Glutamatergic and GABAergic energy metabolism measured in the rat brain by (13) C NMR spectroscopy at 14.1 T.

Energy metabolism supports both inhibitory and excitatory neurotransmission processes. This study investigated the specific contribution of astrocytic metabolism to γ-aminobutyric acid (GABA) synthesis and inhibitory GABAergic neurotransmission that remained to be ilucidated in vivo. Therefore, we measured (13) C incorporation into brain metabolites by dynamic (13) C nuclear magnetic resonance spectroscopy at 14.1 T in rats under α-chloralose anaesthesia during infusion of [1,6-(13) C]glucose. The enhanced sensitivity at 14.1 T allowed to quantify incorporation of (13) C into the three aliphatic carbons of GABA non-invasively. Metabolic fluxes were determined with a mathematical model of brain metabolism comprising glial, glutamatergic and GABAergic compartments. GABA synthesis rate was 0.11 ± 0.01 μmol/g/min. GABA-glutamine cycle was 0.053 ± 0.003 μmol/g/min and accounted for 22 ± 1% of total neurotransmitter cycling between neurons and glia. Cerebral glucose oxidation was 0.47 ± 0.02 μmol/g/min, of which 35 ± 1% and 7 ± 1% was diverted to the glutamatergic and GABAergic tricarboxylic acid cycles, respectively. The remaining fraction of glucose oxidation was in glia, where 12 ± 1% of the TCA cycle flux was dedicated to oxidation of GABA. 16 ± 2% of glutamine synthesis was provided to GABAergic neurons. We conclude that substantial metabolic activity occurs in GABAergic neurons and that glial metabolism supports both glutamatergic and GABAergic neurons in the living rat brain. We performed (13) C NMR spectroscopy in vivo at high magnetic field (14.1 T) upon administration of [1,6-(13) C]glucose. This allowed to measure (13) C incorporation into the three aliphatic carbons of GABA in the rat brain, in addition to those of glutamate, glutamine and aspartate. These data were then modelled to determine fluxes of energy metabolism in GABAergic and glutamatergic neurons and glial cells.

Measurements of glial metabolic fluxes with C-11-acetate using positron emission and an adapted NMR-based metabolic modeling approach

Objectives: Acetate brain metabolism has the particularity to occur specifically in glial cells. Labeling studies, using acetate labeled either with 13C (NMR) or 11C (PET), are governed by the same biochemical reactions and thus follow the same mathematical principles. In this study, the objective was to adapt an NMR acetate brain metabolism model to analyse [1-11C]acetate infusion in rats. Methods: Brain acetate infusion experiments were modeled using a two-compartment model approach used in NMR.1-3 The [1-11C]acetate labeling study was done using a beta scintillator.4 The measured radioactive signal represents the time evolution of the sum of all labeled metabolites in the brain. Using a coincidence counter in parallel, an arterial input curve was measured. The 11C at position C-1 of acetate is metabolized in the first turn of the TCA cycle to the position 5 of glutamate (Figure 1A). Through the neurotransmission process, it is further transported to the position 5 of glutamine and the position 5 of neuronal glutamate. After the second turn of the TCA cycle, tracer from [1-11C]acetate (and also a part from glial [5-11C]glutamate) is transferred to glial [1-11C]glutamate and further to [1-11C]glutamine and neuronal glutamate through the neurotransmission cycle. Brain poster session: oxidative mechanisms S460 Journal of Cerebral Blood Flow & Metabolism (2009) 29, S455-S466 Results: The standard acetate two-pool PET model describes the system by a plasma pool and a tissue pool linked by rate constants. Experimental data are not fully described with only one tissue compartment (Figure 1B). The modified NMR model was fitted successfully to tissue time-activity curves from 6 single animals, by varying the glial mitochondrial fluxes and the neurotransmission flux Vnt. A glial composite rate constant Kgtg=Vgtg/[Ace]plasma was extracted. Considering an average acetate concentration in plasma of 1 mmol/g5 and the negligible additional amount injected, we found an average Vgtg = 0.08±0.02 (n = 6), in agreement with previous NMR measurements.1 The tissue time-activity curve is dominated by glial glutamate and later by glutamine (Figure 1B). Labeling of neuronal pools has a low influence, at least for the 20 mins of beta-probe acquisition. Based on the high diffusivity of CO2 across the blood-brain barrier; 11CO2 is not predominant in the total tissue curve, even if the brain CO2 pool is big compared with other metabolites, due to its strong dilution through unlabeled CO2 from neuronal metabolism and diffusion from plasma. Conclusion: The two-compartment model presented here is also able to fit data of positron emission experiments and to extract specific glial metabolic fluxes. 11C-labeled acetate presents an alternative for faster measurements of glial oxidative metabolism compared to NMR, potentially applicable to human PET imaging. However, to quantify the relative value of the TCA cycle flux compared to the transmitochondrial flux, the chemical sensitivity of NMR is required. PET and NMR are thus complementary.

