Supervisors info:
Ηλίας Μανωλάκος, Καθηγητής, Τμήμα Πληροφορικής και Τηλεπικοινωνιών, Εθνικό και Καποδιστριακό Πανεπιστήμιο Αθηνών
Summary:
Working Memory (WM) refers to the short-term maintenance of information while the subject executes cognitive tasks such as learning and planning. Although many areas in the brain are involved in the function of Working Memory, the Dorsolateral Prefrontal Cortex and the Ventral Tegmental Area of the Midbrain, both being part of the mesocortical dopamine system, seem to play an essential role in WM’s regulation. This is believed to be so because dysfunctions in these two areas are linked with reduced Working Memory performance and disorders such as schizophrenia.
Schizophrenia is a yet unexplained mental disorder with severe consequences in patient’s life. Its symptoms can be grouped into three categories: (a) the positive symptoms, including hallucinations and delusions, (b) the negative symptoms, including decreased motivation and social withdrawal, and (c) the most common cognitive symptoms, which include Working Memory deficits, as well as reduced attention and learning. Among the many factors contributing to the disorder, the neurotransmitter dopamine and its D1 and D2 receptors hold a prominent position, as dysregulation of dopamine release and activation of these receptors is linked with the emergence of schizophrenia’s symptoms. Their involvement is further backed by theories such as the Dual-State theory of schizophrenia and the fact that traditional antipsychotic drugs target especially D2 receptors.
Most computational models attempting to simulate the function of the mesocortical system focus on the D1 receptor. The computational studies for D1 receptors fall into two categories depending on the modeling level of the circuit. Biophysical models concentrate on the Prefrontal Cortex representation and the indirect incorporation of the effects of D1 receptors. On the other hand, neural mass models, describing the average activity of neurons at the population level, attempt to simulate the entire mesocortical pathway’s function, explicitly adding the effects of D1 receptors. However, there are few studies exploring the role of D2 receptors and their interplay with D1 receptors. In addition, these works either build a biophysical circuit, which is inherently complex or model only one receptor in their neuronal populations.
To address these limitations, we focused this research on modeling the interplay of D1 and D2 receptors and their concurrent impact on the mesocortical system and Working Memory function. To that end, we developed a parsimonious dynamical network of the mesocortical pathway using the neural mass approach. The model includes the Dorsolateral Prefrontal Cortex and the Midbrain and their respective neuronal populations and explicitly incorporates the relative activation of both D1 and D2 receptors.
The mathematical analysis and exploration of the model via simulation have shown that dopamine releasability and the ratio of the two receptor sensitivities play a prominent role in modulating the sustained activity of pyramidal neurons on delay-period. More specifically, there is a range of values of both parameters where the system can maintain a Working Memory representation. Conversely, too low dopamine releasability or high sensitivity ratio values push the dynamical system beyond bistability, where it can no longer maintain Working Memory items. Thus exploring the space of these two parameters offers additional ways into interpreting schizophrenia’s symptoms and the action of antipsychotic drugs.
Keywords:
Dynamical Systems, Working Memory, Dopamine receptors, Schizophrenia, Neural circuits, Simulation, Computational Neuroscience
