Maturation of flexible cognitive behavior as result of age-dependent formation of prefrontal ensembles in juvenile mice

• Applicant: Professorin Dr. Ileana L. Hanganu-Opatz
• Subject Area: Developmental Neurobiology ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437610067

Most functions contributing to cognitive flexibility, such as working-memory, are thought to mature in parallel with the development of prefrontal circuits and therefore, to progressively augment from childhood to young adulthood, and to decline only after middle age. However, some aspects of cognitive flexibility, such as decision-making strategies, have been found to reach a maximal performance at juvenile age. The principles that govern the emergence of cognitive flexibility in relationship to corresponding neuronal ensembles, in general, and the performance differences for working-memory and decision-making during development, in particular, are poorly understood. Our previous studies in rodents showed that shortly after birth, the medial prefrontal cortex, the core of the brain circuit underlying cognitive flexibility, undergoes profound functional maturation. The entrainment of neonatal prefrontal circuits into oscillatory rhythms is critical for behavioral performance of young adults; on a flip side, disruption of early temporal coordination is a signature of dysfunction in mouse models of mental illness. Besides neonatal development, juvenile period / adolescence has been proposed as a time window of critical sensitivity for (re)organization of circuits and emergence of complex cognitive abilities. Here, we aim to tackle the dynamic assembling of prefrontal ensembles during working-memory and decision-making at different juvenile ages and identify their task-dependent patterning by hippocampal and thalamic inputs. For this, we will combine electrophysiology and optogenetics in a recently developed behavioral setup for monitoring juvenile behavior. We hypothesize that prefrontal ensembles are differently organized and input controlled during working memory and decision making tasks across juvenile development. First, we will monitor how single neurons and temporally-coordinated ensembles in the prelimbic subdivision of PFC encode the age-dependent performance in working-memory and decision-making tasks. In line with the core hypothesis 1, we propose that synchrony-based linking of prefrontal neurons organized through age-dependent embedding of different interneuronal populations underlies the behavioral performance. Second, following the core hypothesis 3, we will explore the contribution of hippocampal and thalamic inputs to the formation of neuronal ensembles during working-memory and decision-making tasks across development. Finally, we will interrogate whether the temporal coordination of prelimbic ensembles at pre-juvenile / juvenile age is predictive of the adult cognitive performance. We expect that the gained insights will identify the developmental principles of cognitive flexibility in relation with the dynamic formation of prefrontal ensembles.

• DFG Programme: Research Units
• Subproject of: FOR 5159: Resolving the prefrontal circuits of cognitive flexibility