Dopamine neuron activity states are regulated by the ventral subiculum of the hippocampus and the pedunculopontine tegmentum. Stimuli that are behaviorally salient activate the pedunculopontine tegmentum, causing glutamate release onto mesolimbic dopamine neurons and leading them to burst fire. The amplitude of this phasic dopamine signal is dependent on the number of dopamine neurons that the pedunculopontine can activate, since it can only cause burst firing in dopamine neurons that are already spontaneously firing. By controlling the population activity (i.e., proportion of dopamine neurons firing spontaneously), the ventral subiculum regulates the gain of the phasic signal. A) In a safe, benign context, novel salient stimuli activate the pedunculopontine tegmentum. However, because of the benign environmental context, the ventral subiculum only allows a small proportion of dopamine neurons to be firing spontaneously. As a result, the dopamine signal is small, garnering little behavioral activation of the subject. B) In an activating context, stimuli would likely have a strong motivating or threatening association, such as when searching for prey (rewarding) or in dangerous situations (threatening). In this case, the ventral subiculum causes a large proportion of dopamine neurons to be spontaneously firing. Now when a salient stimulus activates the pedunculopontine tegmentum, the dopamine signal is large in amplitude. C) In schizophrenia, a dysfunctional and overactive ventral subiculum overdrives the dopamine system, causing essentially all of the dopamine neurons to fire spontaneously. In this condition, even minor activation of the pedunculopontine tegmentum by salient or even nonsalient stimuli still results in massive activation of the dopamine signal. As a result, the subject is forced to attend to every signal it receives as if it were a life-threatening situation, clamoring for attention.

Diagram illustrating the interconnections of the brain regions regulating dopamine neuron firing. Dopamine neurons in the ventral tegmental area (VTA) are differentially regulated by two projection systems. Spatial location is integrated with limbic and stress-related information from the basolateral amygdala (emotion and stress) and noradrenergic locus coeruleus (attention and stress) within the ventral subiculum, providing a contextual representation of the behavioral contingencies. The ventral subiculum then drives nucleus accumbens neuron activity which, in turn, inhibits the ventral pallidum. The ventral pallidum provides a powerful inhibition to the VTA dopamine neurons, causing a portion to be inhibited and non-firing. By controlling the ventral pallidum, this system determines the number of VTA dopamine neurons that are firing spontaneously. In contrast, the pedunculopontine tegmentum provides a glutamatergic drive over the dopamine neurons that causes only the spontaneously active neurons (determined by the ventral pallidum) to burst fire in response to a phasic stimulus. The ability of the pedunculopontine tegmentum to drive burst firing is gated by the lateral dorsal tegmentum; inhibition of the lateral dorsal tegmentum prevents burst activity altogether. These systems interact to provide phasic behaviorally salient dopamine release (via the pedunculopontine tegmentum) in response to a stimulus, with the amplitude of the phasic release dependent on the number of dopamine neurons firing (via the ventral subiculum). Solid lines = excitatory/facilitatory projections; dashed lines = inhibitory projections

Amphetamine sensitization increases dopamine neuron population activity via activation of the ventral subiculum. A) Acute administration of amphetamine (1.5 mg/kg i.p.) causes a decrease in the population activity of dopamine neurons in the midbrain ventral tegmental area. In contrast, after 5 days repeated amphetamine and 5 days withdrawal, there is a substantial increase in the number of dopamine neurons firing spontaneously. B) Inactivation of the ventral subiculum (cross-hatched) does not produce a strong effect on the population activity in control animals, likely due to its low level of activity in anesthetized rats. In contrast, inactivation of the ventral subiculum in amphetamine sensitized rats restores the increased population activity back to control levels. C) Inactivation of the ventral subiculum with TTX injection does not affect the locomotor response of control rats to amphetamine injection (1.5 mg/kg i.v., vertical dashed line). D) In contrast, in amphetamine-sensitized rats inactivation of the ventral subiculum restores the locomotor response to amphetamine back to control levels. Adapted from (Lodge and Grace, 2008). dPBS = distilled phosphate buffered saline; †Significant group effect of treatment