Faculty Bibliography

In most sensory systems, the sensory cortex is the place where sensation approaches perception. As described in this review, olfaction is no different. The olfactory system includes both primary and higher order cortical regions. These cortical structures perform computations that take highly analytical afferent input and synthesize it into configural odor objects. Cortical plasticity plays an important role in this synthesis and may underlie olfactory perceptual learning. Olfactory cortex is also involved in odor memory and association of odors with multimodal input and contexts. Finally, the olfactory cortex serves as an important sensory gate, modulating information throughput based on recent experience and behavioral state

Ion-selective microelectrodes (ISMs) have been used extensively in neurophysiological studies. ISMs selective for H(+) and Ca(2+) are notable for their sensitivity and selectivity, but suffer from a slow response time, and susceptibility to noise because of the high electrical resistance of the respective ion exchange cocktails. These drawbacks can be overcome by using a 'coaxial' or 'concentric' inner micropipette to shunt the bulk of the ion exchanger resistance. This approach was used decades ago to record extracellular [Ca(2+)] transients in cat cortex, but has not been subsequently used. Here, we describe a method for the rapid fabrication of concentric pH- and Ca(2+)-selective microelectrodes useful for extracellular studies in brain slices or other work in vitro. Construction was simplified compared with previous implementations, by using commercially available, thin-walled borosilicate glass, drawing an outer barrel with a rapid taper (similar to a patch pipette), and by use of a quick and reliable silanization procedure. Using a piezoelectric stepper to effect a rapid solution change, the response time constants of the concentric pH and Ca(2+)-electrodes were 14.9 +/- 1.3 and 5.3 +/- 0.90 ms, respectively. Use of these concentric ISMs is demonstrated in rat hippocampal slices. Activity-dependent, extracellular pH, and [Ca(2+)] transients are shown to arise two- to threefold faster, and attain amplitudes two- to fourfold greater, when recorded by concentric versus conventional ISMs. The advantage of concentric ISMs for studies of ion transport and ion diffusion is discussed

Evidence from a variety of recording methods suggests that many areas of the brain are far more sparsely active than commonly thought. Here, we review experimental findings pointing to the existence of neurons which fire action potentials rarely or only to very specific stimuli. Because such neurons would be difficult to detect with the most common method of monitoring neural activity in vivo-extracellular electrode recording-they could be referred to as "dark neurons," in analogy to the astrophysical observation that much of the matter in the universe is undetectable, or dark. In addition to discussing the evidence for largely silent neurons, we review technical advances that will ultimately answer the question: how silent is the brain?

More than 50 years have passed since the first recording of neuronal responses to an odor stimulus from the primary olfactory brain area, the main olfactory bulb. During this time very little progress has been achieved in understanding neuronal dynamics in the olfactory bulb in awake behaving animals, which is very different from that in anesthetized preparations. In this paper we formulate a new framework containing the main reasons for studying olfactory neuronal dynamics in awake animals and review advances in the field within this new framework.

Regulation of cell survival decisions and neuronal plasticity by neurotrophins are mediated by two classes of receptors, Trks (tropomyosin receptor kinases) and p75, the first discovered member of the tumour necrosis factor receptor superfamily. The p75 receptor participates with the TrkA receptor in the formation of high-affinity nerve growth factor-binding sites to promote survival under limiting concentrations of neurotrophins. Activation of Trk receptors leads to increased phosphorylation of Shc (Src homology and collagen homology), phospholipase C-gamma and novel adaptor molecules, such as the ARMS (ankyrin-rich membrane spanning)/Kidins220 protein. Small ligands that interact with G-protein-coupled receptors can also activate Trk receptor kinase activity. Transactivation of Trk receptors and their downstream signalling pathways raise the possibility of using small molecules to elicit neuroprotective effects for the treatment of neurodegenerative diseases. Like amyloid precursor protein and Notch, p75 is a substrate for gamma-secretase cleavage. The p75 receptor undergoes an alpha-secretase-mediated release of the extracellular domain followed by a gamma-secretase-mediated intramembrane cleavage. Cleavage of p75 may represent a general mechanism for transmitting signals as an independent receptor and as a co-receptor for other signalling systems

Intracellular Ca2+ levels rapidly rise following cross-linking of the T-cell receptor (TCR) and function as a critical intracellular second messenger in T-cell activation. It has been relatively under appreciated that K+ channels play an important role in Ca2+ influx into T lymphocytes by helping to maintain a negative membrane potential which provides an electrochemical gradient to drive Ca2+ influx. Here we show that the Ca2+-activated K+ channel, KCa3.1, which is critical for Ca2+ influx in reactivated naive T cells and central memory T cells, requires phosphatidylinositol-3 phosphatase [PI(3)P] for activation and is inhibited by the PI(3)P phosphatase myotubularin-related protein 6 (MTMR6). Moreover, by inhibiting KCa3.1, MTMR6 functions as a negative regulator of Ca2+ influx and proliferation of reactivated human CD4 T cells. These findings point to a new and unexpected role for PI(3)P and the PI(3)P phosphatase MTMR6 in the regulation of Ca2+ influx in activated CD4 T cells and suggest that MTMR6 plays a critical role in setting a minimum threshold for a stimulus to activate a T cell

