Faculty Bibliography

Cortical networks are composed of glutamatergic excitatory projection neurons and local GABAergic inhibitory interneurons that gate signal flow and sculpt network dynamics. Although they represent a minority of the total neocortical neuronal population, GABAergic interneurons are highly heterogeneous, forming functional classes based on their morphological, electrophysiological, and molecular features, as well as connectivity and in vivo patterns of activity. Here we review our current understanding of neocortical interneuron diversity and the properties that distinguish cell types. We then discuss how the involvement of multiple cell types, each with a specific set of cellular properties, plays a crucial role in diversifying and increasing the computational power of a relatively small number of simple circuit motifs forming cortical networks. We illustrate how recent advances in the field have shed light onto the mechanisms by which GABAergic inhibition contributes to network operations.

Butterflies rely extensively on colour vision to adapt to the natural world. Most species express a broad range of colour-sensitive Rhodopsin proteins in three types of ommatidia (unit eyes), which are distributed stochastically across the retina. The retinas of Drosophila melanogaster use just two main types, in which fate is controlled by the binary stochastic decision to express the transcription factor Spineless in R7 photoreceptors. We investigated how butterflies instead generate three stochastically distributed ommatidial types, resulting in a more diverse retinal mosaic that provides the basis for additional colour comparisons and an expanded range of colour vision. We show that the Japanese yellow swallowtail (Papilio xuthus, Papilionidae) and the painted lady (Vanessa cardui, Nymphalidae) butterflies have a second R7-like photoreceptor in each ommatidium. Independent stochastic expression of Spineless in each R7-like cell results in expression of a blue-sensitive (Spineless(ON)) or an ultraviolet (UV)-sensitive (Spineless(OFF)) Rhodopsin. In P. xuthus these choices of blue/blue, blue/UV or UV/UV sensitivity in the two R7 cells are coordinated with expression of additional Rhodopsin proteins in the remaining photoreceptors, and together define the three types of ommatidia. Knocking out spineless using CRISPR/Cas9 (refs 5, 6) leads to the loss of the blue-sensitive fate in R7-like cells and transforms retinas into homogeneous fields of UV/UV-type ommatidia, with corresponding changes in other coordinated features of ommatidial type. Hence, the three possible outcomes of Spineless expression define the three ommatidial types in butterflies. This developmental strategy allowed the deployment of an additional red-sensitive Rhodopsin in P. xuthus, allowing for the evolution of expanded colour vision with a greater variety of receptors. This surprisingly simple mechanism that makes use of two binary stochastic decisions coupled with local coordination may prove to be a general means of generating an increased diversity of developmental outcomes.

Expanding epidemiologic and physiologic data suggest that urinary stone disease is best conceptualized as a chronic metabolic condition punctuated by symptomatic, preventable stone events. These acute events herald substantial future chronic morbidity, including decreased bone mineral density, cardiovascular disease, and CKD. Urinary stone disease imposes a large and growing public health burden. In the United States, 1 in 11 individuals will experience a urinary stone in their lifetime. Given this high incidence and prevalence, urinary stone disease is one of the most expensive urologic conditions, with health care charges exceeding $10 billion annually. Patient care focuses on management of symptomatic stones rather than prevention; after three decades of innovation, procedural interventions are almost exclusively minimally invasive or noninvasive, and mortality is rare. Despite these advances, the prevalence of stone disease has nearly doubled over the past 15 years, likely secondary to dietary and health trends. The NIDDK recently convened a symposium to assess knowledge and treatment gaps to inform future urinary stone disease research. Reducing the public health burden of urinary stone disease will require key advances in understanding environmental, genetic, and other individual disease determinants; improving secondary prevention; and optimal population health strategies in an increasingly cost-conscious care environment.

