Research Interests

My laboratory focuses on understanding molecular mechanisms involved in information storage and modulation of excitability in the brain, using modern electrophysiological and optical techniques in brain slices. We continue with some work in the hippocampus, a region required for normal formation of long-term memory. However, most recently, our efforts have been concentrated in two brain regions involved in reward. the ventral tegmental area (VTA) and the nucleus accumbens. These areas are essential in the development of drug addiction. The lab is currently testing the idea that drugs of abuse act directly in the VTA to cause long-term synaptic modifications that could mediate the intense craving produced by these drugs. The enhancement of craving appears to result directly from long-term changes in the nucleus accumbens as a result of VTA activation by chronic drug exposure. We are therefore exploring synaptic plasticity in both regions and its modulation by addictive drugs.

Molecular mechanisms underlying synaptic plasticity:

The cellular basis of information storage is likely to involve long-term alterations in the strength of synapses, the connections between neurons. Synaptic modifications in the hippocampus are likely to underlie both physiological mechanisms used for memory formation and pathological changes associated with epileptic activity. The most well-studied examples of adult synaptic plasticity are called long-term potentiation (LTP) and long-term depression (LTD).

Synaptic plasticity in midbrain dopamine neurons and drug addiction:

Recently I have become very interested in the essentially permanent changes in the nervous system that accompany drug addiction. These long-term changes represent a form of neural plasticity that is tightly correlated with behavior, and modifications of midbrain synapses in the reward pathway represent a possible initiation site for drugs of abuse. More generally, the ability of the brain’s reward pathway to undergo plastic changes is important, since this type of ‘learning’ is certainly necessary for survival.

Drug addiction and the brain’s response to drug abuse are complex processes likely to require interactions among many brain regions. However, careful in vivo analysis has defined the ventral tegmental area (VTA) as necessary and sufficient for the initiation of one aspect of drug abuse, sensitization (an animal model of drug craving). Several lines of evidence indicate that the initiation of sensitization occurs in the VTA, so the time is right to bring cellular approaches to bear on this problem. Only a handful of previous studies have been carried out using in vitro electrophysiological recordings to measure responses to addictive drugs. Therefore, any observations we make in this important brain area will add to our store of knowledge about drug action.

My hypothesis is that excitatory synapses between prefrontal cortical afferents onto dopamine neurons in VTA can undergo long-term changes in strength, like those described in hippocampus and elsewhere. We have found that synaptic plasticity indeed occurs at these synapses. Moreover, we find that one form of plasticity, LTD, is entirely blocked during exposure to amphetamine, a highly addictive drug. Abnormally generated synaptic plasticity could represent the first step in long-lasting alterations in brain function as a consequence of addictive drug abuse. We are currently testing this notion, recording directly from VTA dopamine neurons and testing effects of amphetamine. Over the next few years, we intend to study what controls the generation of synaptic plasticity in the VTA, and we will determine whether addictive drugs from chemically distinct classes (e.g. psychostimulants, morphine, nicotine) favor the development of abnormal synaptic plasticity either acutely, or over time in vivo.

Recent Publications

McMahon, L.L., and J. A. Kauer (1997) Hippocampal interneurons express a novel form of synaptic plasticity. Neuron 18: 1-11.

McMahon, L.L. and J.A. Kauer (1997) Hippocampal interneurons are excited by serotonin-gated ion channels. J. Neurophysiol. 78: 2493-2502.

Kandler, K., L.C. Katz, and J.A. Kauer. (1998) Focal photolysis of caged glutamate reveals an entirely postsynaptic form of hippocampal long-term depression. Nature Neurosci. 1: 119-123.

Tecott, L.H., S.F. Logue, J.M. Wehner and J.A. Kauer. (1998) Selective impairments in contextual processing and dentate gyrus function in mice lacking serotonin 5-HT2C receptors. Proc. Natl. Acad. Sci. 95: 15026-15031.

Jones, S. and J.A. Kauer. (1999) Amphetamine depresses excitatory synaptic transmission in the ventral tegmental area via serotonin receptors. J. Neurosci. 19: 9780-9787.

Kornblum, J.L., S. Jones and J.A. Kauer. (2000) Amphetamine blocks long-term depression of ventral tegmental area synapses. J. Neurosci. 20: 5575-5580.

Tim Bliss, Mick Errington, Eric Fransen, Jean-Marie Godfraind, Julie A. Kauer, R. Frank Kooy, Patricia F. Maness and Andrew J.W. Furley. (2000) Long term potentiation in mice without L1CAM. Current Biology 10: 1607-1610.

Biomed Faculty Pages || Biomed || Brown University