Trans‐Synaptic Virus Tracing Reveals Reciprocal Connections of the Interpeduncular Nucleus With the Mood, Exteroceptive, Interoceptive, and Motor Control Systems

The interpeduncular nucleus (IPN) is an evolutionarily conserved brain nucleus that receives direct input from the habenula (Hb). In zebrafish (Danio rerio), it is involved in decision-making dependent on the idiothetic perception of the status of the body, such as head direction and posture. It is also known that the potentiation of the Hb-IPN-griseum centrale (GC) circuit makes fish resilient to stress in coping with fear and social conflict. To address why the same neural circuit controls these two distinctive physiological aspects, we performed anterograde and retrograde trans-synaptic viral tracing, retrograde mono-synaptic viral tracing, and lipophilic dye tracing to map the connectivity from the dorsal and intermediate IPN. We revealed reciprocal connections of d/iIPN and GC neurons with multiple brain regions for sensory inputs, including interoceptive systems that receive proprioception and the perception of balance and water flow, autonomic nervous systems for visceral control, and exteroceptive systems that receive vision and olfaction through the Hb. The positively labeled signals also cover the emotional regulatory system (i.e., serotonin, noradrenaline, and dopamine neurons) and the motor control system that administers the presentation of behaviors. Our anatomical results imply that multimodal sensorimotor information may converge in the Hb-IPN-GC circuit, hinting at its possible involvement in integrating inner states for responses to upcoming external challenges and in regulating allostasis through anticipatory biological reactions.