Target dependent effects of peptide signaling in the VTA

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The long-term goal of my research program is to determine how learning about rewards and motivation to obtain them is encoded in neural activity in an area of the brain responsible for reward-seeking behaviours. The dopamine neurons of the ventral tegmental area (VTA) encode cues in the environment that predict stimuli of positive or negative valence, but how this occurs and if this changes with different motivational states is not well understood. One possibility is that neuropeptides can modulate dopamine neurons in a state-dependent manner. For example, our recent work has demonstrated that satiety peptides suppress the output of dopamine neurons. Furthermore, the neuropeptide orexin released from neurons of the lateral hypothalamus (LH), are activated in response to arousal, and plays a key role in motivating animals to seek rewards. The peptides orexin and dynophin are co-localized in LH neurons that project to the VTA. Interestingly, orexin action in the VTA is stimulatory whereas dynorphin action is inhibitory. Therefore, if both peptides are released simultaneously, it is unclear how reward-seeking effects of orexin are promoted. Understanding how this circuit functions adds a highly novel component to understanding the state-dependency of learning reward-predictive cues. We hypothesize that orexin and dynorphin are co-released in the VTA and modulate independent VTA projections to other brain regions such as the basolateral amygdala (BLA), nucleus accumbens (NAc) or medial prefrontal cortex (mPFC). To address this hypothesis, we propose 2 objectives:***1) Objective 1: Determine if and how orexin and dynorphin independently modulate VTA DA→ BLA, VTA DA→ NAc or VTA DA→ mPFC. Ie. Are all actions of orexin in the VTA are equal?***2) Objective 2: Determine if endogenously co-released orexin and dynorphin can independently modulate excitatory synaptic transmission onto VTA DA neurons that project to either the BLA or the NAc and determine how this modulation contributes to motivated behaviour. ******The overarching goal of the research proposed here is to understand how the LH orexin/dynorphin input to the VTA modulates dopamine neuronal activity in a target-dependent manner. This circuit is an important part of how reward learning occurs and will integrate with the main themes of my lab. This work will be of wide interest because it touches on the foundations of motivation, arousal and reinforcement learning. In addition, the multifaceted nature of this research will provide trainees with extensive technical skills as well as collecting, analyzing and interpreting data.******Ultimately, my research program will further our understanding of how we encode salient cues that drive goal-directed behaviour. ********