State University of New York, Downstate Medical Center, 450 Clarkson Ave., Brooklyn, New York 11203, USAReceived 9 December 2005; revised 18 January 2006; accepted 9 February 2006. Available online 22 March 2006.AbstractCell-attached recording provides a way to record the activity of – and to stimulate – neurons in brain slices without rupturing the cell membrane. This review uses theory and experimental data to address the proper application of this technique and the correct interpretation of the data. Voltage-clamp mode is best-suited for recording cell firing activity, and current-clamp mode is best-suited for recording resting membrane potential and synaptic potentials. The magnitude of the seal resistance determines what types of experiments can be accomplished with a cell-attached recording: a loose seal is adequate for recording action potential currents, and a tight seal is required for evoking action potentials in the attached cell and for recording resting and synaptic potentials. When recording action potential currents, if the researcher does not want to change the firing activity of the cell, then it is important that no current passes from the amplifier through the patch resistance. In order to accomplish this condition, the recording pipette should be held at the potential that gives a holding current of 0. An advantage of cell-attached current-clamp over whole-cell recording is that it accurately depicts whether a synaptic potential is hyperpolarizing or depolarizing without the risk of changing its polarity.Keywords: Hippocampus; Depolarizing GABA; Excitatory GABA; Interneuron; Cell-attached; Patch clamp; GABA; Patch slice

ScienceDirect - Journal of Neuroscience Methods : Cell-attached voltage-clamp and current-clamp recording and stimulation techniques in brain slices

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Retinal organotypic slice

A novel organotypic culture model of the postnatal mouse retina allows the study of glutamate-mediated excitotoxicitystar, openHua Xina, Jo-Ann S. Yannazzoa, R. Scott Duncana, Elaine V. Gregga, Meharvan Singha and Peter KoulenCorresponding Author Contact Information, a, E-mail The Corresponding AuthoraUniversity of North Texas Health Science Center, Department of Pharmacology & Neuroscience, 3500 Camp Bowie Blvd., Fort Worth, TX 76107-2699, USAReceived 30 April 2006; revised 13 June 2006; accepted 21 June 2006. Available online 31 July 2006.AbstractA novel organotypic culture method of mouse retina explants is being introduced and characterized to evaluate its usefulness in studying glutamate excitotoxicity. Retinal whole-mounts were dissected from eyes of C57BL/6 mice aged P10–14 and transferred to poly-d-lysine/laminin coated round coverslips. After 7 days in vitro, retina explants were treated with varying concentrations of l-glutamate and cell death was accessed with TUNEL histochemistry. Neurofilament-68 kDa immunoreactivity was used to identify retinal ganglion cells (RGC) with immunohistochemistry. Additional cell markers were used to further characterize the cytoarchitecture of the organotypic retina cultures. Retina explants attached very well to the coated coverslips allowing for experimental manipulation and pharmacological access to the tissue. Hematoxylin-Eosin (HE) staining of vertical cryostat sections of retina explants demonstrated well preserved intact cytoarchitecture under organotypic culture conditions and PKCα, Calbindin, GABA, Rhodopsin, GFAP and neurofilament immunoreactivities identifying rod bipolar, horizontal, amacrine, photoreceptor, glial, and retinal ganglion cells, respectively, were not different from freshly isolated mouse retina. Dose dependent glutamate toxicity and accompanying RGC apoptotic cell death were determined by TUNEL histochemistry. In contrast to previously published methods using slice or floating whole-mount cultures, the ex vivo culture system presented here combines accessibility to experimental manipulation, and adherence of whole-mount cultures to a substrate with a significant preservation of retinal cell types, numbers and morphology. The described retina explant culture on glass coverslips allows for effective pharmacological manipulation including the study of neuronal cell death and RGC physiology.Keywords: Organotypic culture; Retina explants; Retinal ganglion cells; Glutamate-mediated excitotoxicity; TUNEL

ScienceDirect - Journal of Neuroscience Methods : A novel organotypic culture model of the postnatal mouse retina allows the study of glutamate-mediated excitotoxicity

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One of Sci Direct's Top 25 at the moment

ScienceDirect - Neuron : Neurobiology of Schizophrenia

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V. important

Nonlinear interaction between shunting and adaptation controls a switch between integration and coincidence detection in pyramidal neurons.

