Norepinephrine-producing neurons in the locus coeruleus, a small nucleus in the brainstem, have been found to have two distinct cell types connected linearly via gap junctions — new findings with far-reaching implications for neuropsychiatry — ScienceDaily

A small nucleus in the brainstem called the locus coeruleus (literally the ‘blue spot’) is the main source of a major neuromodulator, norepinephrine (NE), an important mediator of the ‘fight or flight’ response in animals. However, very little is known about the local connections of this small, although extremely important group of neurons. A recent groundbreaking study published in eLife from the laboratory of Dr. Xiaolong Jiang, a researcher at the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children’s Hospital and an assistant professor at Baylor College of Medicine, is now revealing the cellular composition and circuit organization of the locus coeruleus in adult mice.

“In this study, we undertook the arduous task of mapping the local connections of NE-producing neurons in the locus coeruleus,” said Dr. Jiang. “This is the first study of such unprecedented size and detail to be performed on the gene locus and, indeed, on any monoamine neurotransmitter system. Our study revealed that neurons in the gene locus have an unexpectedly rich cellular heterogeneity and local wiring logic.”

Locus coeruleus senses danger and alerts other areas of the brain

Locus coeruleus (LC) is known to house the vast majority of norepinephrine-releasing neurons in the brain and regulates many fundamental brain functions, such as the fight-and-flight response, sleep/wake cycles, and attention control. Present in the brainstem region, LC neurons sense any existential dangers or threats in our external environment and send signals to alert other areas of the brain of impending danger.

The main action of LC neurons is to release norepinephrine, a neurotransmitter and hormone, which increases alertness and promotes arousal, regulating the sleep/wake cycle and memory. Altered norepinephrine levels are associated with depression, anxiety, post-traumatic stress disorder, panic attacks, hyperactivity, heart problems and substance abuse. Thus, a better understanding of how LC neurons function is key to understanding and identifying treatments for many neuropsychiatric and neurodegenerative conditions.

Locus coeruleus has two distinct cell subtypes, homotypically connected via gap junctions

Once considered a homogeneous group of neurons exerting a global, uniform influence throughout the brain, recent studies indicate that LC neurons are a heterogeneous population of noradrenergic cells that exhibit spatial and temporal spinality. These findings piqued the interest of Dr. Jiang and his team to investigate the cellular and circuit mechanisms underlying the functional diversity of LC neurons.

To do this, the team had to overcome some technical hurdles to be able to measure the activity of several LC neurons simultaneously from the brain slices of adult mice. For example, while the technique of intracellular recording of more than two neurons simultaneously has been used to study cortical circuits in recent decades, it is difficult to use this technique to record small nuclei in the brainstem such as the LC due to space limitations and limited number of cells in each brain slice. In this study, by optimizing slice quality and adapting their recording system to small brainstem slices, Andrew McKinney, a graduate student in the Jiang lab and first author of the paper, was able to successfully record up to eight LC neurons simultaneously for the first time time. .

This technical development led Andrew and others in the team to make several unexpected observations about how LC neurons are organized and how they work.

First, consistent with emerging views in the field, they found that norepinephrine-producing neurons in the LC are diverse. Further, they found that these can be classified into at least two main cell types based on their morphology and electrical properties, and these subtypes occupy different spatial locations (anatomical niches) within the LC. This finding provided a solid and much-needed basis for further in-depth studies of LC in adult animals.

Second, they discovered that LC neurons do not form chemical synapses, the most common type of connection between neurons. Instead, they form electrical synapses and connect to each other via gap junctions. This was an unexpected finding because the conventional thinking is that electrical coupling via gap junctions exists primarily in developing LC and not in the LC of adult animals.

Third, they discovered that LC neurons of the same subtype electrically connect to each other but not to neurons of the other species, providing the first cellular and circuit evidence for the functional modularity of the LC and opening avenues to understand how functional modularity arises within the noradrenergic system and dynamically controls various processes. These findings suggest that since each cell type has preferential anatomical locations in LCs and different projection targets, each electrically coupled homotypic network within a cell type may coordinate or synergize their input or output as a whole to engage in distinct functions of the circuits as they carry information from the brain to various targets such as muscles or glands.

Finally, in contrast to the tissue-like connections that are characteristic of chemical synapses between neurons in the central nervous system, LC neurons of a single subtype were found to form unique linear chain electrical connections with each other. This provides the first experimental indication of how electrically coupled neural networks are organized in the brain.

“This study sheds light on many unexplored questions about the cellular and circuit organization of the locus coeruleus and also offers several new insights into other broader aspects of brain physiology,” said Dr. Jiang. “We expect that these new findings will be of interest to a wide range of cellular, systems, and computer neuroscientists and will inspire several future studies to understand how each neuron within the LC interacts with each other to create a synchronized network,” added Dr. Jiang. “Furthermore, since LC dysregulation has been implicated in many neuropsychiatric and neurodegenerative disorders, including autism and Alzheimer’s disease, these findings provide a key knowledge base for deciphering the cellular and circuit mechanisms of these diseases.”

Others involved in the study were Ming Hu, Amber Hoskins, Arian Mohammadyar, Nabeeha Naeem, Junzhang Jing, Saumil Patel and Bhavin Sheth. They are affiliated with one or more of the following institutions: Jan and Dan Duncan Institute for Neurological Research at Texas Children’s Hospital, Baylor College of Medicine, and the University of Houston. The study was supported by various research and training grants from the National Institutes of Health and the Main Street America Fund.

Leave a Comment