The human brain is a wonderfully enigmatic organ, helping to juggle multiple tasks efficiently to help us get through a long day! This feature, called executive function, seats primates like us at the pinnacle of evolution. The prospect of losing the spectacular flow of neural information in our brains because of an accident or disease is, thus, unnerving. In the event of such an unfortunate occurrence, to restore the brain to its previous working condition with full functionality--to reboot it, so to speak--would need a better understanding of the specific neural pathways involved in our daily activities that rely on working memory and decision-making--two important executive functions.

To achieve this objective, a group of researchers were hard at work at devising a technique they call "imaging-guided chemogenetic synaptic silencing" to decipher the specific neural pathways involved in high-order executive functions. In a pioneering study published in Science Advances, the researchers now report successfully delineating specific neural pathways involved in working memory and decision-making using this technique.

The group focused on studying the dorsolateral part of the prefrontal cortex (dlPFC) in the monkey brain, to apply their novel technique, and further identify the neural pathways of interest. It is interesting to note this choice, not only because it is the brain region partially responsible for controlling executive functions, but also since this specialized region is only present in primates.

Importantly, the role of dlPFC is supported by brain regions like the dorsal caudate (dCD) and lateral mediodorsal thalamus (MDl) too. This intricate association is further explained by the first author of the study, as follows, "The primate prefrontal cortex (PFC), especially its dorsolateral part (dlPFC), is well known to serve as the center of higher-order executive functions; it is uniquely developed in primates and underlies their distinctive cognitive abilities. These functions, however, do not solely rely on dlPFC neurons but also on their cooperative interactions with subcortical structures, including the dorsal caudate (dCD) nucleus and lateral mediodorsal thalamus (MDl)."

Next, the researchers wanted to understand the who-does-what for working memory and decision-making. Given that the dlPFC, MDI, and dCD neurons are connected, they selectively silenced specific neuronal synapses to disrupt the flow of information, and achieve just dlPFC-dCD and dlPFC-MDl projections, either unilaterally (involving just one side of the brain), or bilaterally (involving both sides). To achieve this, they made the dlPFC neurons express designer receptors exclusively activated by designer drugs (DREADDs). Further, the monkeys involved in the study were analyzed for behavioral changes, to understand the effect of chemogenetic silencing.

Interestingly, the researchers observed that silencing the bilateral dlPFC-MDl projections in the monkeys, but not their dlPFC-dCD projections, caused problems in the working memory related to their surroundings. On the contrary, silencing their unilateral dlPFC-dCD projections, but not their unilateral dlPFC-MDl projections, altered their preference in decision-making. These results reveal that the two higher-brain functions, working memory and decision-making, which are essential for our daily lives, are controlled by different neural pathways linking specific brain areas.

Overall, this study lays the foundation for further explorations of the intricacies of the complex primate brain. In this regard, the authors explain the potential clinical and research applications of these findings, "Many psychiatric disorders, including depression, are thought to be associated with disturbances in the transmission of neural information through neural circuits between specific brain regions. Our findings are expected to deepen our understanding of mental disorders and lead to the discovery of treatments and remedies. The successful development of a novel technique in our study will serve as a key technology for the next-generation of researchers to investigate primate brain functions, which will contribute to broad areas in life by dramatically deepening our understanding of the mechanism of higher-brain functions."

The world will indeed wait with bated breath for future mysteries to unravel as explorations take researchers deeper into the labyrinthine maze that is the mind.

https://www.qst.go.jp/site/qst-english/20210624.html

https://advances.sciencemag.org/content/7/26/eabg4246

http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Fchemogenetic-dissection&filter=22