There is no doubting the way we are drawn towards the good things in life that promise some kind of reward – whether it’s a brand-new car or a delicious cake. Our ‘reward response’ is something we experience every day. Yet while we have known which brain regions are involved in reward-related behavior for some time, the fine details of the neural activity that takes place at the moment when we respond to something rewarding have been less well understood. 

But new research, published in Neuroscience, provides a clearer picture of the neural control of reward behavior in mice. The research is not only important for our understanding of the basic science of reward response, but it could also inform future research into what happens when our reward response goes awry – in addiction.

A key brain region implicated in reward behavior is the medial prefrontal cortex (mPFC), the region at the front of the brain involved in learning and decision making. While some cells in the mPFC, prelimbic neurons, promote behavioral responses, another group, the infralimbic neurons, are thought to suppress behavioral responses. Together they provide a neural stop/go control on behaviour. It means that when we move towards something that is likely to be rewarding, such as food, the activity of the prelimbic neurons increases, while the infralimbic neurons are dialed down.

Another brain region, the ventral tegmental area (VTA), located in the midbrain, is also known to be important in reward response. Neurons here are activated at times of behavior aimed at gaining a reward.

While lots of research has focused on dopamine neurons in the VTA given that they make up most of this brain region, researchers at Louisiana State University (LSU) in the US set out to investigate the role of glutamate neurons in the VTA in reward response because of the connection they form between the VTA and mPFC. “The parts of the brain involved with learning and memory, like the hippocampus and prefrontal cortex, receive significant amount of glutamate projections from the VTA,” says Dr. Olalekan Ogundele, an Associate Professor at LSU.

Dr. Olalekan Ogundele

To examine the role of the VTA/mPFC glutamate neuronal pathway in reward-related behavior, mouse behavior and neuronal activity were measured both with and without the suppression of glutamate cells in the VTA in reward response tests. Mice were placed in a rectangular chamber containing four reward pots at each corner. In an initial experiment, mice were first presented with food in one pot, and after a break of 45 minutes in their ‘home cage’, they were returned to the chamber and no reward was present. Then the frequency and duration of their visits to the target corner with the pot that previously contained the food reward, and the other three non-target corners were recorded to determine whether they still associated the corner that previously held food with a reward. 

With the same set of mice, the test was repeated after glutamate neurons were inactivated in their VTA as they acquired the food reward. A viral vector was injected into the VTA delivering a gene coding for a light-controlled inhibitory opsin to the glutamate neurons. When this protein is exposed to a specific light wavelength, it inhibits the activity of neurons by hyperpolarizing them, making it harder for them to produce action potentials. This light-mediated control of neurons is an important tool in optogenetics.

In the glutamate neuron inhibition test, when mice reached a pot containing a food reward, an LED light was switched on to activate the inhibitory opsin, inhibiting the glutamate neurons in the VTA, with temporal precision, to see what impact this would have on the behavior of the mice – and activity in their mPFC. Throughout all these tests, electrodes implanted into the infralimbic cortex, within the mPFC of the mice, measured the extracellular action potentials of neurons there. 

Tolulope Adeyelu

In the initial experiment, with the VTA glutamate neurons still active in the mice, they showed a preference for the corner of the chamber where there had previously been a food reward – even when no reward was present, showing they had learned to associate that corner with food. But when the VTA glutamate neurons were inhibited at the moment when a mouse reached a pot containing food, it did not subsequently show a preference for that corner of the chamber – recorded as a decrease in the frequency and duration of visits.

Looking at what was happening inside the brain during these tests, before the glutamate neurons were switched off, the firing rate of infralimbic neurons reduced when mice were experiencing the food rewards and then subsequently exploring a corner of the chamber that previously housed a food reward. But when the VTA glutamate neurons were suppressed, the firing rate of infralimbic neurons was not reduced as much and it reduced for a shorter period. In other words, they were more likely to fire and act as a block or ‘stop’ on a reward-led behavioral response. “This shows us that the glutamate neurons in the VTA are not only involved with learning that there is a reward, but also control the weight associated with that reward,” says Ogundele.

But he says some caution is needed when interpreting the results. “We modulated the glutamate neurons while they were in the VTA. Therefore, in addition to their projections to the mPFC, we also modulated glutamate neurons going from the VTA to the nucleus accumbens, the hippocampus and other brain regions.” This means that it is not possible to say that the reduction in reward-induced behavior after the VTA was suppressed was specifically down to the VTA-mPFC link. Ogundele says the next step will be to inhibit the VTA glutamate terminals that reached the mPFC. “That way we will be able to narrow it down exclusively to that projection.”

While the research is focused on understanding the neural mechanisms of reward, it could also inform the work of others conducting applied research. “Our work has a basic science feel to it,” says Ogundele. “But our findings will also be useful for those studying addiction neurobiology.”

It is the connection between this research and addiction studies that piqued the interest of Tolulope Adeyelu, first author of the Neuroscience study. “When I was studying for my BSc, my research was on the modulation of the brain using drugs to understand addiction patterns using mice models,” he says. “Now I have been able to do research at this magnitude with this confidence and data it has been enriching.” Adeyelu’s undergraduate degree was in biochemistry, followed by an MSc in biomedical science and then a PhD in computational biology. For Tashonda Vaughn, a PhD student who was also involved in the research, this was an opportunity to gain experience in a study involving animals. “The animal handling was a challenge. But becoming a co-author on a paper is my biggest achievement so far,” she says. 

Tashonda Vaughn

Ogundele says advances in neuroscience research technology providing genetic tools to modulate specific neuron types within a targeted brain region are enabling exciting new insights. The ability to record milliseconds of brain activity and make the connection between neural activity patterns and animal behavior is also enabling neuroscience to advance. Ogundele first completed an undergraduate degree in human anatomy, followed by a Master’s and PhD in the same discipline at the University of Ilorin in Nigeria. It was through these studies that he discovered his interest in electrophysiology. “I always thought, wouldn’t it be nice to see how the brain does stuff at the moment it is being done – to see what is happening in real-time.” Funding from IBRO fellowships enabled him to travel to research institutions in different countries and work with mentors who were closely matched to his interests. “It gave me an understanding of the possibilities of what I could do if I had the right tools,” he says.

Ogundele has published research in Neuroscience on several occasions. “I think the peer review process is a blessing. I don’t believe there is a paper I have worked on where the reviewers’ comments have not improved it. I like the fact that you get detailed explanations in the review process.”

This article was written by Dr. Andy Ridgway.

About Neuroscience

Established in 1976, Neuroscience is the flagship journal of IBRO. The journal features papers describing the results of original research on any aspect of the scientific study of the nervous system. Papers of any length are considered for publication provided that they report significant, new, and carefully confirmed findings with full experimental details. Together with IBRO Neuroscience Reports, IBRO’s open access journal, Neuroscience plays a crucial role in supporting the organization’s global neuroscience activities, as ​​proceeds from both journals support more than 90% of IBRO’s initiatives.