Researchers at the University Of North Carolina School Of Medicine have identified for the first time how two brain regions interact to promote emotionally motivated behaviors associated with anxiety and reward. The findings of this work, published online by Nature and led by NARSAD Young Investigator Grantee, Garret Stuber, Ph.D., could lead to new therapies for addiction, anxiety, and depression.

“For many years it’s been known that dopamine neurons in the VTA [ventral tegmental area of the midbrain] are involved in reward processing and motivation. For example, they’re activated during exposure to drugs of abuse and naturally rewarding experiences,” says Dr. Stuber, assistant professor in the departments of Psychiatry and Cell Biology and Physiology, and the UNC Neuroscience Center. “On the one hand, you have this area of the brain – the BNST [bed nucleus of the stria terminalis, an extended portion of the amygdala] – that’s associated with aversion and anxiety, but it’s in direct communication with a brain reward center. We wanted to figure out exactly how these two brain regions interact to promote different types of behavioral responses related to anxiety and reward.”

With the use of optogenetics, Stuber and his team, including fellow NARSAD Grantee, Thomas L. Kash, Ph.D., were able to hone in on specific neurons and track their pathways. They identified a neuron in the BNST that projects into the VTA and then found that there were both excitatory and inhibitory BNST cells projected. The BNST neurons that were excitatory (glutamate) increased their activity in response to mild, aversive foot shocks while the inhibitory (GABAergic) cells showed activity suppression during foot shock. In behavioral response, this meant that excitatory neurons provoked an aversive, avoidance behavioral response and anxiety-like behavior while the inhibitory cells provoked reward-associated behaviors and less anxiety.

“[In animal models] If you activated the [inhibitory] GABA cells, they showed less anxiety. And when we exposed them to foot shock and at the same time activated this GABAergic pathway, it actually reduced the anxiety-associated behavioral consequences of that otherwise 'aversive' stimulation,” Stuber says.

“Because these [BNST excitatory and inhibitory] cells are functionally and genetically distinct from each other, our findings also point to new potential targets for therapeutic interventions in neuropsychiatric disorders associated with alterations in motivated states such as addiction,” says Dr. Stuber.

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