Faculty Bibliography

Dopamine (DA) transmission is governed by processes that regulate release from axonal boutons in the forebrain and the somatodendritic compartment in midbrain, and by clearance by the DA transporter, diffusion, and extracellular metabolism. We review how axonal DA release is regulated by neuronal activity and by autoreceptors and heteroreceptors, and address how quantal release events are regulated in size and frequency. In brain regions densely innervated by DA axons, DA clearance is due predominantly to uptake by the DA transporter, whereas in cortex, midbrain, and other regions with relatively sparse DA inputs, the noradrenaline transporter and diffusion are involved. We discuss the role of DA uptake in restricting the sphere of influence of DA and in temporal accumulation of extracellular DA levels upon successive action potentials. The tonic discharge activity of DA neurons may be translated into a tonic extracellular DA level, whereas their bursting activity can generate discrete extracellular DA transients

Stromal cell-derived factor-1 (SDF-1) is a cytokine that is important in stem and progenitor cell recruitment in tissue repair after injury. Regenerative procedures using collagen membranes (CMs) are presently well established in periodontal and implant dentistry. The objective of this study is to test the subsequent effects of the released SDF-1 from a CM on bone regeneration compared to platelet-derived growth factor (PDGF) in vitro and in vivo. For in vitro studies, cell proliferation, alkaline phosphatase activity, and osteoblastic differentiation marker genes were assessed after MC3T3-E1 mouse preosteoblasts were cultured with CMs containing factors. In vivo effects were investigated by placement of CMs containing SDF-1 or PDGF using a rat mandibular bone defect model. At 4 weeks after the surgery, the new bone formation was measured using micro-computed tomography (microCT) and histological analysis. The results of in vitro studies revealed that CM delivery of SDF-1 significantly induced cell proliferation, ALP activity, and gene expression of all osteogenic markers compared to the CM alone or control, similar to PDGF. Quantitative and qualitative microCT analysis for volume of new bone formation and the percentage of new bone area showed that SDF-1-treated groups significantly increased and accelerated bone regeneration compared to control and CM alone. The enhancement of bone formation in SDF-1-treated animals was dose-dependent and with levels similar to those measured with PDGF. These results suggest that a CM with SDF-1 may be a great candidate for growth factor delivery that could be a substitute for PDGF in clinical procedures where bone regeneration is necessary.

OBJECTIVE: To determine whether patient-specific 3D printed renal tumor models change pre-operative planning decisions made by urological surgeons in preparation for complex renal mass surgical procedures. MATERIALS AND METHODS: From our ongoing IRB approved study on renal neoplasms, ten renal mass cases were retrospectively selected based on Nephrometry Score greater than 5 (range 6-10). A 3D post-contrast fat-suppressed gradient-echo T1-weighted sequence was used to generate 3D printed models. The cases were evaluated by three experienced urologic oncology surgeons in a randomized fashion using (1) imaging data on PACS alone and (2) 3D printed model in addition to the imaging data. A questionnaire regarding surgical approach and planning was administered. The presumed pre-operative approaches with and without the model were compared. Any change between the presumed approaches and the actual surgical intervention was recorded. RESULTS: There was a change in planned approach with the 3D printed model for all ten cases with the largest impact seen regarding decisions on transperitoneal or retroperitoneal approach and clamping, with changes seen in 30%-50% of cases. Mean parenchymal volume loss for the operated kidney was 21.4%. Volume losses >20% were associated with increased ischemia times and surgeons tended to report a different approach with the use of the 3D model compared to that with imaging alone in these cases. The 3D printed models helped increase confidence regarding the chosen operative procedure in all cases. CONCLUSIONS: Pre-operative physical 3D models created from MRI data may influence surgical planning for complex kidney cancer.

