What is it about?

Tobacco smoking increases the risk of lung diseases including chronic obstructive pulmonary disease (COPD). The gene HHIP influences the risk of developing COPD. Our paper reports that HHIP is expressed by neurons in a region of the brain called the medial habenula (MHb). HHIP regulates the ability of nicotine to stimulate MHb neurons. This is important because MHb neurons control aversive behavioral responses to nicotine that protect against tobacco dependence. These findings suggest that HHIP can influence the risk of developing COPD by regulating the aversive properties of nicotine that control tobacco smoking behavior.

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Why is it important?

Our findings may help to explain why the HHIP gene is so heavily implicated in tobacco-related lung diseases. Our data also provide a better understanding of the cellular and molecular mechanisms that influence the actions of nicotine on the habenula and hence vulnerability to tobacco dependence. Ultimately, such advances may identify new targets for the development of more effective smoking cessation agents.


The article resulted from the dedicated efforts of a group of exceptionally talented scientists with diverse skill-sets. It was a pleasure to work with such outstanding colleagues who were willing to apply a "team science" approach to tackle a tough problem.

Paul Kenny
Icahn School of Medicine at Mount Sinai

This is a tour-de-force work that reveals how a gene linked to COPD confers risk through altering behavior. This work also reveals how toxic nicotine use is to the MHb neurons, something that we were not able to elucidate with other methods.

Jessica Ables
Icahn School of Medicine at Mount Sinai

This study provides a novel and very intriguing molecular link between nicotine action in the brain and the hedgehog signaling pathway underlying COPD.

Ines Ibanez-Tallon

This work was the result of a collective of finessed experiments by many skilled scientists. We first realized that alleles of a particular gene, Hedgehog Interaction Protein (HHIP), were associated with many respiratory diseases in humans. It has been speculated that this gene is connected to respiratory disease due to its role in lung development. However, we realized that HHIP is very densely expressed in a brain region that we know to regulate nicotine aversion and nicotine taking behavior. This is when we speculated that the connection of HHIP to respiratory disease may also be due to an enhanced propensity for nicotine use. Throughout this paper, we provide compelling pre-clinical data to support this hypothesis.

Stephanie Caligiuri

Read the Original

This page is a summary of: Hedgehog-interacting protein acts in the habenula to regulate nicotine intake, Proceedings of the National Academy of Sciences, November 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2209870119.
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