Faculty Bibliography

BACKGROUND AND PURPOSE: Schizophrenia is well-known to be associated with hippocampal structural abnormalities. We used 1H-MR spectroscopy to test the hypothesis that these abnormalities are accompanied by NAA deficits, reflecting neuronal dysfunction, in patients compared with healthy controls. MATERIALS AND METHODS: Nineteen patients with schizophrenia (11 men; mean age, 40.6 +/- 10.1 years; mean disease duration, 19.5 +/- 10.5 years) and 11 matched healthy controls (5 men; mean age, 33.7 +/- 10.1 years) underwent MR imaging and multivoxel point-resolved spectroscopy (TE/TR, 35/1400 ms) 1H-MRS at 3T to obtain their hippocampal GM absolute NAA, Cr, Cho, and mIns concentrations. Unequal variance t tests and ANCOVA were used to compare patients with controls. Bilateral volumes from manually outlined hippocampal masks were compared by using unequal variance t tests. RESULTS: Patients' average hippocampal GM Cr concentrations were 19% higher than that of controls, 8.7 +/- 2.2 versus 7.4 +/- 1.2 mmol/L (P < .05); showing no differences, concentrations in NAA were 8.8 +/- 1.6 versus 8.7 +/- 1.2 mmol/L; in Cho, 2.3 +/- 0.7 versus 2.1 +/- 0.3 mmol/L; and in mIns, 6.1 +/- 1.5 versus 5.2 +/- 0.9 (all P > .1). There was a positive correlation between mIns and Cr in patients (r = 0.57, P = .05) but not in controls. The mean bilateral hippocampal volume was approximately 10% lower in patients: 7.5 +/- 0.9 versus 8.4 +/- 0.7 cm3 (P < .05). CONCLUSIONS: These findings suggest that the hippocampal volume deficit in schizophrenia is not due to net loss of neurons, in agreement with histopathology studies but not with prior 1H-MR spectroscopy reports. Elevated Cr is consistent with hippocampal hypermetabolism, and its correlation with mIns may also suggest an inflammatory process affecting some cases; these findings may suggest treatment targets and markers to monitor them.

This Opinion article considers the implications for functional anatomy of how we represent temporal structure in our exchanges with the world. It offers a theoretical treatment that tries to make sense of the architectural principles seen in mammalian brains. Specifically, it considers a factorisation between representations of temporal succession and representations of content or, heuristically, a segregation into when and what. This segregation may explain the central role of the hippocampus in neuronal hierarchies while providing a tentative explanation for recent observations of how ordinal sequences are encoded. The implications for neuroanatomy and physiology may have something important to say about how self-organised cell assembly sequences enable the brain to exhibit purposeful behaviour that transcends the here and now.

Hunger is a powerful drive that stimulates food intake. Yet, the mechanism that determines how the energy deficits that result in hunger are represented in the brain and promote feeding is not well understood. We previously described SLC5A11-a sodium/solute co-transporter-like-(or cupcake) in Drosophila melanogaster, which is required for the fly to select a nutritive sugar over a sweeter nonnutritive sugar after periods of food deprivation. SLC5A11 acts on approximately 12 pairs of ellipsoid body (EB) R4 neurons to trigger the selection of nutritive sugars, but the underlying mechanism is not understood. Here, we report that the excitability of SLC5A11-expressing EB R4 neurons increases dramatically during starvation and that this increase is abolished in the SLC5A11 mutation. Artificial activation of SLC5A11-expresssing neurons is sufficient to promote feeding and hunger-driven behaviors; silencing these neurons has the opposite effect. Notably, SLC5A11 transcript levels in the brain increase significantly when flies are starved and decrease shortly after starved flies are refed. Furthermore, expression of SLC5A11 is sufficient for promoting hunger-driven behaviors and enhancing the excitability of SLC5A11-expressing neurons. SLC5A11 inhibits the function of the Drosophila KCNQ potassium channel in a heterologous expression system. Accordingly, a knockdown of dKCNQ expression in SLC5A11-expressing neurons produces hunger-driven behaviors even in fed flies, mimicking the overexpression of SLC5A11. We propose that starvation increases SLC5A11 expression, which enhances the excitability of SLC5A11-expressing neurons by suppressing dKCNQ channels, thereby conferring the hunger state.

