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Defective Hoxb8 microglia are causative for both chronic anxiety and pathological overgrooming in mice
Donn A Van Deren1,2, Ben Xu1, Naveen Nagarajan1,3
1Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT, 84112, USA.
Abstract:
Disruption of the Hoxb8 gene results in chronic anxiety and pathological overgrooming in mice. Using bilateral intracerebral cell transplantation, we demonstrate that mutant Hoxb8 microglia are causative for both behaviors. Mice contain two microglia lineages, Hoxb8 and non-Hoxb8 microglia. We proposed that the two lineages work as a binary system, in opposition to each other with Hoxb8 microglia functioning to reduce anxiety and grooming (function as brakes), whereas non-Hoxb8 microglia increase the levels of both behaviors (function as accelerators). This model makes a strong, unexpected prediction: mice containing only wild-type canonical non-Hoxb8 microglia should exhibit pathological levels of grooming and anxiety. We demonstrate that this is the case, providing strong support for both microglia functioning as a binary system and for the 'Accelerator/Brake' model. Since mice containing only non-Hoxb8 microglia represent mice with a loss of Hoxb8 function due to the absence of Hoxb8 microglia, the more intensive pathology associated with Hoxb8 mutant mice must reflect that mutant mice have both gain and loss of function components. We identify and quantify the relative contribution of each component.
Insights
Hoxb8 gene disruption causes anxiety and overgrooming in mice. Hoxb8 microglia act as anxiety and grooming brakes, while non-Hoxb8 microglia accelerate these behaviors, forming a binary system.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- The Hoxb8 gene plays a crucial role in regulating specific cellular functions.
- Microglia, the immune cells of the central nervous system, exist in distinct lineages with potentially opposing roles.
- Disruption of Hoxb8 leads to observable behavioral abnormalities, including chronic anxiety and pathological overgrooming in mouse models.
Purpose of the Study:
- To investigate the causative role of Hoxb8 microglia in anxiety and overgrooming behaviors.
- To elucidate the proposed binary system of microglia function, specifically the 'Accelerator/Brake' model.
- To determine the relative contributions of gain-of-function and loss-of-function components in Hoxb8 mutant mice.
Main Methods:
- Bilateral intracerebral cell transplantation in mice.
- Genetic manipulation to isolate and study Hoxb8 and non-Hoxb8 microglia lineages.
- Behavioral assays to quantify anxiety and grooming in different mouse models.
Main Results:
- Mutant Hoxb8 microglia were confirmed as causative for anxiety and overgrooming.
- Mice lacking Hoxb8 microglia (containing only wild-type non-Hoxb8 microglia) exhibited pathological grooming and anxiety, supporting the 'Accelerator/Brake' model.
- The study identified and quantified the distinct contributions of gain and loss of function in Hoxb8 mutant mice.
Conclusions:
- Hoxb8 and non-Hoxb8 microglia function as a binary system, acting as 'brakes' and 'accelerators' for anxiety and grooming, respectively.
- The 'Accelerator/Brake' model provides a framework for understanding microglia's role in these behaviors.
- Understanding these distinct lineage functions is critical for developing targeted therapies for neurological and behavioral disorders.