How single-trial electrical neuroimaging contributes to multisensory research.

This study details a method to statistically determine, on a millisecond scale and for individual subjects, those brain areas whose activity differs between experimental conditions, using single-trial scalp-recorded EEG data. To do this, we non-invasively estimated local field potentials (LFPs) using the ELECTRA distributed inverse solution and applied non-parametric statistical tests at each brain voxel and for each time point. This yields a spatio-temporal activation pattern of differential brain responses. The method is illustrated here in the analysis of auditory-somatosensory (AS) multisensory interactions in four subjects. Differential multisensory responses were temporally and spatially consistent across individuals, with onset at approximately 50 ms and superposition within areas of the posterior superior temporal cortex that have traditionally been considered auditory in their function. The close agreement of these results with previous investigations of AS multisensory interactions suggests that the present approach constitutes a reliable method for studying multisensory processing with the temporal and spatial resolution required to elucidate several existing questions in this field. In particular, the present analyses permit a more direct comparison between human and animal studies of multisensory interactions and can be extended to examine correlation between electrophysiological phenomena and behavior.

Critical role for the alpha-1B adrenergic receptor at the sympathetic neuroeffector junction.

The alpha-1 adrenergic receptors (alpha(1)ARs) are critical in sympathetically mediated vasoconstriction. The specific role of each alpha(1)AR subtype in regulating vasoconstriction remains highly controversial. Limited pharmacological studies suggest that differential alpha(1)AR responses may be the result of differential activation of junctional versus extrajunctional receptors. We tested the hypothesis that the alpha(1B)AR subtype is critical in mediating sympathetic junctional neurotransmission. We measured in vivo integrated cardiovascular responses to a hypotensive stimulus (induced via transient bilateral carotid occlusion [TBCO]) in alpha(1B)AR knockout (KO) mice and their wild-type (WT) littermates. In WT mice, after dissection of the carotid arteries and denervation of aortic baroreceptor buffering nerves, TBCO produced significant pressor and positive inotropic effects. Both responses were markedly attenuated in alpha(1B)AR KO mice (change systolic blood pressure 46+/-8 versus 11+/-2 mm Hg; percentage change in the end-systolic pressure-volume relationship [ESPVR] 36+/-7% versus 12+/-2%; WT versus KO; P<0.003). In vitro alpha(1)AR mesenteric microvascular contractile responses to endogenous norepinephrine (NE; elicited by electrical field stimulation 10 Hz) was markedly depressed in alpha(1B)AR KO mice compared with WT (12.4+/-1.7% versus 21.5+/-1.2%; P<0.001). In contrast, responses to exogenous NE were similar in alpha(1B)AR KO and WT mice (22.4+/-7.3% versus 33.4+/-4.3%; NS). Collectively, these results demonstrate a critical role for the alpha(1B)AR in baroreceptor-mediated adrenergic signaling at the vascular neuroeffector junction. Moreover, alpha(1B)ARs modulate inotropic responses to baroreceptor activation. The critical role for alpha(1B)AR in neuroeffector regulation of vascular tone and myocardial contractility has profound clinical implications for designing therapies for orthostatic intolerance.

Antagonism of neuromuscular blockade but not muscle relaxation affects depth of anaesthesia

