Midbrain dopaminergic innervation of the hippocampus is sufficient to modulate formation of aversive memories

Abstract

Significance The origin and mode of action of dopamine on hippocampus-dependent memory have been a matter of interest for many years. The latest research has pointed toward the locus coeruleus as the main source of hippocampal dopamine, while inputs from midbrain dopaminergic centers remain controversial and understudied. We provide anatomical evidence for a direct dopaminergic projection to the hippocampus from a distinct, identified midbrain population and report a bidirectional modulation of hippocampal-aversive learning by midbrain dopamine. Our data indicate that this modulation is sustained even in the absence of catecholamine release from the locus coeruleus. These results demonstrate that midbrain dopaminergic innervation of the dorsal hippocampus is significant and plays a functional role in the modulation of aversive memory formation. Aversive memories are important for survival, and dopaminergic signaling in the hippocampus has been implicated in aversive learning. However, the source and mode of action of hippocampal dopamine remain controversial. Here, we utilize anterograde and retrograde viral tracing methods to label midbrain dopaminergic projections to the dorsal hippocampus. We identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that sends direct projections to the dorsal hippocampus. Using optogenetic manipulations and mutant mice to control dopamine transmission in the hippocampus, we show that midbrain dopamine potently modulates aversive memory formation during encoding of contextual fear. Moreover, we demonstrate that dopaminergic transmission in the dorsal CA1 is required for the acquisition of contextual fear memories, and that this acquisition is sustained in the absence of catecholamine release from noradrenergic terminals. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus and show that the midbrain dopamine neuromodulation in the dorsal hippocampus is sufficient to maintain aversive memory formation.