Viral Tracing Confirms Paranigral Ventral Tegmental Area Dopaminergic Inputs to the Interpeduncular Nucleus Where Dopamine Release Encodes Motivated

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 that VTA DAergic neurons are functionally heterogeneous with emerging roles in aversive signaling, salience, and novelty, based in part on anatomic location and projection, highlighting a need to functionally characterize the repertoire of VTA DAergic ef-ferents in motivated behavior. Previous work identifying a mesointerpeduncular circuit consisting of VTA DAergic neu-rons 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 tar-geted and retrograde viral tracing in the dopamine transporter-Cre mouse line. Consistent with previous reports, syn-aptic tracing revealed that 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 whether functional DAergic neurotransmission exists 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 investiga-tion of a novel but not familiar conspecific and during exploration of the anxiogenic open arms of the elevated plus maze. Together, these data confirm VTA DAergic neuron projections to the IPN and implicate this circuit in encoding motivated exploration.

Automated summary

Midbrain dopaminergic neurons in the ventral tegmental area (VTA) respond to rewarding stimuli and encode reward prediction error, but recent data suggest they also have roles in aversive signaling, salience, and novelty. This study aimed to functionally characterize the different outputs from VTA dopaminergic neurons and found that they project to the interpeduncular nucleus (IPN) and nucleus accumbens shell. Furthermore, it was confirmed that the VTA-IPN circuit is involved in motivated exploration.