News and Publications

In Vivo Neurophysiology: Functional Correlates of CNS Disease

J.L. Giacchino, S.J. Henriksen, R.-S. Lee, P. Griffin

Our previous investigations on the mechanisms of addiction focused on the neuronal pathways involved in cognition, memory, and learning. Neuronal circuits of the corticolimbic system may play important roles not only in substance abuse but also in dementing neurodegenerative diseases and aging. Specifically, alterations in the neurophysiologic and neuropharmacologic characteristics of the hippocampal formation and the prefrontal cortex may underlie cognitive impairment associated with these processes. Clinical evidence suggests that these brain areas are involved in Alzheimer's disease and in the development of age-related memory impairment.

To elucidate the neuronal correlates of these phenomena, we are examining the function of corticolimbic neuronal networks in aged rats and in transgenic mouse models of Alzheimer's disease. Our goals are to clarify alterations in neurotransmission and synaptic plasticity associated with age and pathologic changes that may contribute to cognitive dysfunction. We are also evaluating the effects of nicotine, a cholinergic agonist, in these systems.

Using single-cell electrophysiologic techniques in both anesthetized and unanesthetized rats, we examined spontaneous and evoked activity in neurons in the medial prefrontal cortex. We found significant age-related changes in neuronal activity. Induction and maintenance of long-term potentiation, a putative neurophysiologic model of memory, are markedly impaired in aged rats, an effect that preliminary data suggest may be ameliorated by administration of systemic nicotine. Furthermore, although nicotine increases neuronal firing in both anesthetized and unanesthetized, freely moving rats, it potentiates afferent-evoked activation of limbic-cortical circuits only in aged rats. Studies in progress target how alterations in glutamatergic and cholinergic systems might contribute to defective synaptic function associated with aging.

In collaboration with scientists at Novartis and Athena Neurosciences, Inc., we have begun electrophysiologic evaluations of hippocampal neuronal networks in animal models of Alzheimer's disease. We use transgenic mice that overexpress different genetic mutations of the ß-amyloid precursor protein. These mutations cause the development of progressive pathologic changes in the CNS similar to the changes observed in Alzheimer's disease. Investigations of alterations in hippocampal and cortical neurotransmission in these models include evaluations of synaptic plasticity and functional assessment of specific endogenous neurochemical systems. These studies will provide insight into the nature of the neurophysiologic perturbations that underlie this neurodegenerative disease and may assist in the development of new therapeutic strategies.

PUBLICATIONS

Giacchino, J.L., Henriksen, S.J. Opioid effects on activation of neurons in the medial prefrontal cortex. Prog. Neuropsychopharm. Biol. Psychiatry, in press.

Lee, R.-S., Criado, J.R., Steffensons, S.C., Giacchino, J.L., Griffin, P., Casalman, S., Berg, G., Henriksen, S.J. Electrophysiological substrates of heroin self-administration. NIDA Res. Monogr. 178:1165, 1998.