Stored memories that we have experienced previously enable us to repeat certain tasks. For example, we remember certain routes that we have driven previously. However, when circumstances change and our usual route is blocked for some reason, we have to find an alternative way to get to our destination. These changes are possible due to our behavioral flexibility in order for us to complete the task and they are partially driven by protein synthesis, which produces experience-dependent changes in neural function and behavior.
In many people, this process is impaired, meaning they are unable to adjust their behavior when faced with different circumstances than those they are accustomed to. The researchers set out to investigate how protein synthesis is regulated during behavioral flexibility and decided to focus on the kinase PERK, an enzyme that regulates protein synthesis and that modifies eIF2alpha, a factor required for proper protein synthesis.
The team conducted an experiment in two groups of ordinary lab mice of which one group had the PERK enzyme and the other group did not. The mice had to navigate a water maze in which they had to lift themselves onto a platform to get out of the water. Both groups of mice accomplished to learn how to complete the task. The next step was to move the platform to a different location within the maze, which allowed the team to study the mice's behavioral flexibility in response to the change. The observed that the mice with PERK managed to locate the platform, whilst those lacking PERK were either unable to do so or it took them considerably longer to complete the task.
The researchers then decided to examine how PERK assists mice in terms of their behavioral flexibility. They conducted a second experiment, in which both normal and mice without PERK heard an audible tone followed by a mild foot shock. Both groups of mice developed a normal response of fear, i.e. they froze when hearing the tone, anticipating the foot shock. The team then removed the foot shock from the procedure so that the mice only heard the tone. After a while they observed that the normal mice adjusted their responses and did not freeze after hearing the tone anymore, whilst the mice lacking PERK continued to respond as if they expected a foot shock to follow.
In order to support their findings that the absence of PERK may contribute to impaired behavioral flexibility in human neurological disorders the team conducted postmortem analyses of human frontal cortex samples from patients afflicted with schizophrenia, who often exhibit behavioral inflexibility, as well as from healthy individuals. They discovered that the healthy individuals' samples had normal levels of PERK, whilst those from schizophrenic patients had considerably lower levels of the protein.
Eric Klann, a professor in NYU's Center for Neural Science, who co-authored the study, concluded:
"A rapidly expanding list of neurological disorders and neurodegenerative diseases, including Alzheimer's disease, Parkinson's disease, and Fragile X syndrome, have already been linked to aberrant protein synthesis. Our results show the significance of PERK in maintaining behavioral flexibility and how its absence might be associated with schizophrenia. Further studies clarifying the specific role of PERK-regulated protein synthesis in the brain may provide new avenues to tackle such widespread and often debilitating neurological disorders."
Written By Petra Rattue