Abstract
Midbrain dopaminergic (DAergic) neurons of the ventral tegmental area (VTA) are engaged by rewarding stimuli and encode reward prediction error to update goal-directed learning. However, recent data indicate VTA DAergic neurons are functionally heterogeneous with emerging roles in aversive signaling, salience, and novelty, based in part on anatomical location and projection, highlighting a need to functionally characterize the repertoire of VTA DAergic efferents in motivated behavior. Previous work identifying a mesointerpeduncular circuit consisting of VTA DAergic neurons projecting to the interpeduncular nucleus (IPN), a midbrain area implicated in aversion, anxiety-like behavior, and familiarity, has recently come into question. To verify the existence of this circuit, we combined presynaptic targeted and retrograde viral tracing in the dopamine transporter (DAT)-Cre mouse line. Consistent with previous reports, synaptic tracing revealed axon terminals from the VTA innervate the caudal IPN; whereas, retrograde tracing revealed DAergic VTA neurons, predominantly in the paranigral region, project to the nucleus accumbens shell, as well as the IPN. To test if functional DAergic neurotransmission exist in the IPN we expressed the genetically encoded DA sensor, dLight 1.2, in the IPN of C57Bl/6J mice and measured IPN DA signals in vivo during social and anxiety-like behavior using fiber photometry. We observed an increase in IPN DA signal during social investigation of a novel but not familiar conspecific and during exploration of the anxiogenic open arm of the elevated plus maze. Together, these data confirm VTA DAergic neuron projections to the IPN and implicate this circuit in encoding perceived motivated exploration.
Significance Statement
Ventral tegmental area (VTA) dopamine (DA) neurons respond to reward but can also be engaged by aversive stimuli highlighting the need to functionally characterize VTA projections to understand how DA signaling underlies motivated behavior. Previous studies identified VTA DA neurons that project to the interpeduncular nucleus (IPN) where they modulate anxiety and novelty preference. In mice, the existence of IPN-projecting VTA DA neurons was confirmed using viral tracing. Expressing a genetically encoded DA sensor in the IPN and monitoring DA revealed that IPN DA is increased in response to novel and anxiogenic stimuli. These data verify that a small population of DA neurons in the VTA project to the IPN where they are engaged during motivated exploration.
Footnotes
All authors report no competing financial interests or potential conflicts of interest.
This work was supported by the National Institute on Drug Abuse award numbers DA041482 (A.R.T.), DA047678 (A.R.T.) and a Brain and Behavior Research Foundation Young Investigator Award (S.M.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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