Faculty Bibliography

The prevalence of atrial conduction defects and sinus node dysfunction increases with age. These age-related changes may play a critical role in establishing the substrate for the development of atrial fibrillation (AF), the most common sustained arrhythmia. Despite the association between atrial arrhythmias and age, little is known of the mechanisms that underlie changes in atrial electrophysiological function. Ongoing studies in our laboratory are focused on determining the mechanisms of atrial conduction defects associated with aging and disease. The purpose of this report is to present some initial studies of the murine sinus node and the approach we have taken to quantify conduction at the site of impulse initiation

The central goal of modern science that evolved during the Enlightenment was the empirical reduction of uncertainty by experimental inquiry. Although there have been challenges to this view in the physical sciences, where profoundly indeterminate events have been identified at the quantum level, the presumption that physical phenomena are fundamentally determinate seems to have defined modern behavioral science. Programs like those of the classical behaviorists, for example, were explicitly anchored to a fully deterministic worldview, and this anchoring clearly influenced the experiments that those scientists chose to perform. Recent advances in the psychological, social, and neural sciences, however, have caused a number of scholars to begin to question the assumption that all of behavior can be regarded as fundamentally deterministic in character. Although it is not yet clear whether the generative mechanisms for human and animal behavior will require a philosophically indeterminate approach, it is clear that behavioral scientists of all kinds are beginning to engage the issues of indeterminacy that plagued physics at the beginning of the twentieth century.

There is increasing evidence that human cognitive functions can be addressed from a robust neuroscience perspective. In particular, the distributed coherent electrical properties of central neuronal ensembles are considered to be a promising avenue of inquiry concerning global brain functions. The intrinsic oscillatory properties of neurons (Llinas, R. (1988) The intrinsic electrophysiological properties of mammalian neurons: Insights into central nervous system function. Science, 242: 1654-1664), supported by a large variety of voltage-gated ionic conductances are recognized to be the central elements in the generation of the temporal binding required for cognition. Research in neuroscience further indicates that oscillatory activity in the gamma band (25-50Hz) can be correlated with both sensory acquisition and pre-motor planning, which are non-continuous functions in the time domain. From this perspective, gamma-band activity is viewed as serving a broad temporal binding function, where single-cell oscillators and the conduction time of the intervening pathways support large multicellular thalamo-cortical resonance that is closely linked with cognition and subjective experience. Our working hypothesis is that although dedicated units achieve sensory processing, the cognitive binding process is a common mechanism across modalities. Moreover, it is proposed that such time-dependent binding when altered, will result in modifications of the sensory motor integration that will affect and impair cognition and conscious perception

Molecular transport in brain extracellular space (ECS) is hindered by the structure of the tissue. Diffusion analysis of small extracellular markers quantifies tissue hindrance, expressed as tortuosity lambda = (D/D*)(1/2), where D is the free diffusion coefficient and D* is the effective diffusion coefficient in tissue. In healthy brain, lambda is approximately 1.6, but the nature of this parameter is poorly understood. We report that the stratum radiatum of the hippocampal CA1 region in vitro, previously shown to be anisotropic (i.e., different along the x-, y-, and z-axes) in in vivo study, is isotropic like somatosensory neocortex but has a reduced lambda. Diffusion of fluorophore-labeled dextran (f-dex, M(r) 3,000) and tetramethylammonium (TMA(+), M(r) 74) was measured in rat brain slices (400 mum) using integrative optical imaging (IOI) and real-time iontophoresis (RTI), respectively. In the stratum radiatum, diffusion of f-dex was similar along the x-, y-, and z-axes (lambda(x), lambda(y); lambda(z) were 1.55, 1.53, and 1.55), but the tortuosity was significantly lower than in the neocortex, where lambda = 1.81. This finding was confirmed by the RTI method, which measured lambda with TMA(+), a much smaller molecule, and determined volume fraction alpha, the proportion of tissue occupied by the ECS. In stratum radiatum, lambda(x), lambda(y), and lambda(z) were 1.47, 1.44, and 1.46, while in neocortex, lambda was 1.65. The ECS volume fraction was similar (0.24) in both regions. It is proposed that in the hippocampus, low lambda reflects a reduced occurrence of concave extracellular microdomains, referred to as dead spaces, which increase tortuosity by transient trapping of markers. Functionally, a low lambda may permit structural plasticity and facilitate extrasynaptic communication. It may also enhance the spread of neuroactive substances and thus contribute to the sensitivity of the hippocampal CA1 region to ischemia and epilepsy