Activation of ventral CA1 hippocampal neurons projecting to the lateral septum during feeding

A number of studies have reported the involvement of the ventral hippocampus (vHip) and the lateral septum (LS) in negative emotional responses. Besides these well-documented functions, they are also thought to control feeding behavior. In particular, optogenetic and pharmacogenetic interventions to LS-projecting vHip neurons have demonstrated that the vHip^→LS neural circuit exerts an inhibition on feeding behavior. However, there have been no reports of vHip neuronal activity during feeding. Here, we focused on LS-projecting vCA1 neurons (vCA1^→LS) and monitored their activity during feeding behaviors in mice. vCA1^→LS neurons were retrogradely labeled with adeno-associated virus carrying a ratiometric Ca²⁺ indicator and measured compound Ca²⁺ dynamics by fiber photometry. We first examined vCA1^→LS activity in random food-exploring behavior and found that vCA1^→LS activation seemed to coincide with food intake; however, our ability to visually confirm this during freely moving behaviors was not sufficiently reliable. We next examined vCA1^→LS activity in a goal-directed, food-seeking lever-press task which temporally divided the mouse state into preparatory, effort, and consummatory phases. We observed vCA1^→LS activation in the postprandial period during the consummatory phase. Such timing- and pathway-specific activation was not observed from pan-vCA1 neurons. In contrast, reward omission eliminated this activity, indicating that vCA1^→LS activation is contingent on the food reward. Sated mice pressed the lever significantly fewer times but still ate food; however, vCA1^→LS neurons were not activated, suggesting that vCA1^→LS neurons did not respond to habitual behavior. Combined, these results suggest that gastrointestinal interoception rather than food-intake motions or external sensations are likely to coincide with vCA1^→LS activity. Accordingly, we propose that vCA1^→LS neurons discriminate between matched or unmatched predictive bodily states in which incoming food will satisfy an appetite. We also demonstrate that vCA1^→LS neurons are activated in aversive/anxious situations in an elevated plus maze and tail suspension test. Future behavioral tests utilizing anxious conflict and food intake may reconcile the multiple functions of vCA1^→LS neurons.