The Dorsal Lateral Habenula-Interpeduncular Nucleus Pathway Is Essential for Left-Right-Dependent Decision Making in Zebrafish

Abstract

Highlights d Zebrafish can exploit the directional or cued information in forage d Zebrafish keep flexibility to use either information following the rule changes d Silencing the habenula-IPN pathway impairs the directionalbased decision making

Ongoing habenular activity is driven by forebrain networks and modulated by olfactory stimuli

“…To investigate ongoing habenular activity, we performed volumetric two-photon calcium imaging across the entire habenula of juvenile Tg(elavl3:GCaMP6s) zebrafish [52, [92][93][94], expressing GCaMP6s panneuronally. In all our experiments, we used 3 to 4-weeks-old zebrafish that were shown to exhibit complex behaviors such as learning [75,95,96] and social interactions [97,98], which are mediated by habenular circuits [64,72,73,75,78]. We observed structured ongoing activity across the entire habenula ( Figure 1A), in line with earlier studies focusing on the dHb [53].…”

“…This would, in turn, increase the robustness of sensory representations to incoming stimuli following first encounter, as it is often the case with olfactory stimuli that are received by repeated exposure to odor plumes [136][137][138]. Finally, resetting the ongoing activity of limbic forebrain networks, might be an important mechanism allowing animals to make new associations, when conditions are altered, as it has been shown during reversal learning [1,75,78,135]. How does the ongoing activity of these networks adapt during behavioral plasticity and learning will require well-established behavioral assays and simultaneous imaging of forebrain and habenular activity in juvenile zebrafish, that can perform cognitively demanding learning tasks [75,[95][96][97].…”

“…This evolutionary conserved diencephalic nucleus [44,[55][56][57] is a major hub relaying information from diverse forebrain inputs [41,[43][44][45][46][47][48]50, 58] to its target regions that directly control animal behavior via the release of dopamine, acetylcholine, and serotonin [40,44,45,[59][60][61][62][63][64][65][66][67][68][69]. Previous studies established a direct role for the habenula in adaptive behaviors [8,64,65,[70][71][72][73][74], learning [45,47,64,73,75,76] and prediction of outcomes [45,71,75,77,78]. Not surprisingly, habenular dysfunction is closely linked to several neurological conditions and mood disorders including depression [54,…”

Neuromodulation and Behavioral Flexibility in Larval Zebrafish: From Neurotransmitters to Circuits

“…A recent study in juvenile zebrafish used a conditioned place avoidance learning protocol similar to the one used by Amo et al (2014) to demonstrate that the dorsolateral habenula (dlHb) is not important for conditioned avoidance learning, but instead mediates reversal learning, which involves the ability to use new information to modify associations learned in the past (Palumbo et al, 2020; Figure 2F). These results, together with another study showing that silencing the dlHb-IPN pathway impairs decision-making in a foraging task (Cherng et al, 2020), suggest that the dlHb in zebrafish is not only critically involved in aversive responses but is also an important regulator of behavioral flexibility.…”

Netrin 1-Mediated Role of the Substantia Nigra Pars Compacta and Ventral Tegmental Area in the Guidance of the Medial Habenular Axons

“…In zebrafish, it has been functionally related with learning, social behavior, and attention ( Nakajo et al, 2020 ; Okamoto et al, 2021 ); decision making ( Cherng et al, 2020 ); aversive reactions ( Amo et al, 2014 ); fear and anxiety ( Agetsuma et al, 2010 ; Jesuthasan, 2012 ; Okamoto et al, 2012 ; Mathuru and Jesuthasan, 2013 ); and helpless behavior ( Lee et al, 2010 ). In mammals, there are a wide variety of functional studies of this system, using lesions, electrical stimulations ( Klemm, 2004 ; Lecourtier and Kelly, 2005 , 2007 ), and optogenetics to unravel its functions in reward-related behaviors (see, for a review, Hikosaka et al, 2008 ; Hikosaka, 2010 ; Batalla et al, 2017 ; Fakhoury, 2018 ).…”