Hypothalamus-hippocampus circuitry regulates impulsivity via melanin-concentrating hormone

Emily E Noble,Lindsey A Schier,Scott E Kanoski,Zhuo Wang,Joel D Hahn,A-Hyun Jung,Matthew R Hayes,Alyssa M Cortella,Lauren M Raycraft,Alexander W Johnson,Sarah J Terrill,Elizabeth A Davis,Linda Tsan,Andrea N Suarez,Ted M Hsu,Martin Darvas,Lauren M Stein,Daniel P Holschneider,Clarissa M Liu

doi:10.1038/s41467-019-12895-y

Abstract

Behavioral impulsivity is common in various psychiatric and metabolic disorders. Here we identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both site-specific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. Furthermore, these effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. Results from additional functional connectivity and neural pathway tracing analyses implicate the nucleus accumbens as a putative downstream target of vHP MCH1 receptor-expressing neurons. Collectively, these data reveal a specific neural circuit that regulates impulsivity and provide evidence of a novel function for MCH on behavior.

Highlights

Behavioral impulsivity is common in various psychiatric and metabolic disorders
Our results identify a novel projection pathway involving melanin-concentrating hormone (MCH) signaling from the lateral hypothalamic area (LHA)/zona incerta (ZI) to the ventral hippocampus subregion (vHP) that regulates behavioral impulsivity
Increased incentive salience for food reward is unlikely to account for MCH vHP-mediated impulsivity, as elevated vHP MCH signaling had no effect on free feeding home cage consumption or motivated operant responding for palatable high-fat/high-sugar food

Summary

Introduction

We identify a hypothalamus to telencephalon neural pathway for regulating impulsivity involving communication from melanin-concentrating hormone (MCH)-expressing lateral hypothalamic neurons to the ventral hippocampus subregion (vHP). Results show that both sitespecific upregulation (pharmacological or chemogenetic) and chronic downregulation (RNA interference) of MCH communication to the vHP increases impulsive responding in rats, indicating that perturbing this system in either direction elevates impulsivity. These effects are not secondary to either impaired timing accuracy, altered activity, or increased food motivation, consistent with a specific role for vHP MCH signaling in the regulation of impulse control. We conclude that the projection pathway from MCH neurons in the LHA/ZI to the vHP plays a role in mediating impulsivity

Methods

Results

Conclusion