Changes in Striatal N-methyl-D-aspartate (NMDA) Stimulation of Dopamine Release and Receptor Subunit Expression During Expression of and Recovery from MPTP-Induced Parkinsonism

Normal and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP)-treated cats were used to examine changes in N-methyl-D-aspartate (NMDA) receptor function. In vivo microdialysis studies showed that NMDA-stimulated dopamine (DA) release was similar in the normal dorso-lateral and ventro-medial caudate nucleus. In symptomatic animals, NMDA-stimulated DA release was significantly decreased in both striatal regions. In symptomatic animals, NMDA-stimulated dopamine release was significantly decreased in both striatal regions. In recovered animals, the dorsal striatum and ventral striatum demonstrated an upregulation in NMDA-stimulated dopamine release compared to symptomatic animals. Receptor autoradiography showed no significant differences in NMDA receptor binding between normal, symptomatic, and recovered animals in the dorso-lateral caudate. NMDA receptor binding was, however, upregulated in the ventro-medial caudate of recovered animals. With Western analysis, NR1 and NR2A subunit levels in the dorso-lateral caudate were shown to decrease significantly in symptomatic animals compared to normal and then increase in recovered animals compared to symptomatic animals. In the ventro-medial caudate, NR1 and NR2A levels in the symptomatic group were significantly increased compared to normal and recovered groups. These data suggest that there may be recovery-induced changes in the functional regulation of the NMDA receptors in the striatum contributing to the behavioral recovery seen in this model

Does Physical Activity Influence Semantic Memory Activation in Amnestic Mild Cognitive Impairment?

The effect of physical activity (PA) on functional brain activation for semantic memory in amnestic mild cognitive impairment (aMCI) was examined using event-related functional magnetic resonance imaging during fame discrimination. Significantly greater semantic memory activation occurred in the left caudate of High- versus Low-PA patients, (P=0.03), suggesting PA may enhance memory-related caudate activation in aMCI

Altered muscarinic and nicotinic receptor densities in cortical and subcortical brain regions in Parkinson's disease

Muscarinic and nicotinic cholinergic receptors and choline acetyltransferase activity were studied in postmortem brain tissue from patients with histopathologically confirmed Parkinson's disease and matched control subjects. Using washed membrane homogenates from the frontal cortex, hippocampus, caudate nucleus, and putamen, saturation analysis of specific receptor binding was performed for the total number of muscarinic receptors with [3H]quinuclidinyl benzilate, for muscarinic M1 receptors with [3H]pirenzepine, for muscarinic M2 receptors with [3H]oxotremorine-M, and for nicotinic receptors with (-)-[3H]nicotine. In comparison with control tissues, choline acetyl-transferase activity was reduced in the frontal cortex and hippocampus and unchanged in the caudate nucleus and putamen of parkinsonian patients. In Parkinson's disease the maximal binding site density for [3H]quinuclidinyl benzilate was increased in the frontal cortex and unaltered in the hippocampus, caudate nucleus, and putamen. Specific [3H]pirenzepine binding was increased in the frontal cortex, unaltered in the hippocampus, and decreased in the caudate nucleus and putamen. In parkinsonian patients Bmax values for specific [3H]oxotremorine-M binding were reduced in the cortex and unchanged in the hippocampus and striatum compared with controls. Maximal (-)-[3H]nicotine binding was reduced in both the cortex and hippocampus and unaltered in both the caudate nucleus and putamen. Alterations of the equilibrium dissociation constant were not observed for any ligand in any of the brain areas examined. The present results suggest that both the innominatocortical and the septohippocampal cholinergic systems degenerate in Parkinson's disease.(ABSTRACT TRUNCATED AT 250 WORDS

Structural correlates of semantic and phonemic fluency ability in first and second languages

