Circuit-based framework for understanding neurotransmitter and risk gene interactions in schizophrenia

Many risk genes interact synergistically to produce schizophrenia and many neurotransmitter interactions have been implicated. We have developed a circuit-based framework for understanding gene and neurotransmitter interactions. NMDAR hypofunction has been implicated in schizophrenia because NMDAR antagonists reproduce symptoms of the disease. One action of antagonists is to reduce the excitation of fast-spiking interneurons, resulting in disinhibition of pyramidal cells. Overactive pyramidal cells, notably those in the hippocampus, can drive a hyperdopaminergic state that produces psychosis. Additional aspects of interneuron function can be understood in this framework, as follows. (i) In animal models, NMDAR antagonists reduce parvalbumin and GAD67, as found in schizophrenia. These changes produce further disinhibition and can be viewed as the aberrant response of a homeostatic system having a faulty activity sensor (the NMDAR). (ii) Disinhibition decreases the power of gamma oscillation and might thereby produce negative and cognitive symptoms. (iii) Nicotine enhances the output of interneurons, and might thereby contribute to its therapeutic effect in schizophrenia.     

Validity of partial protocols to evaluate the prevalence of developmental defects of enamel in permanent dentition: a birth cohort study in Southern Brazil

Clinical Oral Investigations - To evaluate the validity of partial protocols (PP) to assess the prevalence of developmental defects of enamel (DDE) in permanent teeth and identify the strength of...     

Functional neuroanatomical networks associated with expertise in motor imagery

Although numerous behavioural studies provide evidence that there exist wide differences within individual motor imagery (MI) abilities, little is known with regards to the functional neuroanatomical networks that dissociate someone with good versus poor MI capacities. For the first time, we thus compared, through functional magnetic resonance imaging (fMRI), the pattern of cerebral activations in 13 skilled and 15 unskilled imagers during both physical execution and MI of a sequence of finger movements. Differences in MI abilities were assessed using well-established questionnaire and chronometric measures, as well as a new index based upon the subject's peripheral responses from the autonomic nervous system. As expected, both good and poor imagers activated the inferior and superior parietal lobules, as well as motor-related regions including the lateral and medial premotor cortex, the cerebellum and putamen. Inter-group comparisons revealed that good imagers activated more the parietal and ventrolateral premotor regions, which are known to play a critical role in the generation of mental images. By contrast, poor imagers recruited the cerebellum, orbito-frontal and posterior cingulate cortices. Consistent with findings from the motor sequence learning literature and Doyon and Ungerleider's model of motor learning [Doyon, J., Ungerleider, L.G., 2002. Functional anatomy of motor skill learning. In: Squire, L.R., Schacter, D.L. (Eds.), Neuropsychology of memory, Guilford Press, pp. 225-238], our results demonstrate that compared to skilled imagers, poor imagers not only need to recruit the cortico-striatal system, but to compensate with the cortico-cerebellar system during MI of sequential movements.     

Functional MR imaging of the lung

Recent development of MR techniques has overcome many problems, such as susceptibility artifacts or motion artifact, allowing both static and dynamic MR lung imaging and providing quantitative information of pulmonary function, including perfusion, ventilation, and respiratory motion. Dynamic contrast-enhanced MR perfusion imaging is suitable for the evaluation of angiogenesis of pulmonary solitary nodules. (129)Xe MR imaging is potentially a robust technique for the evaluation of various pulmonary function and may replace (3)He. The information provided by these new MR imaging methods is proving useful in research and in clinical applications in various lung diseases.     

Secretion of S100B, an astrocyte-derived neurotrophic protein, is stimulated by fluoxetine via a mechanism independent of serotonin

S100B is a calcium-binding protein, produced and secreted by astrocytes, which has a putative paracrine neurotrophic activity. Clinical studies have suggested that peripheral elevation of this protein is positively correlated with a therapeutic antidepressant response, particularly to selective serotonin reuptake inhibitors (SSRIs); however, the mechanism underlying this response remains unclear. Here, we measured S100B secretion directly in hippocampal astrocyte cultures and hippocampal slices exposed to fluoxetine and observed a significant increment of S100B release in the presence of this SSRI, apparently dependent on protein kinase A (PKA). Moreover, we found that serotonin (possibly via the 5HT1A receptor) reduces S100B secretion and antagonizes the effect of fluoxetine on S100B secretion. These data reinforce the effect of fluoxetine, independently of serotonin and serotonin receptors, suggesting a putative role for S100B in depressive disorders and suggesting that other molecular targets may be relevant for antidepressant activity.     

Plasma C-peptide levels and rates of cognitive decline in older, community-dwelling women without diabetes

BACKGROUND: Both type 2 diabetes and hyperinsulinemia have been related to diminished cognition. To address independent effects of increasing mid-life insulin secretion on late-life cognition, we prospectively examined the relation of plasma C-peptide levels to cognitive decline in a large sample of older women without diabetes or stroke. METHODS: Plasma C-peptide levels were measured in 1187 "young-old" women (mean age=64 years) without diabetes in the Nurses' Health Study. Cognitive decline was assessed approximately 10 years later. Three repeated cognitive batteries were administered over an average of 4.4 years using telephone-based tests of general cognition, verbal memory, category fluency, and attention. Primary outcomes were general cognition (measured by the Telephone interview for Cognitive Status [TICS], as well as a global score averaging all tests) and a verbal memory score averaging four tests of word-list and paragraph recall. Linear mixed effects models were used to compute associations between C-peptide levels and rates of cognitive decline. RESULTS: Higher C-peptide levels were associated with faster decline in global cognition and verbal memory. Compared to those in the lowest C-peptide quartile, multivariable-adjusted mean differences (95% CI) in rates of decline for women in the highest quartile were -0.03 (-0.06,-0.00) units/year for the global score, and -0.05 (-0.09,-0.02) units/year for verbal memory. Each one standard-deviation increase in C-peptide was associated with significantly faster decline on the TICS (p-trend=0.05), global score (p-trend=0.04) and verbal memory (p-trend=0.006). CONCLUSIONS: Higher levels of insulin secretion in those without diabetes may be related to decline in general cognition and verbal memory.