Deciphering the inner workings of the brain; working memory and decision making controlled by the prefrontal cortex

Together with the Primate Research Institute at Kyoto University, Group Leader Takafumi Minamimoto and Researcher Kei Oyama of the Department of Functional Brain Imaging at the National Institutes for Quantum and Radiological Science and Technology reported that "working memory" and "decision-making," which involve the prefrontal cortex, the most well-developed brain region in humans and other primates, are processed by separate neural pathways. Artificial receptors that act as switches and are activated by designer drugs were introduced into monkey neurons and through visualization and manipulation experiments these results were found. These findings could help clarify the higher brain function of primates and pathophysiologic understanding of psychiatric and neurological diseases. The results were published in the June 24 issue of Science Advances, an international journal.

The prefrontal cortex, located in the front portion of the brain, is an important region that functions as a control-tower of sorts, and is a brain site where aging-related functional decline occurs the earliest. The prefrontal cortex plays a central role in human thinking and behavior, including memory, decision-making, attention, and execution. For example, when setting out to shop, the "working memory" function is responsible for remembering what to buy, and the "decision-making" function is responsible for choosing between several products in the shop. These different functions are thought to be directed by the dorsolateral prefrontal cortex. Nevertheless, until now, we were not aware of which brain regions were sent these instructions, or how they were sent by the dorsolateral prefrontal cortex to execute the afore mentioned functions.

Previously, the research group developed a technique for labeling and visualizing neuronal activity on positron emission tomography (PET) by introducing artificial receptors that act like "switches" into neurons via viral vectors. Neuronal activity can be blocked for several hours by administering and activating an agonist (DCZ), and the block is released after a few hours. In this study, the authors applied this technique to visualize which brain regions are connected by introducing artificial receptors in the dorsolateral prefrontal cortex of monkeys.

High accumulation of PET compounds was observed in three areas: the dorsolateral prefrontal cortex, caudate nucleus, and dorsomedial thalamus. These researchers found that neurotransmission involves two pathways, the dorsolateral prefrontal cortex-caudate nucleus pathway and dorsolateral prefrontal cortex-dorsomedial thalamus nucleus pathway. These connections were also confirmed anatomically.

The researchers then investigated which of these two pathways is involved in "working memory" for higher brain functions involving the dorsolateral prefrontal cortex. Because nerve activity can be blocked by agonists, they administered agonists to the caudate or medial dorsal nucleus, blocking those pathways. While each was blocked, monkeys were assigned a task to test their working memory function. In the "working memory" test, food was placed ahead of time in the left or right hole of an experimental apparatus in front of the monkeys. The box was then closed and curtained off, and after a time delay (0.5-30 s), the monkeys were tasked with finding the food. The results showed that when the neural activity of the dorsolateral prefrontal cortex-medial dorsal nucleus pathway was blocked, the correct answer rate reduced greatly, and working memory was impaired. The rate of correct answers did not decrease upon blocking the dorsolateral prefrontal-caudate pathway, and the rate of correct answers remained high.

Next, to test which pathways are involved in decision-making, the monkeys were assigned a separate task that tested their decision-making skills, and different pathways were blocked. Previous studies have found that the right brain hemisphere is strongly involved when choosing something on the left, and the left brain hemisphere is strongly involved when choosing something on the right. Thus, in the decision-making test, an agonist was administered to one side of the caudate or medial dorsal nucleus of the thalamus to block one side of the neural pathway. Monkeys were shown a box with two holes, both containing food, and were tasked with picking one. Blocking the dorsolateral prefrontal-caudate pathway altered the monkeys' choice behavior. Blocking the caudate nucleus on the left significantly increased the frequency of choosing the left hole; conversely, blocking the caudate nucleus on the right significantly increased the frequency of choosing the right hole. Monkeys whose dorsolateral prefrontal-thalamic medial dorsal nucleus pathways were blocked did not exhibit this bias, and they chose the left and right holes with approximately equal preference, just like monkeys in which the pathways were unblocked.

These experimental results revealed that the working memory was processed in the dorsolateral prefrontal-medial dorsal nucleus pathway, and decision-making was processed in the dorsolateral prefrontal-caudate pathway. Since the technique used in this study can be applied to other brain sites, it is expected to contribute significantly to the understanding of higher brain functions of humans and clarifying mechanisms of psychiatric and neurological diseases, which have been difficult until now. "In the future, we hope to clarify the functions of other body parts through this approach," said Dr. Minamimoto. "We are also working to create models of diseases with impulsive symptoms, such as ADHD, and hope to apply these techniques to discover therapeutic agents for these symptoms."