Chronic Recordings in Transgenic Mice

Excerpt

Previous chapters of this book have highlighted technical advances made in recording ensembles of neurons in primates and rats. These advances have created a novel window through which to study brain function, allowing us to interpret an ever-growing body of data describing how the normal brain operates. On the other hand, these techniques have only provided a limited picture of how alterations in brain function generate behavioral pathology, requiring new recording techniques to be manufactured. In this chapter, we describe a novel method for extending previously described electrophysiological recording techniques for use in transgenic mice. This fusion of genetic and neuroscience technologies provides a promising tool for elucidating how changes in gene expression result in the behavioral alterations characteristic of central nervous system (CNS) disease.

During the course of the last century, great strides were made in treating diseases involving the CNS. Much of this progress resulted from an explosion of neuroscience research, which led to the discovery of action potentials, neuromodulators, and the principles of organization of neural circuits. Although these findings facilitated the development of drugs to treat neurological and psychiatric illnesses such as schizophrenia, Alzheimer’s disease, Parkinson’s disease, and depression, little headway was made in elucidating the pathophysiological mechanisms associated with many of these diseases. Thus, treatment options typically focused on managing symptoms, and not on curing the underlying disease. Currently, one of the primary challenges of behavioral brain research lies in the complexity of understanding how changes in patterns of gene expression alter the spatiotemporal firing of widely distributed populations of single neurons that define the large-scale neural interactions underlying the generation of behavior. This issue is further complicated by ethical concerns associated with genetic manipulation in humans and limitations inherent to the techniques currently used to study electrophysiological changes in the brain.

The primary techniques used to study human brain activity are functional magnetic resonance imaging (fMRI) and electroencephalography (EEG). Unfortunately, fMRI, which measures changes in blood flow resulting from activation of neural networks, has significant limitations in temporal resolution, and EEG, which utilizes scalp electrodes to measure brain activity, has significant limitations in spatial resolution. Although intraparenchymal recording protocols can be used to enhance spatial and temporal resolution of brain activity, these techniques are invasive and are thus not typically suitable for studying neurological and psychiatric illness in human populations. To overcome these issues, we have created a protocol for chronically recording brain activity in animal models of CNS disease.

Recently, transgenic mice have gained greater acceptance as models of CNS disease (Dennis 2005). These genetically modified mice display behavioral alterations similar to those observed in humans with neurological or psychiatric illness, and recapitulate several endophenotypes characteristic of these diseases. By chronically implanting these mice with intraparenchymal microelectrode arrays, one is able to assess how changes in gene expression result in changes in neural ensemble firing patterns. Moreover, one can conduct longitudinal observations in animals given drugs used to treat the CNS diseases they model, providing a detailed picture of how changes in neuronal firing patterns result in neurological and psychiatric pathology.