Faculty Bibliography

Thalamocortical dynamics, the millisecond to second changes in activity of thalamocortical circuits, are central to perception, action and cognition. Generated by local circuitry and sculpted by neuromodulatory systems, these dynamics reflect the expression of vigilance states. In sleep, thalamocortical dynamics are thought to mediate "offline" functions including memory consolidation and synaptic scaling. Here, I discuss thalamocortical sleep dynamics and their modulation by the ascending arousal system and locally released neurochemicals. I focus on modulation of these dynamics by electrically silent astrocytes, highlighting the role of purinergic signaling in this glial form of communication. Astrocytes modulate cortical slow oscillations, sleep behavior, and sleep-dependent cognitive function. The discovery that astrocytes can modulate sleep dynamics and sleep-related behaviors suggests a new way of thinking about the brain, in which integrated circuits of neurons and glia control information processing and behavioral output.

Cirrhosis is an important and growing public health problem, affecting millions of Americans and many more people internationally. A pathological hallmark of the progression to cirrhosis is the development of liver fibrosis, so that monitoring the appearance and progression of liver fibrosis can be used to guide therapy. Here, we report a method to use magnetization-tagged magnetic resonance imaging to measure the cardiac-induced motion and deformation in the liver, as a means for noninvasively assessing liver stiffness, which is related to fibrosis. The initial results show statistically significant differences between healthy and cirrhotic subjects in the direct comparisons of the maximum displacement (mm), and the maximum (P1) and minimum (P2) two-dimensional strains, through the cardiac cycle (3.514 +/- 0.793, 2.184 +/- 0.611; 0.116 +/- 0.043, 0.048 +/- 0.011; -0.094 +/- 0.020, -0.041 +/- 0.015; healthy, cirrhosis, respectively; P < 0.005 for all). There are also significant differences in the displacement-normalized P1 and P2 strains (mm(-1) ) (0.030 +/- 0.008, 0.017 +/- 0.007; -0.024 +/- 0.006, -0.013 +/- 0.004; healthy, cirrhosis, respectively; P < 0.005 for all). Therefore, this noninvasive imaging-based method is a promising means to assess liver stiffness using clinically available imaging tools. Magn Reson Med, 2011. (c) 2011 Wiley-Liss, Inc

The present study examined the ability of 6-fluoronorepinephrine (6FNE), a full selective alpha-adrenoceptor agonist, to produce antidepressant-like effects in mice. The drug, administered in the 4th ventricle, produced marked anti-immobility effects at mid-dose range in the acute forced swim, tail suspension and repeated open-space forced swim tests with minimal effect on open-field motor activity and also reversed anhedonia following lipopolysaccharide administration. Its antidepressant effects were equal to or greater than that of an established systemic antidepressant, desmethylimipramine, given subacutely. Experiments with alpha-adrenoceptor antagonists indicated that the drug acts primarily via the alpha2-receptor in contrast to endogenous catecholamines which appear to control depressive behaviour primarily via the alpha1-receptor. Antidepressant activity declined at higher doses signifying a possible pro-depressant effect of one of the alpha-adrenoceptor subtypes. Compared to the selective alpha2-agonist, dexmedetomidine, 6FNE showed equivalent antidepressant action in the tail suspension test but appeared to have a greater efficacy or speed of action in the repeated open-space forced swim test which produces a more sustained depression. Studies of regional brain Fos expression induced during the antidepressant tests showed that 6FNE tended to inhibit neural activity in two stress-responsive regions (locus coeruleus and paraventricular hypothalamus) but to enhance activity in two areas involved in motivated behaviour (nucleus accumbens shell and lateral septal nucleus) producing a neural pattern consistent with antidepressant action. It is concluded that 6FNE elicits a rapid and effective antidepressant and anti-stress response that may compare favourably with available antidepressants

Functional stereotactic lesions in the central lateral nucleus of the medial thalamus have proved to be an effective treatment of neurogenic pain and other neurological disorders associated with thalamocortical dysrhythmia. The mechanisms underlying patient recovery after surgery are currently being explored using quantitative electroencephalography. Here we test the hypothesis that the particular role played by the non-specific medial thalamic nuclei in thalamocortical dysrhythmia is based on the divergent connectivity between these non-specific and reticular nuclei. We built a spiking computer model of the human thalamocortical system consisting of specific, non-specific and reticular thalamic nuclei. In our simulations of the thalamocortical system, deafferentation of peripheral thalamic afferents leads to hyperpolarization and subsequent bursting in the reticular nucleus. This provides strong inhibitory feedback to both the specific and the non-specific thalamic nuclei and initiates a feedback cycle of thalamic bursts in the theta frequency range. The divergent connections between the reticular and non-specific thalamic nuclei provide synchronization of the oscillating circuits. Functional silencing of the non-specific model nucleus limits reverberation and rescues the system from these oscillations. The same effect could be achieved by increasing the input to the non-specific nucleus from cortical areas. The model predicts that the invasiveness of functional neurosurgery can be reduced by targeting only deafferented areas in the medial nuclei as these are the key areas for generation and maintenance of pathological rhythms

