Sensory discrimination involves many different neural components, including sensory processing, decision making and sensory-motor mapping, and processing of trial outcomes. While we understand fairly well the basic sensory processing mechanisms that support discrimination behavior, we know very little about how extrasensory factors modulate them. The goal of the present dissertation was thus to advance our circuit-level understanding of cognitive processes that influence sensory processing and perception.

In the first part of this work, I probe the causal relationship between basal forebrain cholinergic activity-related brain state changes and sensory perception and processing in the primary visual cortex. The basal forebrain provides the primary source of cholinergic input to the cortex, and it plays a crucial role in promoting wakefulness and arousal. However, whether rapid changes in basal forebrain neuron spiking in awake animals can dynamically influence sensory perception has been unclear. I show that optogenetic activation of the cholinergic neurons or their V1 axon terminals improved performance of a visual discrimination task on a trial-by-trial basis. In V1, basal forebrain activation enhances visual responses and desynchronized neuronal spiking, which could partly account for the behavioral improvement. Conversely, optogenetic basal forebrain inactivation decreased behavioral performance, synchronized cortical activity and impaired visual responses, indicating the importance of cholinergic activity in normal visual processing. These results underscore the causal role of basal forebrain cholinergic neurons in fast, bidirectional modulation of cortical processing and sensory perception.

In the second part of the dissertation, I investigate the role of the dorsomedial prefrontal cortex (dmPFC) in sensory discrimination. The dmPFC has been implicated in decision-making, cognitive control and outcome monitoring. Although much work has been done to study behavioral task-related activity in this structure, the principles underlying the functional organization of its microcircuits have remained unclear, both spatially and in terms of the function of different cell types. We trained mice on an auditory go/no-go discrimination task and first confirmed that the dmPFC is involved the task: optogenetically inactivating this structure impaired performance by increasing inappropriate lick responses (false alarms), consistent with its proposed role of inhibitory control. Moreover, using deep-tissue microendoscopic calcium imaging from identified cell types in the dmPFC while the mice performed the task, I show for the first time that pyramidal cells in the dmPFC are organized in small functional clusters, while different classes of inhibitory interneurons are highly correlated among themselves but have distinctive activity profiles. Parvalbumin-positive interneurons tended to signal both the presence of auditory stimuli and intention to lick, somatostatin-positive cells were primarily correlated with licking and vasoactive intestinal peptide-positive cells responded to neither. All cell types signaled trial outcome. Pyramidal cells had diverse response properties, and their signal correlations had a sharp spatial drop off within tens of microns. These results significantly advance our understanding of the organization of dmPFC microcircuitry and its role in sensory discrimination.