Modulating the Excitability of Olfactory Output Neurons Affects Whole-Body Metabolism

Area of Science:

• Neuroscience
• Metabolism
• Genetics

Background:

• Metabolic state influences olfactory sensitivity, but the role of the olfactory bulb (OB) in metabolic homeostasis is unclear.
• Obesity is a growing health crisis, necessitating novel therapeutic targets.

Purpose of the Study:

• To investigate if enhancing mitral/tufted (M/TC) neuron excitability in the OB can improve metabolic health.
• To determine the impact of OB M/TC neuron activity on diet-induced obesity (DIO) and metabolic parameters.

Main Methods:

• CRISPR gene editing was used to increase M/TC neuron excitability by targeting Kv1.3 channels in mice.
• Ex vivo slice recordings confirmed increased neuron excitability (altered resting membrane potential, enhanced action potential firing).
• Chemogenetics (DREADDs) was used to decrease M/TC neuron excitability in a separate cohort.

Main Results:

• CRISPR mice showed enhanced odor discrimination.
• Male CRISPR mice were resistant to DIO, exhibiting reduced weight gain, less adipose tissue, improved glucose clearance, and lower leptin/triglycerides.
• Decreased M/TC excitability led to impaired odor discrimination, increased adiposity, and reduced energy expenditure.

Conclusions:

• Olfactory bulb M/TC neuron activity regulates both olfactory information processing and whole-body metabolism.
• Targeting OB neuron excitability may offer a future therapeutic strategy for obesity and type II diabetes.