Faculty Bibliography

The myelin sheath forms by the spiral wrapping of a glial membrane around the axon. The mechanisms responsible for this process are unknown but are likely to involve coordinated changes in the glial cell cytoskeleton. We have found that inhibition of myosin II, a key regulator of actin cytoskeleton dynamics, has remarkably opposite effects on myelin formation by Schwann cells (SC) and oligodendrocytes (OL). Myosin II is necessary for initial interactions between SC and axons, and its inhibition or down-regulation impairs their ability to segregate axons and elongate along them, preventing the formation of a 1:1 relationship, which is critical for peripheral nervous system myelination. In contrast, OL branching, differentiation, and myelin formation are potentiated by inhibition of myosin II. Thus, by controlling the spatial and localized activation of actin polymerization, myosin II regulates SC polarization and OL branching, and by extension their ability to form myelin. Our data indicate that the mechanisms regulating myelination in the peripheral and central nervous systems are distinct

Evaluation of arterial baroreflex in cardiovascular control is an important topic in cardiology and clinical medicine. In this paper, we present a point process approach to estimate the dynamic baroreflex gain in a closed-loop model of the cardiovascular system. Specifically, the inverse Gaussian probability distribution is used to model the heartbeat interval, whereas the instantaneous mean is modulated by a bivariate autoregressive model that contains the previous R-R intervals and systolic blood pressure (SBP) measures. The instantaneous baroreflex gain is estimated in the feedback loop with a point process filter, while the RR→SBP feedforward frequency response gain can be estimated by a Kalman filter. The proposed estimation approach provides a quantitative assessment of interacting heartbeat dynamics and hemodynamics. We validate our approach with real physiological signals and evaluate the proposed model with established goodness-of-fit tests.

Previous work has demonstrated that the character of mouse cortical interneuron subtypes can be directly related to their embryonic temporal and spatial origins. The relationship between embryonic origin and the character of mature interneurons is likely reflected by the developmental expression of genes that direct cell fate. However, a thorough understanding of the early genetic events that specify subtype identity has been hampered by the perinatal lethality resulting from the loss of genes implicated in the determination of cortical interneurons. Here, we employ a conditional loss-of-function approach to demonstrate that the transcription factor Nkx2-1 is required for the proper specification of specific interneuron subtypes. Removal of this gene at distinct neurogenic time points results in a switch in the subtypes of neurons observed at more mature ages. Our strategy reveals a causal link between the embryonic genetic specification by Nkx2-1 in progenitors and the functional attributes of their neuronal progeny in the mature nervous system

Dopaminergic (DA) neurons of mouse and rat retinas are of the interplexiform subtype (DA-IPC), i.e., they send processes distally toward the outer retina, exhibiting numerous varicosities along their course. The primary question we addressed was whether distally located DA-IPC varicosities, identified by tyrosine hydroxylase (TH) immunoreactivity, had the characteristic presynaptic proteins associated with calcium-dependent vesicular release of neurotransmitter. We found that TH immunoreactive varicosities in the outer retina possessed vesicular monoamine transporter 2 and vesicular GABA transporter, but they lacked immunostaining for any of nine subtypes of voltage-dependent calcium channel. Immunoreactivity for other channels that may permit calcium influx such as certain ionotropic glutamate receptors and canonical transient receptor potential channels (TRPCs) was similarly absent, although DA-IPC varicosities did show ryanodine receptor immunoreactivity, indicating the presence of intracellular calcium stores. The synaptic vesicle proteins sv2a and sv2b and certain other proteins associated with the presynaptic membrane were absent from DA-IPC varicosities, but the vesicular SNARE protein, vamp2, was present in a fraction of those varicosities. We identified a presumed second class of IPC that is GABAergic but not dopaminergic. Outer retinal varicosities of this putative GABAergic IPC did colocalize synaptic vesicle protein 2a, suggesting they possessed a conventional vesicular release mechanism

A long-standing conjecture in neuroscience is that aspects of cognition depend on the brain's ability to self-generate sequential neuronal activity. We found that reliably and continually changing cell assemblies in the rat hippocampus appeared not only during spatial navigation but also in the absence of changing environmental or body-derived inputs. During the delay period of a memory task, each moment in time was characterized by the activity of a particular assembly of neurons. Identical initial conditions triggered a similar assembly sequence, whereas different conditions gave rise to different sequences, thereby predicting behavioral choices, including errors. Such sequences were not formed in control (nonmemory) tasks. We hypothesize that neuronal representations, evolved for encoding distance in spatial navigation, also support episodic recall and the planning of action sequences

