Modulation of hippocampus-prefrontal cortex synaptic transmission and disruption of executive cognitive functions by MK-801.

Noncompetitive N-methyl-d-aspartate receptor antagonists such as phencyclidine and MK-801 are known to impair cognitive function in rodents and humans, and serve as a useful tool to study the cellular basis for pathogenesis of schizophrenia cognitive symptoms. In the present study, we tested in rats the effect of MK-801 on ventral hippocampus (HPC)-medial prefrontal cortex (mPFC) synaptic transmission and the performance in 2 cognitive tasks. We found that single injection of MK-801 (0.1 mg/kg) induced gradual and long-lasting increases of the HPC-mPFC response, which shares the common expression mechanisms with long-term potentiation (LTP). But unlike LTP, its induction required no enhanced or synchronized synaptic inputs, suggesting aberrant characteristics. In parallel, rats injected with MK-801 showed impairments of mPFC-dependent cognitive flexibility and HPC-mPFC pathway-dependent spatial working memory. The effects of MK-801 on HPC-mPFC responses and spatial working memory decayed in parallel within 24 h. Moreover, the therapeutically important subtype 2/3 metabotropic glutamate receptor agonist LY379268, which blocked MK-801-induced potentiation, ameliorated the MK-801-induced impairment of spatial working memory. Our results show a novel form of use-independent long-lasting potentiation in HPC-mPFC pathway induced by MK-801, which is associated with impairment of HPC-mPFC projection-dependent cognitive function.

Inhibition of dopamine transporter activity impairs synaptic depression in rat prefrontal cortex through over-stimulation of D1 receptors.

In rat prefrontal cortex (PFC), long-term depression induced by low-frequency single stimuli has never been studied. Combined with the well-documented involvement of dopamine transporters (DATs) in the regulation of PFC-dependent cognitive processes, it is important to test whether this form of plasticity can be modulated by DAT activity in the PFC. Here, we show first that prolonged 3-Hz stimuli successfully induced synaptic depression in rat PFC slices whose induction depended on endogenous stimulation of D1-like and D2-like receptors and the activation of extracellular signal-regulated kinase 1/2 (ERK1/2). This depression was found to be significantly impaired by selective inhibition of the DAT by GBR12909 (1-200 nM) or GBR12935 (100 nM). The excess amount of extracellular dopamine caused by DAT inhibition acted critically on D1-like receptors to impair depression. Furthermore, this impairment by GBR12 909 was cancelled by the allosteric-positive mGluR5 modulator CDPPB, the drug known to reverse hyperdopaminergia-induced abnormal PFC activity, and the associated cognitive disturbances. Finally, these induction, impairment, and restoration of synaptic depression were correlated by an inverted-U shape manner with the phosphorylation level of ERK1/2. We suggest that abnormal increases of the extracellular dopamine level by DAT inhibition impair synaptic depression in the PFC through over-stimulation of D1-like receptors.

Maternal deprivation induces deficits in temporal memory and cognitive flexibility and exaggerates synaptic plasticity in the rat medial prefrontal cortex.

Early life adverse events can lead to structural and functional impairments in the prefrontal cortex (PFC). Here, we investigated whether maternal deprivation (MD) alters PFC-dependent executive functions, neurons and astrocytes number and synaptic plasticity in adult male Long-Evans rats. The deprivation protocol consisted of a daily separation of newborn Long-Evans pups from their mothers and littermates 3h/day postnatal day 1-14. Cognitive performances were assessed in adulthood using the temporal order memory task (TMT) and the attentional set-shifting task (ASST) that principally implicates the PFC and the Morris water maze task (WMT) that does not essentially rely on the PFC. The neurons and astrocytes of the prelimbic (PrL) area of the medial PFC (mPFC) were immunolabelled respectively with anti-NeuN and anti-GFAP antibodies and quantified by stereology. The field potentials evoked by electrical stimulation of ventral hippocampus (ventral HPC) were recorded in vivo in the PrL area. In adulthood, MD produced cognitive deficits in two PFC-dependent tasks, the TMT and ASST, but not in the WMT. In parallel, MD induced in the prelimbic area of the medial PFC an upregulation of long-term potentiation (LTP), without any change in the number of neurons and astrocytes. We provide evidence that MD leads in adults to an alteration of the cognitive abilities dependent on the PFC, and to an exaggerated synaptic plasticity in this region. We suggest that this latter phenomenon may contribute to the impairments in the cognitive tasks.

Dopaminergic modulation of synaptic plasticity in rat prefrontal neurons.

The prefrontal cortex (PFC) is thought to store the traces for a type of long-term memory - the abstract memory that determines the temporal structure of behavior often termed a "rule" or "strategy". Long-term synaptic plasticity might serve as an underlying cellular mechanism for this type of memory. We therefore studied the induction of synaptic plasticity in rat PFC neurons, maintained in vitro, with special emphasis on the functionally important neuromodulator dopamine. First, the induction of long-term potentiation (LTP) was facilitated in the presence of tonic/background dopamine in the bath, and the dose-dependency of this background dopamine followed an "inverted-U" function, where too high or too low dopamine levels could not facilitate LTP. Second, the induction of long-term depression (LTD) by low-frequency stimuli appeared to be independent of background dopamine, but required endogenous, phasically-released dopamine during the stimuli. Blockade of dopamine receptors during the stimuli and exaggeration of the effect of this endogenously-released dopamine by inhibition of dopamine transporter activity both blocked LTD. Thus, LTD induction also followed an inverted-U function in its dopamine-dependency. We conclude that PFC synaptic plasticity is powerfully modulated by dopamine through inverted-U-shaped dose-dependency.

