Left Habenular Activity Attenuates Fear Responses in Larval Zebrafish

Fear responses are defensive states that ensure survival of an organism in the presence of a threat. Perception of an aversive cue causes changes in behavior and physiology, such as freezing and elevated cortisol, followed by a return to the baseline state when the threat is evaded [1]. Neural systems that elicit fear behaviors include the amygdala, hippocampus, and medial prefrontal cortex. However, aside from a few examples, little is known about brain regions that promote recovery from an aversive event [2]. Previous studies had implicated the dorsal habenular nuclei in regulating fear responses and boldness in zebrafish [3-7]. We now show, through perturbation of its inherent left-right (L-R) asymmetry at larval stages, that the dorsal habenulo-interpeduncular (dHb-IPN) pathway expedites the return of locomotor activity following an unexpected negative stimulus, electric shock. Severing habenular efferents to the IPN, or only those from the left dHb, prolongs the freezing behavior that follows shock. Individuals with a symmetric, right-isomerized dHb also exhibit increased freezing. In contrast, larvae that have a symmetric, left-isomerized dHb, or in which just the left dHb-IPN projection is optogenetically activated, rapidly resume swimming post shock. In vivo calcium imaging reveals a neuronal subset, predominantly in the left dHb, whose activation is correlated with resumption of swimming. The results demonstrate functional specialization of the left dHb-IPN pathway in attenuating the response to fear.