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 Y1 receptor (Y1R+) and application of the Y1R agonist, [Leu31, Pro34]-NPY (LP-NPY), decreases the excitability of Y1R+ neurons. As NPY signaling regulates recurrent excitation in other brain regions, we hypothesized that Y1R+ neurons form interconnected local circuits in the IC and that NPY decreases the strength of recurrent excitation in these circuits. To test this hypothesis, we used optogenetics to activate Y1R+ 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 Y1 receptor, providing extensive opportunities for NPY signaling to regulate local circuits. Additionally, Y1R+ 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 findings show that Y1R+ 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 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 Y1 receptor (Y1R+ neurons) make up 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 Y1R+ neurons in local IC circuits. Thus, our results suggest that local NPY signaling is a key regulator of auditory computations in the IC.

Identifying neuron types and circuit mechanisms in the auditory midbrain.

The inferior colliculus (IC) is a critical computational hub in the central auditory pathway. From its position in the midbrain, the IC receives nearly all the ascending output from the lower auditory brainstem and provides the main source of auditory information to the thalamocortical system. In addition to being a crossroads for auditory circuits, the IC is rich with local circuits and contains more than five times as many neurons as the nuclei of the lower auditory brainstem combined. These results hint at the enormous computational power of the IC, and indeed, systems-level studies have identified numerous important transformations in sound coding that occur in the IC. However, despite decades of effort, the cellular mechanisms underlying IC computations and how these computations change following hearing loss have remained largely impenetrable. In this review, we argue that this challenge persists due to the surprisingly difficult problem of identifying the neuron types and circuit motifs that comprise the IC. After summarizing the extensive evidence pointing to a diversity of neuron types in the IC, we highlight the successes of recent efforts to parse this complexity using molecular markers to define neuron types. We conclude by arguing that the discovery of molecularly identifiable neuron types ushers in a new era for IC research marked by molecularly targeted recordings and manipulations. We propose that the ability to reproducibly investigate IC circuits at the neuronal level will lead to rapid advances in understanding the fundamental mechanisms driving IC computations and how these mechanisms shift following hearing loss.

GluN2D-containing NMDA receptors enhance temporal integration in VIP neurons in the inferior colliculus.

Along the ascending auditory pathway, there is a broad shift from temporal coding, which is common in the lower auditory brainstem, to rate coding, which predominates in auditory cortex. This temporal-to-rate transition is particularly prominent in the inferior colliculus (IC), the midbrain hub of the auditory system, but the mechanisms that govern how individual IC neurons integrate information across time remain largely unknown. Here, we report the widespread expression of GluN2C and GluN2D mRNA in IC neurons. GluN2C/D-containing NMDA receptors are relatively insensitive to voltage-dependent Mg2+ block, and thus can activate at resting membrane potential. Using in situ hybridization and pharmacology, we show that VIP neurons in the IC express GluN2D-containing NMDA receptors that are activatable by ascending input from T-stellate cells in the anteroventral cochlear nucleus and commissural inputs from the contralateral IC. In addition, GluN2D-containing receptors have much slower kinetics than other NMDA receptors, and we found that GluN2D-containing receptors facilitate temporal summation in VIP neurons by prolonging the time window for synaptic integration. These results suggest that GluN2C/D-containing NMDA receptors support the shift from temporal to rate coding in the auditory system by facilitating the integration of ascending inputs.

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 located in the auditory midbrain, Neuropeptide Y (NPY) is expressed by a large class of GABAergic neurons that project locally as well as outside the IC. The IC integrates information from numerous auditory nuclei making the IC an important hub for sound processing. Most neurons in the IC have local axon collaterals, however the organization and function of local circuits in the IC remains largely unknown. We previously found that neurons in the IC can express the NPY Y1 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. To investigate how Y 1 R + neurons and NPY signaling contribute to local IC networks, we used optogenetics to activate Y 1 R + neurons while recording from other neurons in the ipsilateral IC. Here, we show that 78.4% of glutamatergic neurons in the IC express the Y1 receptor, providing extensive opportunities for NPY signaling to regulate excitation in local IC circuits. Additionally, Y 1 R + neuron synapses exhibit 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 decreases recurrent excitation in the IC, suggesting that NPY signaling strongly regulates local circuit function in the auditory midbrain. Together, our data show that excitatory neurons are highly interconnected in the local IC and their influence over local circuits is tightly regulated by NPY signaling.

Teaching Python for Data Science: Collaborative development of a modular & interactive curriculum.

We are bioinformatics trainees at the University of Michigan who started a local chapter of Girls Who Code to provide a fun and supportive environment for high school women to learn the power of coding. Our goal was to cover basic coding topics and data science concepts through live coding and hands-on practice. However, we could not find a resource that exactly met our needs. Therefore, over the past three years, we have developed a curriculum and instructional format using Jupyter notebooks to effectively teach introductory Python for data science. This method, inspired by The Carpentries organization, uses bite-sized lessons followed by independent practice time to reinforce coding concepts, and culminates in a data science capstone project using real-world data. We believe our open curriculum is a valuable resource to the wider education community and hope that educators will use and improve our lessons, practice problems, and teaching best practices. Anyone can contribute to our Open Educational Resources on GitHub.