How do the hippocampus, glutamate, and dopamine work in the brain?

Karl, Australia

How do the hippocampus, glutamate, and dopamine work in the brain?

Anand Mahadevan
biology and science teacher,
Department of Science,
University of Toronto Schools
(former HHMI predoctoral fellow)

This is a broad question, and I can't answer it thoroughly here. I hope to give you enough of a trail through the different parts of the answer so that you can research the areas that really interest you.

Hippocampus
The hippocampus is a seahorse-shaped structure in the brain that is primarily involved in learning and memory. In particular, the formation of long-term memory cannot occur when parts of the medial temporal lobe of the brain, which includes the hippocampus, are removed. This information comes from the famous case of H.M., a patient in the Boston area. He remembers events that occurred years before the surgery that removed his medial temporal lobe, but he has not been able to form any long-term memories since his surgery.

Much research (thousands of papers now) has focused on a phenomenon called LTP, or long-term potentiation, in two regions of the hippocampus (called CA1 and CA3). Studies in numerous labs across the world show that the synapse strengths of cells in the hippocampus can be reliably increased for hours under specific conditions. That is, the cells can be made to remember specific events. However, it is also clear that no long-term or permanent memory is stored in the hippocampus but that the short-term memory stored in the hippocampus is involved in the formation of long-term memory in other areas of the brain.

Glutamate
Glutamate is the primary excitatory chemical neurotransmitter in the brain. It is an amino acid that when released from one neuron (called the presynaptic neuron) onto another (the postsynaptic) causes the postsynaptic neuron to depolarize. By that we mean that the membrane potential, which is usually around -60 to -70 millivolts (mV) for a neuron, comes closer to zero. In some cases, the glutamate can cause a wave of excitation, called an action potential, to arise in the neuron and cause its membrane potential to go up to +40 or +50 mV.

Synapses that use glutamate are some of the best-studied ones. In particular, the receptors on the postsynaptic neuron that sense the glutamate and cause the postsynaptic neuron to become depolarized are well known. They come in primarily two varieties. One is called an AMPA-type receptor, which opens when it comes in contact with glutamate. The other is called an NMDA receptor, which opens when it comes in contact with glutamate and when the postsynaptic cell is already somewhat depolarized (say, to -40 mV). When the NMDA channel opens, it allows calcium ions to flow into the neuron. The NMDA receptor is currently thought to play an important role in learning and memory.

The LTP phenomenon is thought to underlie short-term memory. In a very famous study, Tonegawa and his colleagues at Princeton made a knockout mouse model that lacked the NMDA receptor. The mice could not learn a task called the water-maze test and did not show LTP in the hippocampus. Therefore, even though they had glutamate as a neurotransmitter and used it in their brains, the lack of the NMDA receptor precluded learning and memory formation in these mice. So, there is a lot of convincing evidence that NMDA receptors of the glutamate neurotransmitters are involved in learning and memory.

Dopamine
Dopamine is a very interesting neurotransmitter because it is involved in both the initiation of movement (and studied as a neurotransmitter involved in Parkinson's diseases) and in the addiction pathway.

Addiction to most drugs and alcohol involves the brain's reward system. The pleasure (or highs) of taking some drugs come from the activation of dopamine-containing neurons, which excite a part of our brain called the nucleus accumbens. Activating these specific dopamine-carrying neurons can lead to the sense of pleasure. However, they also affect other parts of our brain that involve systems that control motivation (the caudate nucleus in the basal ganglia) and hence can have effects on social behaviors as well as induce cravings for drugs.

The brain is a complicated structure with trillions of connections among millions of neurons using a wide-ranging family of neurotransmitters and neuromodulators. Our understanding of the brain, while impressive, is remarkably shallow.

A good source book for starting to understand the brain is published by the U.S. Society for Neuroscience, Brain Facts, a primer on the brain and the nervous system. It is available as a free download from the following website:

http://www.sfn.org/index.cfm?pagename=brainFacts

References for the hippocampus
Buwalda, B., Kole, M.H., Veenema, A.H., Huininga, M., de Boer, S.F., Korte, S.M., and Koolhaas, J.M. Long-term effects of social stress on brain and behavior: a focus on hippocampal functioning. Neuroscience and Biobehavioral Reviews 29 (1): 83-97, 2005.

Cammarota, M., Bevilaqua, L.R., Barros, D.M., Vianna, M.R., Izquierdo, L.A., Medina, J.H., and Izquierdo, I. Retrieval and the extinction of memory. Cellular and Molecular Neurobiology 25 (3-4): 465-74, 2005.

Joels, M., Karst, H., Alfarez, D., Heine, V.M., Qin, Y., van Riel, E., Verkuyl, M., Lucassen, P.J., and Krugers, H.J. Effects of chronic stress on structure and cell function in rat hippocampus and hypothalamus. Stress 7 (4): 221-31, 2004.

Lisman, J.E., and Grace, A.A. The hippocampal-VTA loop: Controlling the entry of information into long-term memory. Neuron 46 (5): 703-13, 2005.

Maren, S. Building and burying fear memories in the brain. Neuroscientist 11 (1): 89-99, 2005.

McEwen, B.S. Glucocorticoids, depression, and mood disorders: structural remodeling in the brain. Metabolism 54 (5, Suppl. 1): 20-23, 2005.

Mizuno, K., and Giese, K.P. Hippocampus-dependent memory formation: Do memory type-specific mechanisms exist? Journal of Pharmacological Sciences 98 (3): 19-17, 2004.

Vianna, M.R., Coitinho, A.S., and Izquierdo, I. Role of the hippocampus and amygdala in the extinction of fear-motivated learning. Current Neurovascular Research 1 (1): 55-60, 2004.

References for glutamate
Ammon-Treiber, S., and Hollt, V. Morphine-induced changes of gene expression in the brain. Addiction Biology 10 (1): 81-89, 2005.

Hyman, S.E. Addiction: a disease of learning and memory. American Journal of Psychiatry 162 (8): 1414-22, 2005.

Jones, S., and Bonci, A. Synaptic plasticity and drug addiction. Current Opinion in Pharmacology 5 (1): 20-25, 2005.

Kalivas, P.W. Glutamate systems in cocaine addiction. Current Opinion in Pharmacology 4 (1): 23-29, 2004.

Kelley, A.E. Memory and addiction: shared neural circuitry and molecular mechanisms. Neuron 44 (1): 161-79, 2004.

Kenny, P.J., and Markou, A. The ups and downs of addiction: role of metabotropic glutamate receptors. Trends in Pharmacological Sciences 25 (5): 265-72, 2004.

Nakazawa, K., McHugh, T.J., Wilson, M.A., and Tonegawa, S. NMDA receptors, place cells and hippocampal spatial memory. Nature Reviews Neuroscience 5 (5): 361-72, 2004.

Palucha, A., and Pilc, A. The involvement of glutamate in the pathophysiology of depression. Drug News Perspectives 18 (4): 262-68, 2005.

Perez-Otano, I., and Ehlers, M.D. Homeostatic plasticity and NMDA receptor trafficking. Trends in Neurosciences 28 (5): 229-38, 2005.

Tonegawa S. Mammalian learning and memory studied by gene targeting. Annals of the New York Academy of Sciences 758:213-17, 1995.

Tonegawa, S., Nakazawa, K., and Wilson, M.A. Genetic neuroscience of mammalian learning and memory. Philosophical Transactions of the Royal Society of London B: Biological Sciences 358 (1432): 787-95, 2003.

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