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Nonlinear interaction between shunting and adaptation controls a switch between integration and coincidence detection in pyramidal neurons.

J Neurosci. 2006 Sep 6;26(36):9084-97

Authors: Prescott SA, Ratté S, De Koninck Y, Sejnowski TJ

The membrane conductance of a pyramidal neuron in vivo is substantially increased by background synaptic input. Increased membrane conductance, or shunting, does not simply reduce neuronal excitability. Recordings from hippocampal pyramidal neurons using dynamic clamp revealed that adaptation caused complete cessation of spiking in the high conductance state, whereas repetitive spiking could persist despite adaptation in the low conductance state. This behavior was reproduced in a phase plane model and was explained by a shunting-induced increase in voltage threshold. The increase in threshold allows greater activation of the M current (I(M)) at subthreshold potentials and reduces the minimum adaptation required to stabilize the system; in contrast, activation of the afterhyperpolarization current is unaffected by the increase in threshold and therefore remains unable to stop repetitive spiking. The nonlinear interaction between shunting and I(M) has other important consequences. First, timing of spikes elicited by brief stimuli is more precise when background spikes elicited by sustained input are prohibited, as occurs exclusively with I(M)-mediated adaptation in the high conductance state. Second, activation of I(M) at subthreshold potentials, which is increased in the high conductance state, hyperpolarizes average membrane potential away from voltage threshold, allowing only large, rapid fluctuations to reach threshold and elicit spikes. These results suggest that the shift from a low to high conductance state in a pyramidal neuron is accompanied by a switch from encoding time-averaged input with firing rate to encoding transient inputs with precisely timed spikes, in effect, switching the operational mode from integration to coincidence detection.

PMID: 16957065 [PubMed - indexed for MEDLINE]

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Untitled

Low-dimensional maps encoding dynamics in entorhinal cortex and hippocampus.

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Low-dimensional maps encoding dynamics in entorhinal cortex and hippocampus.

Neural Comput. 2006 Nov;18(11):2617-50

Authors: Pervouchine DD, Netoff TI, Rotstein HG, White JA, Cunningham MO, Whittington MA, Kopell NJ

Cells that produce intrinsic theta oscillations often contain the hyperpolarization-activated current I(h). In this article, we use models and dynamic clamp experiments to investigate the synchronization properties of two such cells (stellate cells of the entorhinal cortex and O-LM cells of the hippocampus) in networks with fast-spiking (FS) interneurons. The model we use for stellate cells and O-LM cells is the same, but the stellate cells are excitatory and the O-LM cells are inhibitory, with inhibitory postsynaptic potential considerably longer than those from FS interneurons. We use spike time response curve methods (STRC), expanding that technique to three-cell networks and giving two different ways in which the analysis of the three-cell network reduces to that of a two-cell network. We show that adding FS cells to a network of stellate cells can desynchronize the stellate cells, while adding them to a network of O-LM cells can synchronize the O-LM cells. These synchronization and desynchronization properties critically depend on I(h). The analysis of the deterministic system allows us to understand some effects of noise on the phase relationships in the stellate networks. The dynamic clamp experiments use biophysical stellate cells and in silico FS cells, with connections that mimic excitation or inhibition, the latter with decay times associated with FS cells or O-LM cells. The results obtained in the dynamic clamp experiments are in a good agreement with the analytical framework.

PMID: 16999573 [PubMed - indexed for MEDLINE]

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Walknet-a biologically inspired network to control six-legged walking.

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Walknet-a biologically inspired network to control six-legged walking.

