Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons

Prevost, E. D.; Phillips, A.; Lauridsen, K.; Enserro, G.; Rubinstein, B.; Alas, D.; McGovern, D. J.; Ly, A.; Banks, M.; McNulty, C. J.; Kim, Y. S.; Fenno, L. E.; Ramakrishnan, C. H.; Deisseroth, K.; Root, D. H.

doi:10.1101/2023.04.06.535959

bioRxiv · 10.1101/2023.04.06.535959

Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons

Prevost, E. D.·Phillips, A.·Lauridsen, K.·Enserro, G.·Rubinstein, B.·Alas, D.·McGovern, D. J.·Ly, A.·Banks, M.·McNulty, C. J.·Kim, Y. S.·Fenno, L. E.·Ramakrishnan, C. H.·Deisseroth, K.·Root, D. H.

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Abstract

A unique population of ventral tegmental area (VTA) neurons co-transmits glutamate and GABA as well as functionally signals rewarding and aversive outcomes. However, the circuit inputs to VTA VGluT2+VGaT+ neurons are unknown, limiting our understanding of the functional capabilities of these neurons. To identify the inputs to VTA VGluT2+VGaT+ neurons, we coupled monosynaptic rabies tracing with intersectional genetic targeting of VTA VGluT2+VGaT+ neurons in mice. We found that VTA VGluT2+VGaT+ neurons received diverse brain-wide inputs. The largest numbers of monosynaptic inputs to VTA VGluT2+VGaT+ neurons were from superior colliculus, lateral hypothalamus, midbrain reticular nucleus, and periaqueductal gray, whereas the densest inputs relative to brain region volume were from dorsal raphe nucleus, lateral habenula, and ventral tegmental area. Based on these and prior data, we hypothesized that lateral hypothalamus and superior colliculus inputs were glutamatergic neurons. Optical activation of glutamatergic lateral hypothalamus neurons robustly activated VTA VGluT2+VGaT+ neurons regardless of stimulation frequency and resulted in flee-like ambulatory behavior. In contrast, optical activation of glutamatergic superior colliculus neurons activated VTA VGluT2+VGaT+ neurons for a brief period of time at high stimulation frequency and resulted in head rotation and arrested ambulatory behavior (freezing). For both pathways, behaviors induced by stimulation were uncorrelated with VTA VGluT2+VGaT+ neuron activity. However, stimulation of glutamatergic lateral hypothalamus neurons, but not glutamatergic superior colliculus neurons, was associated with VTA VGluT2+VGaT+ footshock-induced activity. We interpret these results such that inputs to VTA VGluT2+VGaT+ neurons may integrate diverse signals related to the detection and processing of motivationally-salient outcomes. Further, VTA VGluT2+VGaT+ neurons may signal threat-related outcomes, possibly via input from lateral hypothalamus glutamate neurons, but not threat-induced behavioral kinematics.

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Prevost, E. D., Phillips, A., Lauridsen, K., Enserro, G., Rubinstein, B., Alas, D., McGovern, D. J., Ly, A., Banks, M., McNulty, C. J., Kim, Y. S., Fenno, L. E., Ramakrishnan, C. H., Deisseroth, K., Root, D. H.. 2023-04-07. Monosynaptic inputs to ventral tegmental area glutamate and GABA co-transmitting neurons. https://doi.org/10.1101/2023.04.06.535959

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