2024-12-27

The Variabilities of Dopamine (₯) - PART V: MeSH: D005239 & NBO:0000209 (Fear Comes in to Play)

Do you still remember the 67-year-old dopamine girl in the history of dopamine science this year? She gradually became a spokesperson for happiness in her twenties. However, behind this happiness is actually a little fear. In the early stages of research, scientists used basic tools to explore dopamine's role, focusing on its relevance to psychosis and antipsychotic drugs. Initial claims that dopamine was involved in fear conditioning were dismissed due to the inadequacies of the drugs, tools, and techniques used. However, with the development of science, it turns out that the purple "Fear" in "Inside Out" also has some relationship with the dopamine girl. Let's do some brain teasers together this time!
 
In "Dopamine at Forty," we learned that dopamine (DA) is more than just the "happy molecule" we once thought it was. Thanks to advancements in genetics, chemistry, and other technologies in the 21st century, scientists now understand dopamine and its interactions with neurons (DAN) and receptors much better.

These breakthroughs have shown us how dopamine is involved in both fear conditioning (how we learn to fear things) and fear extinction (how we stop fearing things). For example, a 40-year review of dopamine research revealed that different dopamine receptors play different roles in this process: D1 in the amygdala “promotes” neuronal plasticity; D2 “inhibits” the plasticity of neurons; D3 in the ventral striatum (nucleus accumbens and olfactory tubercle) reflects functions such as fear, anxiety, and depression.
 
Figure 1: Dopamine, worker cells DAN and dopamine receptors are involved in fear conditioning and extinction
 
Canadian scientists, including Hamati, have studied dopamine and fear for almost 66 years. So why don't we hear much about dopamine's role in fear? Early research methods were limited, and most studies focused on animals, with human studies being relatively new. However, fear, like happiness, is one of our most basic emotions. By looking at Hamati's research, we can see which brain areas are active during fear conditioning and extinction. This new information about dopamine and its receptors is helping us understand the full story of dopamine's varied roles in the brain.
 
First, we first use the U.S. National Library of Medicine Medical Subject Title (MeSH) knowledge tree to quickly grasp fear (MeSH: D005239). The knowledge structure in behavior and behavioral mechanisms is shown in Figure 2. And the fear condictioning of Neuro Behavior Ontology (NBO) (NBO:0000209) is shown in Figure 3. According to the NBO's definition of fear conditioning: 
 A type of associative learning that allows organisms to acquire affective responses, such as fear, in situations where a particular context or stimulus is predictably elicits fear via an aversive context.
In other words, fear conditioning is the process by which our brains learn to associate certain things with fear. This mechanism plays a crucial role in how we respond to potentially threatening situations, where the brain makes connections between ordinary things and scary things.
Figure 2: Fear MeSH: D005239 Knowledge Tree｜Source: MeSH and revised by A.H. 
 Figure 3: Fear Conditioning: NBO: 0000209 knowledge tree | Source: NBO and revised by A.H.

Hamati et al. discussed the role of dopamine in classical fear conditioning and extinction. The process of encoding fear roughly includes several stages: Acquisition, Consolidation, Recall, Extinction(training, recall and return) of memory. In fact, what is most fascinating about DA's role in fear is its dual nature. While it helps encode fear, it also plays a role in the extinction of these memories. The study uses the acquisition and recall of conditioned fear stimulus (CS+) in classical conditioning theory to represent the ability to learn fear; the acquisition and recall of conditioned safety stimulus(CS−) as well as extinction training and extinction recall represent the ability to inhibit learned fear. Overall, both fear conditioning and extinction altered the activity of worker DAN cells and altered DA concentration levels in multiple brain regions, see Figure 4.
Figure 4: Effects of fear conditioning and extinction stages on DA levels in the brain｜Source: adapted from Table 2 of Hamati et al.
 
