What is it about?

Cerebral cortex is the highest-evolved part of the brain, which consists of sensory cortex, with which we can feel sensory inputs such as vision, sound, hot, cold, touch and so on, and motor cortex, with which we can produce motor commands for any kinds of movement, and association cortex, with which we can think, interpret sensory information before decision making for movement, and also create personality. In spite of such wide range of functions, each part of the cerebral cortex shares several aspects of anatomical features. One of those is the columnar structure, where axons (output fibers of neurons) project precisely within individual vertical columns, which are roughly the same size throughout the cerebral cortex, and are known to be the fundamental units of cortical information processing. However, how such precise axonal projections arise during development is not well known. We show that endogenous cannabinoid plays a key role in shaping columnar axonal projection of layer 4 neurons in the mouse cerebral cortex. Cannabinoid is an analogue of 9-tetrahydrocannabinol (THC), the active component of marijuana, which binds to cannabinoid receptor (CB1R) located to the nerve fiber terminals. Endogenous ligand that binds to the CB1R is called endocannabinoid, which is synthetized from neural membrane by synthetic enzyme, 2-arachidonoylglycerol (2-AG). We found that mice genetically lacking 2-AG, thus unable to produce endocannabinoid in the brain have disorganized columnar structure. Also, neurons lacking CB1R lacked columnar projection and injection of THC shortened axonal length, thus, endocannabinoid shapes columnar projection by pruning the non-columnar parts (crossing the edge of each column) of nerve fibers.

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Why is it important?

There are two important points. First, although the columnar structure is thought to be important in terms of how brain works, how such an important structure is made has not been known at all, and we first revealed its mechanism. Second, cannabinoid is involved in this process as a key player, by locally pruning the non-columnar part of the neural fibers. This in turn means that cannabinoid intake will shorten the neural fibers overall, thus, will damage the neurons leading to malfunction of the brain.

Perspectives

We show here the importance of endocannabinoid in columnar projection of layer 4 cells, but cells in other layers from layer 2 to 6 also show columnar projection. It is interesting to know whether cells in other layers also depend endocannabinoid for its columnar formation, or they simply follow the precedent columnar structure of layer 4 cells. In addition, CB1R is one of the most abundant receptors in the brain, but its function is not completely known. From its abundance, it is likely that CB1R plays further important roles we still do not know in brain function.

Fumitaka Kimura
Jikei University of Health Care Sciences

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This page is a summary of: Endocannabinoid-dependent formation of columnar axonal projection in the mouse cerebral cortex, Proceedings of the National Academy of Sciences, September 2022, Proceedings of the National Academy of Sciences, DOI: 10.1073/pnas.2122700119.
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