Faculty Bibliography

Despite its ubiquity and significance, behavioral habituation is poorly understood in terms of the underlying neural circuit mechanisms. Here, we present evidence that habituation arises from potentiation of inhibitory transmission within a circuit motif commonly repeated in the nervous system. In Drosophila, prior odorant exposure results in a selective reduction of response to this odorant. Both short-term (STH) and long-term (LTH) forms of olfactory habituation require function of the rutabaga-encoded adenylate cyclase in multiglomerular local interneurons (LNs) that mediate GABAergic inhibition in the antennal lobe; LTH additionally requires function of the cAMP response element-binding protein (CREB2) transcription factor in LNs. The odorant selectivity of STH and LTH is mirrored by requirement for NMDA receptors and GABA(A) receptors in odorant-selective, glomerulus-specific projection neurons(PNs). The need for the vesicular glutamate transporter in LNs indicates that a subset of these GABAergic neurons also releases glutamate. LTH is associated with a reduction of odorant-evoked calcium fluxes in PNs as well as growth of the respective odorant-responsive glomeruli. These cellular changes use similar mechanisms to those required for behavioral habituation. Taken together with the observation that enhancement of GABAergic transmission is sufficient to attenuate olfactory behavior, these data indicate that habituation arises from glomerulus-selective potentiation of inhibitory synapses in the antennal lobe. We suggest that similar circuit mechanisms may operate in other species and sensory systems.

The brain is made of billions of highly metabolically active neurons whose activities provide the seat for cognitive, affective, sensory and motor functions. The cerebral vasculature meets the brain's unusually high demand for oxygen and glucose by providing it with the largest blood supply of any organ. Accordingly, disorders of the cerebral vasculature, such as congenital vascular malformations, stroke and tumors, compromise neuronal function and survival and often have crippling or fatal consequences. Yet, the assembly of the cerebral vasculature is a process that remains poorly understood. Here we exploit the physical and optical accessibility of the zebrafish embryo to characterize cerebral vascular development within the embryonic hindbrain. We find that this process is primarily driven by endothelial cell migration and follows a two-step sequence. First, perineural vessels with stereotypical anatomies are formed along the ventro-lateral surface of the neuroectoderm. Second, angiogenic sprouts derived from a subset of perineural vessels migrate into the hindbrain to form the intraneural vasculature. We find that these angiogenic sprouts reproducibly penetrate into the hindbrain via the rhombomere centers, where differentiated neurons reside, and that specific rhombomeres are invariably vascularized first. While the anatomy of intraneural vessels is variable from animal to animal, some aspects of the connectivity of perineural and intraneural vessels occur reproducibly within particular hindbrain locales. Using a chemical inhibitor of VEGF signaling we determine stage-specific requirements for this pathway in the formation of the hindbrain vasculature. Finally, we show that a subset of hindbrain vessels is aligned and/or in very close proximity to stereotypical neuron clusters and axon tracts. Using endothelium-deficient cloche mutants we show that the endothelium is dispensable for the organization and maintenance of these stereotypical neuron clusters and axon tracts in the early hindbrain. However, the cerebellum's upper rhombic lip and the optic tectum are abnormal in clo. Overall, this study provides a detailed, multi-stage characterization of early zebrafish hindbrain neurovascular development with cellular resolution up to the third day of age. This work thus serves as a useful reference for the neurovascular characterization of mutants, morphants and drug-treated embryos

