Faculty Bibliography

Various kinds of stress are thought to precipitate psychiatric disorders, such as major depression. Whereas studies in rodents have suggested a critical role of medial prefrontal cortex (mPFC) in stress susceptibility, the mechanism of how stress susceptibility is determined through mPFC remains unknown. Here we show a critical role of prostaglandin E(2) (PGE(2)), a bioactive lipid derived from arachidonic acid, in repeated social defeat stress in mice. Repeated social defeat increased the PGE(2) level in the subcortical region of the brain, and mice lacking either COX-1, a prostaglandin synthase, or EP1, a PGE receptor, were impaired in induction of social avoidance by repeated social defeat. Given the reported action of EP1 that augments GABAergic inputs to midbrain dopamine neurons, we analyzed dopaminergic response upon social defeat. Analyses of c-Fos expression of VTA dopamine neurons and dopamine turnover in mPFC showed that mesocortical dopaminergic pathway is activated upon social defeat and attenuated with repetition of social defeat in wild-type mice. EP1 deficiency abolished such repeated stress-induced attenuation of mesocortical dopaminergic pathway. Blockade of dopamine D1-like receptor during social defeat restored social avoidance in EP1-deficient mice, suggesting that disinhibited dopaminergic response during social defeat blocks induction of social avoidance. Furthermore, mPFC dopaminergic lesion by local injection of 6-hydroxydopamine, which mimicked the action of EP1 during repeated stress, facilitated induction of social avoidance upon social defeat. Taken together, our data suggest that PGE(2)-EP1 signaling is critical for susceptibility to repeated social defeat stress in mice through attenuation of mesocortical dopaminergic pathway.

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.

Synchronized spontaneous firing among retinal ganglion cells (RGCs), on timescales faster than visual responses, has been reported in many studies. Two candidate mechanisms of synchronized firing include direct coupling and shared noisy inputs. In neighboring parasol cells of primate retina, which exhibit rapid synchronized firing that has been studied extensively, recent experimental work indicates that direct electrical or synaptic coupling is weak, but shared synaptic input in the absence of modulated stimuli is strong. However, previous modeling efforts have not accounted for this aspect of firing in the parasol cell population. Here we develop a new model that incorporates the effects of common noise, and apply it to analyze the light responses and synchronized firing of a large, densely-sampled network of over 250 simultaneously recorded parasol cells. We use a generalized linear model in which the spike rate in each cell is determined by the linear combination of the spatio-temporally filtered visual input, the temporally filtered prior spikes of that cell, and unobserved sources representing common noise. The model accurately captures the statistical structure of the spike trains and the encoding of the visual stimulus, without the direct coupling assumption present in previous modeling work. Finally, we examined the problem of decoding the visual stimulus from the spike train given the estimated parameters. The common-noise model produces Bayesian decoding performance as accurate as that of a model with direct coupling, but with significantly more robustness to spike timing perturbations.

Sensory neurons have been hypothesized to efficiently encode signals from the natural environment subject to resource constraints. The predictions of this efficient coding hypothesis regarding the spatial filtering properties of the visual system have been found consistent with human perception, but they have not been compared directly with neural responses. Here, we analyze the information that retinal ganglion cells transmit to the brain about the spatial information in natural images subject to three resource constraints: the number of retinal ganglion cells, their total response variances, and their total synaptic strengths. We derive a model that optimizes the transmitted information and compare it directly with measurements of complete functional connectivity between cone photoreceptors and the four major types of ganglion cells in the primate retina, obtained at single-cell resolution. We find that the ganglion cell population exhibited 80% efficiency in transmitting spatial information relative to the model. Both the retina and the model exhibited high redundancy (~30%) among ganglion cells of the same cell type. A novel and unique prediction of efficient coding, the relationships between projection patterns of individual cones to all ganglion cells, was consistent with the observed projection patterns in the retina. These results indicate a high level of efficiency with near-optimal redundancy in visual signaling by the retina.

