The Hippocampus Modulates Dopamine Neuron Responsivity by Regulating the Intensity of Phasic Neuron Activation

Aberrant dopamine (DA) signaling has been advanced as a contributing factor to the pathophysiology of a number of psychiatric conditions including schizophrenia; however, the many factors involved in regulating DA system responsivity have not been completely delineated to date. We have shown previously that DA neuron activity states are independently regulated by distinct afferent pathways. We now provide evidence that these pathways interact to control the population of neurons that are phasically activated. As shown previously, infusions of NMDA into the ventral subiculum (vSub) increases the number of spontaneously active DA neurons (population activity), while having no effect on firing rate or average bursting activity. In contrast, NMDA activation of the pedunculopontine tegmental nucleus (PPTg) results in a significant increase in DA neuron burst firing without significantly affecting population activity. However, simultaneous excitation of the vSub and PPTg induces a significant increase in both DA neuron population activity and burst firing resulting in a approximately 4-fold increase in the number of high-bursting neurons observed per electrode track. These data suggest that DA neuron population activity is not simply associated with the tonic release of DA in forebrain regions, but rather represents a recruitable pool of DA neurons that can be further modulated by excitatory inputs to induce a graded phasic response. Taken as a whole, we propose that the synchronous activity of distinct afferent inputs to the VTA phasically activates selective populations of DA neurons, and hence may be a site of pathological regulation underlying aberrant DA signaling.