The locus coeruleus has been known as the primary producer of norepinephrine (NE) in the brain. This nucleus resides in the pons, a region of the hindbrain. The axonal (outgoing) projections from this area extend to many different brain areas; the cerebellum, hypothalamus, amygdala and the cortex. These neurons that are primarily responsible for transmitting neuronal signals and are mediated by norepinephrine release are called noradrenergic. It has been well-established that the diffuse action of these noradrenergic neurons originating in the locus coeruleus are involved in mediating arousal and priming the brain’s neurons to be activated by stimuli. It is also important to note that this noradrenergic activity is considered excitatory because it increases the activity of regions to which neural transmissions are sent. While a person is awake, arousal of the locus coeruleus shifts attention, can induce anxiety and aids sensory perception [1]. In addition, NE has a role in the control of heart rate and blood pressure and also regulates cognition [2]. So, the locus coeruleus is involved in initiating and regulating a number of functions in the brain, primarily focused around mediating the response to arousing stimuli and keeping the brain, and you, alert and vigilant.

Another important function of this area is the initiation and regulation of rapid-eye movement (REM) sleep. During this period of sleep, GABA (another neurotransmitter, mainly inhibitory in function) activity is elevated and has been implicated to play a role in regulating the activity and behavior associated with REM sleep. A study conducted by Mallick, Kaur and Saxena [3] found that GABA interneurons helped to maintain the length of the REM sleep episode by maintaining a consistent level in the locus coeruleus. Before a recent line of research was explored, it was pretty well understood that this mechanism acted as a quasi on-off switch for consciousness. REM sleep is the stage of sleep most closely related to being awake and it makes sense that typical locus coeruleus activity must be inhibited in order to reach this state of consciousness. However, a recent line of research has investigated the function of GABA activation in the locus coeruleus while awake.

A recent study conducted by Breton-Provencher and Sur [1] was focused on gaining a better understanding of the function of GABA neurons in the locus coeruleus and what this means behaviorally. Their findings suggest that GABA neurons, during wakefulness, inhibit noradrenergic activity and control arousal levels in the brain. This is astounding. They also report that the pre-frontal cortex (PFC), a brain region implicated primarily in executive functioning, has connections with the locus coeruleus but only to those GABA neurons in this region. The PFC is able to directly influence the experience of arousal.

The primary reason that I find this research so interesting is for its implications in everyday life. For every new situation that the brain deems arousing, in order to be successful it is necessary to be alert and aware, however, this depends entirely on what the situation calls for. This most recent research indicates that the influence of GABAergic neurons on the noradrenergic circuits in the locus coeruleus exists on a continuum, meaning that different situations call for different levels of dampening alertness in response to arousal. Interviews are a perfect example of this neural circuitry at work. You got a call back, this is the job you have always dreamed of, and now is your chance to actually get it! Pump-up speech in the rear-view mirror followed by some softer music to calm the nerves, but it didn’t work; cue GABA. In order to perform optimally (and secure the job) it is necessary that the person is alert and vigilant enough to listen to and respond thoughtfully to questions posed at them. In addition, it is also important that this alertness and vigilance is subdued to a level that portrays confidence and calmness to the potential employer. Along these same lines, any public performance or meeting someone famous, someone you really admire would likely involve this locus coeruleus NA/GABA circuitry, as would any situation really that it is better to act more calmly than you feel.

As a final note, one interesting idea that I’ve had after reading this research is the implications of this regulatory mechanism in autism spectrum disorder (ASD). A person with ASD often has trouble processing incoming sensory stimuli and often have difficulty regulating arousal. Keeping in mind that ASD also exists on a spectrum and these symptoms may be more or less prominent in any given person with ASD. I believe that this GABAergic circuitry in the locus coeruleus should be investigated as contributing to the pathology of ASD. Could the stimulation of this pathway potentially aid in the perception of sensory stimuli as well as the regulation of alertness and vigilance responses to arousing stimuli?

References

[1] Breton-Provencher, V & Sur, M, Active control of arousal by a locus coeruleus GABAergic circuit, bioRxiv, Cold Spring Harbor Laboratory.

[2] Mather, M & Harley CW, The locus coeruleus: Essential for maintaining cognitive function and the aging brain, Trends. Cogn. Sci. (2017) 214-226.

[3] Mallick, BN, Kaur, S & Saxena, RN, Interactions between cholinergic and GABAergic neurotransmitters in and around the locus coeruleus for the induction and maintenance of rapid eye movement sleep in rats, Neurosci. (2001) 467-485.