Dependence on drugs of abuse is a major clinical burden in the USA and share the highest comorbidity with anxiety. The ventral tegmental area (VTA) and its dopamine projections are at the core of the neurobiological mechanisms of reward processing whereas the bed nucleus of the stria terminalis (BNST) is one of the major effectors of anxious states. The neuronal connectivity between BNST and VTA anatomically bridges anxiety and addiction centers but their interaction remains obscure. Apart from dopamine neurons, VTA contains non- segregated GABA and glutamate population as well as neurons that can release more than one of these classical small molecule transmitters. VTA VGLUT2 (glutamate) projections to key brain structures can drive behavioral reinforcement upon optogenetic stimulation. Still, a subset of these VGLUT2 neurons co-release dopamine or indirectly recruit DA neurons. Thus, a fundamental open question remains: Is there a dopamine- independent glutamate-driven reinforcement emanating from VTA? We will use a novel genetic mouse model that lacks the ability to synthetize dopamine in VGLUT2 neurons to address this critical question that has the ability to change our understanding of reward neurotransmission in the brain. Our preliminary results are in line with a dopamine-independent positive reinforcement driven by optostimulation of glutamate neurons. Also: Do these glutamate neurons collateralize distally or locally? How are these different tracts integrating rewarding and aversive information? To provide a description of VTA glutamate neurocircuitry and in vivo activity we will use projection-specific manipulation and fiber photometry recordings during behavior. These studies will significantly expand our understanding of VTA glutamate function in reward and will establish new grounds for more focused investigations on modulation of this system by substances of abuse.
These aims have been proposed for investigation during the K99 phase of the award, and have been designed to be complementary but not interdependent. The training acquired during the K99 phase in behavioral optogenetics and fiber photometry will facilitate the transition to the R00 phase where this newly-acquired skillset will be applied. During the first years of independent career the main focus will be on a newly-described neuron population of the BNST, a structure that undergoes modulation by multiple drugs of abuse. Though BNST VGLUT2 and GABA projections to the VTA are implicated in reward modulation, there is a VGLUT3 population that project to brain structures relevant to reward and aversion, including the VTA, but with no known role. The use of mouse models, viral-gene delivery techniques, electrophysiology, behavioral optogenetics and fiber photometry will offer a first description of the role of BNST VGLUT3 neurons on motivated-behaviors and provide much new preliminary characterization at a circuit-based and behavioral level. The results of this study will pave the way for specific targeting of this novel actor in reward and aversion, leading to therapeutic interventions in addiction and the underlying psychiatric diseases that make individuals vulnerable, including anxiety and depression.
The ventral tegmental area (VTA) is central for motivated behaviors through its dopamine and non-dopamine projections that play a significant role in reward. We propose to study the dopamine- independency of glutamate-driven reward mechanisms emanating from VTA, and characterize their local and distal connectivity. The bed nucleus of the stria terminalis sends direct VGLUT3-expressing projections to the VTA and other structures relevant to reward and aversive states processing but the functional significance remains unknown; we will test their functional connectivity, modulation and role in motivated behaviors.