Neural Netw. 1998 Oct;11(7-8):1435-1447

Authors: Cruse H, Kindermann T, Schumm M, Dean J, Schmitz J

To investigate walking we perform experimental studies on animals in parallel with software and hardware simulations of the control structures and the body to be controlled. Therefore, the primary goal of our simulation studies is not so much to develop a technical device, but to develop a system which can be used as a scientific tool to study insect walking. To this end, the animat should copy essential properties of the animals. In this review, we will first describe the basic behavioral properties of hexapod walking, as the are known from stick insects. Then we describe a simple neural network called Walknet which exemplifies these properties and also shows some interesting emergent properties. The latter arise mainly from the use of the physical properties to simplify explicit calculations. The model is simple too, because it uses only static neuronal units. Finally, we present some new behavioral results.

PMID: 12662760 [PubMed - as supplied by publisher]

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Endogenous activation of supraoptic nucleus kappa-opioid receptors terminates spontaneous phasic bursts in rat magnocellular neurosecretory cells.

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Endogenous activation of supraoptic nucleus kappa-opioid receptors terminates spontaneous phasic bursts in rat magnocellular neurosecretory cells.

J Neurophysiol. 2006 May;95(5):3235-44

Authors: Brown CH, Leng G, Ludwig M, Bourque CW

Phasic activity in magnocellular neurosecretory vasopressin cells is characterized by alternating periods of activity (bursts) and silence. During phasic bursts, action potentials (spikes) are superimposed on plateau potentials that are generated by summation of depolarizing after-potentials (DAPs). Burst termination is believed to result from autocrine feedback inhibition of plateau potentials by the kappa-opioid peptide, dynorphin, which is copackaged in vasopressin neurosecretory vesicles and exocytosed from vasopressin cell dendrites during phasic bursts. Here we tested this hypothesis, using intracellular recording in vitro to show that kappa-opioid receptor antagonist administration enhanced plateau potential amplitude to increase postspike excitability during spontaneous phasic activity. The antagonist also increased postburst DAP amplitude in vitro, indicating that endogenous dynorphin probably reduces plateau potential amplitude by inhibiting the DAP mechanism. However, the kappa-opioid receptor antagonist did not affect the slow depolarization that follows burst termination, suggesting that recovery from endogenous kappa-opioid inhibition does not contribute to the slow depolarization. We also show, by extracellular single-unit recording, that that there is a strong random element in the timing of burst initiation and termination in vivo. Administration of a kappa-opioid receptor antagonist eliminated the random element of burst termination but did not alter the timing of burst initiation. We conclude that dendritic dynorphin release terminates phasic bursts by reducing the amplitude of plateau potentials to reduce the probability of spike firing as bursts progress. By contrast, dendritic dynorphin release does not greatly influence the membrane potential between bursts and evidently does not influence the timing of burst initiation.

PMID: 16495366 [PubMed - indexed for MEDLINE]

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Cav2.3

Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Cav2.3 E/R-type voltage-gated calcium channel.

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Hippocampal seizure resistance and reduced neuronal excitotoxicity in mice lacking the Cav2.3 E/R-type voltage-gated calcium channel.

J Neurophysiol. 2007 Mar 21;

