Nestler Lab

Laboratory of Molecular Psychiatry

Brain Rewards Pathways

The most important reward pathway in brain is the mesolimbic dopamine system. This circuit (VTA-NAc) is a key detector of a rewarding stimulus. Under normal conditions, the circuit controls an individual’s responses to natural rewards, such as food, sex, and social interactions, and is therefore an important determinant of motivation and incentive drive. In simplistic terms, activation of the pathway tells the individual to repeat what it just did to get that reward. It also tells the memory centers in the brain to pay particular attention to all features of that rewarding experience, so it can be repeated in the future. Not surprisingly, it is a very old pathway from an evolutionary point of view. The use of dopamine neurons to mediate behavioral responses to natural rewards is seen in worms and flies, which evolved 1-2 billion years ago.

The VTA-NAc pathway is part of a series of parallel, integrated circuits, which involve several other key brain regions.

The VTA is the site of dopaminergic neurons, which tell the organism whether an environmental stimulus (natural reward, drug of abuse, stress) is rewarding or aversive.

The NAc, also called ventral striatum, is a principle target of VTA dopamine neurons. This region mediates the rewarding effects of natural rewards and drugs of abuse.

The amygdala is particularly important for conditioned forms of learning. It helps an organism establish associations between environmental cues and whether or not that particular experience was rewarding or aversive, for example, remembering what accompanied finding food or fleeing a predator. It also interacts with the VTA-NAc pathway to determine the rewarding or aversive value of an environmental stimulus (natural reward, drug of abuse, stress).

The hippocampus is critical for declarative memory, the memory of persons, places, or things. Along with the amygdala, it establishes memories of drug experiences which are important mediators of relapse.

The hypothalamus is important for coordinating an individual’s interest in rewards with the body’s physiological state. This region integrates brain function with the physiological needs of the organism.

Probably the most important, but least understood, are frontal regions of cerebral cortex, such as medial prefrontal cortex, anterior cingulate cortex, and orbitofrontal cortex, which provide executive control over choices made in the environment (for example, whether to seek a reward).

The locus coeruleus is the primary site of noradrenergic neurons in the brain, which pervasively modulate brain function to regulate the state of activation and mood of the organism.

The dorsal raphe is the primary site of serotonergic neurons in the brain, which, like noradrenergic neurons, pervasively modulate brain function to regulate the state of activation and mood of the organism.
Of course, these various brain regions, and many more, do not function separately. Rather, they function in a highly inter-related manner and mediate an individual’s responses to a range of environmental stimuli.