Faculty Bibliography

Previous studies have shown that a cellular inflammatory response is initiated, and inflammatory cytokines are synthesized, following experimental spinal cord injury (SCI). In the present study, we tested the hypothesis that the complement cascade, a major component of both the innate and adaptive immune response, is also activated following experimental SCI. We investigated the pathways, cellular localization, timecourse, and degree of complement activation in rat spinal cord following acute contusion-induced SCI using the New York University (NYU) weight drop impactor. Mild and severe injuries (12.5 and 50 mm drop heights) at 1, 7, and 42 days post injury time points were evaluated. Classical (C1q and C4), alternative (Factor B) and terminal (C5b-9) complement pathways were strongly activated within 1 day of SCI. Complement protein immunoreactivity was predominantly found in cell types vulnerable to degeneration, neurons and oligodendrocytes, and was not generally observed in inflammatory or astroglial cells. Surprisingly, immunoreactivity for complement proteins was also evident 6 weeks after injury, and complement activation was observed as far as 20 mm rostral to the site of injury. Axonal staining by C1q and Factor B was also observed, suggesting a potential role for the complement cascade in demyelination or axonal degeneration. These data support the hypothesis that complement activation plays a role in SCI

The importance of long-term synaptic plasticity as a cellular substrate for learning and memory is well established. By contrast, little is known about how learning and memory are regulated by voltage-gated ion channels that integrate synaptic information. We investigated this question using mice with general or forebrain-restricted knockout of the HCN1 gene, which we find encodes a major component of the hyperpolarization-activated inward current (Ih) and is an important determinant of dendritic integration in hippocampal CA1 pyramidal cells. Deletion of HCN1 from forebrain neurons enhances hippocampal-dependent learning and memory, augments the power of theta oscillations, and enhances long-term potentiation (LTP) at the direct perforant path input to the distal dendrites of CA1 pyramidal neurons, but has little effect on LTP at the more proximal Schaffer collateral inputs. We suggest that HCN1 channels constrain learning and memory by regulating dendritic integration of distal synaptic inputs to pyramidal cells

BACKGROUND: At the mitral annulus-aorta (MA-Ao) junction, the left atrium is continuous through the subaortic curtain with the musculature of the anterior mitral leaflet. Under experimental conditions, this region can generate abnormal electrical activity. In patients with left atrial tachycardia, we investigated whether this region could be the source of this arrhythmia. METHODS AND RESULTS: In 10 (28%) of 35 consecutive patients with left atrial tachycardia, the arrhythmia originated from the MA-Ao junction. Sustained, self-limited episodes of atrial tachycardia (cycle length, 340+/-56 ms; duration, 125+/-69 seconds) were repeatedly induced. Prematurity of the extrastimulus and time to first atrial tachycardia complex were directly correlated (R=0.66; P<0.001). During tachycardia, bipolar electrograms at the earliest site preceded onset of the P wave by 44+/-14 ms and were of longer duration and lower amplitude than those recorded from nearby left atrial sites (52+/-8 versus 24+/-4 ms, P<0.001; and 0.53+/-0.08 versus 3.45+/-0.96 mV, respectively; P<0.001). Ablation eliminated the tachycardia with no recurrence after a mean follow-up of 24+/-19 months. A comparative study in mouse embryos demonstrated the presence of the developing specialized conduction system in the MA-Ao region starting at embryonic age 11.5. CONCLUSIONS: The MA-Ao junction can be a frequent source of left atrial tachycardia. This previously unrecognized site of origin may explain why catheter ablation has been less successful in eliminating left versus right atrial tachycardias. Remnants of the developing specialized conduction system could be the underlying substrate of this arrhythmia

Connexin43 (Cx43), the predominant ventricular gap junction protein, is critical for maintaining normal cardiac electrical conduction, and its absence in the mouse heart results in sudden arrhythmic death. The mechanisms linking reduced Cx43 abundance in the heart and inducibility of malignant ventricular arrhythmias have yet to be established. In this report, we investigate arrhythmic susceptibility in a murine model genetically engineered to express progressively decreasing levels of Cx43. Progressively older cardiac-restricted Cx43 conditional knockout (CKO) mice were selectively bred to produce a heart-specific Cx43-deficient subline ('O-CKO' mice) in which the loss of Cx43 in the heart occurs more gradually. O-CKO mice lived significantly longer than the initial series of CKO mice but still died suddenly and prematurely. At 25 days of age, cardiac Cx43 protein levels decreased to 59% of control values (P<0.01), but conduction velocity was not significantly decreased and no O-CKO mice were inducible into sustained ventricular tachyarrhythmias. By 45 days of age, cardiac Cx43 abundance had decreased in a heterogeneous fashion to 18% of control levels, conduction velocity had slowed to half of that observed in control hearts, and 80% of O-CKO mice were inducible into lethal tachyarrhythmias. Enhanced susceptibility to induced arrhythmias was not associated with altered invasive hemodynamic measurements or changes in ventricular effective refractory period. Thus, moderately severe reductions in Cx43 abundance are associated with slowing of impulse propagation and a dramatic increase in the susceptibility to inducible ventricular arrhythmias

