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Monosynaptic Inputs to Ventral Tegmental Area Glutamate and GABA Co-transmitting Neurons

Year: 2024
Type: article
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.
DOI: 10.1523/jneurosci.2184-23.2024
Authors: Emily D. Prévost, Alysabeth Phillips, Kristoffer Lauridsen, Gunnar Enserro, Bodhi Rubinstein, Daniel Alas, Dillon J. McGovern, Annie Ly, Hayden Hotchkiss, Makaila Banks, Connor McNulty, Yoon Seok Kim, Lief E. Fenno, Charu Ramakrishnan, Karl Deisseroth, David H. Root
Institutions: University of Colorado Boulder, Stanford Medicine, Stanford University, The University of Texas at Austin, Howard Hughes Medical Institute, University of Colorado System
Language: English
Open Access status: hybrid
Funders: Brain and Behavior Research Foundation, Boettcher Foundation, National Alliance for Research on Schizophrenia and Depression, Shurl and Kay Curci Foundation, National Institutes of Health, National Institute of Standards and Technology, University of Colorado Boulder, National Institute of Mental Health, National Institute on Drug Abuse
Awards: Opera Phenix High Throughput and High Content Confocal Microscope, Genetic dissection of ventral tegmental area glutamate and GABA neurons in reward and aversion, G1766166545, G2464515878, G3428418025, G3869925363, NIST-CU COOPERATIVE AGREEMENT 2015-2020 (FOR JILA), G4588088165, G8928662560, Neural circuit dynamics of drug action:revealing, uncoupling, and restoring altered brain states
OpenAlex ID: W4402892292
FWCI: 0.942
Cites: 70
Cited by: 6
Related to: 10