The Plastic Brain: Neurotransmitter Switching

What comes to mind when you think of the word “plastic”? For me, this word conjures images of water bottles and tupperware. So in my high school psychology class, when we were told that our brains are “plastic”, I was pretty confused. However, we soon learned that the word “plastic” can be used to describe materials that are easily shaped and molded. Neuroscientists often use the term “neuroplasticity” to refer to the brain’s ability to change and adapt over time. This is crucial for us to be able to grow, learn, and shape our personalities throughout our lives.

Our brains function by sending messages and building connections (also called synapses) between individual neurons. In order for the brain to change and adapt, these connections have to be altered somehow. Indeed, some of the most prominent forms of neuroplasticity involve synaptic modifications. For instance, changes can be made to synapse strength as well as number. However, in recent years evidence has accumulated which shows that neurons are also capable of modifying the language that they use to communicate with each other. To understand why this is such a big deal, let’s first review the basics of neural communication.

Neurotransmission Basics

Neurons send messages to each other through a process called neurotransmission; this involves one neuron sending a chemical (a neurotransmitter) across a very small gap (the synapse) to the next neuron.

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[Source: khanacademy.org]

The content of the message sent from one neuron to another depends on the identity of the neurotransmitter being released (and depending on how you count, there may be over 100 different neurotransmitters!). Some of these neurotransmitters are viewed as “excitatory”, meaning they make the post-synaptic neuron more likely to fire an action potential (send a message to the next neuron), while others are viewed as “inhibitory”, and make the post-synaptic neuron less likely to fire an action potential.

For a long time, we thought that an individual neuron produced and released only one type of neurotransmitter, and the identity of this particular neurotransmitter was set for the life of the neuron. This idea has been widely known as Dale’s Principle, which states that “the nature of the chemical function…is characteristic for each particular neurone, and unchangeable” [1]. This concept was taught as “one neuron, one neurotransmitter” for several decades. After we learned that neurons can often release two or more different types of neurotransmitters (a process called co-transmission) [2], some scientists reinterpreted Dale’s Principle to mean that neurons always release the same set of neurotransmitters. However, we now know that this isn’t completely true, either.

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Neurotransmitter switching

In 2013, work from Dr. Nick Spitzer’s lab at UCSD was the first to demonstrate that neurons in the intact, adult brain can actually switch the neurotransmitters that they produce and release [3]. This happens when the neurons are exposed to a sustained stimulus over a long period of time. In this experiment, the authors wanted to test whether alterations in light exposure would cause anxious and depressive behavior in rats, and more importantly, if these behavioral changes were due to neurotransmitter switching.

They exposed adult rats to short-day (5 hours of light, 19 hours of dark) and long-day (19 hours of light, 5 hours of dark) photoperiods to mimic seasonal changes. As expected, the authors found that during the long-day photoperiods, the rats showed more anxious and depressive behaviors than during the short-day photoperiods. This effect is similar to the “Seasonal Affective Disorder” (SAD) that we see in some humans during the winter months, when the days are shorter and darker. However, since rats are nocturnal, these effects are triggered by longer periods of light.

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[Source: Birren & Marder (2013) [4]

To examine the effects of differing photoperiods on neurotransmitter expression, the authors looked at neurons in the hypothalamus (a brain region involved with regulating circadian and seasonal rhythms, among other things). They found that a population of neurons shifted between the expression of two neurotransmitters- dopamine and somatostatin. Dopamine is involved in a wide range of functions such as motivation, mood, memory, and learning, while somatostatin is thought to be involved with the regulation of stress responses. During the long-day photoperiods, neurons shifted from expressing dopamine to somatostatin. This switching could explain the increase in anxious and depressive behaviors, as somatostatin has been shown to upregulate corticotropin-releasing factor, a hormone released by the hypothalamus in response to stress. The opposite was found during the short-day photoperiods (neurons switched from expressing somatostatin to dopamine).

Implications

This work has huge implications for understanding the brain in health and disease. It shows that a change in the environment (such as changes in day length) can change the neurotransmitter that is released by a certain area of the brain, and that this change in neurotransmitter identity has a major effect on behavior. In fact, as more evidence for transmitter switching has accumulated, neuroscientists have noticed that the switch is often between an excitatory and an inhibitory neurotransmitter. This supports the idea that the switch drives a change in behavior meant to adapt to a changing environment.

Further, the authors suggest that neurotransmitter switching may directly contribute to neurological disorders:

“Because the long photoperiods are stressful to rodents (analogous to short-day photoperiods for people), the findings raise the possibility that various forms of stress may induce transmitter switching that contributes to the chemical imbalances in the brain underlying many psychiatric conditions” (Spitzer interview with UCSD News Center)

They even propose that finding a way to intentionally trigger neurotransmitter switching in certain brain areas implicated with psychiatric disorders may be an avenue for noninvasive treatment of these conditions in the future.

In fact, this group recently published another study looking deeper into the mechanism behind this neurotransmitter switch [5]. They found that higher activity of dopamine-releasing neurons in a portion of the adult rat hypothalamus (the paraventricular nucleus) was required for the switch from dopamine to somatostatin expression. They then demonstrated that suppressing the activity of these neurons successfully prevented the switch! They were able to manipulate the activity of the brain in a way that prevented an event known to elicit anxious and depressive behavior; this work has major implications for research on psychiatric disorders, and opens the doors for promising future studies on treating mental health.

References

[1] Dale HH (1934). “Pharmacology and Nerve-endings (Walter Ernest Dixon Memorial Lecture): (Section of Therapeutics and Pharmacology)”. Proceedings of the Royal Society of Medicine. 28 (3): 319–30. PMC 2205701

[2] Burnstock G (1976). “Do some nerve cells release more than one neurotransmitter?”. Neuroscience, 1(4): 239-248. PMID: 11370511

[3] Dulcis D, Jamshidi P, Leutgeb S, Spitzer N (2013). “Neurotransmitter switching in the adult brain regulates behavior”. Science, 340(6131): 449-53. PMID: 23620046

[4] Birren S, Marder E (2013). “Plasticity in the Neurotransmitter Repertoire”. Science, 340(436). DOI: 10.1126/science.1238518

[5] Meng D, Li H, Deisseroth K, Leutgeb S, Spitzer N (2018). “Neuronal activity regulates neurotransmitter switching in the adult brain following light-induced stress”. PNAS, 115(20): 5064-5071. PMID: 29686073

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