Code-switching across brainstorming sessions: implications for the revised hierarchical model of bilingual language processing.

The revised hierarchical model (RHM) of bilingual language processing posits independent word form representations for the dominant language (L1) and the nondominant language (L2), facilitated translation from L2 words to L1 words, access to common concepts for L1 and L2, and stronger activation of concepts for L1 than for L2. Spanish-English and English-Spanish bilinguals brainstormed for two sessions; half switched languages (L1-L2 or L2-L1) and half stayed in the same language (L1-L1 or L2-L2) across sessions. In both sessions, L1 brainstorming resulted in more efficient idea productivity than L2 brainstorming, supporting stronger concept activation for L1, consistent with the RHM. Switching languages from L2 to L1 resulted in the most efficient idea productivity in Session 2, suggesting that switching to L1 not only permits strong concept activation, but also the activation of concepts that are relatively different than those activated by L2, inconsistent with the RHM. Switching languages increased the proportion of Session 1 ideas repeated during Session 2, despite instructions not to repeat. This finding suggests that there is activation of concepts as well as word forms in same language brainstorming and that this dual activation aids in following instructions not to repeat, consistent with the RHM. It is suggested that the RHM be re-specified to accommodate the notion that L1 and L2 access relatively different concepts.

The effect of non-competitive NMDA receptor antagonist MK-801 on neuronal activity in rodent prefrontal cortex: an animal model for cognitive symptoms of schizophrenia.

Schizophrenia affects about 1% of the world population and is a major socio-economical problem in ours societies. Cognitive symptoms are particularly resistant to current treatments and are believed to be closely related to an altered function of prefrontal cortex (PFC). Particularly, abnormalities in the plasticity processes in the PFC are a candidate mechanism underlying cognitive symptoms, and the recent evidences in patients are in line with this hypothesis. Animal pharmacological models of cognitive symptoms, notably with non-competitive NMDA receptor antagonists such as MK-801, are commonly used to investigate the underlying cellular and molecular mechanisms of schizophrenia. However, it is still unknown whether in these animal models, impairments in plasticity of PFC neurons are present. In this article, we briefly summarize the current knowledge on the effect of non-competitive NMDA receptor antagonist MK-801 on medial PFC (mPFC) neuronal activity and then introduce a form of plasticity found after acute exposure to MK-801, which was accompanied by cognitive deficits. These observations suggest a potential correlation between cognitive deficits and the aberrant plasticity in the mPFC in the animal model of schizophrenia.

The development and validation of sensory and emotional scales of touch perception.

No comprehensive language exists that describes the experience of touch. Three experiments were conducted to take steps toward establishing a touch lexicon. In Experiment I, 49 participants rated how well 262 adjectives described sensory, emotional and evaluative aspects of touch. In Experiment II, participants rated pairwise dissimilarities of the most descriptive words of the set. Multidimensional scaling (MDS) solutions representing semantic-perceptual spaces underlying the words resulted in a touch perception task (TPT) consisting of 26 'sensory' attributes (e.g., bumpiness) and 14 'emotional' attributes (e.g., pleasurable). In Experiment III, 40 participants used the TPT to rate unseen textured materials that were moved actively or received passively against the index fingerpad, volar forearm, and two underarm sites. MDS confirmed similar semantic-perceptual structures in Experiments II and III. Factor analysis of Experiment III data decomposed the sensory attribute ratings into factors labeled Roughness, Slip, Pile and Firmness, and the emotional attribute ratings into Comfort and Arousal factors. Factor scores varied among materials and sites. Greater intensity of sensory and emotional responses were reported when participants passively, as opposed to actively, received stimuli. The sensitivity of the TPT in identifying body site and mode of touch-related perceptual differences affirms the validity and utility of this novel linguistic/perceptual tool.

Sensory and affective judgments of skin during inter- and intrapersonal touch.

Here we report two experiments that investigated the tactile perception of one's own skin (intrapersonal touch) versus the skin of other individuals (interpersonal touch). In the first experiment, thirteen female participants rated, along four perceptual attributes, the skin of their own palm and volar forearm, then that of several of the other participants. Ratings were made using visual analogue scales for perceived smoothness, softness, stickiness, and pleasantness. One's own skin was rated less pleasant than the skin of others. For both intra- and interpersonal touch, the forearm skin was rated smoother, softer, less sticky and more pleasant than the palmar skin. In the second experiment, ten pairs of female participants rated each other's palm and volar forearm skin, with the skin of the touched individual being assessed before and after the application of skin emollients that alter skin feel. As in the first experiment, the untreated skin of others was rated more pleasant than the participants' own skin, and the forearm versus palm differences were replicated. However, the emollient had generally larger effects on self-assessments than the assessments of others, and the site effect showed greater positive sensory and pleasantness increases for palm versus volar forearm. The disparate results of the two experiments suggest that attention, influenced by the ecological importance of the stimulus, is more important to assessment of touched skin than ownership of the skin or the contribution to self-touch made by the additional receptors in the passively touched skin. In both experiments, the pleasantness of touched skin was associated with the skin's perceived smoothness and softness, with weak trends toward negative associations with its perceived stickiness, consistent with prior research using inanimate surfaces (e.g., textiles and sandpapers).