Within the last few years, optogenetic techniques within the neuroscience field have been providing important insights into the underlying neural mechanisms of drug addiction and other brain disorders. Optogenetic methods selectively target and control the activity of specific neurons that have been modified to express either light-sensitive cation channels that can depolarize the neuron, or chloride pumps that can produce hyperpolarization. Optogenetics has the advantage of selectively targeting neurons for stimulation or inhibition. This selective targeting can be accomplished using more traditional electrical or pharmacological neuron-modulatory techniques. This session provided a brief overview of this technology, with additional presentations focusing on the use of optogenetics in exploring the neuronal mechanisms of drug addiction.
Activation of Ventral Tegmental Area GABAergic Neurons Disrupts Reward Consumption
Garret D. Stuber, Ph.D., University of North Carolina at Chapel Hill
The ventral tegmental area (VTA) is a brain structure containing groups of neurons essential for the expression of behaviors related to addiction and other neuropsychiatric illnesses. Some of these neuron groups work together to control behavioral responses; however, it has been difficult for researchers to precisely test these mechanisms in a living organism.
Dopaminergic (DAergic) neurons, those that contain dopamine—the neurotransmitter that helps control the brain’s reward and pleasure centers, are combined with GABAergic neurons in the VTA. Although 30-40 percent of neurons in the VTA are GABAergic, their function is not yet understood. Dr. Stuber and his team of researchers used optogenetic strategies to study how modulating the activity of GABAergic neurons in the VTA influences reward-seeking behavior by decreasing or increasing levels of dopamine in the brain.
To examine how reward-related behaviors are influenced by the activation of GABAergic neurons, the team used a light stimulus to predict the delivery of a sucrose reward to adult mice. They then activated GABAergic neurons timelocked either to a reward-predictive cue or to reward consumption. Results showed that optogenetic activation of neurons timelocked to reward-predictive cues did not alter reward-seeking during the cue presentation or during reward consumption. However, optogenetic activation did significantly disrupt reward consumption in GABAergic neurons timelocked to reward delivery. Results also showed that the firing rates of DAergic neurons in the VTA were reduced when GABAergic neurons were activated. This presentation demonstrated that by modulating specific neuron groups in the VTA, researchers can alter the brain’s response to rewards and pleasure.
Genetic and Optogenetic Manipulation of Medium Spiny Neuron Subtypes
Mary Kay Lobo, Ph.D., University of Maryland School of Medicine
The nucleus accumbens (NAc) plays a crucial role in mediating the rewarding effects of drugs of abuse, but until recently, little was known about the pathways and processes of the NAc’s medium spiny neurons (MSNs). MSNs account for more than 95 percent of all NAc neurons and they are divided into two subtypes based on their expression of specific genes including dopamine receptors 1 and 2 (D1 and D2) and the regions they project to in the brain. To understand the role of MSNs in cocaine-reward behaviors, Dr. Lobo and her team of researchers used genetic mouse models to manipulate BDNF signaling, which is involved in the regulation of stress response and the biology of mood and addiction disorders. They specifically deleted TrkB, the BDNF receptor, from D1 containing vs. D2 containing MSNs.
The team then used optogenetic methods to manipulate neuronal firing in each MSN for comparison with TrkB deletion. Data revealed that loss of TrKB and turning on neuronal firing selectively in each MSN resulted in opposing behavioral responses to cocaine. Deletion of TrKB in D1 MSNs and activation of D1 MSNs with optogenetics increased the effects of cocaine reward, while deletion of TrKB in D2 MSNs and activation of D2 MSNs reduced the effects of cocaine reward. Dr. Lobo explained that her team’s findings were consistent with current models of opposing functions of the two MSN subtypes, with respect to other behaviors including motor control. Her presentation provided insight into how neuronal activity is controlled on the molecular level and how dopamine receptor cell types contribute to reward triggers in the brain.
Decreased Excitability of Prelimbic Pyramidal Neurons Induced by Extended Cocaine Self-Administration Contributes To Compulsive Drug Seeking
Billy T. Chen, Ph.D., NIDA Intramural Research Program
Research shows that different brain regions are involved in an individual’s transition to drug abuse. As the ability of neurons to compensate for injury and disease fluctuates within these regions, drug seeking behaviors can become more compulsive. Previous studies suggest that compulsive drug-seeking may result from inadequate functioning of the decision-making centers in the prefrontal cortex. This presentation expanded on those previous studies, as it explored whether long-term cocaine self-administration caused the decision making parts of the prefrontal cortex to fail and neuronal activity to change, thereby influencing compulsive drug use.
To test this hypothesis, Dr. Chen and his research team trained adult male rats to self-administer cocaine on a seek-take chain schedule for about 2 months. After this period, they were exposed to foot shock punishment during self-administration. Researchers observed both a shock-resistant group (continued to self-administer despite shocks) and a shock-sensitive group (suspended all cocaine-seeking when shocked) before performing ex vivo studies of deep-layer pyramidal neurons in the prelimbic area. Results showed that neurons in the prelimbic area of cocaine-experienced rats showed significant decreases in membrane excitability compared to cocaine-naïve rats. Furthermore, this effect was more pronounced in shock-resistant rats than in shock-sensitive rats.
The research team also used in vivo optogenetic stimulation to rescue cocaine-induced hypoactivity in the prelimbic area in the shock-resistant rats. Dr. Chen’s findings showed that prolonged cocaine self-administration decreased excitability in prelimbic neurons, which may contribute to compulsive cocaine-seeking behaviors.