The Neuroscience Behind Your Mood: Neurotransmitter Switching in the Adult Brain

For many of us, our mood changes with the outside environment. When it rains, we tend to feel “sad”, and perhaps somewhat lonely. When it is sunny, we feel happier and more jubilant inside. Some people feel more comfortable in daylight, while others prefer the quiet darkness at night. What exactly is happening to our brain that leads us to feel a certain way in different environmental situations? A recent finding by Davide Dulcis and others published in the internationally renowned Science magazine may help to elucidate this interesting phenomenon.

Inside the brain are billions of important cells called neurons. These cells are crucial for brain function, as they direct activity and control. In order to communicate with each other, they fire chemicals called neurotransmitters. Every time neurotransmitters are fired, they cross a small gap between neurons called the synaptic cleft to bind to receptors on the recipient cell. The binding of the neurotransmitter to the receptor triggers a series of chemical changes inside neurons, facilitating various pathways.

 

Figure 1: Communication between two neurons. There are two important structures on a neuron that function in communication: axons (to send messages) and dendrites (to receive messages).  To talk to other neurons, an electrical conduction (called action potential) will run across the axon. When the electrical conduction reaches the ends of the axon, neurotransmitters are released. These released neurotransmitters then bind to receptors located on the dendrites of the recipient neuron, catalyzing a series of chemical pathways. Image taken from Wikipedia (https://en.wikipedia.org/wiki/File:Chemical_synapse_schema_cropped.jpg).

For many years in the neuroscience field, it was thought that an individual neuron makes only one neurotransmitter. However, it is becoming more and more apparent that many neurons have the ability to generate and release two or more neurotransmitters, including neuromodulators that are often released alongside small-molecular neurotransmitters ((Nusbaum, Blitz, Swensen, Wood, & Marder. (2001) The roles of co-transmission in neural network modulation. Trends in Neurosciences, 146-154)). Past studies using cultured neurons show that individual neurons can undergo a molecular switch to fire different neurotransmitters. One example is the peripheral sympathetic neurons that normally release norepinephrine as their neurotransmitter ((Birren, S., & Marder, E. (2013). Plasticity in the Neurotransmitter Repertoire. Science, 436,437)). These sympathetic neurons innervate (connect to) various organs, controlling our fight or flight responses. Works done on these sympathetic neurons demonstrate that they release acetylcholine when innervating sweat glands, whereas they secrete norepinephrine when innervating the heart ((Schotzinger, & Landis. (1988). Cholinergic phenotype developed by noradrenergicsympathetic neurons after innervation of a novel cholinergic target in vivo. Nature)). Subsequent studies show that these molecular switches are activity-dependent in adult rodent brains, and that these molecular switches can give rise to new behavior such as pigmentation changes in amphibians ((Birren, S., & Marder, E. (2013). Plasticity in the Neurotransmitter Repertoire. Science, 436,437)).

Although neuronal plasticity is well characterized in the adult brain, it remains unclear how sensory stimuli can alter the release of neurotransmitters. Changes in light exposure and circadian rhythm can lead to anxiogenic and depressive behavior in adult mammals ((Ashkenazy, Einat, & Kronfeld-Schor. (2009). Effects of bright light treatment on depression- and anxiety-like behaviors of diurnal rodents maintained on a short daylight schedule. Behavioral Brain Research, 343-346.)). These behavioral changes are thought to be mediated by neurotransmitter switching by specific neurons. A new report by Davide Dulcis and others showed that altering the photoperiods (or the time during which an animal is exposed to light) led to switching of neurotransmitters fired by adult rat neurons in the hypothalamus region ((Dulcis, D., Jimshidi, P., Leutgeb, S., & Spitzer, N. (2013). Neurotransmitter Switching in the Adult Brain Regulates Behavior. . Science, 449-453.)).

In the study, adult rats were raised in either long-day (19 hours of light and 5 hours of dark) or short-day (5 hours of light and 19 hours of dark) cycles. After one week, researchers found that there is a shift in the neurotransmitter release by hypothalamic neurons from dopamine to somatostatin during long-day cycles. The opposite was seen in short-days (switch from somatostatin to do dopamine). The changes in photoperiods influenced the individual neurons to change expression of neurotransmitters, a striking finding in neuroscience. Dopamine is a neurotransmitter that plays a role in cognition, motivation, mood, memory, and learning, while somatostain is a neuromodulator that is believed to be involved in the regulation of stress responses ((Birren, S., & Marder, E. (2013). Plasticity in the Neurotransmitter Repertoire. Science, 436,437)). Additionally, increase of somatostatin correlated with upregulation of corticotrophin releasing factor (CRF). The presence of CRF raises concentration of circulating corticosteroids, which play a role in stress and depression. Thus, it may be implied that the nocturnal rats are stressed by long-day cycles.

To investigate whether the changes in neurotransmitter firing had any consequence on animal behavior, the researchers tested the rats in a maze and forced swim test, since these two assays are thought to be indicators of mood, anxiety, and depression. Relative to control rats (12 hours light and 12 hours dark), rats exposed to short-day cycles spent more time exploring the maze and had better endurance in the swim test. In contrast, long-day exposure produced the opposite effects: rats explored the maze less and had decreased swimming endurance. These behavioral experiments indicate that long-day photoperiods are stressful to the rats, which makes sense considering that they are nocturnal.

 

Figure 2: Alteration of neurotransmitter release. During short days, neurons in the adult rat hypothalamus change from firing somatostatin to dopamine. The opposite shift is seen in long days. An increase of somatostatin leads to upregulation of CRF, and consequently less corticosteroid. These conditions likely account for the stress behaviors in nocturnal rodents exposed to long days, as somatostatin is thought to be a regular of stress response. Image taken from Birren and Marder, 2013.

This work by Dulcis and others may have major implications for understanding the human brain in health and disease. Of course, the work was done in nocturnal rodents, but there are two major findings that are applicable to humans: 1) Sensory stimulation is able to change what type of neurotransmitter is fired and 2) The type of neurotransmitter fired has a major influence on behavior and mood. Further work to elucidate the molecular mechanism behind neurotransmitter release may allow us to target psychological problems such as stress at the molecular level. Although humans may have a mechanism that is different, the mice still is still a great learning tool for us in order to fully understand the neuroscience behind our mood.

featured image: http://www.dukehealth.org/repository/dukehealth/2013/04/23/16/25/47/0177/astrocyte1_crop2.jpg

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