Neuropeptide Y signaling regulates recurrent excitation in the auditory midbrain.

Neuropeptides play key roles in shaping the organization and function of neuronal circuits. In the inferior colliculus (IC), which is in the auditory midbrain, Neuropeptide Y (NPY) is expressed by a class of GABAergic neurons that project locally and outside the IC. Most neurons in the IC have local axon collaterals, however the organization and function of local circuits in the IC remain unknown. We previously found that excitatory neurons in the IC can express the NPY Y 1 receptor (Y 1 R + ) and application of the Y 1 R agonist, [Leu 31 , Pro 34 ]-NPY (LP-NPY), decreases the excitability of Y 1 R + neurons. Since NPY signaling regulates recurrent excitation in other brain regions, we hypothesized that Y 1 R + neurons form interconnected local circuits in the IC and that NPY decreases the strength of recurrent excitation in this circuits. To test this hypothesis, we used optogenetics to activate Y 1 R + neurons in mice of both sexes while recording from other neurons in the ipsilateral IC. We found that nearly 80% of glutamatergic IC neurons express the Y 1 receptor, providing extensive opportunities for NPY signaling to regulate local circuits. Additionally, Y 1 R + neuron synapses exhibited modest short-term synaptic plasticity, suggesting that local excitatory circuits maintain their influence over computations during sustained stimuli. We further found that application of LP-NPY decreased recurrent excitation in the IC, suggesting that NPY signaling strongly regulates local circuit function in the auditory midbrain. Our show that Y 1 R + excitatory neurons form interconnected local circuits in the IC, and their influence over local circuits is regulated by NPY signaling. Significance Statement Local networks play fundamental roles in shaping neuronal computations in the brain. The inferior colliculus (IC), localized in the auditory midbrain, plays an essential role in sound processing, but the organization of local circuits in the IC is largely unknown. Here we show that IC neurons that express the Neuropeptide Y 1 receptor (Y 1 R + neurons) comprise most of the excitatory neurons in the IC and form interconnected local circuits. Additionally, we found that NPY, which is a powerful neuromodulator known to shape neuronal activity in other brain regions, decreases the extensive recurrent excitation mediated by Y 1 R + neurons in local IC circuits. Thus, our results suggest that local NPY signaling is a key regulator of auditory computations in the IC.