Dr Luebke's laboratory is interested in the electrophysiological and morphological properties of neocortical neurons in the rodent and primate prefrontal cortex across the lifespan. Our current work on neocortical pyramidal cells is divided into three areas:

1. Studies of intrinsic membrane properties (eg. action potentials and ionic currents).
2. Studies of glutamatergic and GABAergic synaptic response properties.
3. Studies of detailed morphological properties (eg. dendritic architecture and spines).

Pyramidal Cells of the Prefrontal Cortex.
Working memory, which is essential for abilities such as abstract thinking, problem solving, and cognitive flexibility, is mediated in large part by pyramidal cells of the prefrontal cortex (PFC). We are interested in determining the basic properties of layer 2/3 and layer 5 pyramidal cells in both young and aged subjects. We employ whole-cell patch clamp and intracellular dye-filling techniques to examine the detailed properties of individual pyramidal cells in in vitro slices (see Image 1 and Image 2).

Effects of Normal Aging on Pyramidal Cells of the Prefrontal Cortex in the Rhesus Monkey.
Working memory is significantly impaired with normal aging in a large proportion of humans and non-human primates; currently the specific neural substrates of age-related decline in PFC function are not known. Given our aging population, this is a highly relevant question that we directly address in our studies, which employ a unique experimental model- the behaviorally characterized rhesus monkey. Information during working memory tasks is encoded in a temporally dynamic and specific manner by the action potential (AP) firing rates of layer 3 pyramidal cells in the PFC, and we have shown that there is a significant age-related increase in the firing rates of these cells in vitro, and their firing rates are significantly associated with cognitive performance. Our current research goal is to comprehensively and simultaneously examine, within individual pyramidal cells, age-related alterations in interrelated cellular properties (ionic currents, synaptic responses, morphology), which likely contribute to functionally significant alterations in firing rate. Aged and young rhesus monkeys are assessed on a battery of cognitive tasks, enabling determination of degree of cognitive impairment. Whole-cell patch-clamp recordings and Lucifer Yellow (LY) filling of layer 3 pyramidal cells in PFC slices prepared from these monkeys are then employed in 3 highly integrated areas of investigation. First, intrinsic membrane and AP firing properties are assessed with current-clamp recordings; subsequently, currents that influence the temporal pattern of AP firing, (IC, IAHP, sIAHP and Ih), are examined with voltage-clamp analyses. Second, voltage-clamp recordings are used to assess age-related changes glutamatergic and GABAergic postsynaptic currents in these cells. Third, we explore whether there are age-related changes in the detailed dendritic architecture and dendritic spines of LY filled pyramidal cells. Data from each of these areas are cross-correlated and also correlated with cognitive performance scores within the aged group of subjects. This multi-faceted approach will provide unique information on the effects of age on diverse but interrelated cellular properties within individual neurons. Such information is vital to developing an understanding of the cellular mechanisms of cognitive decline and a prerequisite to future development of therapeutic interventions.