To explore the relative development of the dorsal and ventral extrastriate processing streams, we studied the development of sensitivity to form and motion in macaque monkeys (Macaca nemestrina). We used Glass patterns and random dot kinematograms (RDK) to assay ventral and dorsal stream function, respectively. We tested 24 animals, longitudinally or cross-sectionally, between the ages of 5 weeks and 3 years. Each animal was tested with Glass patterns and RDK stimuli with each of two pattern types--circular and linear--at each age using a two alternative forced-choice task. We measured coherence threshold for discrimination of the global form or motion pattern from an incoherent control stimulus. Sensitivity to global motion appeared earlier than to global form and was higher at all ages, but performance approached adult levels at similar ages. Infants were most sensitive to large spatial scale (Deltax) and fast speeds; sensitivity to fine scale and slow speeds developed more slowly independently of pattern type. Within the motion domain, pattern type had little effect on overall performance. However, within the form domain, sensitivity for linear Glass patterns was substantially poorer than that for concentric patterns. Our data show comparatively early onset for global motion integration ability, perhaps reflecting early development of the dorsal stream. However, both pathways mature over long time courses reaching adult levels between 2 and 3 years after birth.

the molecular characterization of melanoma has ex- panded to include studies of microRNA (miRNA) ex- pression. As miR-16 has been utilized as a normalizer in serum-based miRNA studies in several cancers, we evaluated miR-16 expression as a potential reference for normalization of serum miRNA expression in melanoma patients. Methods: 143 primary cutaneous melanoma patients who presented to New York Uni- versity (NYU) Langone Medical Center for surgical resection of AJCC stage I-III disease were studied. In addition, sera samples from 60 control subjects were utilized including 22 healthy volunteers, 13 rheuma- toid arthritis patients, 20 non-melanoma cancer pa- tients (10 renal cell carcinoma and 10 bladder cancer), and 5 Atypical Mole Syndrome patients. The Kruskal- Wallis test (k = 6) or Wilcoxon test (k = 2) with Bon- ferroni correction was used for analyses of miR-16 expression in melanoma patients compared to various control groups, using raw Ct values directly. The Kruskal-Wallis test was used to compare miR-16 ex- pression across stages of melanoma. The equivalence test for independent samples was used to test the equivalence of miR-16 expression among different groups. Results: No significant differential expression of miR-16 was observed between melanoma patients and healthy volunteers (Wilcoxon test, p = 0.37). How- ever, miR-16 did show a significant difference in ex- pression as it related to stage of melanoma (p = 0.015). Additionally, the equivalence test was unable to con- firm equivalent expression of miR-16 in any melanoma versus control group pair. Conclusion: Our data in- dicate that miR-16 cannot be used as a universal normalizer in sera studies of melanoma patients

Recently, we had the opportunity to review the progress that has been made in the field of cardiovascular disease over the past century in The FASEB Journal and, based on those thoughts, in this article we predict what may transpire inthis 'century of biology'. Although it is true that 'the best way to predict the future is to invent it', we gaze through the prism of modern biomolecular science for a vision of a possible future and see cardiology practice that is transformed. In the second half of the 20th century, we developed a more fundamental understanding of atherosclerotic vascular disorders and invented life-saving therapeutics. We saw a similar development of mechanism-based pharmacotherapy to address heart failure, primarily through agents that antagonize the excessive concentration of circulating neurohumoral agents. Now we are in the midst of the device era, from stents to cardiac resynchronization therapy to transcatheter valves.The next wave of treatments will build on an increasingly sophisticated understanding of the molecular determinants of cardiovascular disorders and engineering feats that are barely perceptible now. Genomic profiling, molecular prescriptions for prevention and personalized therapeutics, regenerative medicine and the new field of cardiovascular tissue bioengineering will transform cardiovascular medicine. If the human species can survive threats of our own doing, such as the related epidemics of obesity and diabetes, by the turn of the next century, treatment of cardiovascular disease will not resemble the present in almost any way. Touch Medical Media 2012

