Synaptic function and plasticity in identified inhibitory inputs onto VTA dopamine neurons

Abstract

Ventral tegmental area (VTA) dopaminergic neurons are key components of the reward pathway, and their activity is powerfully controlled by a diverse array of inhibitory GABAergic inputs. Two major sources of GABAergic nerve terminals within the VTA are local VTA interneurons and neurons in the rostromedial tegmental nucleus (RMTg). Here, using optogenetics, we compared synaptic properties of GABAergic synapses on VTA dopamine neurons using selective activation of afferents that originate from these two cell populations. We found little evidence of co-release of glutamate from either input, but RMTg-originating synaptic currents were reduced by strychnine, suggesting co-release of glycine and GABA. VTA-originating synapses displayed a lower initial release probability, and at higher frequency stimulation, short-term depression was more marked in VTA- but not RMTg-originating synapses. We previously reported that nitric oxide (NO)-induced potentiation of GABAergic synapses on VTA dopaminergic cells is lost after exposure to drugs of abuse or acute stress; in these experiments, multiple GABAergic afferents were simultaneously activated by electrical stimulation. Here we found that optogenetically-activated VTA-originating synapses on presumptive dopamine neurons also exhibited NO-induced potentiation, whereas RMTg-originating synapses did not. Despite providing a robust inhibitory input to the VTA, RMTg GABAergic synapses are most likely not those previously shown by our work to be persistently altered by addictive drugs and stress. Our work emphasises the idea that dopamine neuron excitability is controlled by diverse inhibitory inputs expected to exert varying degrees of inhibition and to participate differently in a range of behaviours.

Nitric Oxide-Mediated Plasticity of Interconnections Between T-Stellate cells of the Ventral Cochlear Nucleus Generate Positive Feedback and Constitute a Central Gain Control in the Auditory System

“…Recordings from T-stellate cells showed no sign of changes to the input resistance, resting potentials, or shapes and thresholds of action potentials, suggesting that NO affects synaptic machinery rather than electrical excitability, but it is possible that NO alters the electrical excitability of distant terminals or interneurons. NO is implicated in potentiation in many parts of the brain, including the hippocampus (Zhuo et al, 1994;Castillo, 2012), cerebellum (Shin and Linden, 2005;Qiu and Knöpfel, 2007), and ventral tegmental area (Polter et al, 2018), and increases the quantal content of cholinergic efferent fibers in the cochlea (Kong et al, 2013) through signaling pathways that have not been completely elucidated. T-stellate cells contain NMDA receptors for regulating Ca 2ϩ entry, nNOS for generating NO, and NO-GC for detecting NO (Figs.…”

Neurochemical signaling of reward and aversion by ventral tegmental area glutamate neurons

“…After at least three weeks, mice were shipped to George Washington University for slice physiology recording. After one week of acclimation, acute slices were prepared as previously described 22 . Following perfusion, the brain was rapidly dissected and horizontal slices (220 μM) were prepared in warmed NMDG ringer using a vibratome.…”

Alpha-1 Adrenergic Receptors Modulate Glutamate and GABA Neurotransmission onto Ventral Tegmental Dopamine Neurons during Cocaine Sensitization

“…Also, the presence of local Glu neurons has been demonstrated [28,29]. On the other hand, the mesopontine tegmentum, the lateral habenula via the rostromedial tegmentum, nucleus accumbens, and the periaqueductal gray provide GABAergic innervation to the VTA [30][31][32].…”

“…Also, the presence of local Glu neurons has been demonstrated [28,29]. On the other hand, the mesopontine tegmentum, the lateral habenula via the rostromedial tegmentum, nucleus accumbens, and the periaqueductal gray provide GABAergic innervation to the VTA [30][31][32].Chronic cocaine exposure leads to a progressive increase in locomotor activity in rats termed, behavioral sensitization [33,34]. As a result of chronic drug exposure, neuroadaptations in mesocorticolimbic synapses, including DA, Glu, and GABA neurotransmission, occur [35][36][37].…”