Optogenetic Dissection of Prefrontal Cortex-Subcortical Circuits in Decision-Making: Recent Advances

Understanding the neural basis of decision-making critically relies on elucidating how different brain regions communicate to integrate sensory information, value, and context to guide behavior. The prefrontal cortex (PFC), particularly its interactions with subcortical structures like the amygdala and basal ganglia, plays a pivotal role in these complex processes. Optogenetics has emerged as a powerful tool to causally investigate these long-range neural circuits by enabling precise control over neuronal activity. This review synthesizes recent advancements, focusing on studies from the last five years that employ optogenetics in mice, combined with in vivo electrophysiology or functional imaging, to map and dissect the function of PFC projections involved in decision-making, with a particular emphasis on value-based and evidence-accumulation tasks.

The intricate circuitry connecting the PFC with subcortical nuclei is fundamental for decision-making. For instance, the basolateral amygdala (BLA) is crucial for processing emotional and value-related information that influences choices. Recent work has begun to delineate the specific projection pathways from distinct BLA subregions to PFC areas. A key study by Manoocheri and Carter (2022) utilized anatomical tracing, ex vivo recordings, and in vivo silicon probe recordings alongside optogenetics to map projections from the rostral (rBLA) and caudal (cBLA) BLA to the prelimbic (PL) and infralimbic (IL) PFC in mice. Their findings revealed a distinct circuit organization, where rBLA preferentially targets layer 2 cortico-amygdalar neurons in the PL, while cBLA targets layer 5 pyramidal tract neurons in the IL. Furthermore, rBLA influences PL layer 5 neurons indirectly through local circuits. This research provides a detailed map of how different amygdala subregions engage specific PFC networks, thereby shaping the output of these critical decision-making hubs (1). Such precise circuit mapping is essential for understanding how affective states and learned values are integrated into decision processes.

Complementing these amygdala-PFC pathways, other subcortical inputs also shape PFC function in decision-making. A review by Sieveritz et al. (2018) highlights the significant, yet often underappreciated, role of ventral motor thalamic nuclei in providing inputs to the PFC. Beyond the well-established mediodorsal thalamus projections, these ventral nuclei project to layer 1 of the PFC and are implicated in associative learning and action selection, processes central to motor decision-making. This work underscores the importance of considering diverse thalamic inputs when mapping PFC circuitry for decision-making, alongside inputs from structures like the amygdala and basal ganglia (2).

Collectively, these studies exemplify the progress made in using optogenetics to dissect the functional connectivity of long-range circuits relevant to decision-making. The combination of optogenetic manipulation with in vivo electrophysiology allows researchers to not only identify projection targets but also to directly assess the causal impact of activating or inhibiting specific pathways on neural activity and behavior during decision tasks. While Paper 1 provides a direct example of this methodology applied to amygdala-PFC circuits, Paper 2 offers a broader perspective on the network architecture, emphasizing the convergence of inputs from various subcortical regions onto the PFC. Future research could further leverage these techniques to explore how these distinct PFC-subcortical circuits interact during more complex value-based and evidence-accumulation decision-making paradigms, potentially integrating functional imaging to observe population activity alongside targeted optogenetic control.