Dopamine Projection Neurons in the VTA Have Distinct Roles in Reward Association and Motivation

Post by Amanda McFarlan 

What's the science?

The ventral tegmental area (VTA) is a midbrain structure with a large population of dopaminergic neurons that innervate the two major regions of the nucleus accumbens (NAc): the core and the shell. It is well known that dopamine projection neurons from the VTA to the NAc facilitate reward association and motivation. However, how dopamine release in the two regions of the NAc acts to facilitate these distinct functions remains unclear. This week in Neuron, Heymann and colleagues investigated the role of dopamine release in the NAc core versus the NAc shell in reward association and motivation.

How did they do it?

The authors used patterns of expression of different neuropeptide-associated genes in the VTA to identify distinct populations of dopamine neurons in the VTA that project to either the core or the shell of the NAc. Then, to understand the importance of these VTA to NAc connections during reward learning, they optogenetically inhibited projection neurons from the VTA to either the NAc shell or core in mice that were being trained in a Pavlovian conditioning paradigm. In this paradigm, mice were conditioned to expect a reward following the presentation of a lever, and had to press the lever and enter their head into an area with food to receive a reward. Next, the authors determined whether optogenetic activation of dopamine projection neurons from the VTA to the NAc would be sufficient to promote intracranial optical self-stimulation (i.e. a rewarding stimulation) in mice. To do this, they targeted the expression of Channelrhodopsin-2 (an excitatory light-gated ion channel) to VTA neurons that project to either the NAc shell or core and allowed mice to lever press for optical stimulation of these neurons. Additionally, the authors investigated the role of VTA projection neurons in reward-seeking behaviour: they trained calorie-restricted mice on a fixed-ratio schedule of food reinforcement (where food is delivered after a set number of responses) for 5 days and then switched the mice to 5 days of intracranial optical self-stimulation. Finally, the authors assessed the effect of simultaneous activation of VTA projection neurons to the NAc core and shell on reward seeking behaviours. 

What did they find?

The authors found that the dopamine neurons in the VTA expressing corticotropin-releasing hormone receptor 1, preferentially innervated neurons in the NAc core, while dopamine neurons in the VTA expressing cholecystokinin, preferentially innervated neurons in the NAc shell. Then, they revealed that inhibiting VTA projection neurons that target the NAc core, but not the shell, during the Pavlovian conditioning paradigm significantly reduced the number of head entries in response to the conditioned stimulus. Similarly, they determined that optogenetic activation of VTA neurons innervating the NAc core, but not the shell, was sufficient to promote intracranial optical self-stimulation in mice, suggesting that VTA to NAc core connections are important for reward association. 

Next, the authors showed that the switch from food reinforcement to intracranial optical self-stimulation in calorie-restricted mice resulted in an acute increase in lever pressing for optogenetic activation of VTA neurons innervating the NAc core on day 1 that decreased over time. However, there was an increase in lever pressing for optogenetic activation of VTA neurons innervating the NAc shell that persisted all 5 days, suggesting that the VTA to NAc shell connections may be important for the motivation involved in maintaining reward-seeking behavior. Finally, the authors revealed that simultaneous activation of the VTA neurons that innervate the NAc core and shell resulted in robust self-stimulation in mice, suggesting that robust behavioural responses emerge from coincident activation of pathways involved in reward association and motivation.

What’s the impact?

This is the first study to show that dopamine neurons in the VTA that preferentially innervate either the NAc core or shell can be isolated using neuropeptide-associated genes. The authors revealed that dopamine neurons in the VTA that project to the NAc core are important for reward association, while dopamine neurons in the VTA that project to the NAc shell are involved in motivation. Altogether, these findings highlight how the coincident activation of both VTA to NAc pathways leads to robust behavioural changes in response to a reward. 

Heymann et al. Synergy of Distinct Dopamine Projection Populations in Behavioral Reinforcement. Neuron (2019). Access the original scientific publication here.