Cardiac fibrosis occurs in a number of cardiovascular diseases associated with a high incidence of arrhythmias. A critical event in the development of fibrosis is the transformation of fibroblasts into an active phenotype or myofibroblast. This transformation results in functional changes including increased proliferation and changes in the release of signaling molecules and extracellular matrix deposition. Traditionally, fibroblasts have been considered to affect cardiac electrophysiology indirectly by physically isolating myocytes and creating conduction barriers. There is now increasing evidence that cardiac fibroblasts may play a direct role in modulating the electrophysiological substrate in diseased hearts. The purpose of this review is to summarize the functional changes associated with fibroblast activation, the membrane currents that have been identified in adult cardiac fibroblasts, and describe recent studies of fibroblast-myocyte electrical interactions with emphasis on the changes that occur with cardiac injury. Further analysis of fibroblast membrane electrophysiology and their interactions with myocytes will lead to a more complete understanding of the arrhythmic substrate. These studies have the potential to generate new therapeutic approaches for the prevention of arrhythmias associated with cardiac fibrosis

Risk avoidance is a hallmark of psychopathological conditions such as anxiety disorders. Yet few studies have examined its neural basis. The present work sought to identify the neural correlates of risk avoidance. While functional MRI scans were acquired, healthy adults (N=23) played a Wheel of Fortune game during which they chose to bet or pass on each of 104 proposed gamble trials. Participants also completed the Cognitive Appraisal of Risky Events (CARE, Fromme et al., 1997), a self-report measure of 'real world' risky behavior. As expected, decision-making was associated with activation, as measured by increased BOLD responses, of the striatum, insula, anterior cingulate cortex, dorsolateral prefrontal cortex, and parietal lobe. Risk avoidance during probabilistic trials (percent of trials passed) was significantly correlated with precuneus and striatal responses to trials with a certain outcome (No-Risk). Similarly, 'real world' risk avoidance, as measured by the CARE, was significantly correlated with precuneus activity during No-Risk trials. Collectively, these data suggest that precuneus and striatal responses to decision-making under certainty represent putative neural markers of risk avoidance in the laboratory and in the 'real world.' Further, they underline the need to extend neuroimaging research on risk avoidance, and associated anxiety disorders, to posterior cortical regions

Upon activation by nerve growth factor (NGF), TrkA is internalized, trafficked and sorted through different endosomal compartments. Proper TrkA trafficking and sorting are crucial events as alteration of these processes hinders NGF-mediated functions. However, it is not fully known which proteins are involved in the trafficking and sorting of TrkA. Here we report that Nedd4-2 regulates the trafficking of TrkA and NGF functions in sensory neurons. Depletion of Nedd4-2 disrupts the correct sorting of activated TrkA at the early and late endosome stages, resulting in an accumulation of TrkA in these compartments and, as a result of the reduced trafficking to the degradative pathway, TrkA is either reverted to the cell surface through the recycling pathway or retrogradely transported to the cell body. In addition, Nedd4-2 depletion enhances TrkA signaling and the survival of NGF-dependent dorsal root ganglion neurons, but not those of brain-derived neurotrophic factor-dependent neurons. Furthermore, neurons from a knock-in mouse expressing a TrkA mutant that does not bind Nedd4-2 protein exhibit increased NGF-mediated signaling and cell survival. Our data indicate that TrkA trafficking and sorting are regulated by Nedd4-2 protein

The ability to accurately infer functional connectivity between ensemble neurons using experimentally acquired spike train data is currently an important research objective in computational neuroscience. Point process generalized linear models and maximum likelihood estimation have been proposed as effective methods for the identification of spiking dependency between neurons. However, unfavorable experimental conditions occasionally results in insufficient data collection due to factors such as low neuronal firing rates or brief recording periods, and in these cases, the standard maximum likelihood estimate becomes unreliable. The present studies compares the performance of different statistical inference procedures when applied to the estimation of functional connectivity in neuronal assemblies with sparse spiking data. Four inference methods were compared: maximum likelihood estimation, penalized maximum likelihood estimation, using either l(2) or l(1) regularization, and hierarchical Bayesian estimation based on a variational Bayes algorithm. Algorithmic performances were compared using well-established goodness-of-fit measures in benchmark simulation studies, and the hierarchical Bayesian approach performed favorably when compared with the other algorithms, and this approach was then successfully applied to real spiking data recorded from the cat motor cortex. The identification of spiking dependencies in physiologically acquired data was encouraging, since their sparse nature would have previously precluded them from successful analysis using traditional methods.

The objective of this prospective observational study was to assess the association between dysrhythmia of EEG background (disturbance of cerebral connectivity) and sleep difficulties. Sixty children, aged 4 to 12 years, participated. Hospital records were reviewed, and sleep histories were obtained by interviewing the parents. EEGs of 39 subjects were normal, showed epileptiform activity, and/or mild to moderate background dysrhythmia. Severe unilateral dysrhythmia was noted in 6 and bilaterally in 15 EEGs, with all 15 children having profound neurodevelopmental disabilities and 14 of these 15 having long-standing severe chaotic sleep/wake patterns. Thus, there was a highly significant association between EEG evidence of severe bilateral dysrhythmia and chronic sleep/wake dysregulation. Unilateral dysrhythmia was not associated with sleep difficulties. This study delineates a specific sleep disorder in a group of children with marked neurodevelopmental disabilities and offers insight into how disturbed cerebral connectivity impacts the thalamocortical dynamics relating to neurodevelopmental disabilities, sleep, and melatonin production.