Brain extracellular space (ECS) is an interconnected channel that allows diffusion-mediated transport of signaling molecules, metabolites, and drugs. We tested the hypothesis that beta-adrenergic receptor (betaAR) activation impacts extracellular diffusion-mediated transport of molecules through alterations in the morphology of astrocytes. Two structural parameters of ECS-volume fraction and tortuosity-govern extracellular diffusion. Volume fraction (alpha) is the volume of ECS relative to the total tissue volume. Tortuosity (lambda) is a measure of the hindrance that molecules experience in the ECS, compared to a free medium. The real-time iontophoretic (RTI) method revealed that treatment of acutely prepared visual cortical slices of adult female rats with a betaAR agonist, DL-isoproterenol (ISO), decreases alpha significantly, from 0.22 +/- 0.03 (mean +/- SD) for controls without agonist to 0.18 +/- 0.03 with ISO, without altering lambda (control: 1.64 +/- 0.04; ISO: 1.63 +/- 0.04). Electron microscopy revealed that the ISO treatment significantly increased the cytoplasmic area of astrocytic distal endings per unit area of neuropil by 54%. These findings show that norepinephrine decreases alpha, in part, through an increase in astrocytic volume following betaAR activation. Norepinephrine is recognized to be released within the brain during the awake state and increase neurons' signal-to-noise ratio through modulation of neurons' biophysical properties. Our findings uncover a new mechanism for noradrenergic modulation of neuronal signals. Through astrocytic activation leading to a reduction of alpha, noradrenergic modulation increases extracellular concentration of neurotransmitters and neuromodulators, thereby facilitating neuronal interactions, especially during wakefulness. Synapse 70:307-316, 2016. (c) 2016 Wiley Periodicals, Inc.

To provide a detailed analysis of the molecular components and underlying mechanisms associated with ovarian cancer, we performed a comprehensive mass-spectrometry-based proteomic characterization of 174 ovarian tumors previously analyzed by The Cancer Genome Atlas (TCGA), of which 169 were high-grade serous carcinomas (HGSCs). Integrating our proteomic measurements with the genomic data yielded a number of insights into disease, such as how different copy-number alternations influence the proteome, the proteins associated with chromosomal instability, the sets of signaling pathways that diverse genome rearrangements converge on, and the ones most associated with short overall survival. Specific protein acetylations associated with homologous recombination deficiency suggest a potential means for stratifying patients for therapy. In addition to providing a valuable resource, these findings provide a view of how the somatic genome drives the cancer proteome and associations between protein and post-translational modification levels and clinical outcomes in HGSC.

Type 2 diabetes mellitus is characterized by the deposition of islet amyloid polypeptide (IAPP) as amyloid in islets, a process thought to be toxic to beta-cells. To determine the feasibility of targeting these aggregates therapeutically, we vaccinated transgenic (Tg) mice that overexpress human IAPP and were fed a high-fat diet to promote their diabetic phenotype. Our findings indicate that prophylactic vaccination with IAPP and its derivative IAPP7-19-TT, protects wild-type female mice, but not males, from obesity-induced early mortality, and the derivative showed a strong trend for prolonging the lifespan of Tg females but not males. Furthermore, IAPP7-19-TT-immunized Tg females cleared a glucose bolus more efficiently than controls, while IAPP-immunized Tg females showed an impaired ability to clear a glucose bolus compared to their adjuvant injected Tg controls. Interestingly, IAPP or IAPP7-19-TT treatments had no effect on glucose clearance in Tg males. Overall, these beneficial effects of IAPP targeted immunization depend on Tg status, sex, and immunogen. Hence, future studies in this field should carefully consider these variables that clearly affect the therapeutic outcome. In conclusion, IAPP targeting immunotherapy may have benefits in patients with type 2 diabetes.

An initiative to design and build magnetic resonance imaging (MRI) and spectroscopy (MRS) instruments at 14 T and beyond to 20 T has been underway since 2012. This initiative has been supported by 22 interested participants from the USA and Europe, of which 15 are authors of this review. Advances in high temperature superconductor materials, advances in cryocooling engineering, prospects for non-persistent mode stable magnets, and experiences gained from large-bore, high-field magnet engineering for the nuclear fusion endeavors support the feasibility of a human brain MRI and MRS system with 1 ppm homogeneity over at least a 16-cm diameter volume and a bore size of 68 cm. Twelve neuroscience opportunities are presented as well as an analysis of the biophysical and physiological effects to be investigated before exposing human subjects to the high fields of 14 T and beyond.

Neurons in area MT/V5 of the macaque visual cortex encode visual motion. Some cells are selective for the motion of oriented features (component direction-selective, CDS); others respond to the true direction of complex patterns (pattern-direction selective, PDS). There is a continuum of selectivity in MT, with CDS cells at one extreme and PDS cells at the other; we compute a pattern index that captures this variation. It is unknown how a neuron's pattern index is related to its other tuning characteristics. We therefore analyzed the responses of 792 MT cells recorded in the course of other experiments from opiate-anesthetized macaque monkeys, as a function of the direction, spatial frequency, drift rate, size, and contrast of sinusoidal gratings and of the direction and speed of random-dot textures. We also compared MT responses to those of 718 V1 cells. As expected, MT cells with higher pattern index tended to have stronger direction selectivity and broader direction tuning to gratings, and they responded better to plaids than to gratings. Strongly PDS cells also tended to have smaller receptive fields and stronger surround suppression. Interestingly, they also responded preferentially to higher drift rates and higher speeds of moving dots. The spatial frequency preferences of PDS cells depended strongly on their preferred temporal frequencies, whereas these preferences were independent in component-selective cells. Pattern direction selectivity is statistically associated with many response properties of MT cells but not strongly associated with any particular property. Pattern-selective signals are thus available in association with most other signals exported by MT.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.