Faculty Bibliography

BACKGROUND: Stress sensitivity and HPA axis activity may be relevant to the development and expression of psychotic disorders. Cortisol secretion has been associated with positive symptoms both in patients with psychotic disorders and in young people at clinical risk for psychosis. Herein, we aimed to replicate these findings, to determine which positive symptoms may be associated with cortisol levels, and to explore any associations with affective symptoms and impaired stress tolerance. METHODS: Thirty-one clinical high risk patients were evaluated in cross-section for associations between salivary cortisol levels upon clinic entry at 11 am, demographic variables, and clinical symptoms. RESULTS: Salivary cortisol levels were unrelated to medication exposure or demographics, except for higher levels in the ten females studied. Salivary cortisol bore no relationship to overall positive symptom severity but was associated with anxiety, as well as with suspiciousness and impaired stress tolerance, which were themselves highly intercorrelated. CONCLUSIONS: Cortisol secretion in the context of a putative novel social situation (i.e. clinic entry) may be a biological correlate of suspiciousness, impaired stress tolerance and affective symptoms in individuals vulnerable to developing psychosis. These associations are consistent with findings from experience sampling studies in individuals at risk for psychosis as well as basic studies of animal models of schizophrenia.

After extinction, the reappearance of a conditioned response induced by an unconditioned stimulus which is weaker than that used during the conditioning training indicates that the extinction procedure does not eliminate the original conditioned memory. Recent studies on fear conditioning have shown that rats exhibited little or no recovery of conditioned responding if the time interval between fear acquisition and extinction was short, suggesting that the extinction process may erase the original conditioning trace in this situation. In the present study, a saving experiment was conducted in rats to investigate whether an aversive response could be recovered following extinction training with different time intervals after acquisition of conditioned taste aversion (CTA). Male Long-Evans rats developed CTA by associating a 0.2% sucrose solution with malaise induced by intraperitoneal injection of 4 ml/kg 0.15 M LiCl and were subjected to extinction training with an interval of 5 h (5H group) or 24 h (24H group) after acquisition of CTA. Rats in the 5H group, but not in the 24H group, exhibited no aversive responding to the sucrose solution followed by the injection of a lower dose of LiCl (1 ml/kg). These findings indicate that the extinction procedure administered at different time points following the acquisition of CTA affects recovery of extinguished aversive memory and suggest that an unlearning process may be involved in the mechanisms of CTA extinction with short intervals between acquisition and extinction.

Since ion channels move electrical charge during their activity, they have traditionally been studied using electrophysiological approaches. This was sometimes combined with mathematical models, for example with the description of the ionic mechanisms underlying the initiation and propagation of action potentials in the squid giant axon by Hodgkin and Huxley. The methods for studying ion channels also have strong roots in protein chemistry (limited proteolysis, the use of antibodies, etc.). The advent of the molecular cloning and the identification of genes coding for specific ion channel subunits in the late 1980s introduced a multitude of new techniques with which to study ion channels and the field has been rapidly expanding ever since (e.g. antibody development against specific peptide sequences, mutagenesis, the use of gene targeting in animal models, determination of their protein structures) and new methods are still in development. This review focuses on techniques commonly employed to examine ion channel function in an electrophysiological laboratory. The focus is on the K(ATP) channel, but many of the techniques described are also used to study other ion channels.

Local anesthetics effectively suppress pain sensation, but most of these compounds act nonselectively, inhibiting activity of all neurons. Moreover, their actions abate slowly, preventing precise spatial and temporal control of nociception. We developed a photoisomerizable molecule, quaternary ammonium-azobenzene-quaternary ammonium (QAQ), that enables rapid and selective optical control of nociception. QAQ is membrane-impermeant and has no effect on most cells, but it infiltrates pain-sensing neurons through endogenous ion channels that are activated by noxious stimuli, primarily TRPV1. After QAQ accumulates intracellularly, it blocks voltage-gated ion channels in the trans form but not the cis form. QAQ enables reversible optical silencing of mouse nociceptive neuron firing without exogenous gene expression and can serve as a light-sensitive analgesic in rats in vivo. Because intracellular QAQ accumulation is a consequence of nociceptive ion-channel activity, QAQ-mediated photosensitization is a platform for understanding signaling mechanisms in acute and chronic pain.

A robust and scalable synthesis of a novel, cyano-substituted Danishefsky-type diene and its use in the Diels-Alder reaction with various dienophiles is reported. The diene allows for the rapid construction of highly substituted aminonaphthoquinones that occur in numerous ansamycin antibiotics.