An increasing number of studies have reported blood-brain barrier (BBB) dysfunction after blast-induced traumatic brain injury (bTBI). Despite this evidence, there is limited quantitative understanding of the extent of BBB opening and the time course of damage after blast injury. In addition, many studies do not report kinematic parameters of head motion, making it difficult to separate contributions of primary and tertiary blast-loading. Detailed characterization of blast-induced BBB damage may hold important implications for serum constituents that may potentially cross the compromised barrier and contribute to neurotoxicity, neuroinflammation, and persistent neurologic deficits. Using an in vivo bTBI model, systemic administration of sodium fluorescein (NaFl; 376 Da), Evans blue (EB; 69 kDa when bound to serum albumin), and dextrans (3-500 kDa) was used to estimate the pore size of BBB opening and the time required for recovery. Exposure to blast with 272 +/- 6 kPa peak overpressure, 0.69 +/- 0.01 ms duration, and 65 +/- 1 kPa*ms impulse resulted in significant acute extravasation of NaFl, 3 kDa dextran, and EB. However, there was no significant acute extravasation of 70 kDa or 500 kDa dextrans, and minimal to no extravasation of NaFl, dextrans, or EB 1 day after exposure. This study presents a detailed analysis of the time course and pore size of BBB opening after bTBI, supported by a characterization of kinematic parameters associated with blast-induced head motion.

Heart disease is a worldwide public health problem; assessment of cardiac function is an important part of the diagnosis and management of heart disease. Magnetic resonance imaging (MRI) of the heart can provide clinically useful information on cardiac function, although it is still not routinely used in clinical practice, in part because of limited imaging speed. New accelerated methods for performing cardiovascular MRI (CMR) have the potential to provide both increased imaging speed and robustness to CMR, as well as access to increased functional information. In this review, we will briefly discuss the main methods currently employed to accelerate CMR methods, such as parallel imaging, k-t undersampling and compressed sensing, as well as new approaches that extend the idea of compressed sensing and exploit sparsity to provide richer information of potential use in clinical practice.

Moderate-to-severe fatigue occurs in up to 94% of oncology patients undergoing active treatment. Current interventions for fatigue are not efficacious. A major impediment to the development of effective treatments is a lack of understanding of the fundamental mechanisms underlying fatigue. In the current study, differences in phenotypic characteristics and gene expression profiles were evaluated in a sample of breast cancer patients undergoing chemotherapy (CTX) who reported low (n = 19) and high (n = 25) levels of evening fatigue. Compared to the low group, patients in the high evening fatigue group reported lower functional status scores, higher comorbidity scores, and fewer prior cancer treatments. One gene was identified as upregulated and 11 as downregulated in the high evening fatigue group. Gene set analysis found 24 downregulated and 94 simultaneously up- and downregulated pathways between the two fatigue groups. Transcript origin analysis found that differential expression (DE) originated primarily from monocytes and dendritic cell types. Query of public data sources found 18 gene expression experiments with similar DE profiles. Our analyses revealed that inflammation, neurotransmitter regulation, and energy metabolism are likely mechanisms associated with evening fatigue severity; that CTX may contribute to fatigue seen in oncology patients; and that the patterns of gene expression may be shared with other models of fatigue (e.g., physical exercise and pathogen-induced sickness behavior). These results suggest that the mechanisms that underlie fatigue in oncology patients are multifactorial.

Background: We have previously demonstrated that anti-beta-sheet conformational monoclonal antibodies (mAbs) recognize pathological oligomeric forms of Abeta and Tau in tissue samples of human Alzheimer's Disease (AD) brains and in AD mouse models (Goni et al 2015, Alzheimer & Dementia pp 845-6). We have now tested one of our mAbs in aged 3xTg AD animals with extensive preexisting Abeta and Tau related pathology with weekly injections of the TABP1 mAb. Methods: Two groups of 16 months old 3xTg AD animals were inoculated i.p. biweekly for three weeks and weekly thereafter for 5 weeks with either 100 mug of TABP1 in 100 muL of sterile saline or with 100 muL of vehicle alone. Radial Arm Maze behavioral analysis was performed after the treatment, followed by sacrifice and harvesting of the brains for immuno-histochemical and biochemical analyses. Results: No adverse reactions were demonstrated during the treatment. The TABP1 infused animals showed significant cognitive rescue compared to the controls. No significant differences were noted with the immunohistochemical quantitation of amyloid plaques or tau pathology; although there was a trend for reduced deposition in the infused animals. However, there was a significant decrease of the soluble and oligomeric Abeta (mainly Abeta1-42) and pathological Tau in the infused animals versus the controls. Conclusions: Anti-conformational monoclonal antibodies infused i.p. can ameliorate behavioral deficits in AD model mice. The mechanism is likely related to reductions of the levels of soluble oligomeric forms of Abeta and Tau; these species have been most closely linked to the cognitive deficits in AD patients. The results are encouraging for the further testing of humanized versions of these mAbs in clinical trials