The pinceau is a cerebellar structure formed by descending GABA-ergic basket cell axonal terminals converging on the initial axonal segment of Purkinje cell. Although basket cells exert a powerful inhibitory influence on the output of the cerebellar cortex, the function and mode of action of the pinceau are not understood because the majority of basket cell axons fail to make identifiable synaptic contacts with the Purkinje cell axon. Several proteins were previously reported to cluster specifically in this area, including a number of voltage-activated potassium channel subunits. In this study, we used immunohistochemistry, electron microscopy, and electron tomography to examine the ultrastructural localization of a novel voltage-gated potassium channel subunit, Kv3.2, in the pinceau. We found strong, selective localization of Kv3.2 to basket cell axons. Additionally, because potassium buffering is often conducted through water channels, we studied the extent of a brain-specific water channel, aquaporin-4 (AQP4), using confocal and electron microscopy. As expected, we found AQP4 was heavily localized to astrocytic processes of the pinceau. The abundance of potassium channels and AQP4 in this area suggests rapid ionic dynamics in the pinceau, and the unusual, highly specialized morphology of this region implies that the structural features may combine with the molecular composition to regulate the microenvironment of the initial segment of the Purkinje cell axon

Wild-type alpha-synuclein, a protein of unknown function, has received much attention because of its involvement in a series of diseases that are known as synucleinopathies. We find that long-lasting potentiation of synaptic transmission between cultured hippocampal neurons is accompanied by an increase in the number of alpha-synuclein clusters. Conversely, suppression of alpha-synuclein expression through antisense nucleotide and knockout techniques blocks the potentiation, as well as the glutamate-induced increase in presynaptic functional bouton number. Consistent with these findings, alpha-synuclein introduction into the presynaptic neuron of a pair of monosynaptically connected cells causes a rapid and long-lasting enhancement of synaptic transmission, and rescues the block of potentiation in alpha-synuclein null mouse cultures. Also, we report that the application of nitric oxide (NO) increases the number of alpha-synuclein clusters, and inhibitors of NO-synthase block this increase, supporting the hypothesis that NO is involved in the enhancement of the number of alpha-synuclein clusters. Thus, alpha-synuclein is involved in synaptic plasticity by augmenting transmitter release from the presynaptic terminal

Muscle, cutaneous and joint afferents continuously signal information about the position and movement of individual joints. How does the nervous system extract more global information, for example about the position of the foot in space? To study this question we used microelectrode arrays to record impulses simultaneously from up to 100 discriminable nerve cells in the L6 and L7 dorsal root ganglia (DRG) of the anaesthetized cat. When the hindlimb was displaced passively with a random trajectory, the firing rate of the neurones could be predicted from a linear sum of positions and velocities in Cartesian (x, y), polar or joint angular coordinates. The process could also be reversed to predict the kinematics of the limb from the firing rates of the neurones with an accuracy of 1-2 cm. Predictions of position and velocity could be combined to give an improved fit to limb position. Decoders trained using random movements successfully predicted cyclic movements and movements in which the limb was displaced from a central point to various positions in the periphery. A small number of highly informative neurones (6-8) could account for over 80% of the variance in position and a similar result was obtained in a realistic limb model. In conclusion, this work illustrates how populations of sensory receptors may encode a sense of limb position and how the firing of even a small number of neurones can be used to decode the position of the limb in space.

Recent advances in CT technology have allowed the development of systems with multiple rows of detectors and rapid rotation. These new imaging systems have permitted the acquisition of high resolution, spatially registered, and cardiac gated 3D heart data. In this paper, we present a framework that makes use of these data to reconstruct the 3D cardiac anatomy with resolutions that were not previously possible. We use an improved 3D hybrid segmentation framework which integrates Gibbs prior models, deformable models, and the marching cubes method to achieve a sub-pixel accuracy of the reconstruction of cardiac objects. To improve the convergence at concavities on the object surface, we introduce a new type of external force, which we call the scalar gradient. The scalar gradient is derived from a gray level edge map using local configuration information and can help the deformable models converge into deep concavities on object's surface. The 3D segmentation and reconstruction have been conducted on 8 high quality CT data sets. Important features, such as the structure of papillary muscles, have been well captured, which may lead to a new understanding of the cardiac anatomy and function. All experimental results have been evaluated by clinical experts and the validation shows the method has a very strong performance

In this study we have developed and tested a novel pain questionnaire to measure the pain experienced by patients with oral squamous cell carcinoma. The questionnaire consisted of 8 questions rated by the patient on a visual analog scale. Patients completed the questionnaire at the time of initial presentation before surgical treatment. None of the patients were taking analgesics. The responses were then scored and compiled with patient data and pathology reports. Of the 15 completed questionnaires, 14 patients reported some level of functional restriction from pain (mean, 46.6 +/- 25.2, scale of 0 to 100 mm). On average, patients experienced significantly higher function-related, rather than spontaneous, pain intensity and sharpness. Men (n = 8) had a significantly higher level of function-related pain intensity and sharpness than women had (n = 7). There was a strong correlation between nodal disease and increased levels of spontaneous intensity, sharpness, throbbing, and overall functional restriction. PERSPECTIVE: The results of this study indicate the heterogeneous nature and function dependence of oral cancer pain. The questionnaire we have developed in this study will allow for correlations between pain parameters and specific tumor biology in future studies