Have you ever tried to hold back a sneeze? Maybe you’re in a pivotal meeting with your employers about your future at your company, or you’re in the audience of a dramatic play and the lead character just made a huge reveal that has left the audience in a stunned silence, or you’re on a first date and you think your date may be leaning in for a kiss? And it feels as if your life depends on holding back that sneeze? Unfortunately, thanks to the anatomy and physiology of the human body, you’re fighting a losing battle. You’re going to sneeze. You have no control over that impulse.
Now, how would you feel if that same impulse, that same inescapable drive, was not something as innocuous—albeit embarrassing—as a sneeze? What if instead, the impulse you were straining against was the impulse to use drugs? This is the battle that addicts trying to stay clean and sober fight on a daily, sometimes hourly, sometimes moment-to-moment basis. The brain of an addict, whether from genetic predisposition or environmental influence, is wired in such a way that resisting the impulse to take another hit, another drink, another puff is nearly impossible to combat.
If that situation is hard for you to imagine, take a look at the plethora of television series that depict a character struggling to stay clean and sober (Breaking Bad’s Jesse Pinkman, Sherlock’s Sherlock Holmes and the analogous House’s Gregory House, Mad Men’s Don Draper, The Wire’s Bubbles, and Lost’s Charlie Pace, to name a few). In all of these cases, the characters’ struggles show how, despite their desperate desire to stay clean, despite the wreckage their drug use imposes on their lives, the insidious disease of addiction finds its way back to the surface, pulling the addict down again and again.
While the medical community is unfortunately nowhere near finding a conclusive solution to this problem, scientists around the world are chipping away at the neurobiological basis of this disease. Vincent Pascoli and colleagues in Christian Lüscher’s lab at The University of Geneva published a paper in Nature that highlights just how tricky the effects of drugs of abuse in the brain are to identify and reverse. In particular, the researchers sought to identify how neural input from three disparate brain regions converge on one important brain nucleus (i.e. a group of neurons that serve a particular function) to drive continuous drug-seeking behavior.
The information-relaying brain regions they chose to investigate were the medial prefrontal cortex (mPFC), the ventral hippocampus (vHIPP), and the basolateral amygdala (BLA). They chose these regions because each provides an important piece of information for an animal when they want to perform a certain behavior, in this case to seek out drugs. The mPFC is important for making connections between an action and its outcome, the vHIPP provides contextual information about the animal’s current circumstances, and the BLA signals the animal’s emotional state.
These regions all project to a nucleus called the nucleus accumbens (NAc), which processes information about reward and the behavior an animal must perform to obtain a reward--in this case, pressing a lever to receive an infusion of cocaine. When neuroscientists say that one brain region “projects” to another brain region, this means that neurons in brain region A send long branches called axons to brain region B. The endings of those axons, called terminals, contact neurons in brain region B and transmit information to neurons in brain region B. We call these connections “synapses”.
They performed these experiments in mice, an animal model for which many genetic tools are available. These tools allow scientists to express certain proteins in specific locations of the mouse’s brain. In this study, the experimenters expressed a protein called channelrhodopsin (ChR2), a light-activated protein that allows neurons to fire in response to a blue light. By filling neurons in the mPFC, vHIPP, and BLA with ChR2, the researchers could shine a blue light specifically on the NAc, where terminals from each of those projecting regions contact neurons within the NAc, and induce transmission of information at synapses from each projecting region to neurons in the NAc. This way, they could selectively induce information transfer from each brain region separately.
The researchers first wanted to see how previous cocaine use affected neurotransmission at each synapse individually. When a neuron receives input from another neuron, it encodes that message in electrical activity. To look at how the NAc encoded those messages, they expressed ChR2 in each projecting brain region, shone a blue light on the NAc and recorded electrical activity from neurons in the NAc. They found that previous cocaine use changed how NAc neurons respond to information from the mPFC and the vHIPP, but found no changes in input from the BLA. This result was interesting, but not entirely unexpected: there have been decades of research showing that drugs of abuse change synaptic connections between these regions. However, the most interesting part of this study came next.
Information transfer between neurons is not always restricted to the synapse. Due to internal cellular processes within a neuron, information from one synapse can travel to another synapse and change how it responds to neural input. The authors examined this phenomenon next. They found that information from the mPFC can affect synapses between vHIPP neurons and NAc neurons. Furthermore, they found the converse relationship is also true: information from the vHIPP can affect synapses between the mPFC and NAc. This result sheds light on the complex effects that drugs of abuse can have on the brain and, furthermore, how scientists must probe multiple explanations before making assertions about how the brain works.
Finally, the authors sought to examine how the results they found at the cellular level impact drug seeking behavior in the mouse. They found that when they restored neural transmission to pre-cocaine levels at only one of the two synapses, the animal continued to seek cocaine. However, if they restored transmission at both synapses, the animal no longer sought cocaine. This final experiment was probably the most important in the paper; understanding the neural processes that mediate addiction are only important in the context of their translational potential.
This paper tackled an important facet of the brain’s functioning: they showed that single lines of communication in the brain are not enough to explain a complex behavior. Instead, multiple converging lines of information work together to drive an animal’s decisions. They showcase this characteristic of neural communication in the context of addiction. They highlight the intricacies of the neural adaptations induced by drugs of abuse, highlighting how difficult addiction is to treat. With excellent research such as that done in this paper, however, we are continuously moving closer to understanding and treating the cause of addiction.