Authors: Weiergraber M, Henry M, Radhakrishnan K, Hescheler J, Schneider T

Voltage-gated calcium channels are key components in the etiology and pathogenesis of epilepsies. Former studies mainly focussed on P/Q-type Cav2.1 and T-type Cav3.2 Ca(2+)-channels involved in absence epileptogenesis, but recent findings also point to an intriguing role of the Cav2.3 E/R-type Ca(2+) channel in ictogenesis and seizure propagation. Based on the observation that Cav2.3 is thought to induce plateau potentials in CA1 pyramidal cells, which can trigger epileptiform activity, our recent investigation revealed reduced PTZ-seizure susceptibility and altered seizure architecture in Cav2.3(-/-) mice compared to controls. In the present study we tested hippocampal seizure susceptibility in Cav2.3 deficient mice using surface and deep intrahippocampal telemetric EEG recordings as well as phenotypic seizure video analysis. Administration of kainic acid (30 mg/kg i.p.) revealed clear alteration in behavioral seizure architecture and dramatic resistance to limbic seizures in Cav2.3(-/-) mice compared to controls whereas no difference in hippocampal EEG seizure activity between both genotypes could be detected at this suprathreshold dosage. The same tendency was observed for NMDA seizure susceptibility (150 mg/kg i.p.) approaching the level of significance. In addition, histochemical analysis within the hippocampus revealed that excitotoxic effects following kainic acid administration are absent in Cav2.3(-/-) mice, whereas Cav2.3(+/+) animals exhibited clear and typical signs of excitotoxic cell death. These findings clearly indicate that the Cav2.3 voltage-gated calcium channel plays a crucial role in both hippocampal ictogenesis and seizure generalization and is of central importance in neuronal degeneration following excitotoxic events.

PMID: 17376845 [PubMed - as supplied by publisher]

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WM and alpha

Modulation of Gamma and Alpha Activity during a Working Memory Task Engaging the Dorsal or Ventral Stream.

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Modulation of Gamma and Alpha Activity during a Working Memory Task Engaging the Dorsal or Ventral Stream.

J Neurosci. 2007 Mar 21;27(12):3244-51

Authors: Jokisch D, Jensen O

Despite extensive experimental work in both animals and humans, the actual role of oscillatory brain activity for working memory maintenance remains elusive. Gamma band activity (30-100 Hz) has been hypothesized to reflect either the maintenance of neuronal representations or changing demands in attention. Regarding posterior alpha activity (8-13 Hz), it is under debate whether it reflects functional inhibition or neuronal processing required for the task. The aim of the present study was to further elucidate the role of oscillatory brain activity in humans using a working memory task engaging either the dorsal or ventral visual stream. We recorded brain activity using magnetoencephalography from subjects performing a delayed-match-to-sample task. Subjects were instructed to remember either the identity or the spatial orientation of shortly presented faces. The analysis revealed stronger alpha power around the parieto-occipital sulcus during retention of face identities (ventral stream) compared with the retention of face orientations (dorsal stream). In contrast, successful retention of face orientations was associated with an increase in gamma power in the occipital lobe relative to the face identity condition. We propose that gamma activity reflects the actual neuronal maintenance of visual representations, whereas the alpha increase is a result of functional inhibition.

PMID: 17376984 [PubMed - in process]

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WM

Brain Networks Subserving the Extraction of Sentence Information and Its Encoding to Memory.

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Brain Networks Subserving the Extraction of Sentence Information and Its Encoding to Memory.

Cereb Cortex. 2007 Mar 19;

Authors: Hasson U, Nusbaum HC, Small SL

Sentences are the primary means by which people communicate information. The information conveyed by a sentence depends on how that sentence relates to what is already known. We conducted an fMRI study to determine how the brain establishes and retains this information. We embedded sentences in contexts that rendered them more or less informative and assessed which functional networks were associated with comprehension of these sentences and with memory for their content. We identified two such networks: A frontotemporal network, previously associated with working memory and language processing, showed greater activity when sentences were informative. Independently, greater activity in this network predicted subsequent memory for sentence content. In a separate network, previously associated with resting-state processes and generation of internal thoughts, greater neural activity predicted subsequent memory for informative sentences but also predicted subsequent forgetting for less-informative sentences. These results indicate that in the brain, establishing the information conveyed by a sentence, that is, its contextually based meaning, involves two dissociable networks, both of which are related to processing of sentence meaning and its encoding to memory.

PMID: 17372276 [PubMed - as supplied by publisher]

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Hypothalamus

Patch-clamp studies in the CNS illustrate a simple new method for obtaining viable neurons in rat brain slices: glycerol replacement of NaCl protects CNS neurons.

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Patch-clamp studies in the CNS illustrate a simple new method for obtaining viable neurons in rat brain slices: glycerol replacement of NaCl protects CNS neurons.

