Arousal regulates frequency tuning in primary auditory cortex.

Changes in arousal influence cortical sensory representations, but the synaptic mechanisms underlying arousal-dependent modulation of cortical processing are unclear. Here, we use 2-photon Ca2+ imaging in the auditory cortex of awake mice to show that heightened arousal, as indexed by pupil diameter, broadens frequency-tuned activity of layer 2/3 (L2/3) pyramidal cells. Sensory representations are less sparse, and the tuning of nearby cells more similar when arousal increases. Despite the reduction in selectivity, frequency discrimination by cell ensembles improves due to a decrease in shared trial-to-trial variability. In vivo whole-cell recordings reveal that mechanisms contributing to the effects of arousal on sensory representations include state-dependent modulation of membrane potential dynamics, spontaneous firing, and tone-evoked synaptic potentials. Surprisingly, changes in short-latency tone-evoked excitatory input cannot explain the effects of arousal on the broadness of frequency-tuned output. However, we show that arousal strongly modulates a slow tone-evoked suppression of recurrent excitation underlying lateral inhibition [H. K. Kato, S. K. Asinof, J. S. Isaacson, Neuron, 95, 412-423, (2017)]. This arousal-dependent "network suppression" gates the duration of tone-evoked responses and regulates the broadness of frequency tuning. Thus, arousal can shape tuning via modulation of indirect changes in recurrent network activity.

Circuit specificity in the inhibitory architecture of the VTA regulates cocaine-induced behavior.

Afferent inputs to the ventral tegmental area (VTA) control reward-related behaviors through regulation of dopamine neuron activity. The nucleus accumbens (NAc) provides one of the most prominent projections to the VTA; however, recent studies have provided conflicting evidence regarding the function of these inhibitory inputs. Using optogenetics, cell-specific ablation, whole cell patch-clamp and immuno-electron microscopy, we found that NAc inputs synapsed directly onto dopamine neurons, preferentially activating GABAB receptors. GABAergic inputs from the NAc and local VTA GABA neurons were differentially modulated and activated separate receptor populations in dopamine neurons. Genetic deletion of GABAB receptors from dopamine neurons in adult mice did not affect general or morphine-induced locomotor activity, but markedly increased cocaine-induced locomotion. Collectively, our findings demonstrate notable selectivity in the inhibitory architecture of the VTA and suggest that long-range GABAergic inputs to dopamine neurons fundamentally regulate behavioral responses to cocaine.