Faculty Bibliography

T-cells have evolved the unique ability to discriminate "self" from "non-self" with high sensitivity and selectivity. However, tissue-specific autoimmunity, tolerance or eradication of cancer does not fit into the self/non-self paradigm because the T-cell responses in these situations are most often directed to non-mutated self-proteins. To determine the TCR affinity threshold defining the optimal balance between effective antitumor activity and autoimmunity in vivo, we used a novel self-antigen system comprised of seven human melanoma gp100209-217-specific TCRs spanning physiological affinities (1 to 100 muM). We found that in vitro and in vivo T cell responses are determined by TCR affinity. Strikingly, we found that T cell antitumor activity and autoimmunity are closely coupled but plateau at a defined TCR affinity of 10 muM, likely due to diminished contribution of TCR affinity to avidity above the threshold. Our results suggest a relatively low affinity threshold is necessary for the immune system to avoid selfdamage given the close relationship between antitumor activity and autoimmunity. This, in turn, indicates that treatment strategies focusing on TCRs in the intermediate affinity range (KD ~10 muM) or targeting or targeting shared tumor antigens would dampen the potential for autoimmunity during adoptive T cell therapy for the treatment of cancer

Netrin-1 is a secreted protein that directs long-range axon guidance during early stages of neural circuit formation and continues to be expressed in the mammalian forebrain during the postnatal period of peak synapse formation. Here we demonstrate a synaptogenic function of netrin-1 in rat and mouse cortical neurons and investigate the underlying mechanism. We report that netrin-1 and its receptor DCC are widely expressed by neurons in the developing mammalian cortex during synapse formation and are enriched at synapses in vivo. We detect DCC protein distributed along the axons and dendrites of cultured cortical neurons and provide evidence that newly translated netrin-1 is selectively transported to dendrites. Using gain and loss of function manipulations, we demonstrate that netrin-1 increases the number and strength of excitatory synapses made between developing cortical neurons. We show that netrin-1 increases the complexity of axon and dendrite arbors, thereby increasing the probability of contact. At sites of contact, netrin-1 promotes adhesion, while locally enriching and reorganizing the underlying actin cytoskeleton through Src family kinase signaling and m-Tor-dependent protein translation to locally cluster presynaptic and postsynaptic proteins. Finally, we demonstrate using whole-cell patch-clamp electrophysiology that netrin-1 increases the frequency and amplitude of mEPSCs recorded from cortical pyramidal neurons. These findings identify netrin-1 as a synapse-enriched protein that promotes synaptogenesis between mammalian cortical neurons.

How epilepsy affects brain functional networks remains poorly understood. Here we investigated resting state functional connectivity of the temporal region in temporal lobe epilepsy. Thirty-two patients with unilateral temporal lobe epilepsy underwent resting state blood-oxygenation level dependent functional magnetic resonance imaging. We defined regions of interest a priori focusing on structures involved, either structurally or metabolically, in temporal lobe epilepsy. These structures were identified in each patient based on their individual anatomy. Our principal findings are decreased local and inter-hemispheric functional connectivity and increased intra-hemispheric functional connectivity ipsilateral to the seizure focus compared to normal controls. Specifically, several regions in the affected temporal lobe showed increased functional coupling with the ipsilateral insula and immediately neighboring subcortical regions. Additionally there was significantly decreased functional connectivity between regions in the affected temporal lobe and their contralateral homologous counterparts. Intriguingly, decreased local and inter-hemispheric connectivity was not limited or even maximal for the hippocampus or medial temporal region, which is the typical seizure onset region. Rather it also involved several regions in temporal neo-cortex, while also retaining specificity, with neighboring regions such as the amygdala remaining unaffected. These findings support a view of temporal lobe epilepsy as a disease of a complex functional network, with alterations that extend well beyond the seizure onset area, and the specificity of the observed connectivity changes suggests the possibility of a functional imaging biomarker for temporal lobe epilepsy.

It is well known that even under identical task conditions, there is a tremendous amount of trial-to-trial variability in both brain activity and behavioral output. Thus far the vast majority of event-related potential (ERP) studies investigating the relationship between trial-to-trial fluctuations in brain activity and behavioral performance have only tested a monotonic relationship between them. However, it was recently found that across-trial variability can correlate with behavioral performance independent of trial-averaged activity. This finding predicts a U- or inverted-U- shaped relationship between trial-to-trial brain activity and behavioral output, depending on whether larger brain variability is associated with better or worse behavior, respectively. Using a visual stimulus detection task, we provide evidence from human electrocorticography (ECoG) for an inverted-U brain-behavior relationship: When the raw fluctuation in broadband ECoG activity is closer to the across-trial mean, hit rate is higher and reaction times faster. Importantly, we show that this relationship is present not only in the post-stimulus task-evoked brain activity, but also in the pre-stimulus spontaneous brain activity, suggesting anticipatory brain dynamics. Our findings are consistent with the presence of stochastic noise in the brain. They further support attractor network theories, which postulate that the brain settles into a more confined state space under task performance, and proximity to the targeted trajectory is associated with better performance.