J Neurosci Methods. 2006 Dec 15;158(2):251-9

Authors: Ye JH, Zhang J, Xiao C, Kong JQ

Viable neurons in brain slices are crucial for electrophysiological studies. The present study describes a new method for obtaining viable cells in several regions of the central nervous system including the ventral tegmental area, the hypothalamus, the periaqueductal grey matter and the spinal cord. The essence of the method was to use a modified artificial cerebrospinal fluid (ACSF) in which all NaCl was replaced initially by equi-osmotic glycerol. This modified glycerol-based ACSF was used during slice preparation. The underlying principle for the modification is to prevent the possible acute neurotoxic effects of passive chloride entry, subsequent cell swelling and lysis. This method significantly increased the live/dead ratio in morphology compared to the normal ACSF or sucrose-base ACSF, in which NaCl was replaced by sucrose. An examination of some electrophysiological and pharmacological properties of the neurons in these preparations, by means of current-clamp and voltage-clamp recordings, revealed similar properties of those neurons obtained with the traditional ACSF method. Due to the increase in the number of viable neurons, the new ACSF increases the productivity of experiments. Based on our data, we propose that this glycerol-based solution may protect CNS neurons.

PMID: 16842860 [PubMed - indexed for MEDLINE]

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For Ataxia UK proposal

Marijuana intoxication presenting as seizure--comment.

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Marijuana intoxication presenting as seizure--comment.

Pediatr Emerg Care. 2006 Feb;22(2):141

Authors: Tilelli JA, Spack LD

PMID: 16481936 [PubMed - indexed for MEDLINE]

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Interesting....

[Neuroscience] An in vivo correlate of exercise-induced neurogenesis in the adult dentate gyrus

Contributed by Fred H. Gage, December 30, 2006 (sent for review November 26, 2006)

With continued debate over the functional significance...

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Cannabinoids: very relevant

Medical efficacy of cannabinoids and marijuana: a comprehensive review of the literature.

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Medical efficacy of cannabinoids and marijuana: a comprehensive review of the literature.

J Palliat Care. 2002;18(2):111-22

Authors: Bagshaw SM, Hagen NA

PMID: 12164099 [PubMed - indexed for MEDLINE]

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Cannabis

On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

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On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

Biochem Pharmacol. 2004 Nov 1;68(9):1691-8

Authors: Lutz B

Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids. Systemic activation of CB1 receptors by exogenous cannabinoids, however, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.

PMID: 15450934 [PubMed - indexed for MEDLINE]

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Just plain interesting

PFC lesion can change your ethical philosophy

A set of 6 subjects with bilateral damage to the ventromedial prefrontal cortex (VMPC) answered ethical questions in a way more consistent with utilitarian ethical philosophy than the control subjects. For example, they would be more willing to kill someone by pushing them off a bridge if that would save 5 other people. This supports the view that social emotions underly ethical judgments.

Michael Koenigs, Liane Young, Ralph Adolphs, Daniel Tranel, Fiery Cushman, Marc Hauser and Antonio Damasio.Damage to the prefrontal cortex increases utilitarian moral judgements. Nature. Published online 21 March 2007

Utilitarianism in a nutshell

Utilitarianism is an ethical philosophy where, rather than classifying types of actions into good or evil, you look at the consequences of an action in a given situation and make ethical decisions so as to maximize overall good. So, a utilitarian would consider it ethical to kill one person in order to save five other people (assuming they valued everyone’s life equally, etc). Think Spock, the Vulcan from Star Trek.

Normal people think it is more unethical to directly, personally harm someone else, compared to harming them indirectly in an impersonal way. A good example was given in the nytimes article The Brain on the Stand by Jeffrey Rosen:

Imagine a train heading toward five people who are going to die if you don’t do anything. If you hit a switch, the train veers onto a side track and kills another person. Most people confronted with this scenario say it’s O.K. to hit the switch. By contrast, imagine that you’re standing on a footbridge that spans the train tracks, and the only way you can save the five people is to push an obese man standing next to you off the footbridge so that his body stops the train. Under these circumstances, most people say it’s not O.K. to kill one person to save five.

