Neuronal connectivity within the mesolimbic system

National Institute On Drug Abuse

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Abstract

PThe ventral tegmental area (VTA) contains dopamine neurons intermixed with GABA-releasing (expressing vesicular GABA transporter, VGaT), glutamate-releasing (expressing vesicular glutamate transporter 2, VGluT2), and co-releasing (co-expressing VGaT and VGluT2) neurons. By delivering INTRSECT viral vectors into the VTA of double vglut2-Cre/vgat-Flp transgenic mice, we targeted specific VTA cell populations for ex vivo recordings. We found that VGluT2+ VGaT- and VGluT2+ VGaT+ neurons on average had relatively hyperpolarized resting membrane potential, greater rheobase, and lower spontaneous firing frequency compared to VGluT2- VGaT+ neurons, suggesting that VTA glutamate-releasing and glutamate-GABA co-releasing neurons require stronger excitatory drive to fire than GABA-releasing neurons. In addition, we detected expression of Oprm1mRNA (encoding opioid receptors, MOR) in VGluT2+ VGaT- and VGluT2- VGaT+ neurons, and that the MOR agonist DAMGO hyperpolarized neurons with these phenotypes. Collectively, we demonstrate the utility of the double transgenic mouse to access VTA glutamate, glutamate-GABA, and GABA neurons to determine their electrophysiological properties. The VTA dopamine, GABA, and glutamate neurons have been implicated in both reward and aversion. Given that innate defensive escape is triggered by aversive stimuli, we determined whether VTA glutamate or GABA neurons play a role in innate defensive behavior. By VTA cell-type specific genetic ablation, we found that ablation of glutamate, but not GABA, neurons abolishes escape behavior in response to threatening stimuli (presence of a predator odor and the attack of a predator). We determined that escape behavior is also decreased by chemogenetic inhibition of VTA-glutamate neurons, and detected increases in activity in VTA-glutamate neurons in response to threatening stimuli. By ultrastructural and electrophysiological analysis, we established that VTA-glutamate neurons receive a major monosynaptic glutamate input from the lateral hypothalamic area (LHA) and found that photoinhibition of this input decreases escape responses to threatening stimuli. Collectively, our findings indicate that VTA-glutamate neurons are activated by and required for innate defensive responses, and that information on threatening stimuli to VTA-glutamate neurons is relayed by LHA-glutamate neurons.