A widely held assumption is that spontaneous and task-evoked brain activity sum linearly, such that the recorded brain response in each single trial is the algebraic sum of the constantly changing ongoing activity and the stereotypical evoked activity. Using functional magnetic resonance imaging signals acquired from normal humans, we show that this assumption is invalid. Across widespread cortices, evoked activity interacts negatively with ongoing activity, such that higher prestimulus baseline results in less activation or more deactivation. As a consequence of this negative interaction, trial-to-trial variability of cortical activity decreases following stimulus onset. We further show that variability reduction follows overlapping but distinct spatial pattern from that of task-activation/deactivation and it contains behaviorally relevant information. These results favor an alternative perspective to the traditional dichotomous framework of ongoing and evoked activity. That is, to view the brain as a nonlinear dynamical system whose trajectory is tighter when performing a task. Further, incoming sensory stimuli modulate the brain's activity in a manner that depends on its initial state. We propose that across-trial variability may provide a new approach to brain mapping in the context of cognitive experiments.

When faced with ambiguous sensory inputs, subjective perception alternates between the different interpretations in a stochastic manner. Such multistable perception phenomena have intrigued scientists and laymen alike for over a century. Despite rigorous investigations, the underlying mechanisms of multistable perception remain elusive. Recent studies using multivariate pattern analysis revealed that activity patterns in posterior visual areas correlate with fluctuating percepts. However, increasing evidence suggests that vision--and perception at large--is an active inferential process involving hierarchical brain systems. We applied searchlight multivariate pattern analysis to functional magnetic resonance imaging signals across the human brain to decode perceptual content during bistable perception and simple unambiguous perception. Although perceptually reflective activity patterns during simple perception localized predominantly to posterior visual regions, bistable perception involved additionally many higher-order frontoparietal and temporal regions. Moreover, compared with simple perception, both top-down and bottom-up influences were dramatically enhanced during bistable perception. We further studied the intermittent presentation of ambiguous images--a condition that is known to elicit perceptual memory. Compared with continuous presentation, intermittent presentation recruited even more higher-order regions and was accompanied by further strengthened top-down influences but relatively weakened bottom-up influences. Taken together, these results strongly support an active top-down inferential process in perception.

RATIONALE: Analysis of local in vivo inflammation is relevant to the understanding of pathogenesis and disease progression in emphysema. Bronchial reactivity is an early marker of disease in asthma but the relevance of reactivity to the natural history of emphysema is not understood. We hypothesize that bronchial reactivity is a phenotype of early emphysema that might be related to the degree of inflammation in the lung. METHODS: Normal subjects were enrolled as part of a normal volunteer protocol. Emphysema subjects were identified from the NYU Lung Cancer Biomarker Center CT-scan screening cohort. All patients underwent spirometry, plethysmography, diffusion, and oscillometry, as well as bronchoscopy with bronchoalveolar lavage (BAL). Bronchial reactivity was assessed by changes in FEV1, V50 and R5 . From the BAL fluid, cell count differential was obtained, as well as measurement of 39 cytokines in concentrated BAL fluid with Luminex using Human Cytokine Panel I (Millipore). Results amongst the groups were compared with ANOVA and post-hoc LSD comparison. RESULTS: Twenty patients were available for analysis: Six subjects in the control group, 6 emphysema subjects without bronchial reactivity (BR-), and 8 emphysema subjects with bronchial reactivity (BR+). Baseline demographics and pertinent spirometry/oscillometry are listed in Table 1. Emphysema subjects were all GOLD stage 0 or 1. Post-bronchodilator spirometric and oscillometric parameters were not significantly different between BR- and BR+ emphysema groups. There were 28/39 cytokines with reliably measurable levels. Both emphysema groups had elevated neutrophils and higher degree of inflammation as compared to controls (significant data shown Table 1). However, the BR+ emphysema group evidenced higher degree of neutrophils, IL-6, IL-8, G-CSF, Eotaxin, GRO and Fractalkine as compared with the BR- emphysema group. CONCLUSION: These data suggest that in early emphysema a phenotype of proximal and/or distal bronchial reactivity is associated with an increased degree of inflammation as assessed by neutrophils and in vivo inflammatory cytokines. In contrast with early asthma, the phenotype of bronchial reactivity in early emphysema may be characterized by neutrophilic inflammation produced by increased IL-8 in the lung. The role of IL-6, G-CSF, Eotaxin, GRO and Fractalkine in producing emphysema related bronchial reactivity requires further investigation. (Table Presented)