Dr. Spock would probably think that “normal people” are being illogical when they distinguish between direct, personal and indirect, impersonal harm. The VMPC subjects still made this distinction, but not as strongly. The VMPC subjects acted like control subjects on the second sort of question (the impersonal harm), but were more likely than controls to endorse pushing someone off a bridge to save others. Accordings This is the sense in which they are “more utilitarian”. Dr. Spock would approve.

You can read the exact questions which were asked in the supplementary info (PDF). The questions that the VMPC subjects differed on are those questions in the last section, section “personal moral scenarios”, which were labeled “high-conflict”.

About the VMPC

From the article,

“The VMPC projects to basal forebrain and brainstem regions that execute bodily components of emotional responses, and neurons within the VMPC encode the emotional value of sensory stimuli. Patients with VMPC lesions exhibit generally diminished emotional responsivity and markedly reduced social emotions (for example, compassion, shame and guilt) that are closely associated with moral values, and also exhibit poorly regulated anger and frustration tolerance in certain circumstances. Despite these patent defects both in emotional response and emotion regulation, the capacities for general intelligence, logical reasoning, and declarative knowledge of social and moral norms are preserved. ”

Reminds me of the replicants in the sci-fi movie Blade Runner. Remember that in Blade Runner, replicants were distinguished from humans by the “Voight-Kampff test” which measured empathy response. Replicants were supposed to have less empathy than real humans. However, they do seem to get angry and frustrated.

“All six VMPC patients had impaired autonomic activity in response to emotionally charged pictures (Table 2), as well as severely diminished empathy, embarrassment and guilt (Table 2).”

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CVS MEAs

Drug profiling using planar microelectrode arrays.

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Drug profiling using planar microelectrode arrays.

Anal Bioanal Chem. 2007 Feb 22;

Authors: Yeung CK, Sommerhage F, Wrobel G, Offenhäusser A, Chan M, Ingebrandt S

Microelectrode arrays (MEAs) with evenly distributed multiple sensor spots have been designed for specific applications. Using the MEAs, we determined the relative profiles of potassium channel openers (KCOs) on cultured embryonic Sprague-Dawley rat cardiac myocytes. KCO, pinacidil (PIN), cromakalim (CROM), SDZ PCO400 (SDZ), or its vehicle, was added to the myocytes cumulatively. The action potential signal shapes in the presence of PIN and SDZ show that the changes in voltage over time and the magnitudes of the associated voltage change were reduced concentration-dependently. CROM affected sodium influx more than PIN and SDZ. The comparisons of changes in the rate of beating and propagation speed in the presence of KCOs were made using their corresponding pD(2) values (the negative log of EC(50)). All KCOs caused concentration-dependent reductions in the rate of beating and propagation speed, with SDZ being the most potent. In addition to the signal shapes, rate of beating, and propagation speed, the origin of excitation and the excitation pattern inside the culture can be also extracted. The results show that the present system can differentiate the effects of different KCOs on myocytes. It might be possible to utilise the MEA as a means to classify drug action based upon a combined interpretation of the three different datasets gained from the extracellular recordings. The combination of these observations might be used as 'drug signatures' when profiling drugs in the future.

PMID: 17318515 [PubMed - as supplied by publisher]

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Cannabinoids

Neuropsychobiological Evidence for the Functional Presence and Expression of Cannabinoid CB2 Receptors in the Brain.

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Neuropsychobiological Evidence for the Functional Presence and Expression of Cannabinoid CB2 Receptors in the Brain.

Neuropsychobiology. 2007 Mar 15;54(4):231-246

Authors: Onaivi ES

For over a decade, until recently, it was thought that marijuana acts by activating brain-type cannabinoid receptors called CB1, and that a second type called CB2 cannabinoid receptor was found only in peripheral tissues. Neuronal CB2 receptors in the brain had been controversial. We reported the discovery and functional presence of CB2 cannabinoid receptors in the mammalian brain that may be involved in depression and drug abuse and this was supported by reports of identification of neuronal CB2 receptors that are involved in emesis. RT-PCR, immunoblotting, hippocampal cultures, immunohistochemistry, transmission electron microscopy, and stereotaxic techniques with behavioral assays were used to determine the functional expression of CB2 cannabinoid receptors in the rat brain and mouse brain exposed to chronic mild stress or treated with abused drugs. RT-PCR analyses supported the expression of brain CB2 receptor transcripts at levels much lower than those of CB1 receptors. In situ hybridization revealed CB2 mRNA in cerebellar neurons of wild-type but not of CB2 knockout mice. Abundant CB2 receptor immunoreactivity (iCB2) in neuronal and glial processes was detected in the brain. The effect of direct CB2 antisense oligonucleotide injection into the brain and treatment with JWH015 in motor function and plus-maze tests also demonstrated the functional presence of CB2 cannabinoid receptors in the central nervous system. In humans, there was a high incidence of Q63R polymorphism in the CB2 gene in Japanese alcoholics and depressed subjects. Contrary to the prevailing view that CB2 cannabinoid receptors are restricted to peripheral tissues and predominantly in immune cells, we demonstrated that CB2 cannabinoid receptors and their gene transcripts are widely distributed in the brain. This multifocal expression of iCB2 in the brain suggests that CB2 receptors may play broader roles than previously anticipated and may therefore be exploited as new targets in the treatment of depression and substance abuse. Copyright (c) 2006 S. Karger AG, Basel.

PMID: 17356307 [PubMed - as supplied by publisher]

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MEAs

The analysis of electrode-recording-horizon in multi-electrode array(MEA).

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The analysis of electrode-recording-horizon in multi-electrode array(MEA).

Conf Proc IEEE Eng Med Biol Soc. 2005;7(1):7345-7348

Authors: Lin Y, Chen C, Chen L, Zeng S, Luo Q

There is a problem that can't be ignored in the MEA collected-signal-sorting process: When a neuron positions in two adjacent microelectrodes, can its activity be detected at the same time by both microelectrodes? Under certain conditions, the contact between the electrode and the cultured cell could be simplified as capacitive contact. Because the distance and the covering area affect the capacitance the amplitude of potential decreases rapidly with the increase of distance to the microelectrode. We show that common MEA chip whose spacing of electrodes is 200 &#956; m can't detect the neuronal potential in its adjacent electrodes simultaneously. About 100-recorded experiments data in our lab confirm this conclusion.

PMID: 17281977 [PubMed - as supplied by publisher]

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Animats

Synchronized spontaneous spikes on multi-electrode array show development of cultured neuronal network.

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Synchronized spontaneous spikes on multi-electrode array show development of cultured neuronal network.

Conf Proc IEEE Eng Med Biol Soc. 2005;2:2134-7

Authors: Li X, Zhou W, Liu M, Luo Q

Spontaneous firing play an important role in development of neuronal network. Activity-dependent modification of synaptic efficacy is widely recognized as a cellular basis of learning, memory, and development plasticity. Little is known of the activity-dependent modification of the synchronized spontaneous firing of the hippocampal networks. Long-term recording of spontaneous activity in cultured hippocampal neuronal networks was carried out using substrates containing multi-electrode array (MEA). Spontaneous uncorrelated firing appeared within a week and transformed progressively into synchronized pattern. During the development, these synchronized firings became into oscillation pattern and the synchronization has little change. By paired stimulation from adjacent electrodes in the network, the synchronized firing form a larger network burst. These results suggest that synchronized spontaneous spikes show the development of neuronal network and electronical stimulation could change the development.

PMID: 17282651 [PubMed - in process]

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Animats

Animats: computer-simulated animals in behavioral research.