OBJECTIVE: The aim of this study was to assess quantitatively structural changes in myelin content occurring during demyelination and remyelination by magnetization transfer imaging (MTI). MATERIALS AND METHODS: In a reversible model of demyelination with no axonal loss, mice intoxicated by cuprizone were studied by MTI in vivo at 9.4 T. MRI data were compared to histopathological examinations. RESULTS: Data revealed that the magnetization transfer ratio (MTR) decreased significantly during demyelination and increased during remyelination with strong correlation to the myelin content (r=0.79, P=0.01). CONCLUSIONS: This study demonstrated that MTR is a sensitive and reproducible quantitative marker to assess myelin loss and repair. This may lead to in vivo monitoring of therapeutic strategies promoting remyelination

The immense range of human behaviours is rooted in the complex neural networks of the cerebrum. The creation of these networks depends on the precise integration of specific neuronal subtypes that are born in different regions of the telencephalon. Here, using the mouse as a model system, we review how these proliferative zones are established. Moreover, we discuss how these regions can be traced back in development to the function of a few key genes, including those that encode fibroblast growth factors (FGFs), sonic hedgehog (SHH), bone morphogenetic proteins (BMPs), forkhead box G1 (FOXG1), paired box 6 (PAX6) and LIM homeobox protein 2 (LHX2), that pattern the early telencephalon

Memantine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been shown to improve learning and memory in several preclinical models of Alzheimer's disease (AD). Memantine has also been shown to reduce the levels of amyloid beta (Abeta) peptides in human neuroblastoma cells as well as to inhibit Abeta oligomer-induced synaptic loss. In this study, we assessed whether NMDA receptor inhibition by memantine in transgenic mice expressing human amyloid-beta precursor protein (APP) and presenilin 1 (PS1) is associated with cognitive benefit and amyloid burden reduction by using object recognition, micromagnetic resonance imaging (muMRI), and histology. APP/PS1 Tg mice were treated either with memantine or with vehicle for a period of 4 months starting at 3 months of age. After treatment, the mice were subjected to an object recognition test and analyzed by ex vivo muMRI, and histological examination of amyloid burden. muMRI was performed following injection with gadolinium-DTPA-Abeta(1-40). We found that memantine-treated Tg mice performed the same as wild-type control mice, whereas the performance of vehicle-treated Tg mice was significantly impaired (P = 0.0081, one-way ANOVA). Compared with vehicle-treated animals, memantine-treated Tg mice had a reduced plaque burden, as determined both histologically and by muMRI. This reduction in amyloid burden correlates with an improvement in cognitive performance. Thus, our findings provide further evidence of the potential role of NMDA receptor antagonists in ameliorating AD-related pathology. In addition, our study shows, for the first time, the utility of muMRI in conjunction with gadolinium-labeled Abeta labeling agents to monitor the therapeutic response to amyloid-reducing agents. (c) 2008 Wiley-Liss, Inc

BACKGROUND AND PURPOSE: Despite the prominent peak of N-acetylaspartate (NAA) in proton MR spectroscopy ((1)H-MR spectroscopy) of the adult brain and its almost exclusive presence in neuronal cells, the total amount of NAA, regarded as their marker, is difficult to obtain due to signal contamination from the skull lipids. This article compares the performance of 2 methods that overcome this difficulty to yield the whole-brain NAA signal, important for the assessment of the total disease load in diffuse neurologic disorders. MATERIALS AND METHODS: The heads of 12 healthy volunteers, 3 women and 9 men, 31.0 +/- 7.1 years of age, were scanned at 3T by using 2 nonlocalizing (1)H-MR spectroscopy sequences: One nulls the NAA (TI = 940 ms) every second acquisition by inversion-recovery to cancel the signals of the lipids (T1 << TI) in an add-subtract scheme. The other nulls the signal of the lipids (TI = 155 ms) directly after each acquisition, requiring half as many averages for the same signal-to-noise ratio. Each sequence was repeated 3 times back-to-back on 3 occasions, and the comparison criteria were intrasubject precision (reproducibility) and total measurement duration. RESULTS: NAA nulling is nearly twice as precise in its intrinsic back-to-back (5.8% versus 8.6%) as well as longitudinal (10.6% versus 19.7%) coefficients of variation compared with lipid nulling, but at the cost of double the acquisition time. CONCLUSION: When speed is a more stringent requirement than precision, the new lipid-nulling sequence is a viable alternative. For precision in cross-sectional or longitudinal global NAA quantification, however, NAA nulling is still the approach of choice despite its x2 ( approximately 5 minutes) time penalty compared with the lipid-nulling approach