Top-down modulation of sensory processing allows the animal to select inputs most relevant to current tasks. We found that the cingulate (Cg) region of mouse frontal cortex powerfully influences sensory processing in primary visual cortex (V1) through long-range projections that activate local GABAergic circuits. Optogenetic activation of Cg neurons enhanced V1 neuron responses and improved visual discrimination. Focal activation of Cg axons in V1 caused a response increase at the activation site but decrease at nearby locations (center-surround modulation). While somatostatin-positive GABAergic interneurons contributed preferentially to surround suppression, vasoactive intestinal peptide-positive interneurons were crucial for center facilitation. Long-range cortico-cortical projections thus act through local microcircuits to exert spatially specific top-down modulation of sensory processing.

Dopamine (DA) is a central monoamine neurotransmitter involved in many physiological and pathological processes. A longstanding yet largely unmet goal is to measure DA changes reliably and specifically with high spatiotemporal precision, particularly in animals executing complex behaviors. Here we report the development of genetically-encoded GPCR-Activation-Based-DA (GRABDA) sensors that enable these measurements. In response to extracellular DA, GRABDA sensors exhibit large fluorescence increases (ΔF/F0 ~90%) with subcellular resolution, sub-second kinetics, nanomolar to sub-micromolar affinities, and excellent molecular specificity. GRABDA sensors can resolve a-single-electrical-stimulus evoked DA release in mouse brain slices, and detect endogenous DA release in living flies, fish, and mice. In freely-behaving mice, GRABDA sensors readily report optogenetically elicited nigrostriatal DA release and depict dynamic mesoaccumbens DA signaling during Pavlovian conditioning or during sexual behaviors. Thus, GRABDA sensors enable spatiotemporally precise measurements of DA dynamics in a variety of model organisms while exhibiting complex behaviors.

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 is unclear. Here we show that basal forebrain cholinergic neurons rapidly regulate cortical activity and visual perception in awake, behaving mice. 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 enhanced 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.