Faculty Bibliography

Fundamental to living cells is the capacity to differentiate into subtypes with specialized attributes. Understanding the way cells acquire their fates is a major challenge in developmental biology. How cells adopt a particular fate is usually thought of as being deterministic, and in the large majority of cases it is. That is, cells acquire their fate by virtue of their lineage or their proximity to an inductive signal from another cell. In some cases, however, and in organisms ranging from bacteria to humans, cells choose one or another pathway of differentiation stochastically, without apparent regard to environment or history. Stochasticity has important mechanistic requirements. We speculate on why stochasticity is advantageous-and even critical in some circumstances-to the individual, the colony, or the species.

This article addresses the current understanding of the neurobiological bases of attention deficit hyperactivity disorder (ADHD), focusing on empiric research findings that connect genetic and environmental factors to structural and functional brain abnormalities, ultimately leading to a set of age-dependent behavioral manifestations. Section one presents evidence for genetic risk factors for ADHD and discusses the role of potential environmental factors in the etiology of the disorder. Section two focuses on brain imaging studies and how they have helped generate different hypotheses regarding the pathophysiology of ADHD. Finally, the article addresses the longitudinal course of symptoms in ADHD from infancy to adulthood in an attempt to place biological findings for this complex brain disorder in the context of maturation and development

Chondroitin sulfate proteoglycans (CSPGs) inhibit axonal growth, and treatment with chondroitinase ABC promotes axonal regeneration in some models of central nervous system (CNS) injury. The aims of this study were (1) to compare the spatiotemporal appearance of CSPG expression between spinal cord contusion and hemisection models, and (2) to evaluate chondroitinase treatment effects on axonal regrowth in the two injury models. After hemisection, CSPG-immunoreactivity (IR) in the injury site rose to peak levels at 18 days but then decreased dramatically by 49 days; in contrast, CSPG-IR remained high for at least 49 days after contusion. After hemisection, many anterogradely labeled corticospinal tract (CST) axons remained close to CSPG-rich lesion sites, but after contusion, most CST axons retracted by approximately 1 mm rostral from the rostral-most CSPG-rich cyst. Intraspinal injection of chondroitinase at 0, 1, 2, and 4 weeks following injury dramatically reduced CSPG-IR in both injury models within 4 days, and CSPG-IR remained low for at least 3 weeks. After the chondroitinase treatment, many axons grew around the lesion site in hemisected spinal cords but not in contused spinal cords. We propose that improved axonal growth in hemisected spinal cords is due to decreased inhibition resulting from degradation of CSPGs located adjacent to severed CST axons. However, in spinal cord contusions, retracted CST axons fail to grow across gliotic regions that surround CSPG-rich injury sites despite efficient degradation with chondroitinase, suggesting that other inhibitors of axonal growth persist in the gliotic regions

In this study, we investigated the role of the peripheral endothelin-1 (ET-1) concentration in a cancer pain model. To test the hypothesis that the concentration of ET-1 in the tumor microenvironment is important in determining the level of cancer pain we used two cancer pain mouse models that differed significantly in production of ET-1. The two mouse cancer models were produced by injection of cells derived from a human oral squamous cell carcinoma (SCC) and melanoma into the hind paw of female mice. Pain, as indicated by reduction in withdrawal thresholds in response to mechanical stimulation, was significantly greater in the SCC group than the melanoma group. The peripheral concentration of ET-1 within the cancer microenvironment was significantly greater in the SCC group. Intra-tumor expression of both ET-1 mRNA and ET-1 protein were significantly higher in the SCC model compared to the melanoma model. ET receptor antagonism was effective as an analgesic for cancer pain in the SCC model only. To address the potential confounding factor of tumor volume we evaluated the contribution of tumor volume to cancer pain in the two models. The mean volumes of the tumors in the melanoma group were significantly greater than the tumors in the SCC group. In both groups, the pain level correlated with tumor volume, but the correlation was stronger in the melanoma group. We conclude that ET-1 concentration is a determinant of the level of pain in a cancer pain mouse model and it is a more important factor than tumor volume in producing cancer pain. These results suggest that future treatment regimens for cancer pain directed at ET-1 receptor antagonism show promise and may be tumor type specific

Due to the overall similarity of their brains' structure and physiology to its human counterpart, nonhuman primates provide excellent model systems for the pathogenesis of neurological diseases and their response to treatments. Its much smaller size, 80 versus 1250 cm(3), however, requires proportionally higher spatial resolution to study, nondestructively, as many analogous regions as efficiently as possible in anesthetized animals. The confluence of these requirements underscores the need for the highest sensitivity, spatial coverage, resolution, and exam speed. Accordingly, we demonstrate the feasibility of 3D multi-voxel, proton ((1)H) MRSI at (0.375 cm)(3)=0.05 cm(3) isotropic spatial resolution over 21 cm(3) (approximately 25%) of the anesthetized rhesus macaques brain at 7T in 25 min. These voxels are x10(2)-10(1) times smaller than the 8-1 cm(3) common to (1)H-MRS in humans, retaining similar proportions between the macaque and human brain. The spectra showed a signal-to-noise-ratio (SNR) approximately 9-10 for the major metabolites and the interanimal SNR spatial distribution reproducibility was in the +/-10% range for the standard error of their means (SEMs). Their metabolites' linewidths, 9+/-2 Hz, yield excellent spectral resolution as well. These results indicate that 3D (1)H-MRSI can be integrated into comprehensive MR studies in primates at such high fields