A01
Cognitive flexibility is defined as the ability of the brain to adapt mental processes and behavior in response to changes in the environment. We are interested in cognitive flexibility because age- and disease-related deficits in cognitive flexibility are observed in humans and laboratory rodents. We want to understand how such deficits develop and how they can be treated. In our project, we investigate which factors can improve or impair cognitive flexibility by focusing on NMDA receptor signaling in the prefrontal cortex.
Principal Investigators
Prof. Dr. Daniela Dieterich
Prof. Dr. Markus Fendt
Co-Workers
Dr. Samia Afzal
Nora Broda
Archana Durairaja
Julius Duske
Dr. Peter Landgraf
Lisa Seifried
Julia Poppke
Why is cognitive flexibility important?
Greater cognitive flexibility is generally associated with favorable outcomes and abilities like flexible thinking, creativity, resilience to negative life events, and the ability to understand the emotions, thoughts, and intentions of others. Simply put, cognitive flexibility has a positive impact on the quality of life.
How to measure cognitive flexibility in humans and mice?
For humans, there are tests such as the computer-based CANTAB (Cambridge Neuropsychological Test Automated Battery) or the Wisconsin Card Sorting Test. These tests are sensitive to positive and negative pharmacological, genetic, and environmental effects in healthy and patient populations.
In laboratory mice, we use the attentional set-shifting task (ASST) to measure cognitive flexibility. This task involves several cognitive transfers, such as reversal learning, intra-, and extra-dimensional shifts. For our research, we use the ‘digging version’ of the ASST. In this version, a food reward is presented in one of two bowls; these bowls have different odors and different filling materials in which the food reward is hidden. The mouse has to learn that either a particular odor or a particular material predicts the reward, while other stimuli have to be ignored. In the course of the test, the contingencies are repeatedly changed, and also new odors and materials are used, as soon as a mouse has learned a particular contingency.
Which factors affect cognitive flexibility?
Many factors can impair cognitive flexibility, such as aging, diseases ranging from neuropsychiatric conditions (e.g., depression, autism spectrum disorders, and post-traumatic stress disorder) to neurological disorders (e.g., Alzheimer’s disease). Neuropathologically, dysfunctions of neural circuitries within the prefrontal cortex (PFC) and dysregulation of NMDA receptors are factors leading to impaired cognitive flexibility. Better cognitive flexibility can also be observed, for example during specific developmental phases (early childhood, puberty), during positive emotions, after cognitive enrichment (“brain training”), and after voluntary aerobic exercise. Pharmacologically, positive modulation of NMDA receptor signaling can improve cognitive flexibility and thereby rescue age- or disease-induced deficits.
Which brain regions are important
for cognitive flexibility?
Cognitive flexibility is associated with a defined circuitry within the prefrontal cortex. Studies in laboratory rodents have demonstrated that the orbitofrontal cortex plays a key role in reversal learning, while the anterior cingulate cortex and medial prefrontal cortex (in humans: dorsolateral prefrontal cortex) are important for intra-dimensional and extra-dimensional shifts, respectively.
What is the NMDA receptor?
Glutamate receptors are the most abundant type of excitatory receptors in the mammalian forebrain and are –among others– required for synaptic plasticity, learning, and memory. The NMDA receptor is one of the three types of ionotropic glutamate receptors, containing two obligatory NMDAR-type 1 subunits (GluN1), in combination with two regulatory GluN2 (GluN2A-D) and/or GluN3 (GluN3A-B) subunits. Many studies showed that the expression of these regulatory subunits changes during development, as well as in some diseases.
Both hyperfunction and hypofunction of NMDA receptors can contribute to disease pathophysiology. Hyperfunction and overexpression of NMDA receptors can cause excitotoxicity, which is involved in some neurodegenerative disorders and might also be increased by aging. Hypofunction of NMDA receptors is for example involved in the impairment of synaptic plasticity. That means that a normal so-called “physiological” functioning of the NMDA receptor is required for a healthy brain and healthy cognitive flexibility.
What is our hypothesis?
Previous findings suggest that the different components of the NMDA receptor (e.g., its subunits), as well as the associated signaling pathways and scaffolding proteins, play distinct roles in cognitive flexibility. Thus, our hypothesis is that specific modulation of particular components will rescue deficits in cognitive flexibility. Furthermore, we hypothesize that these components are influenced by environmental and/or life history factors –which play an important role in age-related cognitive decline in humans and thereby contribute to individual cognitive flexibility.
What is our goal and how to reach it?
The overall goal of the project is to understand the role of the NMDA receptor signaling complex in cognitive flexibility using state-of-the-art molecular, cell biological, and proteomic tools in combination with behavioral assessment of cognitive flexibility in mice. Based on this knowledge, we hope to be able to develop pharmacological interventions that can rescue impaired cognitive flexibility.