RÉSUMÉ Introduction L'effet des agents myorelaxants ainsi que des anticholinestérases sur la profondeur d'anesthésie a été étudié avec des résultats contradictoires. C'est pourquoi nous avons évalué l'effet de l'atracurium et de la néostigmine sur le BIS (bispectral index) ainsi que sur les potentiels auditives évoqués (middle-latency auditory evoked potentials, A-Line® autoregressive index [AAI]). Méthodes Après avoir obtenu l'accord du comité d'éthique local, nous avons étudié 40 patients ayant donné leur consentement écrit, ASA I-II, âgé de 18-69 ans. L'anesthésie générale a consisté en anesthésie intra-veineuse à objectif de concentration avec du propofol et du remifentanil. La fonction de la jonction neuromusculaire était monitorée en continu au moyen d'un électromyographe. Le BIS et l'AAI ont été enregistrés en continu. Après avoir atteint des valeurs stables au niveau du BIS, les patients ont été attribués à deux groupes par randomisation. Les patients du groupe 1 ont reçu 0.4 mg kg-1 d'atracurium et 5 minutes plus tard le même volume de NaCI 0.9%, dans le groupe 2 la séquence d'injection était inversée, le NaCI 0.9% en premier et l'atracurium en deuxième. Au moment où le premier « twitch » d'un train de quatre atteignait 10% de l'intensité avant la relaxation, les patients ont été randomisés une deuxième fois. Les patients du groupe N ont reçu 0.04 mg kg-1 de néostigmine et 0.01 rn9 kg-1 de glycopyrrolate alors que le groupe contrôle (G) ne recevait que 0.01 mg kg-] de glycopyrrolate. Résultats : L 'injection d'atracurium ou de NaCI 0.9% n'a pas eu d'effet sur le BIS ou l'AAI. Après l'injection de néostigmine avec glycopyrrolate, le BIS et I `AAI a augmenté de manière significative (changement maximal moyen du BIS 7.1 ± 7.5, P< 0.001, de l'AAI 9.7 ± 10.5, P< 0.001). Suite à l'injection de glycopyrrolate seule, le BIS et l'AAI a augmenté également (changement maximal moyen du BIS 2.2 ± 3.4, P< 0.008, de l'AAI 3.5 ± 5.7, P< 0.012), mais cette augmentation était significativement moins importante que dans le groupe N (P< 0.012 pour le BIS, P< 0.027 pour l'AAI). Conclusion Ces résultats laissent supposer que la néostigmine peut altérer la profondeur de l'anesthésie. La diminution de la profondeur d'anesthésie enregistrée par le BIS et l'AAI correspond probablement à une réapparition brusque d'une stimulation centrale liée à la proprioception. Au contraire, lors de la curarisation, le tonus musculaire diminue de manière beaucoup plus progressive, pouvant ainsi expliquer l'absence d'effet sur la profondeur d'anesthésie. ABSTRACT Background. Conflicting effects of neuromuscular blocking drugs and anticholinesterases on depth of anaesthesia have been reported. Therefore we evaluated the effect of atracurium and neostigmine on bispectral index (BIS) and middle-latency auditory evoked potentials (AAI). Methods. We studied 40 patients (ASA I-II) aged 18-69 yr. General anaesthesia consisted of propofol and remifentanil by target-controlled infusion and neuromuscular function was monitored by electromyography. When BIS reached stable values, patients were randomly assigned to one of two groups. Group I received atracurium 0.4 mg kg-1 and, 5 min later, the same volume of NaCl 0.9%; group 2 received saline first and then atracurium. When the first twitch of a train of four reached 10% of control intensity, patients were again randomized: one group (N) received neostigmine 0.04 mg kg-1 and glycopyrrolate 0.01 mg kg-1, and the control group (G) received only glycopyrrolate. Results. Injection of atracurium or NaCl 0.9% had no effect on BIS or AAI. After neostigmine¬glycopyrrolate, BIS and AAI increased significantly (mean maximal change of BIS 7.1 [SD 7.5], P<0.001; mean maximal change of AAI 9.7 [10.5], P<0.001). When glycopyrrolate was injected alone BIS and AAI also increased (mean maximal change of BIS 2.2 [3.4], P=0.008; mean maximal change of AAI 3.5 [5.7], P=0.012), but this increase was significantly less than in group N (P=0.012 for BIS; P=0.027 for AAI). Conclusion. These data suggest that neostigmine alters the state of propofol-remifentanil anaesthesia and may enhance recovery.

The thalamocortical projection systems in primate: an anatomical support for multisensory and sensorimotor interplay.

Multisensory and sensorimotor integrations are usually considered to occur in superior colliculus and cerebral cortex, but few studies proposed the thalamus as being involved in these integrative processes. We investigated whether the organization of the thalamocortical (TC) systems for different modalities partly overlap, representing an anatomical support for multisensory and sensorimotor interplay in thalamus. In 2 macaque monkeys, 6 neuroanatomical tracers were injected in the rostral and caudal auditory cortex, posterior parietal cortex (PE/PEa in area 5), and dorsal and ventral premotor cortical areas (PMd, PMv), demonstrating the existence of overlapping territories of thalamic projections to areas of different modalities (sensory and motor). TC projections, distinct from the ones arising from specific unimodal sensory nuclei, were observed from motor thalamus to PE/PEa or auditory cortex and from sensory thalamus to PMd/PMv. The central lateral nucleus and the mediodorsal nucleus project to all injected areas, but the most significant overlap across modalities was found in the medial pulvinar nucleus. The present results demonstrate the presence of thalamic territories integrating different sensory modalities with motor attributes. Based on the divergent/convergent pattern of TC and corticothalamic projections, 4 distinct mechanisms of multisensory and sensorimotor interplay are proposed.

