Research Highlights

Research News
Tuesday, August 6, 2013
Author: Erin Bryant

Recent research from the National Institute on Alcohol Abuse and Alcoholism (NIAAA) sheds new light on habitual behaviors, specifically the circuits in the brain that allow mice to break from routine actions. Such shifting between old habits and new behavior aimed at accomplishing a particular goal are critical to flexible decision-making in everyday life. It also has important implications for mental health and substance abuse interventions. The inability to shift between routine behavior and new goal-directed actions may underlie disorders such as addiction and obsessive compulsive disorder.  

“While habits are important to efficient-decision making, we encounter situations in which it is necessary to ‘break habits’ and re-evaluate actions based on their consequences,” said the study’s first author, Dr. Christina Gremel of the NIAAA Laboratory for Integrative Neuroscience. “These findings give us insight into the neural basis of such adaptability.”

In the study, published in Nature Communications, researchers set out to identify the neural circuitry involved in the shift between habit and goal-directed behavior. Previous studies indicate the involvement of two neighboring regions in the forebrain – the dorsal medial striatum is necessary for goal-directed actions, while the dorsal lateral striatum is needed for habitual actions.

In the present study, researchers found that the orbital frontal cortex, a region associated with obsessive compulsive disorder, is critical to shifting to goal-directed actions.  

To uncover this finding, researchers developed an instrumental feeding task in which mice would shift between habitual and goal-directed behavior. Use of this newly-developed procedure allowed the researchers to probe the brain mechanisms involved when the animals shifted action strategies.

The researchers found that using light to activate individual neurons in the orbital frontal cortex, a process known as optogenetics, increased goal-directed actions in the mice. Inhibiting these neurons using a chemical and genetic approach interfered with the shift to goal-directed behavior, leaving the mice acting out of habit.  

“Our findings indicate that shifts in activity of the orbital frontal cortex and the striatum mediate the shifting between goal-directed and habitual actions,” said the study’s senior author, Rui Costa, Ph.D., of the Champalimaud Foundation, in Portugal and a guest researcher at NIAAA. “Interestingly, these neural circuits appear to work in parallel, enabling both automatic and goal-directed actions to be learned.”    
 

Research News
Friday, August 2, 2013
Author: Shuly Babitz
New data offers a glimpse into the neurobiological mechanisms underlying the formation of habitual actions, such as addiction to alcohol.

In a study conducted in mice and rats, scientists in NIAAA’s Laboratory for Integrative Neuroscience examined the cellular basis for learning and memory in the dorsolateral striatum, a part of the brain involved in habit learning. A particular receptor in the dorsolateral striatum, the cannabinoid type 1 receptor (CB1), is critical for habit learning.
Dorsolateral striatum
“We know that CB1 in this brain region is involved in habit learning, but we have very little idea about how CB1 acts to sculpt this neural circuitry to ultimately result in the expression of habits,” said first author Brian Mathur, Ph.D.He explained that direct and indirect pathways originating in the striatum are composed of medium-sized spiny neurons (MSNs) have opposing effects on movement.The relative activation of the direct pathway over the indirect pathway, known as a“go signal,” is believed to encode for reinforcement of an action. A Change in a neural pathway associated with learning a behavior is called neuroplasticity.

The researchers examined the role of CB1 in a form of neuroplasticity known as long-term depression of synaptic transmission (LTD). LTD refers to the long-lasting decrease in the strength of signal transmission at a synapse, where signals pass from one neuron to another. A synapse that has undergone LTD is less able to influence the activity of the postsynaptic neuron.“We hypothesized that because CB1 is necessary for this long lasting form of the cellular substrate for learning and memory known as LTD, that this neuroplasticity allows for ‘go signal’ generation,” continued Mathur.

Using a novel combination of brain slice electrophysiology and optogenetics, a technique allowing for the activation of specific neural circuits with light, the investigators were able to determine the specific contribution of different inputs onto direct and indirect pathway MSNs to LTD. They found that MSNs express two forms of CB1-dependent LTD depending upon whether the MSN membrane voltage is in an excited “up state” or a more refractory “down state” These two different forms of LTD are each mediated by a separate signaling molecule capable of activating CB1: 2-AG and anandamide. The down state, anandamide-mediated form of LTD occurred only at inhibitory synapses onto direct pathway MSNs, offering a mechanism for go signal generation.

“This is a big step forward in understanding the possible molecular and circuit dynamics underlying habit formation,” said Mathur. The research team hopes their research will help uncover novel therapeutic strategies for the treatment of alcohol use disorders. A report of the study was published online in Nature Neuroscience on July 28, 2013.

Research News
Friday, July 26, 2013
Author: Jo-Ann Kriebel

New research supported by NIAAA suggests that a drug currently used to prevent the rejection of transplanted organs could someday help lessen the alcohol cravings that often lead to relapse among people with drinking problems. Alcohol-related memories, or cues—such as the smell of alcohol—can trigger cue-induced alcohol craving. Previous research has found that the mammalian target of rapamycin complex 1 (mTORC1), a group of proteins found in cells throughout the body, is involved in memory processes in the brain, and also plays an important role in alcohol-seeking behavior. In a study published online in Nature Neuroscience, researchers from the University of California San Francisco examined whether inhibiting mTORC1 could disrupt memories of alcohol cues—and thus diminish alcohol relapses in rats that had been trained to binge drink. After a period of alcohol abstinence, researchers exposed the rats to a small amount of alcohol to provide an odor and taste cue to the animals. The researchers then administered a dose of rapamycin, an mTORC1 inhibitor. Compared with a control group that did not receive rapamycin, rats that received the rapamycin sought and consumed less alcohol for the duration of the experiment. Researchers found that by disrupting memories of alcohol cues, rats were less likely to relapse to drinking than those whose memories were intact.

