Amyloid-beta peptide is elevated in the brains of patients with Alzheimer disease and is believed to be causative in the disease process. Amyloid-beta reduces glutamatergic transmission and inhibits synaptic plasticity, although the underlying mechanisms are unknown. We found that application of amyloid-beta promoted endocytosis of NMDA receptors in cortical neurons. In addition, neurons from a genetic mouse model of Alzheimer disease expressed reduced amounts of surface NMDA receptors. Reducing amyloid-beta by treating neurons with a gamma-secretase inhibitor restored surface expression of NMDA receptors. Consistent with these data, amyloid-beta application produced a rapid and persistent depression of NMDA-evoked currents in cortical neurons. Amyloid-beta-dependent endocytosis of NMDA receptors required the alpha-7 nicotinic receptor, protein phosphatase 2B (PP2B) and the tyrosine phosphatase STEP. Dephosphorylation of the NMDA receptor subunit NR2B at Tyr1472 correlated with receptor endocytosis. These data indicate a new mechanism by which amyloid-beta can cause synaptic dysfunction and contribute to Alzheimer disease pathology.

Choi EY, Yeo BT, Buckner RL. The organization of the human striatum estimated by intrinsic functional connectivity. J Neurophysiol 108: 2242-2263, 2012. First published July 25, 2012 doi:10.1152/jn.00270.2012.-The striatum is connected to the cerebral cortex through multiple anatomical loops that process sensory, limbic, and heteromodal information. Tract-tracing studies in the monkey reveal that these corticostriatal connections form stereotyped patterns in the striatum. Here the organization of the striatum was explored in the human with resting-state functional connectivity MRI (fcMRI). Data from 1,000 subjects were registered with nonlinear deformation of the striatum in combination with surface-based alignment of the cerebral cortex. fcMRI maps derived from seed regions placed in the foot and tongue representations of the motor cortex yielded the expected inverted somatotopy in the putamen. fcMRI maps derived from the supplementary motor area were located medially to the primary motor representation, also consistent with anatomical studies. The topography of the complete striatum was estimated and replicated by assigning each voxel in the striatum to its most strongly correlated cortical network in two independent groups of 500 subjects. The results revealed at least five cortical zones in the striatum linked to sensorimotor, premotor, limbic, and two association networks with a topography globally consistent with monkey anatomical studies. The majority of the human striatum was coupled to cortical association networks. Examining these association networks further revealed details that fractionated the five major networks. The resulting estimates of striatal organization provide a reference for exploring how the striatum contributes to processing motor, limbic, and heteromodal information through multiple large-scale corticostriatal circuits. somatotopy; limbic network; prefrontal cortex; association cortex; fMRI; functional connectivity; default network ANIMAL STUDIES and human patient cases demonstrate that the basal ganglia are involved in diverse functional domains including movement, cognition, and reward (Alexander et al. 1986;DeLong and Georgopoulos 1981;Haber and Gdowski 2004;MacLean 1972). Providing an anatomical basis for functional diversity, tract-tracing studies show that the basal ganglia are connected to distributed regions of the cerebral cortex through multiple, partially parallel anatomical loops (Alexander et al. 1986(Alexander et al. , 1990. Each loop includes projections from the cerebral cortex, through the basal ganglia, to the thalamus, and back to the cerebral cortex. Cortical efferents to the striatum (the main input nucleus of the basal ganglia) form distinct patterns depending on their cortical origin. The posterior putamen and the dorsolateral anterior putamen receive projections from motor and motor association cortex, the central anterior striatum from cognitive regions including prefrontal cortex, and the ventral anterior striatum from regions associated with the limbic syste...

The thalamus and its nuclei are largely indistinguishable on standard T1 or T2 weighted MRI. While diffusion tensor imaging based methods have been proposed to segment the thalamic nuclei based on the angular orientation of the principal diffusion tensor, these are based on echo planar imaging which is inherently limited in spatial resolution and suffers from distortion. We present a multi-atlas segmentation technique based on white-matter-nulled MP-RAGE imaging that segments the thalamus into 12 nuclei with computation times on the order of 10 minutes on a desktop PC; we call this method THOMAS (THalamus Optimized Multi Atlas Segmentation). THOMAS was rigorously evaluated on 7T MRI data acquired from healthy volunteers and patients with multiple sclerosis by comparing against manual segmentations delineated by a neuroradiologist, guided by the Morel atlas. Segmentation accuracy was very high, with uniformly high Dice indices: at least 0.85 for large nuclei like the pulvinar and mediodorsal nuclei and at least 0.7 even for small structures such as the habenular, centromedian, and lateral and medial geniculate nuclei. Volume similarity indices ranged from 0.82 for the smaller nuclei to 0.97 for the larger nuclei. Volumetry revealed that the volumes of the right anteroventral, right ventral posterior lateral, and both right and left pulvinar nuclei were significantly lower in MS patients compared to controls, after adjusting for age, sex and intracranial volume. Lastly, we evaluated the potential of this method for targeting the Vim nucleus for deep brain surgery and focused ultrasound thalamotomy by overlaying the Vim nucleus segmented from pre-operative data on post-operative