New research reveals how everyday cues secretly shape your habits
Researchers at Georgetown University Medical Center have identified a way the brain’s learning system can shift depending on the
Researchers at Georgetown University Medical Center have identified a way the brain’s learning system can shift depending on the activity of a particular protein. Their work shows that the ability to connect cues with rewarding outcomes can be strengthened or weakened when this protein becomes more or less active. This process helps determine whether the brain responds to signals that lead to positive behaviors or ignores cues tied to harmful habits, including those involved in smoking addiction.
“Our ability to link certain cues or stimuli with positive or rewarding experiences is a basic brain process, and it is disrupted in many conditions such as addiction, depression, and schizophrenia,” says Alexey Ostroumov, PhD, assistant professor in the Department of Pharmacology & Physiology at Georgetown University School of Medicine and senior author of the study. “For example, drug abuse can cause changes in the KCC2 protein that is crucial for normal learning. By interfering with this mechanism, addictive substances can hijack the learning process.”
The study, supported by the National Institutes of Health (NIH), was published December 9 in Nature Communications.
How KCC2 Shapes Dopamine Activity and Reward Learning
The team found that changes in learning can occur when levels of the KCC2 protein shift. When KCC2 levels are reduced, dopamine neurons fire more rapidly, which encourages the formation of new reward associations. These dopamine neurons produce and release dopamine, a neurotransmitter essential for motivation, reward processing, and motor control.
To better understand this relationship, researchers studied rodent brain tissue and monitored the behavior of rats during Pavlovian cue-reward tests. In these classic experiments, a brief sound alerts the rats that a sugar cube is on the way. Beyond analyzing how KCC2 affects the pace of neuron firing, the investigators discovered that neurons firing in a coordinated pattern can amplify dopamine activity in a surprising way. Short bursts of dopamine appear to serve as potent learning signals that help the brain assign meaning and value to shared experiences.
Why Everyday Cues Can Trigger Cravings
“Our findings help explain why powerful and unwanted associations form so easily, like when a smoker who always pairs morning coffee with a cigarette later finds that just drinking coffee triggers a strong craving to smoke,” notes Ostroumov. “Preventing even relatively benign drug-induced associations with situations or places, or restoring healthy learning mechanisms, can help develop better treatments for addiction and related disorders.”
How Diazepam and Other Drugs Influence Neuron Coordination
The researchers also examined whether drugs that act on specific cellular receptors, including benzodiazepines such as diazepam, could alter learning processes. Earlier work showed that shifts in KCC2 production, and therefore in neuron activity, can change how diazepam (valium) produces its calming effects in the brain. The current study adds another layer to this understanding by showing that neurons do more than increase or decrease activity. They can coordinate their firing patterns, and when that coordination occurs, they transmit information more effectively. The team found that diazepam can support this coordinated activity in their experiments.
Methods and the Importance of Using Rats for Behavioral Tests
“To reach our conclusions, we combined many experimental approaches, including electrophysiology, pharmacology, fiber photometry, behavior, computational modeling, and molecular analyses,” says the study’s first author Joyce Woo, a PhD candidate in Ostroumov’s lab.
She explained that rats were chosen for the behavioral portion of the research because they typically perform more consistently than mice on longer and more complex tasks. Their reliability in reward-learning experiments allowed the research team to gather more stable and informative data.
Broader Implications for Brain Disorders and Treatment Strategies
“We believe these discoveries extend beyond basic learning research,” says Ostroumov. “They reveal new ways the brain regulates communication between neurons. And because this communication can go wrong in different brain disorders, our hope is that by preempting these disruptions, or by fixing normal communication when it’s impaired, we can help develop better treatments for a wide range of brain disorders.”
Additional Georgetown contributors include Ajay Uprety, Daniel Reid, Irene Chang, Aelon Ketema Samuel, Helena de Carvalho Schuch and Caroline C Swain.
Ostroumov and his co-authors report having no personal financial interests related to the study.
This work was supported by NIH grants MH125996, DA048134, NS139517, DA061493, as well as grants from the Brain & Behavior Research Foundation, the Whitehall Foundation and the Brain Research Foundation.
