Faculty Bibliography

Neurons in the Primary Motor Cortex (MI) are known to form functional ensembles with one another in order to produce voluntary movement. Neural network changes during skill learning are thought to be involved in improved fluency and accuracy of motor tasks. Unforced errors during skilled tasks provide an avenue to study network connections related to motor learning. In order to investigate network activity in MI, microwires were implanted in the MI of cats trained to perform a reaching task. Spike trains from eight groups of simultaneously recorded cells (95 neurons in total) were acquired. A point process generalized linear model (GLM) was developed to assess simultaneously recorded cells for functional connectivity during reaching attempts where unforced errors or no errors were made. Whilst the same groups of neurons were often functionally connected regardless of trial success, functional connectivity between neurons was significantly different at fine time scales when the outcome of task performance changed. Furthermore, connections were shown to be significantly more robust across multiple latencies during successful trials of task performance. The results of this study indicate that reach-related neurons in MI form dynamic spiking dependencies whose temporal features are highly sensitive to unforced movement errors.

Background: Patients with familial dysautonomia (FD) fail to increase respiratory drive in response to low oxygen and high CO₂ levels. Many hypoventilate and have frequent apneic events during sleep, a time associated with an increased incidence of sudden death. To assess the need for non-invasive ventilation, patients with FD routinely undergo sleep studies with end-tidal CO₂ monitoring. Because most have severe lung disease, it is not known, however, whether end-tidal CO₂ levels accurately reflect arterial blood CO₂ levels. Methods: We studied 88 patients with FD (mean age 25 +/- 1, 45; females:43 males). We measured the partial pressure of CO₂ in blood obtained from the radial artery at the wrist (ABL80 FLEX, Radiometer, Denmark). End-tidal CO₂ was continuously sampled from a nasal canula (infrared analysis 5200 Ohmeda, USA). The average CO₂ value obtained over 10 full tidal breaths was used. All measurements were obtained during relaxed spontaneous breathing in the supine position. The relationship between end-tidal and arterial CO₂ measurements was examined using Pearson correlations. Results: All patients had a history of at least one aspiration pneumonia. The average partial pressure of oxygen in arterial blood was 87 +/- 2 mmHg. Thirty-one patients (36%) had arterial oxygen levels B80 mmHg. The average partial pressure of CO₂ was 43 +/- 0.4 mmHg (range 34-57 mmHg). Thirty-four patients (39%) had hypercapnia with CO₂ in arterial blood >=45 mmHg. Measurements of end-tidal CO₂ correlated tightly with CO₂ measured in arterial blood (y = 0.88x + 2.23, R² = 0.50, p<0.001). Conclusions: Our results show that in patients with FD, despite severe lung disease, the partial pressure of CO₂ measured in expired air (i.e. end tidal CO₂) accurately reflects the partial pressure ofCO₂ in arterial blood. Monitoring end tidal CO₂ is critically important to determine the potential role of apnea/hypoventilation in sudden death during sleep

Endothelial cells (ECs) are constantly exposed to blood flow-induced shear forces in the vessels and this is a major determinant of endothelial function. Ion channels have a major role in endothelial function and in the control of vascular tone. We hypothesized that shear force is a general regulator of ion channel expression, which will have profound effects on endothelial function. We examined this hypothesis using large-scale quantitative real-time RT-PCR. Human coronary artery ECs were exposed to two levels of flow-induced shear stress for 24 h, while control cells were grown under static conditions. The expression of ion channel subunits was compared between control and flow-adapted cells. We used primers against 55 ion channel and exchanger subunits and were able to detect 54 subunits. Five dyn/cm(2) of shear induced downregulation of 1 (NCX1) and upregulation of 18 subunits, including K(Ca)2.2, K(Ca)2.3, CX37, K(v)1.5 and HCN2. Fifteen dyn/cm(2) of shear stress induced the expression of 30 ion channel subunits, including K(Ca)2.3, K(Ca)2.2, CX37, K(ir)2.3 and K(Ca)3.1. Our data demonstrate that substantial remodeling of endothelial ion channel subunit expression occurs with flow adaptation and suggest that altered ion channel expression may significantly contribute to vascular pathology associated with flow-induced alterations

The glutamate neurotransmitter system has the potential to transform our knowledge of the pathophysiology of schizophrenia and help us identify potential treatment targets. In this section of the supplement, the dopamine system is first reviewed as it relates to schizophrenia and its treatment with the currently available antipsychotics, followed by a discussion of glutamate receptors and how they, too, can impact on positive, negative, and cognitive symptoms. Symptoms of schizophrenia can be theoretically explained by a hyper-dopaminergic state existing in the mesolimbic pathway and a hypodopaminergic state in the mesocortical pathways; the former results in positive symptoms and the latter leads to negative, cognitive, and affective symptoms. Current FDA-approved pharmacologic options for the treatment of schizophrenia involve dopamine blockade at the dopamine D2 receptor. Although commercially available antipsychotic agents have at least some degree of antagonism at the dopamine D2 receptor, there are some investigational agents that produce an antipsychotic effect in the absence of direct dopamine D2 receptor antagonism. The glutamate-dopamine model of schizophrenia offers new therapeutic targets, including NMDA agonists, glycine transport inhibitors, and metabotropic glutamate receptor agonists.

Recent studies have shown that immunotherapy clears amyloid beta (Abeta) plaques and reduces Abeta levels in mouse models of Alzheimer's disease (AD), as well as in AD patients. Tangle pathology is also relevant for the neurodegeneration in AD, and our studies have shown that active immunization with an AD related phospho-tau peptide reduces aggregated tau within the brain and slows the progression of tauopathy-induced behavioral impairments. Thus, clearance of neurofibrillary tangles and/or their precursors may reduce synaptic and neuronal loss associated with AD and other tauopathies. So far the mechanisms involved in antibody-mediated clearance of tau pathology are yet to be elucidated. In this study we have used a mouse brain slice model to examine the uptake and localization of FITC labeled anti-tau antibodies. Confocal microscopy analysis showed that the FITC labeled anti-tau antibody co-stained with phosphorylated tau, had a perinuclear appearance and co-localized with markers of the endosomal/lysosomal pathway. Additionally, tau and FITC-IgG were found together in an enriched lysosome fraction. In summary, antibody-mediated clearance of intracellular tau aggregates appears to occur via the lysosomal pathway

Consider the decomposition of a signal into features that undergo transformations drawn from a continuous family. Current methods discretely sample the transformations and apply sparse recovery methods to the resulting finite dictionary. These methods do not exploit the underlying continuous structure, thereby limiting the ability to produce sparse solutions. Instead, we employ interpolation functions which linearly approximate the manifold of scaled and transformed features. Coefficients are interpreted as interpolation weights, and we formulate a convex optimization problem for obtaining them, enforcing both reconstruction accuracy and sparsity. We compare our method, which we call continuous basis pursuit (CBP) with the standard basis pursuit approach on a sparse deconvolution task. CBP yields substantially sparser solutions without sacrificing accuracy, and does so with a smaller dictionary. We conclude that for signals generated by transformation-invariant processes, a representation that explicitly accommodates the transformation(s) can yield sparser and more interpretable decompositions.