Category and letter fluency tasks are commonly used clinically to investigate the semantic and phonological processes central to speech production, but the neural correlates of these processes are difficult to establish with functional neuroimaging because of the relatively unconstrained nature of the tasks. This study investigated whether differential performance on semantic (category) and phonemic (letter) fluency in neurologically normal participants was reflected in regional gray matter density. The participants were 59 highly proficient speakers of 2 languages. Our findings corroborate the importance of the left inferior temporal cortex in semantic relative to phonemic fluency and show this effect to be the same in a first language (L1) and second language (L2). Additionally, we show that the pre-supplementary motor area (pre-SMA) and head of caudate bilaterally are associated with phonemic more than semantic fluency, and this effect is stronger for L2 than L1 in the caudate nuclei. To further validate these structural results, we reanalyzed previously reported functional data and found that pre-SMA and left caudate activation was higher for phonemic than semantic fluency. On the basis of our findings, we also predict that lesions to the pre-SMA and caudate nuclei may have a greater impact on phonemic than semantic fluency, particularly in L2 speakers

An approach for identifying brainstem dopaminergic pathways using resting state functional MRI.

Here, we present an approach for identifying brainstem dopaminergic pathways using resting state functional MRI. In a group of healthy individuals, we searched for significant functional connectivity between dopamine-rich midbrain areas (substantia nigra; ventral tegmental area) and a striatal region (caudate) that was modulated by both a pharmacological challenge (the administration of the dopaminergic agonist bromocriptine) and a dopamine-sensitive cognitive trait (an individual's working memory capacity). A significant inverted-U shaped connectivity pattern was found in a subset of midbrain-striatal connections, demonstrating that resting state fMRI data is sufficiently powerful to identify brainstem neuromodulatory brain networks

The role of the left head of caudate in suppressing irrelevant words

Suppressing irrelevant words is essential to successful speech production and is expected to involve general control mechanisms that reduce interference from task-unrelated processing. To investigate the neural mechanisms that suppress visual word interference, we used fMRI and a Stroop task, using a block design with an event-related analysis. Participants indicated with a finger press whether a visual stimulus was colored pink or blue. The stimulus was either the written word "BLUE," the written word "PINK," or a string of four Xs, with word interference introduced when the meaning of the word and its color were "incongruent" (e.g., BLUE in pink hue) relative to congruent (e.g., BLUE in blue) or neutral (e.g., XXXX in pink). The participants also made color decisions in the presence of spatial interference rather than word interference (i.e., the Simon task). By blocking incongruent, congruent, and neutral trials, we identified activation related to the mechanisms that suppress interference as that which was greater at the end relative to the start of incongruency. This highlighted the role of the left head of caudate in the control of word interference but not spatial interference. The response in the left head of caudate contrasted to bilateral inferior frontal activation that was greater at the start than at the end of incongruency, and to the dorsal anterior cingulate gyrus which responded to a change in the motor response. Our study therefore provides novel insights into the role of the left head of caudate in the mechanisms that suppress word interference

How choice reveals and shapes expected hedonic outcome

Humans tend to modify their attitudes to align with past action. For example, after choosing between similarly valued alternatives, people rate the selected option as better than they originally did, and the rejected option as worse. However, it is unknown whether these modifications in evaluation reflect an underlying change in the physiological representation of a stimulus' expected hedonic value and our emotional response to it. Here, we addressed this question by combining participants' estimations of the pleasure they will derive from future events, with brain imaging data recorded while they imagined those events, both before, and after, choosing between them. Participants rated the selected alternatives as better after the decision stage relative to before, whereas discarded alternatives were valued less. Our functional magnetic resonance imaging findings reveal that postchoice changes in preference are tracked in caudate nucleus activity. Specifically, the difference in blood oxygenation level-dependent (BOLD) signal associated with the selected and rejected stimuli was enhanced after a decision was taken, reflecting the choice that had just been made. This finding suggests that the physiological representation of a stimulus' expected hedonic value is altered by a commitment to it. Furthermore, before any revaluation induced by the decision process, our data show that BOLD signal in this same region reflects the choices we are likely to make at a later time

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis