Thalamic-cortical-striatal circuitry subserves working memory during delayed responding on a radial arm maze.
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The medial dorsal nuclei of the thalamus (MDNt), the prefrontal cortex, and the ventral striatum form an interconnected neural circuit that may subserve certain types of working memory. The present series of experiments investigated functional interactions between these brain regions in rats during the performance of delayed and nondelayed spatially cued radial-arm maze tasks. In Experiment 1, transient inactivation of the MDNt by a bilateral injection of lidocaine selectively disrupted performance on a delayed task but not on a nondelayed random foraging version of the radial arm maze task. In Experiment 2, asymmetrical lidocaine injections into the MDNt on one side of the brain and the prefrontal cortex on the other transiently disconnected these two brain regions and significantly impaired foraging during the delayed task. Similarly, disconnections between the prefrontal cortex and the nucleus accumbens also disrupted foraging on this task, whereas disconnections between the MDNt and the nucleus accumbens had no effect. These data suggest that serial transmission of information among the MDNt, the prefrontal cortex, and the nucleus accumbens is required when trial-unique, short-term spatial memory is used to guide prospective search behavior. The results are discussed with respect to a distributed neural network linking limbic, thalamic, cortical, and striatal regions, which mediates executive functions of working memory. (+info)
Physiological antagonism between 5-hydroxytryptamine(2A) and group II metabotropic glutamate receptors in prefrontal cortex.
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In prefrontal cortex, 5-hydroxytryptamine(2A) (5-HT(2A)) receptors have been linked to the action of hallucinogens and atypical antidepressant/antipsychotic drugs. Previously, we have shown in cortical layer V pyramidal cells that a nonselective metabotropic glutamate (mGlu) receptor agonist suppresses the induction of excitatory postsynaptic potentials/currents (EPSPs/EPSCs) via activation of 5-HT(2A) receptors. In this study, we tested the ability of the selective mGlu2/3 agonist (1S,2S,5R, 6S)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylate monohydrate (LY354740) and the selective mGlu2/3 antagonist 2S-2-amino-2-(1S, 2S-2-carboxycycloprop-1-yl)-3(xanthy-9-yl)propanoic acid (LY341495) to modulate serotonin(5-HT)-induced EPSPs and electrically evoked EPSPs by using intracellular recording from layer V pyramidal cells in medial prefrontal cortex. The mGlu2/3 antagonist LY341495 increased the frequency and amplitude of 5-HT-induced EPSCs, suggesting a role for mGlu2/3 receptors in mediating the action of endogenous glutamate on autoreceptors. Conversely, the mGlu2/3 agonist LY354740 was highly effective and potent (EC(50) = 89 nM) in suppressing glutamate release induced by 5-HT(2A) receptor activation in the medial prefrontal cortex, probably via a presynaptic mechanism. The mGlu2/3 antagonist LY341495 potently blocked the suppressant effect of LY354740 on 5-HT-induced EPSCs as well as electrically evoked early EPSPs. Autoradiography with the radioligands [(3)H]LY354740 and [(125)I](+/-)-1-(2, 5-dimethoxy-4-iodophenyl)-2-aminopropane showsa striking overlap of the laminar distribution of mGlu2/3 and 5-HT(2A) receptors in the medial prefrontal cortex that is not apparent in other cortical regions. These findings suggest a close coupling between mGlu2/3 and 5-HT(2A) receptors in the prefrontal cortex that may be relevant for novel therapeutic approaches in the treatment of neuropsychiatric syndromes such as depression and schizophrenia. (+info)
Inattentional blindness versus inattentional amnesia for fixated but ignored words.
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People often are unable to report the content of ignored information, but it is unknown whether this reflects a complete failure to perceive it (inattentional blindness) or merely that it is rapidly forgotten (inattentional amnesia). Here functional imaging is used to address this issue by measuring brain activity for unattended words. When attention is fully engaged with other material, the brain no longer differentiates between meaningful words and random letters, even when they are looked at directly. These results demonstrate true inattentional blindness for words and show that visual recognition wholly depends on attention even for highly familiar and meaningful stimuli at the center of gaze. (+info)
Prefrontal cortex and episodic memory retrieval mode.
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A multistudy analysis of positron emission tomography data identified three right prefrontal and two left prefrontal cortical sites, as well as a region in the anterior cingulate gyrus, where neuronal activity is correlated with the maintenance of episodic memory retrieval mode (REMO), a basic and necessary condition of remembering past experiences. The right prefrontal sites were near the frontal pole [Brodmann's area (BA) 10], frontal operculum (BA 47/45), and lateral dorsal area (BA 8/9). The two left prefrontal sites were homotopical with the right frontal pole and opercular sites. The same kinds of REMO sites were not observed in any other cerebral region. Many previous functional neuroimaging studies of episodic memory retrieval have reported activations near the frontal REMO sites identified here, although their function has not been clear. Many of these, too, probably have signaled their involvement in REMO. We propose that REMO activations largely if not entirely account for the frontal hemispheric asymmetry of retrieval as described by the original hemispheric encoding retrieval asymmetry model. (+info)
Role of pseudorabies virus Us9, a type II membrane protein, in infection of tissue culture cells and the rat nervous system.
