Alcohol, Memory Blackouts and the Brain

Alcohol, Memory, and the Hippocampus
by National Institute of Health

(Page 5 of 6)

More than 30 years ago, both Ryback and Goodwin and colleagues speculated that alcohol might impair memory formation by disrupting activity in the hippocampus. This speculation was based on the observation that acute alcohol exposure produces a syndrome of memory impairments similar in many ways to the impairments produced by hippocampal damage. Specifically, both acute alcohol exposure and hippocampal damage impair the ability to form new long-term, explicit memories but do not affect short-term memory storage or, in general, the recall of information from long-term storage.

Research conducted in the past few decades using animal models supports the hypothesis that alcohol impairs memory formation, at least in part, by disrupting activity in the hippocampus. Such research has included behavioral observation; examination of slices of and brain tissue, neurons in cell culture, and brain activity in anesthetized or freely behaving animals; and a variety of pharmacological techniques.

As mentioned above, damage limited to the CA1 region of the hippocampus dramatically disrupts the ability to form new explicit memories. In rodents, the actions of CA1 pyramidal cells have striking behavioral correlates. Some cells tend to discharge electrical signals that result in one cell communicating with other cells (action potentials) when the rodent is in a distinct location in its environment. The location differs for each cell. For instance, while a rat searches for food on a plus-shaped maze, one pyramidal cell might generate action potentials primarily when the rat is at the far end of the north arm, while another might generate action potentials primarily when the rat is in the middle of the south arm, and so on. Collectively, the cells that are active in that particular environment create a spatial, or contextual map that serves as a framework for event memories created in that environment. Because of the location-specific firing of these cells, they often are referred to as "place-cells," and the regions of the environment in which they fire are referred to as "place-fields". Given that CA1 pyramidal cells are critically important to the formation of memories for facts and events, and the clear behavioral correlates of their activity in rodents, it is possible to assess the impact of alcohol on hippocampal output in an intact, fully functional brain by studying these cells.

In recent work with awake, freely behaving rats, White and Best showed that alcohol profoundly suppresses the activity of pyramidal cells in region CA1. The researchers allowed the rats to forage for food for 15 minutes in a symmetric, Y-shaped maze and measured the animals' hippocampal activity using tiny wires implanted in their brains. The activity - which corresponds to the middle portion of the lower left arm of the maze - is shown before alcohol administration, 45 to 60 minutes after alcohol administration, and 7 hours after alcohol administration. The dose of alcohol used in the testing session was 1.5 grams per kilogram of body weight - enough to produce a peak BAC of about 0.16 percent. The cell's activity was essentially shut off by alcohol. Neural activity returned to near-normal levels within about 7 hours of alcohol administration.

White and Best administered several doses of alcohol in this study, ranging from 0.5 g/kg to 1.5 g/kg. They found that the dose affected the degree of pyramidal cell suppression. Although 0.5 g/kg did not produce a significant change in the firing of hippocampal pyramidal cells, 1.0 and 1.5 g/kg produced significant suppression of firing during a 1-hour testing session following alcohol administration. The dose-dependent suppression of CA1 pyramidal cells is consistent with the dose-dependent effects of alcohol on episodic memory formation.

Alcohol and Hippocampal Long-Term Potentiation

In addition to suppressing the output from pyramidal cells, alcohol has several other effects on hippocampal function. For instance, alcohol severely disrupts the ability of neurons to establish long-lasting, heightened responsiveness to signals from other cells. This heightened responsiveness is known as long-term potentiation (LTP). Because researchers have theorized that something like LTP occurs naturally in the brain during learning, many investigators have used LTP as a model for studying the neurobiology underlying the effects of drugs, including alcohol, on memory.

In a typical LTP experiment, two electrodes are lowered into a slice of hippocampal tissue kept alive by bathing it in oxygenated artificial cerebral spinal fluid. A small amount of current is passed through electrode A, causing the neurons in this area to send signals to cells located near electrode B. Electrode B then is used to record how the cells in the area respond to the incoming signals. This response is the baseline response. Next, a specific pattern of stimulation intended to model the pattern of activity that might occur during an actual learning event is delivered through electrode A. When the original stimulus that elicited the baseline response is delivered again through electrode A, the response recorded at electrode B is larger (potentiated). In other words, as a result of the patterned input, cells at position B now are more responsive to signals sent from cells at position A. The potentiated response often lasts for an extended period of time, hence the term long-term potentiation.

Alcohol interferes with the establishment of LTP and this impairment begins at concentrations equivalent to those produced by consuming just one or two standard drinks (a 12-oz beer, 1.5-oz of liquor in a shot or mixed drink, or a 5-oz glass of wine). If sufficient alcohol is present in the ACSF bathing the slice of hippocampal tissue when the patterned stimulation is given, the response recorded later at position B will not be larger than it was at baseline (that is, it will not be potentiated). And, just as alcohol tends not to impair recall of memories established before alcohol exposure, alcohol does not disrupt the expression of LTP established before alcohol exposure.

One of the key requirements for the establishment of LTP in the hippocampus is that a type of signal receptor known as the NMDA2 receptor becomes activated. ( N-methyl-D-aspartate [NMDA] is a receptor for the neurotransmitter glutamate.) Activation of the NMDA receptor allows calcium to enter the cell, which sets off a chain of events leading to long-lasting changes in the cell's structure or function, or both. Alcohol interferes with the activation of the NMDA receptor, thereby preventing the influx of calcium and the changes that follow. This is believed to be the primary mechanism underlying the effects of alcohol on LTP, though other transmitter systems probably are also involved.

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