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Animats: computer-simulated animals in behavioral research.

J Anim Sci. 1998 Oct;76(10):2596-604

Authors: Watts JM

The term animat refers to a class of simulated animals. This article is intended as a nontechnical introduction to animat research. Animats can be robots interacting with the real world or computer simulations. In this article, the use of computer-generated animats is emphasized. The scientific use of animats has been pioneered by artificial intelligence and artificial life researchers. Behavior-based artificial intelligence uses animats capable of autonomous and adaptive activity as conceptual tools in the design of usefully intelligent systems. Artificial life proponents view some human artifacts, including informational structures that show adaptive behavior and self-replication, as animats may do, as analogous to biological organisms. Animat simulations may be used for rapid and inexpensive evaluation of new livestock environments or management techniques. The animat approach is a powerful heuristic for understanding the mechanisms that underlie behavior. The simple rules and capabilities of animat models generate emergent and sometimes unpredictable behavior. Adaptive variability in animat behavior may be exploited using artificial neural networks. These have computational properties similar to natural neurons and are capable of learning. Artificial neural networks can control behavior at all levels of an animat's functional organization. Improving the performance of animats often requires genetic programming. Genetic algorithms are computer programs that are capable of self-replication, simulating biological reproduction. Animats may thus evolve over generations. Selective forces may be provided by a human overseer or be part of the simulated environment. Animat techniques allow researchers to culture behavior outside the organism that usually produces it. This approach could contribute new insights in theoretical ethology on questions including the origins of social behavior and cooperation, adaptation, and the emergent nature of complex behavior. Animat studies applied to domestic animals have been few so far, and have involved simulations of space use by swine. I suggest other applications, including modeling animal movement during human handling and the effects of environmental enrichment on the satisfaction of behavioral needs. Appropriate use of animat models in a research program could result in savings of time and numbers of animals required. This approach may therefore come to be viewed as both ethically and economically advantageous.

PMID: 9814899 [PubMed - indexed for MEDLINE]

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Untitled

Opposing effects on muscarinic acetylcholine receptors in the piriform cortex of odor-trained rats.

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Opposing effects on muscarinic acetylcholine receptors in the piriform cortex of odor-trained rats.

Learn Mem. 2007 May-Jun;14(3):224-8

Authors: Saar D, Dadon M, Leibovich M, Sharabani H, Grossman Y, Heldman E

We combined pharmacological studies and electrophysiological recordings to investigate modifications in muscarinic acetylcholine (ACh) receptors (mAChR) in the rat olfactory (piriform) cortex, following odor-discrimination rule learning. Rats were trained to discriminate between positive and negative cues in pairs of odors, until they reached a phase of high capability to learn unfamiliar odors, using the same paradigm ("rule learning"). It has been reported that at 1-3 d after the acquisition of odor-discrimination rule learning, pyramidal neurons in the rat piriform cortex show enhanced excitability, due to a reduction in the spike-activated potassium current I(AHP), which is modulated by ACh. Further, ACh and its analog, carbachol (CCh), lost the ability to reduce the I(AHP) in neurons from trained rats. Here we show that the reduced sensitivity to CCh in the piriform cortex results from a decrease in the number of mAChRs, as well as a reduction in the affinity of the receptors to CCh. Also, it has been reported that 3-8 d after the acquisition of odor-discrimination rule learning, synaptic transmission in the piriform cortex is enhanced, and paired-pulse facilitation (PPF) in response to twin stimulations is reduced. Here, intracellular recordings from pyramidal neurons show that CCh increases PPF in the piriform cortex from odor-trained rats more than in control rats, suggesting enhanced effect of ACh in inhibiting presynaptic glutamate release after odor training.

PMID: 17353547 [PubMed - in process]

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Testing Blogger site with Flock

University of Reading Top Ranking University for Research

Just a quick first post to test the integration between Blogger and Flock. Not sure if I'll have much chance to keep this blog up but it's about time...

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