(Fe)male rat brain - the effect of sex on the individual behavioral strategies and their neuronal correlates

• Applicant: Professorin Dr. Ilka Diester
• Subject Area: Experimental and Theoretical Network Neuroscience ; Cognitive, Systems and Behavioural Neurobiology
• Term: since 2021
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437610067

Adaptive decision-making depends on the prefrontal cortex (PFC), which integrates information about rewards, actions, and outcomes. Recent studies highlight that individual differences, including sex and hormonal status, critically shape decision-making strategies. Specific neural circuits, including the prelimbic cortex and anterior cingulate cortex, show sex-dependent encoding of motivational outcomes with hormonal modulation of risk-taking behavior. Furthermore, thalamic nuclei such as the mediodorsal and ventral medial/anterior thalamus have emerged as critical hubs supporting prefrontal functions including cognitive flexibility, effort-based decision-making, and motor planning.To study how internal and external environmental factors shape decision-making, we developed a novel reward- and effort-based behavioral task, the HillY-maze. This setup allows rats to balance reward probabilities against effort costs by varying both reward magnitude and arm slope within a Y-maze design. Using this platform, we characterized individual decision-making strategies, revealed sex-dependent biases, and modeled behavioral dynamics with reinforcement learning and Markov process-based approaches. We further combined chronic Neuropixels recordings, optogenetic manipulation, and pose estimation to link individual behavioral strategies to prefrontal cortical activity patterns, uncovering flexible neuronal ensemble dynamics and unexpected effects of prelimbic cortex modulation on decision-making efficiency.In the upcoming funding period, we aim to uncover how prefrontal circuits contribute to individual and sex-specific differences in decision-making. Building on our first-phase findings that prefrontal dynamics reflect task parameters, that optogenetic stimulation in the prelimbic cortex shift strategies, and that rats adopt individual, sex-biased strategies, we will now investigate intra- and inter-individual behavioral variability and its neural underpinnings. Specifically, we will (1) characterize individual and sex-dependent decision-making strategies, (2) define their neuronal correlates in prefrontal cortex subregions, (3) identify prefrontal activity patterns predicting or driving strategies through targeted manipulations, and (4) determine the role of prefrontal outputs to thalamic nuclei in shaping behavioral variability. This work will advance our understanding of how cognitive flexibility arises from individual- and sex-specific neuronal network dynamics in the PFC.

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