While apolipoprotein (Apo)E4 is linked to increased incidence of Alzheimer's disease (AD), there is growing evidence that it plays a role in functional brain irregularities that are independent of AD pathology. However, ApoE4-driven functional differences within olfactory processing regions have yet to be examined. Utilizing knock-in mice humanized to ApoE4 versus the more common ApoE3, we examined a simple olfactory perceptual memory that relies on the transfer of information from the olfactory bulb (OB) to the piriform cortex (PCX), the primary cortical region involved in higher order olfaction. In addition, we have recorded in vivo resting and odor-evoked local field potentials (LPF) from both brain regions and measured corresponding odor response magnitudes in anesthetized young (6-month-old) and middle-aged (12-month-old) ApoE mice. Young ApoE4 compared to ApoE3 mice exhibited a behavioral olfactory deficit coinciding with hyperactive odor-evoked response magnitudes within the OB that were not observed in older ApoE4 mice. Meanwhile, middle-aged ApoE4 compared to ApoE3 mice exhibited heightened response magnitudes in the PCX without a corresponding olfactory deficit, suggesting a shift with aging in ApoE4-driven effects from OB to PCX. Interestingly, the increased ApoE4-specific response in the PCX at middle-age was primarily due to a dampening of baseline spontaneous activity rather than an increase in evoked response power. Our findings indicate that early ApoE4-driven olfactory memory impairments and OB network abnormalities may be a precursor to later network dysfunction in the PCX, a region that not only is targeted early in AD, but may be selectively vulnerable to ApoE4 genotype.

The introduction of compressed sensing for increasing imaging speed in magnetic resonance imaging (MRI) has raised significant interest among researchers and clinicians, and has initiated a large body of research across multiple clinical applications over the last decade. Compressed sensing aims to reconstruct unaliased images from fewer measurements than are traditionally required in MRI by exploiting image compressibility or sparsity. Moreover, appropriate combinations of compressed sensing with previously introduced fast imaging approaches, such as parallel imaging, have demonstrated further improved performance. The advent of compressed sensing marks the prelude to a new era of rapid MRI, where the focus of data acquisition has changed from sampling based on the nominal number of voxels and/or frames to sampling based on the desired information content. This article presents a brief overview of the application of compressed sensing techniques in body MRI, where imaging speed is crucial due to the presence of respiratory motion along with stringent constraints on spatial and temporal resolution. The first section provides an overview of the basic compressed sensing methodology, including the notion of sparsity, incoherence, and nonlinear reconstruction. The second section reviews state-of-the-art compressed sensing techniques that have been demonstrated for various clinical body MRI applications. In the final section, the article discusses current challenges and future opportunities. LEVEL OF EVIDENCE: 5 J. Magn. Reson. Imaging 2016.

It is widely appreciated that reactive stroma or carcinoma-associated fibroblasts can influence epithelial tumor progression. In prostate cancer (PCa), the second most common male malignancy worldwide, the amount of reactive stroma is variable and has predictive value for tumor recurrence. By analyzing human PCa protein and RNA expression databases, we found smooth muscle cells (SMCs) are decreased in advanced tumors, whereas fibroblasts are maintained. In three mouse models of PCa, we found the composition of the stroma is distinct. SMCs are greatly depleted in advanced PB-MYC tumors and locally reduced in ERG/PTEN prostates, whereas in TRAMP tumors the SMC layers are increased. In addition, interductal fibroblast-like cells expand in PB-MYC and ERG/PTEN tumors, whereas in TRAMP PCa they expand little and stromal cells invade into intraductal adenomas. Fate mapping of SMCs showed that in PB-MYC tumors the cells are depleted, whereas they expand in TRAMP tumors and interestingly contribute to the stromal cells in intraductal adenomas. Hedgehog (HH) ligands secreted by epithelial cells are known to regulate prostate mesenchyme expansion differentially during development and regeneration. Any possible role of HH signaling in stromal cells during PCa progression is poorly understood. We found that HH signaling is high in SMCs and fibroblasts near tumor cells in all models, and epithelial Shh expression is decreased while Ihh and Dhh are increased. In human primary PCa IHH is expressed the highest, and elevated HH signaling correlates with high stromal gene expression. Moreover, increasing HH signaling in the stroma of PB-MYC PCa resulted in more intact SMC layers and decreased tumor progression (micro-invasive carcinoma). Thus, we propose HH signaling restrains tumor progression by maintaining the smooth muscle and preventing invasion by tumor cells. Our studies highlight the importance of understanding how HH signaling and stromal composition impact on PCa to optimize drug treatments.