Background: The neuropathological hallmarks of Alzheimer's disease (AD) are senile plaques (SP) and neurofibrillary tangles (NFTs). Passive immunization with anti-Abeta antibodies is a promising therapeutic approach for AD with several on-going clinical trials; however, toxicity with amyloid related imaging abnormalities (ARIA) is problematic in many of these trails. This toxicity is in part related to the effector function of the antibodies used. Recently, an affibody molecule that lacks effector function, but binds to monomeric Abeta peptides, with aggregation inhibition capacity, was generated and tested in AD model transgenic fruit flies, demonstrating abolition of Abeta related neurotoxic effects and restoration of their life span. Here we assessed the efficacy of passive immunization with the affibody in a mouse model of AD. Methods: APP/ PS1 transgenic AD model mice were injected intraperitoneally twice a week with the Abeta-binding ZSYM73-ABD Affibody molecule from the age of 6 months (at a point where the mice already have amyloid deposition). Control mice received a non-Abeta binding affibody. Their behavior was assessed at 9 months of age and brain tissue subsequently was harvested for analysis of treatment efficacy. Results: The treated (Abeta-binding ZSYM73-ABD) mice didn't show a significant difference from controls on locomotor testing. ZSYM73- ABD treated-mice performed the same as wild-type mice. The amyloid burden of in treated animals was reduced by 49 % in the cortex and 50% in the hippocampus. There was no significant difference in astrogliosis or microhemorrhages between treated and control mice. Conclusions: These results indicate that passive immunization with an Affibody molecule can significantly decrease the amyloid burden and improve cognitive function in a transgenic mouse model of AD

Aberrant neuronal translation is implicated in the etiology of numerous brain disorders. Although mTORC1-p70 ribosomal S6 kinase 1 (S6K1) signaling is critical for translational control, pharmacological manipulation in vivo has targeted exclusively mTORC1 due to the paucity of specific inhibitors to S6K1.However, small molecule inhibitors of S6K1 could potentially ameliorate pathological phenotypes of diseases which are based on aberrant translation and protein expression. One such condition is Fragile X syndrome (FXS), which is considered to be caused by exaggerated neuronal translation and is the most frequent heritable cause of autism spectrum disorders (ASD). To date, potential therapeutic interventions in FXS have focused largely on targets upstream of translational control to normalize FXS-related phenotypes. Here we test the ability of two S6K1 inhibitors, PF-4708671 and FS-115, to normalize translational homeostasis and other phenotypes exhibited by FXS model mice. We found that although the pharmacokinetic profiles of the two S6K1 inhibitors differed, they overlapped in reversing multiple disease-associated phenotypes in FXS model mice including exaggerated protein synthesis, inappropriate social behavior, behavioral inflexibility, altered dendritic spine morphology, and macro-orchidism. In contrast, the two inhibitors differed in their ability to rescue stereotypic marble burying behavior and weight gain. These findings provide an initial pharmacological characterization of the impact of S6K1 inhibitors in vivo for FXS and have therapeutic implications for other neuropsychiatric conditions involving aberrant mTORC1-S6K1 signaling.Neuropsychopharmacology accepted article preview online, 28 December 2015. doi:10.1038/npp.2015.369.