News and Publications

Neurophysiology of Learning and Memory

S.C. Steffensen, S.J. Henriksen, J.R. Criado, R.A. Gallegos, R.-S. Lee, T. Krucker, R.H. Purdy, V.M. Pickel,* A.L. Svingos

*Cornell University Medical College, New York, NY

NEUROPHYSIOLOGY OF ALCOHOL ADDICTION

According to Prof. Gordon Shepherd, "The behavioral consequences of synaptic transmission are expressed in terms of neuronal circuits." Echoing this perspective, our research efforts are devoted to characterizing the circuits and neurotransmitters that underlie the amnestic, intoxicating, and rewarding properties of alcohol.

In humans, acute alcohol intoxication produces deficits in learning and memory. Long-term potentiation, a model of synaptic plasticity extensively studied in the hippocampus in rodents, correlates with the acquisition of several learning tasks. Current dogma, predicated mostly on in vitro studies with hippocampal slices, maintains that alcohol impairs cognition and blocks hippocampal long-term potentiation, primarily by pharmacologic action at the N-methyl-d-aspartate (NMDA) receptor. However, we found that alcohol has 2 primary effects on hippocampal synaptic transmission in vivo. One effect appears to be direct, perhaps via NMDA receptor--mediated responses, but the other is due to actions on a remote structure that increases inhibition mediated by -aminobutyric acid (GABA) receptors solely in the dentate gyrus subfield of the hippocampus. We hypothesize that the ventral tegmental area (VTA), a midbrain structure containing dopamine neurons implicated in rewarding behaviors, mediates the effects of alcohol on hippocampal synaptic plasticity, because similar to systemic administration of alcohol, microinjections of alcohol into the VTA increase GABA-mediated recurrent inhibition and suppress long-term potentiation in the dentate gyrus.

Using intracellular electrophysiologic and immunocytochemical techniques in vivo, we recently identified a homogeneous population of VTA nondopamine neurons that are especially sensitive to alcohol. We determined that they are GABAergic projection neurons that contact VTA dopamine neurons. The spontaneous activity of these neurons is driven by synaptic input and is strongly regulated by physiologically relevant NMDA receptor--mediated synaptic transmission from the cortex. Because of their wideband activity and widespread mesolimbic connectivity (Fig. 1), these neurons may be critical neuronal transducers of the intoxicating and reinforcing properties of alcohol.

NEUROSTEROIDS, NEUROACTIVE STEROIDS, AND HIPPOCAMPAL EXCITABILITY

Several recent studies established a role for estrogens in ameliorating some neurodegenerative disorders, including Alzheimer's disease, associated with specific abnormalities in cholinergic neurons of the basal forebrain and in the targets of these neurons in the cortex and hippocampus. We evaluated the effects of the neurosteroid dehydroepiandrosterone 3-sulfate (DHEAS) and the estrogens estrone 3-sulfate, estriol 3-sulfate, estradiol 3-sulfate, and 17-deoxyestrone 3-sulfate (negative control) on cellular activity and synaptic transmission in the dentate gyrus and CA1 subfields of the hippocampus in male rats and in control (sham ovariectomy) and ovariectomized female rats in vivo and in vitro.

All 3 estrogen sulfates and DHEAS markedly decreased GABA-mediated recurrent inhibition in the CA1 hippocampus of female control rats. The order of potency was DHEAS > estrone 3-sulfate > estriol 3-sulfate > estradiol 3-sulfate. The lack of effect of 17-deoxyestrone 3-sulfate indicated the selectivity of the effect of the estrogens. The magnitude of the disinhibition of CA1 responses was considerably reduced in male rats and was increased in ovariectomized female rats. This finding suggests a sex-related bias and possible sensitization of estrogen-reactive elements.

To more fully characterize the cellular actions of these neurosteroids and neuroactive steroids, we evaluated their effects on pharmacologically isolated synaptic responses in hippocampal slices. Although DHEAS appeared to increase NMDA excitatory postsynaptic potentials evoked in the CA1, estrone 3-sulfate did not significantly alter them. However, both DHEAS and estrone 3-sulfate markedly reduced inhibitory postsynaptic potentials evoked in the CA1. Furthermore, although DHEAS decreased both GABA_A and GABA_B receptor--mediated components of the inhibitory postsynaptic potentials, estrone 3-sulfate reduced only the GABA_A component. These findings indicate that neurosteroids may be involved in the regulation of both excitatory and inhibitory neurotransmission and that sulfated estrogens may increase hippocampal excitability by selectively reducing GABA_A receptor--mediated inhibition.

PUBLICATIONS

Steffensen, S.C., Svingos, A., Pickel, V.M., Henriksen, S.J. Electrophysiological characterization of ventral tegmental area GABAergic neurons. J. Neurosci., in press.