Sign language in Landau-Kleffner syndrome.

This article reviews the history of sign language (SL) and the rationale for its use in children with profound auditory agnosia due to Landau-Kleffner syndrome (LKS), illustrated by studies of children and adults followed for many years and rare cases from the literature. The reasons that SL was successful and brought some children out of isolation while it could not be implemented in others are discussed. The nowadays earlier recognition and treatment of LKS and better awareness of the crucial need to maintain communication have certainly improved the outcome of affected children. Alternatives to oral language, even for less severe cases, are increasingly accepted. SL can be learned at different ages with a clear benefit, but the ambivalence of the patients and their families with the world and culture of the deaf may sometimes explain its refusal or limited acceptance. There are no data to support the fear that SL learning may delay or prevent oral language recovery in children with LKS. On the contrary, SL may even facilitate this recovery by stimulating functionally connected core language networks and by helping speech therapy and auditory training.

De la perception à l'apprentissage [From perception to learning]

Dans le domaine de la perception, l'apprentissage est contraint par la présence d'une architecture fonctionnelle constituée d'aires corticales distribuées et très spécialisées. Dans le domaine des troubles visuels d'origine cérébrale, l'apprentissage d'un patient hémi-anopsique ou agnosique sera limité par ses capacités perceptives résiduelles, mais un déficit de reconnaissance visuelle de nature apparemment perceptive, peut également être associé à une altération des représentations en mémoire à long terme. Des réseaux neuronaux distincts pour la reconnaissance - cortex temporal - et pour la localisation des sons - cortex pariétal - ont été décrits chez l'homme. L'étude de patients cérébro-lésés confirme le rôle des indices spatiaux dans un traitement auditif explicite du « where » et dans la discrimination implicite du « what ». Cette organisation, similaire à ce qui a été décrit dans la modalité visuelle, faciliterait les apprentissages perceptifs. Plus généralement, l'apprentissage implicite fonde une grande partie de nos connaissances sur le monde en nous rendant sensible, à notre insu, aux règles et régularités de notre environnement. Il serait impliqué dans le développement cognitif, la formation des réactions émotionnelles ou encore l'apprentissage par le jeune enfant de sa langue maternelle. Le caractère inconscient de cet apprentissage est confirmé par l'étude des temps de réaction sériels de patients amnésiques dans l'acquisition d'une grammaire artificielle. Son évaluation pourrait être déterminante dans la prise en charge ré-adaptative. [In the field of perception, learning is formed by a distributed functional architecture of very specialized cortical areas. For example, capacities of learning in patients with visual deficits - hemianopia or visual agnosia - from cerebral lesions are limited by perceptual abilities. Moreover a visual deficit in link with abnormal perception may be associated with an alteration of representations in long term (semantic) memory. Furthermore, perception and memory traces rely on parallel processing. This has been recently demonstrated for human audition. Activation studies in normal subjects and psychophysical investigations in patients with focal hemispheric lesions have shown that auditory information relevant to sound recognition and that relevant to sound localisation are processed in parallel, anatomically distinct cortical networks, often referred to as the "What" and "Where" processing streams. Parallel processing may appear counterintuitive from the point of view of a unified perception of the auditory world, but there are advantages, such as rapidity of processing within a single stream, its adaptability in perceptual learning or facility of multisensory interactions. More generally, implicit learning mechanisms are responsible for the non-conscious acquisition of a great part of our knowledge about the world, using our sensitivity to the rules and regularities structuring our environment. Implicit learning is involved in cognitive development, in the generation of emotional processing and in the acquisition of natural language. Preserved implicit learning abilities have been shown in amnesic patients with paradigms like serial reaction time and artificial grammar learning tasks, confirming that implicit learning mechanisms are not sustained by the cognitive processes and the brain structures that are damaged in amnesia. In a clinical perspective, the assessment of implicit learning abilities in amnesic patients could be critical for building adapted neuropsychological rehabilitation programs.]

The neuroanatomical model of post-stroke depression: towards a change of focus?