Cardiac KATP channels are formed by Kir6.2 and SUR2A subunits. We produced transgenic mice which express dominant negative Kir6.x pore-forming subunits (Kir6.1-AAA or Kir6.2-AAA) in cardiac myocytes by driving their expression with the alpha-myosin heavy chain promoter. Weight gain and development after birth of these mice were similar to wild-type mice, but an increased mortality was noted after the age of 4-5 months. Transgenic mice lacked cardiac KATP channel activity as assessed with patch clamp techniques. Consistent with a decreased current density observed at positive voltages, the action potential duration was increased in these mice. Some myocytes developed early afterdepolarizations following isoproterenol treatment. Hemodynamic measurements revealed no significant effects on ventricular function (apart from a slightly elevated heart rate) whereas in-vivo electrophysiological recordings revealed a prolonged ventricular effective refractory period in transgenic mice. The transgenic mice tolerated stress less well as evident from treadmill stress tests. The pro-arrhythmogenic features and lack of adaptation to a stress response in transgenic mice suggests that these features are intrinsic to the myocardium and that KATP channels in the myocardium have an important role in protecting the heart from lethal arrhythmias and adaptation to stress situations

Speckle-field long- and short-exposure spatial correlation characteristics for target-in-the-loop (TIL) laser beam propagation and scattering in atmospheric turbulence are analyzed through the use of two different approaches: the conventional Monte Carlo (MC) technique and the recently developed brightness function (BF) method. Both the MC and the BF methods are applied to analysis of speckle-field characteristics averaged over target surface roughness realizations under conditions of 'frozen' turbulence. This corresponds to TIL applications where speckle-field fluctuations associated with target surface roughness realization updates occur within a time scale that can be significantly shorter than the characteristic atmospheric turbulence time. Computational efficiency and accuracy of both methods are compared on the basis of a known analytical solution for the long-exposure mutual correlation function. It is shown that in the TIL propagation scenarios considered the BF method provides improved accuracy and requires significantly less computational time than the conventional MC technique. For TIL geometry with a Gaussian outgoing beam and Lambertian target surface, both analytical and numerical estimations for the speckle-field long-exposure correlation length are obtained. Short-exposure speckle-field correlation characteristics corresponding to propagation in 'frozen' turbulence are estimated using the BF method. It is shown that atmospheric turbulence-induced static refractive index inhomogeneities do not significantly affect the characteristic correlation length of the speckle field, whereas long-exposure spatial correlation characteristics are strongly dependent on turbulence strength

While the classical pathway of NF-kappaB activation plays critical roles in a wide range of biological processes, the more recently described 'non-canonical' NF-kappaB pathway has important but more restricted roles in both normal and pathological processes. The non-canonical NF-kappaB pathway, based on processing of the nf-kappab2 gene product p100 to generate p52, appears to be involved in B-cell maturation and lymphoid development. Deregulated activation of this pathway has been observed in a variety of malignant and autoimmune diseases, thus inhibitors that specifically target p100 processing might be predicted to have potential roles as immunomodulators and in the therapy of malignant diseases. We review current understandings of NF-kappaB activation, particularly the mechanisms of p100 processing under both physiological and pathological conditions

Reactive oxygen species (ROS) are required in a number of critical cellular signaling events, including those underlying hippocampal synaptic plasticity and hippocampus-dependent memory; however, the source of ROS is unknown. We previously have shown that NADPH oxidase is required for N-methyl-D-aspartate (NMDA) receptor-dependent signal transduction in the hippocampus, suggesting that NADPH oxidase may be required for NMDA receptor-dependent long-term potentiation (LTP) and hippocampus-dependent memory. Herein we present the first evidence that NADPH oxidase is involved in hippocampal synaptic plasticity and memory. We have found that pharmacological inhibitors of NADPH oxidase block LTP. Moreover, mice that lack the NADPH oxidase proteins gp91(phox) and p47(phox), both of which are mouse models of human chronic granulomatous disease (CGD), also lack LTP. We also found that the gp91(phox) and p47(phox) mutant mice have mild impairments in hippocampus-dependent memory. The gp91(phox) mutant mice exhibited a spatial memory deficit in the Morris water maze, and the p47(phox) mutant mice exhibited impaired context-dependent fear memory. Taken together, our results are consistent with NADPH oxidase being required for hippocampal synaptic plasticity and memory and are consistent with reports of cognitive dysfunction in patients with CGD