Chronic Alcohol Use Rewires Brain Circuitry

Doctors have long recognized a link between alcoholism and anxiety disorders such as post-traumatic stress disorder (PTSD). Those who drink heavily are at increased risk for traumatic events like car accidents and domestic violence, but that only partially explains the connection. New research using mice reveals heavy alcohol use actually rewires brain circuitry, making it harder for alcoholics to recover psychologically following a traumatic experience.

“There’s a whole spectrum to how people react to a traumatic event,” said study author Thomas Kash, PhD, assistant professor of pharmacology at the University of North Carolina School of Medicine. “It’s the recovery that we’re looking at — the ability to say ‘this is not dangerous anymore.’ Basically, our research shows that chronic exposure to alcohol can cause a deficit with regard to how our cognitive brain centers control our emotional brain centers.”

The study, was conducted by scientists at the National Institute on Alcohol Abuse and Alcoholism (NIAAA) and UNC’s Bowles Center for Alcohol Studies.

“A history of heavy alcohol abuse could impair a critical mechanism for recovering from a trauma, and in doing so put people at greater risk for PTSD,” said NIAAA scientist Andrew Holmes, PhD, the study’s senior author. “The next step will be to test whether our preclinical findings translate to patients currently suffering from comorbid PTSD and alcohol abuse. If it does, then this could lead to new thinking about how we can better treat these serious medical conditions.”

Over the course of a month, the researchers gave one group of mice doses of alcohol equivalent to double the legal driving limit in humans. A second group of mice was given no alcohol. The team then used mild electric shocks to train all the mice to fear the sound of a brief tone.

When the tone was repeatedly played without the accompanying electric shock, the mice with no alcohol exposure gradually stopped fearing it. The mice with chronic alcohol exposure, on the other hand, froze in place each time the tone was played, even long after the electric shocks had stopped.
The pattern is similar to what is seen in patients with PTSD, who have trouble overcoming fear even when they are no longer in a dangerous situation.

The researchers traced the effect to differences in the neural circuitry of the alcohol-exposed mice. Comparing the brains of the mice, researchers noticed nerve cells in the prefrontal cortex of the alcohol-exposed mice actually had a different shape than those of the other mice. In addition, the activity of a key receptor, NMDA, was suppressed in the mice given heavy doses of alcohol.

Holmes said the findings are valuable because they pinpoint exactly where alcohol causes damage that leads to problems overcoming fear. “We’re not only seeing that alcohol has detrimental effects on a clinically important emotional process, but we’re able to offer some insight into how alcohol might do so by disrupting the functioning of some very specific brain circuits,” said Holmes.

Understanding the relationship between alcohol and anxiety at the molecular level could offer new possibilities for developing drugs to help patients with anxiety disorders who also have a history of heavy alcohol use. “This study is exciting because it gives us a specific molecule to look at in a specific brain region, thus opening the door to discovering new methods to treat these disorders,” said Kash.

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Neurologists Identify a Genetic ‘Switch’ That Could Improve Memory

A neural circuit mechanism involved in preserving the specificity of memories has been identified by investigators from the Massachusetts General Hospital (MGH) Center for Regenerative Medicine and the Harvard Stem Cell Institute (HSCI).

They also identified a genetic “switch” that can slow down memory generalization — the loss of specific details over time that occurs in both age-related memory impairment and in post-traumatic stress disorder (PTSD), in which emotions originally produced by traumatic experiences are elicited in response to innocuous cues that have little resemblance to the traumatic memory.

“The circuit mechanism we identified in mice allows us to preserve the precision or the details of memories over the passage of time in adult as well as aged animals,” says Amar Sahay of the MGH Center for Regenerative Medicine and HSCI, corresponding author of a paper appearing in Nature Medicine. “These findings have implications for the generalization of traumatic memories in PTSD and for memory imprecision in aging.”

Memories are generated in the seahorse-shaped brain structure called the hippocampus and stored in the prefrontal cortex at the front of the brain. Memory formation involves cells in a portion of the hippocampus called the dentate gyrus, and memories are thought to be conveyed to the prefrontal cortex via the CA subregions of the hippocampus, specifically subregions CA3 and CA1. The hippocampus also is believed to play a continuing role in the stabilization of memories in the cortex — maintaining the precise details that keep one memory from being confused with another and preventing issues ranging from not being able to remember last week’s dinner selections to age-related memory loss.

Hyperactivity of this hippocampal circuitry has been observed in aged animals — rodents, non-human primates, and humans — and alterations in hippocampal structure are seen in patients with PTSD. The current study was designed to investigate the hypothesis that inhibitory signals passing from dentate gyrus cells (DGCs) to the CA3 subregion help constrain hyperactivity and maintain the stability and precision of memories over time.

A key finding by Sahay’s team was identification of a protein called abLIM3 — highly expressed in DGCs but absent in the CA field of mouse brains. The protein acts as a molecular brake on the inhibitory signals DGCs exert onto the CA3 subregion. Experimental manipulation of abLIM3 levels in DGCs in adult mice revealed that decreasing abLIM3 levels increased the delivery of inhibitory signals to CA3 neurons. A series of experiments with mouse models showed that manipulation of abLIM3 levels within DGCs could slow down the process of memory generalization.

Using a classical behavioral-conditioning protocol, the investigators first trained the animals to expect an unpleasant sensation, a mild but not painful foot shock, in a particular context, such as being placed into a box with dark walls. Typically, when animals are placed in the same context, they will “freeze” in expectation of the shock but will not react to a context not associated with the shock, such as a box with light walls. But after two weeks, the memory will generalize and the animals will “freeze” when placed in any context, even one with little resemblance to that in which they received the foot shock.

In contrast, decreasing abLIM3 levels within DGCs maintained the specificity of the memory over time so that, even two weeks later, the mice would only freeze when placed into the foot-shock-associated context. The investigators also found that decreasing abLIM3 levels in aged mice reversed age-related alterations in DGC-CA3 circuitry and improved memory precision. A recent study by another group found significantly increased abLIM3 levels in the circulation of aged humans who are beginning to show signs of memory impairment.

“Our ability to improve memory precision in both adult and aged mice by essentially ‘flipping a genetic switch’ suggests that targeting abLIM3 expression in DGCs may lead to similar improvement in aged humans, a strategy we are actively pursuing,” says Sahay, who is an associate professor of psychiatry at Harvard Medical School and principal faculty of the Harvard Stem Cell Institute. “Since overgeneralization of traumatic memories is a hallmark of PTSD, we are also keen to assess abLIM3 levels in patients with PTSD and investigate whether reducing abLIM3 expression could prevent the activation of traumatic memories.”

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