One third of all stroke survivors develop post-stroke depression (PSD). Depressive symptoms adversely affect rehabilitation and significantly increase risk of death in the post-stroke period. One of the theoretical views on the determinants of PSD focuses on psychosocial factors like disability and social support. Others emphasize biologic mechanisms such as disruption of biogenic amine neurotransmission and release of proinflammatory cytokines. The "lesion location" perspective attempts to establish a relationship between localization of stroke and occurrence of depression, but empirical results remain contradictory. These divergences are partly related to the fact that neuroimaging methods, unlike neuropathology, are not able to assess precisely the full extent of stroke-affected areas and do not specify the different types of vascular lesions. We provide here an overview of the known phenomenological profile and current pathogenic hypotheses of PSD and present neuropathological data challenging the classic "single-stroke"-based neuroanatomical model of PSD. We suggest that vascular burden due to the chronic accumulation of small macrovascular and microvascular lesions may be a crucial determinant of the development and evolution of PSD.

Increased eeg synchronization in schizophrenia patients by the glutathione precursor, n-acetyl-cysteine

Background: Glutathione (GSH) dysregulation at the gene, protein and functional levels observed in schizophrenia patients, and schizophrenia-like anomalies in GSH deficit experimental models, suggest that genetic glutathione synthesis impairments represent one major risk factor for the disease (Do et al., 2009). In a randomized, double blind, placebo controlled, add-on clinical trial of 140 patients, the GSH precursor N-Acetyl-Cysteine (NAC, 2 g/day, 6 months) significantly improved the negative symptoms and reduced side-effects due to antipsychotics (Berk et al., 2008). In a subset of patients (n=7), NAC (2 g/day, 2 months, cross-over design) also improved auditory evoked potentials, the NMDAdependent mismatch negativity (Lavoie et al, 2008). Methods: To determine whether increased GSH levels would modulate the topography of functional brain connectivity, we applied a multivariate phase synchronization (MPS) estimator (Knyazeva et al, 2008) to dense-array EEGs recorded during rest with eyes closed at the protocol onset, the point of crossover, and at its end. Phase synchronization phenomena are appealing because they can be associated to synchronized phases while the amplitudes stay uncorrelated. MPS measures the degree of interactions among the recorded neuronal oscillators by quantifiying to what extent they behave like a macro-oscillator (i.e. the oscillators are phase synchronous). To assess the whole-head synchronization topography, we computed the MPS sensor-wise over the cluster of locations defined by the sensor itself and he surrounding ones belonging to its second-order neighborhood (Carmeli et al, 2005). Such a cluster spans about 12 cm on average. Abstracts 245 Results: The whole-head imaging revealed a specific synchronization landscape in NAC compared to placebo condition. In particular, NAC increased MPS over frontal and left temporal regions in a frequency-specific manner. Importantly, the topography and direction of MPS changes were similar and robust in all 7 patients. Moreover, these changes correlated with the changes in the Liddle's score of disorganization (Liddle, 1987) thus linking EEG synchronization to the improvement of clinical picture. Discussion: The data suggest an important pathway towards new therapeutic strategies that target GSH dysregulation in schizophrenia. They also show the utility of MPS mapping as a marker of treatment efficacy.

Contributions of pitch and bandwidth to sound-induced enhancement of visual cortex excitability in humans.

Multisensory interactions have been documented within low-level, even primary, cortices and at early post-stimulus latencies. These effects are in turn linked to behavioral and perceptual modulations. In humans, visual cortex excitability, as measured by transcranial magnetic stimulation (TMS) induced phosphenes, can be reliably enhanced by the co-presentation of sounds. This enhancement occurs at pre-perceptual stages and is selective for different types of complex sounds. However, the source(s) of auditory inputs effectuating these excitability changes in primary visual cortex remain disputed. The present study sought to determine if direct connections between low-level auditory cortices and primary visual cortex are mediating these kinds of effects by varying the pitch and bandwidth of the sounds co-presented with single-pulse TMS over the occipital pole. Our results from 10 healthy young adults indicate that both the central frequency and bandwidth of a sound independently affect the excitability of visual cortex during processing stages as early as 30 msec post-sound onset. Such findings are consistent with direct connections mediating early-latency, low-level multisensory interactions within visual cortices.

Plastic modifications within inhibitory control networks induced by practicing a stop-signal task: an electrical neuroimaging study.