The brain-derived neurotrophic factor (BDNF) Val66Met polymorphism is a common human single nucleotide polymorphism (SNP) that affects the regulated release of BDNF, and has been implicated in affective disorders and cognitive dysfunction. A decreased activation of the infralimbic medial prefrontal cortex (IL-mPFC), a brain region critical for the regulation of affective behaviors, has been described in BDNF(Met) carriers. However, it is unclear whether and how the Val66Met polymorphism affects the IL-mPFC synapses. Here, we report that spike timing-dependent plasticity (STDP) was absent in the IL-mPFC pyramidal neurons from BDNF(Met/Met) mice, a mouse that recapitulates the specific phenotypic properties of the human BDNF Val66Met polymorphism. Also, we observed a decrease in NMDA and GABA receptor-mediated synaptic transmission in the pyramidal neurons of BDNF(Met/Met) mice. While BDNF enhanced non-NMDA receptor transmission and depressed GABA receptor transmission in the wild-type mice, both effects were absent in BDNF(Met/Met) mice after BDNF treatment. Indeed, exogenous BDNF reversed the deficits in STDP and NMDA receptor transmission in BDNF(Met/Met) neurons. BDNF-mediated selective reversal of the deficit in plasticity and NMDA receptor transmission, but its lack of effect on GABA and non-NMDA receptor transmission in BDNF(Met/Met) mice, suggests separate mechanisms of Val66Met polymorphism upon synaptic transmission. The effect of the Val66Met polymorphism on synaptic transmission and plasticity in the IL-mPFC represents a mechanism to account for this impact of SNP on affective disorders and cognitive dysfunction.

The heterogeneous nature of mammalian PRC1 complexes has hindered our understanding of their biological functions. Here, we present a comprehensive proteomic and genomic analysis that uncovered six major groups of PRC1 complexes, each containing a distinct PCGF subunit, a RING1A/B ubiquitin ligase, and a unique set of associated polypeptides. These PRC1 complexes differ in their genomic localization, and only a small subset colocalize with H3K27me3. Further biochemical dissection revealed that the six PCGF-RING1A/B combinations form multiple complexes through association with RYBP or its homolog YAF2, which prevents the incorporation of other canonical PRC1 subunits, such as CBX, PHC, and SCM. Although both RYBP/YAF2- and CBX/PHC/SCM-containing complexes compact chromatin, only RYBP stimulates the activity of RING1B toward H2AK119ub1, suggesting a central role in PRC1 function. Knockdown of RYBP in embryonic stem cells compromised their ability to form embryoid bodies, likely because of defects in cell proliferation and maintenance of H2AK119ub1 levels.

Myelinating Schwann cells regulate the localization of ion channels on the surface of the axons they ensheath. This function depends on adhesion complexes that are positioned at specific membrane domains along the myelin unit. Here we show that the precise localization of internodal proteins depends on the expression of the cytoskeletal adapter protein 4.1G in Schwann cells. Deletion of 4.1G in mice resulted in aberrant distribution of both glial adhesion molecules and axonal proteins that were present along the internodes. In wild-type nerves, juxtaparanodal proteins (i.e., Kv1 channels, Caspr2, and TAG-1) were concentrated throughout the internodes in a double strand that flanked paranodal junction components (i.e., Caspr, contactin, and NF155), and apposes the inner mesaxon of the myelin sheath. In contrast, in 4.1G(-/-) mice, these proteins "piled up" at the juxtaparanodal region or aggregated along the internodes. These findings suggest that protein 4.1G contributes to the organization of the internodal axolemma by targeting and/or maintaining glial transmembrane proteins along the axoglial interface.

BACKGROUND: Mandibular osteoradionecrosis is the most devastating complication after radiation therapy for head and neck malignancies. Quality of life (QOL) after surgical treatment is unclear. METHODS: A retrospective cohort analysis (1997-2007) was conducted of all patients treated at our institution for stage II and III mandibular osteoradionecrosis. Nineteen of 35 patients responded to a modified University of Washington QOL questionnaire. Twenty had undergone reconstruction using free flaps, and the remainder with plates, plates and local flaps, or debridement alone. RESULTS: Complications included 3 infections, 5 with hardware, 5 flap-specific, and 1 nonunion. Four patients had recurrent squamous cell carcinoma (SCC). The factors of greatest concern to patients were appearance, swallowing, and chewing. Average overall QOL was good to very good, and very good compared to preoperative. CONCLUSION: Despite a 37% complication rate, a multidisciplinary team approach with adequate debridement, resection, and reconstruction can greatly improve QOL. (c) 2011 Wiley Periodicals, Inc. Head Neck, 2012.

Greater intra-subject variability (ISV) in response time is a heritable endophenotype of attention-deficit/hyperactivity disorder (ADHD). Spontaneous low frequency oscillations (LFO: 0.01-0.1 Hz) observed in brain functional magnetic resonance signals might account for such behavioral variability. Recently, we demonstrated that ISV in response time (RT) explained ratings of ADHD symptoms. Building on this finding, here we hypothesized that LFO in RT time series would explain these ratings, both independently and in addition to RT coefficient of variation (CV). To measure RT LFO, we applied Morlet wavelet transform to the previously collected RT data. Our community sample consisted of 98 children (including 66 boys, mean age 9.9 +/- 1.4 years), who completed four computer Tasks of Executive Control. Conners' Parent Rating Scale ratings were obtained. RT LFO of three tasks significantly explained ratings of inattention, hyperactivity and three global Conners' subscales. In addition, RT LFO during two tasks that included an inhibitory component increased the proportions of variance explained in subscales of both inattention and hyperactivity/impulsivity, beyond the effects of RT-CV. Three specific low frequency bands (Slow-5: 0.01-0.027 Hz; Slow-4: 0.027-0.073 Hz; Slow-3: 0.073-0.20 Hz) were strongly related to the ADHD scales. We conclude that RT LFO predict dimensional ratings of ADHD symptoms both independently and in addition to RTCV. Results suggest that frequency analyses are a suitable methodology to link behavioral responses to putative underlying physiological processes.