  • Areas with increased DA activity levels: The amygdala is the most critical area in fear conditioning. DA increases during the acquisition and recall stages, along with terminal activity in the prefrontal cortex and most ventral midbrain periaqueductal gray matter (PAG)/ In the dorsal raphe nucleus (DRN) area, DA was increased.
  • Varies according to its location: Ventral tegmental area (VTA) in the animal literature suggests that DA is released in the medial prefrontal cortex (mPFC) during all stages of fear conditioning and extinction, but DAN activity in the medial and lateral VTA may depend on anatomy location and species. Because the number of active DANs in the substantia nigra pars compacta (SNpc) did not change after fear acquisition, the involvement of the SNpc in fear conditioning was not supported in the initial study. However, with the advancement of technology, during the fear acquisition process, the dorsolateral part of the SNpc has been suggested that regional DAN activity tends to increase, and the ventromedial region activity tends to decrease, which suggests that similar to the VTA, DA neuron activity in the SNpc varies depending on its location.
  • Uncertain region: Although the striatum, together with the amygdala, is considered a hub for coordinating fear responses and has the highest density of DA receptors relative to other brain regions, due to technical differences, the causal discussion on DA fear is still inconsistent and open for discussion.
Both D1-like and D2-like dopamine receptors help in learning and unlearning fear. D1-like receptors are important for picking up and solidifying memories, while D2-like receptors help in storing and recalling these memories. These receptors can work together in some brain areas or have their own unique roles. They work by sending signals through different brain regions like the amygdala, prefrontal cortex, hippocampus, and thalamus. See Figure 5.

Figure 5: Fear conditioning and extinction binding receptors｜Source: adapted from Hamati et al. Figure 3
  • Amygdala and Prefrontal Cortex: Both these brain areas help in fear learning and unlearning. D1-like and D2-like receptors work together here. In the amygdala, when dopamine binds to these receptors, it helps create and stabilize fear memories. When recalling these memories, the brain reactivates them. On the other hand, getting rid of fear, like during fear extinction training, creates new circuits to suppress fear. In the medial prefrontal cortex (mPFC), dopamine helps inhibit fear, influenced by different subregions and types of neurons.
  • Hippocampus: The D1-like and D2-like receptors in the CA1 part of the hippocampus help in consolidating fear memories, recalling them, and unlearning them during extinction training.
  • Thalamus: Here, D2 receptors help in fear learning, while D1 receptors help in unlearning fear.
  • Olfactory Tubercle: This area, part of the nucleus accumbens, has neurons with dopamine receptors that respond to fear conditioning cues.
In the past, we thought of dopamine mainly as the chemical behind pleasure, motivation, and setting goals. But thanks to scientific progress, we now know dopamine does much more. Think of dopamine and the cells it works with (DAN) as storytellers, recording tales of curiosity, fear, and safety. Our brain isn't just a static memory bank; it's like a constantly changing landscape, shaped by our experiences. Dopamine sends signals through receptors that help form, strengthen, and retrieve memories of fear and how to overcome it.

Dopamine isn't just hanging out; it's a key player in learning fear. When we're conditioned to fear something, DAN cells light up, record fear memories, and send signals to parts of the brain like the amygdala and prefrontal cortex, which handle fear processing. Overcoming fear, or fear extinction, is like turning on a light in a dark room, slowly making the fear disappear. During this process, the brain learns that the once-feared thing is no longer a threat. Dopamine plays a dual role here, working with DAN cells and receptors to update and overwrite fear memories. Fear becomes a useful emotion, helping us prepare for danger. In the end, there's a balance between fear and safety, and dopamine helps maintain that balance.

Reference
  • Kawahata, I., Finkelstein, D. I., & Fukunaga, K. (2024). Dopamine D1–D5 Receptors in Brain Nuclei: Implications for Health and Disease. Receptors, 3(2), 155-181.
  • Hamati, Rami, et al. "65 years of research on dopamine's role in classical fear conditioning and extinction: A systematic review." European Journal of Neuroscience 59.6 (2024): 1099-1140
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