RATIONALE: Residents and area workers who inhaled dust and fumes from the World Trade Center disaster reported lower respiratory symptoms in two World Trade Center Health Registry surveys (2003-2004 and 2006-2007), but lung function data were lacking. OBJECTIVES: To examine the relationship between persistent respiratory symptoms and pulmonary function in a nested case-control study of exposed adult residents and area workers 7-8 years post-9/11/2001. METHODS: Registrants reporting post-9/11 onset of a lower respiratory symptom in the first survey and the same symptom in the second survey were solicited as potential cases. Registrants without lower respiratory symptoms in either Registry survey were solicited as potential controls. Final case-control status was determined by lower respiratory symptoms at a third interview (the study), when spirometry and impulse oscillometry were also performed. MAIN RESULTS: We identified 180 cases and 473 controls. Cases were more likely than controls to have abnormal spirometry (19% versus 11%, P<0.05), and impulse oscillometry measurements of elevated airway resistance, R5 (68% versus 27%, P<0.0001) and frequency dependence of resistance, R5-20 (36% versus 7%, P<0.0001). When spirometry was normal, cases were more likely than controls to have elevated R5 and R5-20 (62% versus 25% and 27% versus 6% respectively, both P<0.0001). Associations between symptoms and oscillometry held when factors significant in bivariate comparisons (BMI, spirometry, exposures) were analyzed using logistic regression. CONCLUSIONS: This study links persistent respiratory symptoms and oscillometric abnormalities in WTC-exposed residents and area workers. Elevated R5 and R5-20 in cases despite normal spirometry suggested distal airway dysfunction as a mechanism for symptoms

Diffusional kurtosis imaging (DKI) is a clinically feasible extension of diffusion tensor imaging that probes restricted water diffusion in biological tissues using magnetic resonance imaging. Here we provide a physically meaningful interpretation of DKI metrics in white matter regions consisting of more or less parallel aligned fiber bundles by modeling the tissue as two non-exchanging compartments, the intra-axonal space and extra-axonal space. For the b-values typically used in DKI, the diffusion in each compartment is assumed to be anisotropic Gaussian and characterized by a diffusion tensor. The principal parameters of interest for the model include the intra- and extra-axonal diffusion tensors, the axonal water fraction and the tortuosity of the extra-axonal space. A key feature is that these can be determined directly from the diffusion metrics conventionally obtained with DKI. For three healthy young adults, the model parameters are estimated from the DKI metrics and shown to be consistent with literature values. In addition, as a partial validation of this DKI-based approach, we demonstrate good agreement between the DKI-derived axonal water fraction and the slow diffusion water fraction obtained from standard biexponential fitting to high b-value diffusion data. Combining the proposed WM model with DKI provides a convenient method for the clinical assessment of white matter in health and disease and could potentially provide important information on neurodegenerative disorders

INTRODUCTION This protocol describes imaging of the living mouse brain through a thinned skull using two-photon microscopy. This transcranial two-photon laser-scanning microscope (TPLSM) imaging method allows high-resolution imaging of fluorescently labeled neurons, microglia, astrocytes, and blood vessels, as well as subcellular structures such as dendritic spines and axonal varicosities. The surgical procedure that is required to allow imaging thins the cranium so that it becomes optically transparent. Once learned, the surgery can be performed in approximately 30 min, and imaging can follow immediately. The procedure can be repeated multiple times, allowing brain cells and tissues to be studied in the same animals over short or long time intervals, depending on the design of the experiment. Two-photon imaging through a thinned and intact skull avoids side effects caused by skull removal and is a minimally invasive method for studying the living mouse brain under physiological and pathological conditions

The contention of this commentary, focused on the vestibulocerebellum (particularly the flocculus), is that the great importance for our understanding of cerebellar organization in terms of climbing fiber zones, begun years ago by Voogd [1969, 2011] and Oscarsson [1969], needs to be matched by coming more to grips with the other fundamental geometrical organization of the cerebellum, the parallel fibers. The central issue is the selection of those parallel fiber signals to be transformed into Purkinje cell activity in the different zones. At present, in comparison to our knowledge of vestibulocerebellar climbing fiber inputs, the deficiencies in our knowledge of the zonal anatomy and physiology of vestibulocerebellar mossy fibers and granule cells are glaring. The recent emphasis on molecularly oriented investigations points to the need to reinvigorate pursuit of unanswered questions about cerebellar anatomy, the handmaiden of physiology