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The protein product of the pseudorabies virus (PRV) Us9 gene is a phosphorylated, type II membrane protein that is inserted into virion envelopes and accumulates in the trans-Golgi network. It is among a linked group of three envelope protein genes in the unique short region of the PRV genome which are absent from the attenuated Bartha strain. We found that two different Us9 null mutants exhibited no obvious phenotype after infection of PK15 cells in culture. Unlike those of gE and gI null mutants, the plaque size of Us9 null mutants on Madin-Darby bovine kidney cells was indistinguishable from that of wild-type virus. However, both of the Us9 null mutants exhibited a defect in anterograde spread in the visual and cortical circuitry of the rat. The visual system defect was characterized by restricted infection of a functionally distinct subset of visual projections involved in the temporal organization of behavior, whereas decreased anterograde spread of virus to the cortical projection targets was characteristic of animals receiving direct injections of virus into the cortex. Spread of virus through retrograde pathways in the brain was not compromised by a Us9 deletion. The virulence of the Us9 null mutants, as measured by time to death and appearance of symptoms of infection, also was reduced after their injection into the eye, but not after cortical injection. Through sequence analysis, construction of revertants, measurement of gE and gI protein synthesis in the Us9 null mutants, and mixed-infection studies of rats, we conclude that the restricted-spread phenotype after infection of the rat nervous system reflects the loss of Us9 and is not an indirect effect of the Us9 mutations on expression of glycoproteins gE and gI. Therefore, at least three viral envelope proteins, Us9, gE, and gI, function together to promote efficient anterograde transneuronal infection by PRV in the rat central nervous system. (+info)
Destruction and creation of spatial tuning by disinhibition: GABA(A) blockade of prefrontal cortical neurons engaged by working memory.
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Local circuit neurons in the dorsolateral prefrontal cortex (dPFC) of monkeys have been implicated in the cellular basis of working memory. To further elucidate the role of inhibition in spatial tuning, we iontophoresed bicuculline methiodide (BMI) onto functionally characterized neurons in the dPFC of monkeys performing an oculomotor delayed response task. This GABA(A) blockade revealed that both putative interneurons and pyramidal cells possess significant inhibitory tone in the awake, behaving monkey. In addition, BMI application primarily resulted in the loss of previously extant spatial tuning in both cell types through reduction of both isodirectional and cross-directional inhibition. This tuning loss occurred in both the sensorimotor and mnemonic phases of the task, although the delay activity of prefrontal neurons appeared to be particularly affected. Finally, application of BMI also created significant spatial tuning in a sizable minority of units that were untuned in the control condition. Visual field analysis of such tuning suggests that it is likely caused by the unmasking of normally suppressed spatially tuned excitatory input. These findings provide the first direct evidence of directional inhibitory modulation of pyramidal cell and interneuron firing in both the mnemonic and sensorimotor phases of the working memory process, and they implicate a further role for GABAergic interneurons in the construction of spatial tuning in prefrontal cortex. (+info)
Cortical activity in precision- versus power-grip tasks: an fMRI study.
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Most manual grips can be divided in precision and power grips on the basis of phylogenetic and functional considerations. We used functional magnetic resonance imaging to compare human brain activity during force production by the right hand when subjects used a precision grip and a power grip. During the precision-grip task, subjects applied fine grip forces between the tips of the index finger and the thumb. During the power-grip task, subjects squeezed a cylindrical object using all digits in a palmar opposition grasp. The activity recorded in the primary sensory and motor cortex contralateral to the operating hand was higher when the power grip was applied than when subjects applied force with a precision grip. In contrast, the activity in the ipsilateral ventral premotor area, the rostral cingulate motor area, and at several locations in the posterior parietal and prefrontal cortices was stronger while making the precision grip than during the power grip. The power grip was associated predominately with contralateral left-sided activity, whereas the precision-grip task involved extensive activations in both hemispheres. Thus our findings indicate that in addition to the primary motor cortex, premotor and parietal areas are important for control of fingertip forces during precision grip. Moreover, the ipsilateral hemisphere appears to be strongly engaged in the control of precision-grip tasks performed with the right hand. (+info)
Theta oscillations index human hippocampal activation during a working memory task.
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Working memory (WM) is the ability to retain and associate information over brief time intervals. Functional imaging studies demonstrate that WM is mediated by a distributed network including frontal and posterior cortices, hippocampus, and cerebellum. In rodents, the presentation of stimuli in a WM task is followed by a reset of the phase of hippocampal theta. In this paper we report the observation of a similar phenomenon in normal human subjects. Neuromagnetic responses were recorded during presentation of a set of digits and a subsequent probe of the retained items. All stimuli were presented with a fixed temporal pattern. We observed phase reset of approximately 7 Hz theta in left hippocampus approximately 120 ms after probe stimuli, whereas reset of theta in right hippocampus was visible approximately 80 ms prior to these anticipated stimuli. The duration of stimulus-locked theta increased with memory load, with a limiting value of approximately 600 ms for 5-7 retained items. We suggest that, as in rats, stimulus-locked theta may index involvement of human hippocampal networks in the cognitive processing of sensory input. The anticipatory phase reset of theta indicates involvement of hippocampus in right hemisphere and cerebellar timing networks. Hippocampal structures are essential for orientation to perturbations in the sensory scene, a function that requires use of a context established by a constellation of stimuli. We suggest that the initiation and maintenance of stimulus-locked hippocampal theta observed here may facilitate processing of potentially salient and/or novel input with respect to a context established by the contents of WM. (+info)