Hunger Potentiates the Habenular Winner Pathway for Social Conflict by Orexin-Promoted Biased Alternative Splicing of the AMPA Receptor Gene

• Published in: Cell reports (Cambridge) Vol. 31; no. 12; p. 107790
• Main Authors: Nakajo, Haruna, Chou, Ming-Yi, Kinoshita, Masae, Appelbaum, Lior, Shimazaki, Hideaki, Tsuboi, Takashi, Okamoto, Hitoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.06.2020
• Subjects: alternative splicing; Alternative Splicing - genetics; Amino Acid Sequence; AMPA receptor; Animals; Animals, Genetically Modified; Behavior, Animal; Excitatory Postsynaptic Potentials; Flip/flop; habenula; Habenula - physiology; hunger; Hunger - physiology; interpeduncular nucleus; Male; orexin; Orexins - metabolism; Receptors, AMPA - genetics; Receptors, AMPA - metabolism; Signal Transduction; Social Behavior; social conflict; starvation; Starvation - genetics; Zebrafish; starvation; Flip/flop; AMPA receptor; interpeduncular nucleus; social conflict; alternative splicing; zebrafish; orexin; habenula; hunger
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.107790

Many animals fight for dominance between conspecifics. Because winners could obtain more resources than losers, fighting outcomes are important for the animal’s survival, especially in a situation with insufficient resources, such as hunger. However, it remains unclear whether and how hunger affects fighting outcomes. Herein, we investigate the effects of food deprivation on brain activity and fighting behaviors in zebrafish. We report that starvation induces winning in social conflicts. Before the fights, starved fish show potentiation of the lateral subregion of the dorsal habenula (dHbL)-dorsal/intermediate interpeduncular nucleus (d/iIPN) pathway, which is known to be essential for and potentiated after winning fights. Circuit potentiation is mediated by hypothalamic orexin/hypocretin neuropeptides, which prolong AMPA-type glutamate receptor (AMPAR) activity by increasing the expression of a flip type of alternative splicing variant of the AMPAR subunit. This mechanism may underlie how hungry vertebrates win fights and may be commonly shared across animal phylogeny. [Display omitted] •A 6-day starvation makes zebrafish win in social conflict•Starvation causes potentiation of the winner pathway from the habenula to the IPN•Starvation-induced orexin signal biases splicing of the AMPAR gene in the IPN•Activity of the AMPAR splice variant is prolonged, driving synaptic potentiation in the IPN Nakajo et al. show that 6-day starvation potentiates the winner-associated dHbL-d/iIPN pathway by prolonging AMPAR activity in the dIPN region through increasing the expression level of an alternative splicing variant of AMPAR subunits, gria3b-flip. These neuromodulations in the dIPN are induced by the orexin/hypocretin signal that is activated in a starved state.