Cancers often cause excruciating pain and rapid weight loss, severely reducing quality of life in cancer patients. Cancer-induced pain and cachexia are often studied and treated independently, although both symptoms are strongly linked with chronic inflammation and sustained production of proinflammatory cytokines. Because nerve growth factor (NGF) plays a cardinal role in inflammation and pain, and because it interacts with multiple proinflammatory cytokines, we hypothesized that NGF acts as a key endogenous molecule involved in the orchestration of cancer-related inflammation. NGF might be a molecule common to the mechanisms responsible for clinically distinctive cancer symptoms such as pain and cachexia as well as cancer progression. Here we reported that NGF was highly elevated in human oral squamous cell carcinoma tumors and cell cultures. Using two validated mouse cancer models, we further showed that NGF blockade decreased tumor proliferation, nociception, and weight loss by orchestrating proinflammatory cytokines and leptin production. NGF blockade also decreased expression levels of nociceptive receptors TRPV1, TRPA1, and PAR-2. Together, these results identified NGF as a common link among proliferation, pain, and cachexia in oral cancer. Anti-NGF could be an important mechanism-based therapy for oral cancer and its related symptoms

Neurofibrillary tangles (NFTs) are one of the pathological hallmarks of Alzheimer's disease (AD) and are primarily composed of aggregates of hyperphosphorylated forms of the microtubule associated protein tau. It is likely that an imbalance of kinase and phosphatase activities leads to the abnormal phosphorylation of tau and subsequent aggregation. The wide ranging therapeutic approaches that are being developed include to inhibit tau kinases, to enhance phosphatase activity, to promote microtubule stability, and to reduce tau aggregate formation and/or enhance their clearance with small molecule drugs or by immunotherapeutic means. Most of these promising approaches are still in preclinical development whilst some have progressed to Phase II clinical trials. By pursuing these lines of study, a viable therapy for AD and related tauopathies may be obtained

Short-term plasticity (STP) comprises several rapid synaptic processes that operate on millisecond-to-minute timescales and modulate synaptic efficacy in an activity-dependent manner. Facilitation and augmentation are two major STP components in central synapses that work to enhance synaptic strength, while various forms of short-term depression work to decrease it. These multiple components of STP interact to perform a variety of synaptic computations. Using a modeling approach in excitatory hippocampal synapses, we recently described the contributions of individual STP components to synaptic operations. In this mini-review, we summarize the recent findings that revealed a wide palette of functions that STP components play in neural operations and discuss their roles in information processing, working memory and decision making.

Purpose: To explore the neural correlates of the thalamus by using resting-state functional magnetic resonance (MR) imaging and to investigate whether thalamic resting-state networks (RSNs) are disrupted in patients with mild traumatic brain injury (MTBI). Materials and Methods: This HIPAA-compliant study was approved by the institutional review board, and written informed consent was obtained from 24 patients with MTBI and 17 healthy control subjects. The patients had varying degrees of symptoms, with a mean disease duration of 22 days. The resting-state functional MR imaging data were analyzed by using a standard seed-based whole-brain correlation method to characterize thalamic RSNs. Student t tests were used to perform comparisons. The association between thalamic RSNs and performance on neuropsychologic and neurobehavioral measures was also investigated in patients with MTBI by using Spearman rank correlation. Results: A normal pattern of thalamic RSNs was demonstrated in healthy subjects. This pattern was characterized as representing relatively symmetric and restrictive functional thalamocortical connectivity, suggesting an inhibitory property of the thalamic neurons during the resting state. This pattern was disrupted, with significantly increased thalamic RSNs (P </= .005) and decreased symmetry (P = .03) in patients with MTBI compared with healthy control subjects. Increased functional thalamocortical redistributive connectivity was correlated with diminished neurocognitive functions and clinical symptoms in patients with MTBI. Conclusion: These findings of abnormal thalamic RSNs lend further support to the presumed subtle thalamic injury in patients with MTBI. Resting-state functional MR imaging can be used as an additional imaging modality for detection of thalamocortical connectivity abnormalities and for better understanding of the complex persistent postconcussive syndrome. (c) RSNA, 2011