A fundamental question in developmental neuroscience is how hundreds of diverse cell types are generated to form specialized brain regions. The ganglionic eminences (GEs) are embryonic brain structures located in the ventral telencephalon that produce many inhibitory GABA (gamma-Aminobutyric acid)-ergic cell types, including long-range projection neurons and local interneurons (INs), which disperse widely throughout the brain. While much has been discovered about the origin and wiring of these cells, a major question remains: how do neurons originating in the GEs become specified during development as one differentiated subtype versus another? This review will cover recent work that has advanced our knowledge of the mechanisms governing cortical interneuron subtype specification, particularly progenitors' spatial origin, birthdates, lineage, and mode of division.

Execution of motor behaviors relies on the ability of circuits within the nervous system to engage functionally relevant subtypes of spinal motor neurons. While much attention has been given to the role of networks of spinal interneurons on setting the rhythm and pattern of output from locomotor circuits, recent studies suggest that motor neurons themselves can exert an instructive role in shaping the wiring and functional properties of locomotor networks. Alteration in the distribution of motor neuron subtypes also appears to have contributed to evolutionary transitions in the locomotor strategies used by land vertebrates. This review describes emerging evidence that motor neuron-derived cues can have a profound influence on the organization, wiring, and evolutionary diversification of locomotor circuits.

Neurotrophins, such as brain-derived neurotrophic factor (BDNF), are prominent regulators of neuronal survival, growth and differentiation during development. While trophic factors are viewed as well-understood but not innovative molecules, there are many lines of evidence indicating that BDNF plays an important role in the pathophysiology of many neurodegenerative disorders, depression, anxiety and other psychiatric disorders. In particular, lower levels of BDNF are associated with the aetiology of Alzheimer's and Huntington's diseases. A major challenge is to explain how neurotrophins are able to induce plasticity, improve learning and memory and prevent age-dependent cognitive decline through receptor signalling. This article will review the mechanism of action of neurotrophins and how BDNF/tropomyosin receptor kinase B (TrkB) receptor signaling can dictate trophic responses and change brain plasticity through activity-dependent stimulation. Alternative approaches for modulating BDNF/TrkB signalling to deliver relevant clinical outcomes in neurodegenerative and neuropsychiatric disorders will also be described.

Chronic cancer pain is a serious complication of malignancy or its treatment. Currently, no comprehensive, universally accepted cancer pain classification system exists. Clarity in classification of common cancer pain syndromes would improve clinical assessment and management. Moreover, an evidence-based taxonomy would enhance cancer pain research efforts by providing consistent diagnostic criteria, ensuring comparability across clinical trials. As part of a collaborative effort between the Analgesic, Anesthetic, and Addiction Clinical Trial Translations Innovations Opportunities and Networks (ACTTION) and the American Pain Society (APS), the ACTTION-APS Pain Taxonomy (AAPT) initiative worked to develop the characteristics of an optimal diagnostic system.59, 65 Following the establishment of these characteristics, a working group consisting of clinicians and clinical and basic scientists with expertise in cancer and cancer-related pain was convened to generate core diagnostic criteria for an illustrative sample of 3 chronic pain syndromes associated with cancer (i.e., bone pain and pancreatic cancer pain as models of pain related to a tumor) or its treatment (i.e., chemotherapy-induced peripheral neuropathy). A systematic review and synthesis was conducted to provide evidence for the dimensions that comprise this cancer pain taxonomy. Future efforts will subject these diagnostic categories and criteria to systematic empirical evaluation of their feasibility, reliability and validity and extension to other cancer-related pain syndromes. PERSPECTIVE: The ACTTION-APS chronic cancer pain taxonomy provides an evidence-based classification for 3 prevalent syndromes, namely malignant bone pain, pancreatic cancer pain, and chemotherapy-induced peripheral neuropathy. This taxonomy provides consistent diagnostic criteria, common features, co-morbidities, consequences, and putative mechanisms for these potentially serious cancer pain conditions that can be extended and applied with other cancer-related pain syndromes.