Circuit organization of Tac2-expressing neurons from established functions to testable hypotheses

Tac2-expressing neurons participate in behavioral and neuroendocrine functions through regionally specialized circuits. Building on a 2021 review of the Tac2/neurokinin B (NKB) pathway, we examine how cell- and projection-specific studies have refined this organization. Fear-memory and isolation-stress studies provide convergent evidence for NKB-neurokinin 3 receptor (NK3R) signaling, whereas other studies establish functions of Tac2-expressing populations without demonstrating peptide dependence. We distinguish interventions targeting neurons, the Tac2-encoded peptide, NK3R, and NK3R-expressing cells, and assess classical-transmitter evidence separately. We then integrate descriptive Allen Brain Cell Atlas MERFISH visualizations with regional circuit knowledge to formulate hypotheses for the medial habenula, dorsal tegmental nucleus, and spinal trigeminal nucleus interpolaris. Established reinforcement in a Tac2-driver-defined habenular subset motivates tests of output specialization; tegmental and trigeminal expression patterns motivate hypotheses about orientation-arousal coupling and sensory gating. Atlas annotations identify candidate molecular phenotypes, not validated transmitter release or behavioral functions. Together, the literature supports a region- and state-dependent account of Tac2-expressing populations and defines where additional molecular evidence is needed to establish NKB-NK3R mechanisms.