Dopamine and Norepinephrine Modulate the Formation of Aversive Memories in the Hippocampus

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 combine optogenetic and pharmacological manipulations to control dopamine transmission in the hippocampus during encoding of contextual fear memory. We show in mice that hippocampal dopamine can potently modulate aversive memory formation during contextual fear conditioning. Using retrograde tracing, we identify a population of midbrain dopaminergic neurons near the border of the substantia nigra pars compacta and the lateral ventral tegmental area that send direct projections to the dorsal hippocampus. We separately demonstrate that activation of norepinephrine release in the hippocampus during encoding can also facilitate aversive memory formation. Moreover, we find that increasing norepinephrine release can ameliorate contextual fear learning impairments due to dopaminergic dysregulation in the hippocampus. Our findings identify a cluster of midbrain dopamine neurons that innervate the hippocampus, and we show that both dopamine from the midbrain and norepinephrine from the locus coeruleus modulate hippocampal contextual fear memory.