The researchers note memory disruption has shown success in humans who are addicted to heroin and suggest that it may prove helpful in developing new relapse-prevention strategies in alcoholics as well.

Research News
Thursday, July 25, 2013
Author:

Computerized image analysis can be a useful tool for detecting the sometimes subtle changes in facial features that occur when children are exposed to alcohol before birth, according to a recent study conducted through the NIAAA-funded Collaborative Initiative on Fetal Alcohol Spectrum Disorders (CIFASD).  As reported in the journal Pediatrics, the study suggests that three-dimensional (3-D) imaging could soon help clinicians identify children at high risk for cognitive impairments due to prenatal alcohol exposure.

“This important work could help pediatricians and clinicians make earlier identification of children at high risk for cognitive deficits due to prenatal alcohol exposure, especially those heavily exposed individuals who lack the classic facial characteristics of fetal alcohol syndrome (FAS),” said NIAAA acting director Kenneth R. Warren, Ph.D.

Prenatal alcohol exposure causes a continuum of effects.  FAS is the most serious consequence of heavy drinking during pregnancy and involves a specific pattern of facial abnormalities, including small eye width, smoothing of the ridges between the base of the nose and the upper lip, and a thin upper lip border, as well as growth deficits, and neurocognitive problems.

Collaborating with other CIFASD investigators and additional researchers in South Africa, lead investigator Peter Hammond, Ph.D., of the University College London identified novel strategies for detecting facial effects of prenatal alcohol exposure among a sample of children from a community clinic in Cape Town, South Africa, where the incidence of heavy alcohol use during pregnancy and FAS are among the highest in the world.

Using three-dimensional photography and computerized image analysis techniques, the researchers examined facial characteristics of children either not exposed or heavily exposed to alcohol and compared their observations with clinically-determined FASD categorizations. They found that 3-D facial image analyses substantially enhanced the ability to detect a broad range of alcohol-induced facial changes in children.  Importantly, their computer-based approach should help identify affected children who have cognitive impairments but lack facial features necessary for a FAS diagnosis. They note that more substantial testing of these techniques is planned in South Africa, the United States, and the Ukraine.  For more information on the CIFASD consortium, visit http://www.cifasd.org.

Research News
Thursday, April 11, 2013
Author: Shuly Babitz

A new study provides evidence that endocannabinoids, natural compounds that are chemically similar to the active ingredient in marijuana, play a role in the development of Fetal Alcohol Spectrum Disorders (FASD). Researchers led by Balapal S. Basavarajappa (aka: Basavaraj S. Balapal), Ph.D., of the Nathan Kline Institute for Psychiatric Research and New York State Psychiatric Institute, investigated the effect of alcohol on the endocannabinoid system and how those effects influence brain development in mice. The molecules and receptors that comprise the body’s endocannabinoid system work together to affect physiological processes such as brain development, appetite, pain, mood, and memory – the very processes also affected by using marijuana.

In this study, published in the April 10, 2013 issue of the Journal of Neuroscience, researchers exposed 7-day-old mice to binge-like amounts of alcohol to examine the resulting changes in the brain’s structure and functions. In terms of brain development, this is comparable to exposing a human in the third trimester of fetal development to alcohol. What they found is that the endocannabinoid anandamide (AEA) and its receptor, CB1, both increase in response to alcohol. Elevated AEA and CB1 receptor causes the extracellular signal-regulated kinases (ERK 1/2) to change from its active, or phosphorylated, form to its inactive or dephosphorylated form. The authors hypothesized that it is this change in ERK 1/2 that causes neurodegeneration in neonates and deficits in synaptic plasticity and cognitive function in adults that are characteristic of FASD.

The researchers further tested this hypothesis by blocking CB1 receptors in two ways. One was to pharmacologically block CB1 activity with an antagonist. The other was by using mice that were genetically engineered to have no CB1 receptor. Both of these manipulations prevented alcohol-induced neurodegeneration in neonates and long-lasting synaptic and memory deficits in adult mice.

Dr. Shivakumar Subbanna, the study’s first author explains that “elevated AEA/CB1 receptor signaling occurred through transcriptional activation of genes responsible for AEA biosynthetic enzymes and CB1 receptor protein.”

Dr. Balapal, who is also a faculty at Department of Psychiatry, College of Physicians and Surgeons, Columbia University, NY, and his colleagues note that AEA/CB1 receptor/pERK1/2 signaling molecules that regulate the formation of proper synaptic connections in the developing brain might be directly responsible for the synaptic and memory deficits associated with FASD.

Dr. Antonio Noronha, director of NIAAA’s Division of Neuroscience and Behavior, believes the study’s findings have important implications for the prevention of FASD.

“Understanding the mechanism leading to the neurodegeneration that underlies the development of FASD is a critical step in developing novel treatments to block alcohol-induced neurotoxicity in the developing brain. Potentially, these data can lead to the development of drugs or other tools that target the endocannabinoid/CB1 receptor-ERK 1/2 signaling pathways, and avoid or reverse brain damages,” said Dr. Noronha.

 

Source: Anandamide–CB1 Receptor Signaling Contributes to Postnatal Ethanol-Induced Neonatal Neurodegeneration, Adult Synaptic, and Memory Deficits. Subbanna, S, et al. J. Neuroscience.

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