Excitatory VTA to DH projections provide a valence signal to memory circuits

The positive or negative value (valence) of past experiences is normally integrated into neuronal circuits that encode episodic memories and plays an important role in guiding behavior. Here, we show, using mouse behavioral models, that glutamatergic afferents from the ventral tegmental area to the dorsal hippocampus (VTA→DH) signal negative valence to memory circuits, leading to the formation of fear-inducing context memories and to context-specific reinstatement of fear. To a lesser extent, these projections also contributed to opioid-induced place preference, suggesting a role in signaling positive valence as well, and thus a lack of dedicated polarity. Manipulations of VTA terminal activity were more effective in females and paralleled by sex differences in glutamatergic signaling. By prioritizing retrieval of negative and positive over neutral memories, the VTA→DH circuit can facilitate the selection of adaptive behaviors when current and past experiences are valence congruent.


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Data used for analyses included: (i) mice with virus expression in the VTA of 50% or more of the mean number of VTA-infected neurons across all experiments, (ii) mice with detectable VTA-originating terminals in DH (in four cases there were no detectable signals despite string VTA labeling and these data were excluded), (iii) mice with correctly implanted cannulas in DH), and (iv) mice showing over 80% preference for a CPP chamber before training (five cases).
All behavioral experiments were replicated twice, and the main effects of vGlut2-Cre silencing on fear reinstatement and M-CPP were replicated three times for each sex. Immunohistochemical findings were replicated multiple times because all brains were collected and immunostained with mCherry after each experiment.
Randomization was performed by assigning similar numbers of littermates to the different treatment conditions.
The behavioral experiments were performed by two experimenters of which one was blind to genotypes and drug treatments. Provide details on animals observed in or captured in the field; report species, sex and age where possible. Describe how animals were caught and transported and what happened to captive animals after the study (if killed, explain why and describe method; if released, say where and when) OR state that the study did not involve wild animals.