INTRODUCTION: Inhibitory control refers to our ability to suppress ongoing motor, affective or cognitive processes and mostly depends on a fronto-basal brain network. Inhibitory control deficits participate in the emergence of several prominent psychiatric conditions, including attention deficit/hyperactivity disorder or addiction. The rehabilitation of these pathologies might therefore benefit from training-based behavioral interventions aiming at improving inhibitory control proficiency and normalizing the underlying neurophysiological mechanisms. The development of an efficient inhibitory control training regimen first requires determining the effects of practicing inhibition tasks. METHODS: We addressed this question by contrasting behavioral performance and electrical neuroimaging analyses of event-related potentials (ERPs) recorded from humans at the beginning versus the end of 1 h of practice on a stop-signal task (SST) involving the withholding of responses when a stop signal was presented during a speeded auditory discrimination task. RESULTS: Practicing a short SST improved behavioral performance. Electrophysiologically, ERPs differed topographically at 200 msec post-stimulus onset, indicative of the engagement of distinct brain network with learning. Source estimations localized this effect within the inferior frontal gyrus, the pre-supplementary motor area and the basal ganglia. CONCLUSION: Our collective results indicate that behavioral and brain responses during an inhibitory control task are subject to fast plastic changes and provide evidence that high-order fronto-basal executive networks can be modified by practicing a SST.

Role of glutamate in neuron-glia metabolic coupling.

The coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiologic principle of brain function that has provided the basis for 2-deoxyglucose-based functional imaging with positron emission tomography. Approximately 10 y ago we provided experimental evidence that indicated a central role of glutamate signaling on astrocytes in neurometabolic coupling. The basic mechanism in neurometabolic coupling is the glutamate-stimulated aerobic glycolysis in astrocytes, such that the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na(+)-K(+) ATPase triggers glucose uptake and its glycolytic processing, which results in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fueling of the neuronal energy demands associated with synaptic transmission. Analyses of this coupling have been extended in vivo and have defined the methods of coupling for inhibitory neurotransmission as well as its spatial extent in relation to the propagation of metabolic signals within the astrocytic syncytium. On the basis of a large body of experimental evidence, we proposed an operational model, "the astrocyte-neuron lactate shuttle." A series of results obtained by independent laboratories have provided further support for this model. This body of evidence provides a molecular and cellular basis for interpreting data that are obtained with functional brain imaging studies.

Glucose-dependent insulinotropic polypeptide receptor knockout mice are impaired in learning, synaptic plasticity, and neurogenesis.

Glucose-dependent insulinotropic polypeptide (GIP) is a key incretin hormone, released from intestine after a meal, producing a glucose-dependent insulin secretion. The GIP receptor (GIPR) is expressed on pyramidal neurons in the cortex and hippocampus, and GIP is synthesized in a subset of neurons in the brain. However, the role of the GIPR in neuronal signaling is not clear. In this study, we used a mouse strain with GIPR gene deletion (GIPR KO) to elucidate the role of the GIPR in neuronal communication and brain function. Compared with C57BL/6 control mice, GIPR KO mice displayed higher locomotor activity in an open-field task. Impairment of recognition and spatial learning and memory of GIPR KO mice were found in the object recognition task and a spatial water maze task, respectively. In an object location task, no impairment was found. GIPR KO mice also showed impaired synaptic plasticity in paired-pulse facilitation and a block of long-term potentiation in area CA1 of the hippocampus. Moreover, a large decrease in the number of neuronal progenitor cells was found in the dentate gyrus of transgenic mice, although the numbers of young neurons was not changed. Together the results suggest that GIP receptors play an important role in cognition, neurotransmission, and cell proliferation.

Mechanisms of cross-modal plasticity in early-blind subjects.

A variety of studies have demonstrated enhanced blood oxygenation level dependent responses to auditory and tactile stimuli within occipital cortex as a result of early blindness. However, little is known about the organizational principles that drive this cross-modal plasticity. We compared BOLD responses to a wide variety of auditory and tactile tasks (vs. rest) in early-blind and sighted subjects. As expected, cross-modal responses were larger in blind than in sighted subjects in occipital cortex for all tasks (cross-modal plasticity). Within both blind and sighted subject groups, we found patterns of cross-modal activity that were remarkably similar across tasks: a large proportion of cross-modal responses within occipital cortex are neither task nor stimulus specific. We next examined the mechanisms underlying enhanced BOLD responses within early-blind subjects. We found that the enhancement of cross-modal responses due to early blindness was best described as an additive shift, suggesting that cross-modal plasticity within blind subjects does not originate from either a scaling or unmasking of cross-modal responsivities found in sighted subjects.