CONTEXT Prospective studies of childhood attention-deficit/hyperactivity disorder (ADHD) have not extended beyond early adulthood. OBJECTIVE To examine whether children diagnosed as having ADHD at a mean age of 8 years (probands) have worse educational, occupational, economic, social, and marital outcomes and higher rates of ongoing ADHD, antisocial personality disorder (ASPD), substance use disorders (SUDs), adult-onset psychiatric disorders, psychiatric hospitalizations, and incarcerations than non-ADHD comparison participants at a mean age of 41 years. DESIGN Prospective, 33-year follow-up study, with masked clinical assessments. SETTING Research clinic. PARTICIPANTS A total of 135 white men with ADHD in childhood, free of conduct disorder, and 136 men without childhood ADHD (65.2% and 76.4% of original cohort, respectively). MAIN OUTCOME MEASURES Occupational, economic, and educational attainment; marital history; occupational and social functioning; ongoing and lifetime psychiatric disorders; psychiatric hospitalizations; and incarcerations. RESULTS Probands had significantly worse educational, occupational, economic, and social outcomes; more divorces; and higher rates of ongoing ADHD (22.2% vs 5.1%, P < .001), ASPD (16.3% vs 0%, P < .001), and SUDs (14.1% vs 5.1%, P = .01) but not more mood or anxiety disorders (P = .36 and .33) than did comparison participants. Ongoing ADHD was weakly related to ongoing SUDs (varphi = 0.19, P = .04), as well as ASPD with SUDs (varphi = 0.20, P = .04). During their lifetime, probands had significantly more ASPD and SUDs but not mood or anxiety disorders and more psychiatric hospitalizations and incarcerations than comparison participants. Relative to comparisons, psychiatric disorders with onsets at 21 years or older were not significantly elevated in probands. Probands without ongoing psychiatric disorders had worse social, but not occupational, functioning. CONCLUSIONS The multiple disadvantages predicted by childhood ADHD well into adulthood began in adolescence, without increased onsets of new disorders after 20 years of age. Findings highlight the importance of extended monitoring and treatment of children with ADHD.

Background: Diagnosis and management of squamous cell carcinoma of head and neck (SCCHN) involves a multidisciplinary approach. Navigation at a public hospital can be difficult and lead to delays. In a previous study, we reported English-speaking and employed patients having longer provider delays (Lai 2011). In July 2010, we instituted the use of patient navigators, bimonthly management conferences, and improved inter-disciplinary communication in order to improve the patient experience. Aims: 1. Study differences in "provider delay" (time between first contact with health care provider and positive biopsy) between patients in cohort A (diagnosed between 1/2007 and 6/2010) and cohort "B" (diagnosed between 7/2010 and 6/ 2011). 2. Study differences in "treatment delay" (time between biopsy and initiation of treatment) between the two cohorts. 3. Determine what factors influence delays in both cohorts. Methods: The delays of the two cohorts were compared using the student t-test. Independent t-test and chi-square tests were used to examine associations between delays and the following characteristics: language, employment, presence of partner, gender, ethnicity, age, cancer sub-site, staging, number of co-morbidities, tobacco use, and alcohol use. The likelihood ratio test was used for multivariate analysis. Results: 133 patients in cohort A and 20 patients in cohort B were evaluable. Both provider and treatment delays in cohort B (50.5 and 39.3 days, respectively) were shorter than cohort A (60.2 and 41.6 days), but this was not statistically significant. The standard deviations of both delays were lower in cohort B, pointing towards a greater consistency in this group. In cohort A, provider delay was significantly shorter (p-value=0.003) for non-English speakers than English speakers on univariate and multivariate analysis. Other trends were not observed. Conclusions: Simple interventions can reduce provider and treatment delays. Our observations suggest that these interventions can mitigate t!