2024-09-21

The Variabilities of Dopamine (₯) - PART III: CL:0000700 & SIO:000823

dopaminergic neurons (DAN) & curiosity
In the intricate drama of the brain, where countless characters play their parts, the dopaminergic neurons (DAN) emerge as the leading actors. These neurons, with their insatiable appetite for novelty and puzzle-solving, resemble a cerebral Sherlock Holmes, ever on the hunt for the new and the intriguing. Their steadfast companion, the neurotransmitter dopamine, the supporting role, supports them in this relentless quest, ensuring that curiosity and neuronal activity are seamlessly intertwined.

However, as with all compelling narratives, there is a twist. With the passage of time, these once-vibrant neurons begin to falter, their capacity for seeking out novelty diminishing. This decline in curiosity, a poignant reflection of our own aging, prompts a profound inquiry: what are the neural mechanisms behind this gradual loss? What hidden processes cause our inner Holmes to lose his fervor for the unknown?

Fig 1: underlying neural mechanisms of curiosity
Did you know? Within the labyrinth of your brain resides a cell that bears a striking resemblance to a slender ginseng root, complete with dendrites that mimic ginseng whiskers. This remarkable cell is the dopaminergic neuron (DAN). When we encounter something novel, it ignites a unique spark within the brain’s neural circuits, propelling us to explore, learn, and discover. DAN is akin to a detective in the brain, perpetually drawn to the new and the unknown, ever eager to be stimulated by wonder and to acquire fresh knowledge. 

Yet, as we age, this curiosity seems to wane. Like a firework losing its brilliance, the elderly gradually lose their sense of novelty, both social and inanimate, until they are no longer captivated by it. Why is our Curious Detective DAN so intrigued by novelty? And as we grow older, what transformations occur within DAN that cause this once-curious detective to lose his inquisitiveness? After reading this, has this phenomenon successfully piqued the interest of the curious detective within your own brain?

It turns out that dopamine, that versatile neurotransmitter, is not only linked to our happiness, desires, and motivational goals but also intricately connected to our “cognitive curiosity” and “empathic curiosity.” As you read this, your brain is responding, much like it would if you were truly thirsty or hungry. The dopamine-sensitive regions in your midbrain light up, a phenomenon we refer to as “cognitive curiosity.” This type of curiosity drives us to explore and understand the world around us.

The knowledge tree of curiosity: SIO:000823

Another form of curiosity is rooted in our social interactions. When we find ourselves in comfortable social settings and seek to understand the thoughts and feelings of others, our brains release a significant amount of dopamine, a process known as “empathic curiosity.” Today’s exploration of our curious detective, DAN, delves into the neural mechanisms and the role of dopamine in triggering these two types of curiosity.

The Chinese version of Curiosity’s Knowledge Tree was added after the article was published on 2024/09/06. Since the knowledge ontology-driven popular science articles I and II had not yet been published at the time of writing this article, A.H. was not sure of reader acceptance, so when writing the popular science articles on dopamine and curiosity, he returned to the traditional popular science writing method. After Part I and II were published, I learned that the writing method of popular science articles driven by knowledge ontology was loved by readers, so I added the description of curiosity in Semanticscience Integrated Ontology (SIO) as shown in Figure 3. Curiosity is a positive emotion. In the family, the descendants of desire.

The key to understanding this relationship lies in the dopamine released by dopaminergic neurons (DAN) in the ventral tegmental area (VTA) and substantia nigra pars compacta (SNc). Neuroimaging studies have shown that high levels of curiosity and novel stimuli increase activity in these midbrain areas. A 2023 study published in “Communications Biology,” a sub-journal of “Nature,” titled “Reduced activity of VTA/SNc dopaminergic neurons underlies aging-related decline in novelty,” thoroughly examined the neural mechanisms of curiosity. It revealed why our enthusiasm for novelty diminishes over time. Through experiments with mice, excluding socioeconomic factors, the study confirmed that the decrease in spontaneous discharge of VTA and SNc and the reduction in DAN activity are consequences of aging-related declines in curiosity.

This
Fig 2: experiment on social and inanimate curiosity
study employs experimental mice to delve into the intricate relationship between brain neurons and curiosity, unraveling the causal connections of the underlying neural mechanisms. Figure 2 illustrates the results of testing social curiosity and curiosity about inanimate objects in young mice (referred to as mice) and older rats (referred to as mice) within the study. Scientists observed the states of curiosity in these experimental subjects towards two types of stimuli: A - social novelty or empathic curiosity (making new mouse friends), and B - inanimate novelty or new objects (such as shiny toys). The findings reveal that young mice explore both A and B states more frequently than older rats. Over time, the young mice’s interest in new partners (A state) increases, while the older rats show relatively stable changes in both A and B states.

In general, older rats exhibit lower levels of “cognitive curiosity” and “empathic curiosity” compared to young mice, with these changes remaining stable. To determine the statistical significance of the experimental results and the effects of aging, researchers standardized the exploration rate and leveraged the characteristics of the DAN family of firing nerve cells. These curious dopamine sparks tend to flash in the brain, and the results of spontaneous firing of VTA and SNc dopaminergic neurons in both young and old subjects confirmed a decrease in spontaneous firing in older rats.

Furthermore, chemical genetic methods were employed to use specific drug properties to turn on or off dopamine release, thereby controlling both neuronal burst firing and neuronal chemical inhibition of the VTA/SNc neural circuit. The results indicated that inhibiting the activity of VTA/SNc dopaminergic neurons in older rats reduced curious behavior and spontaneous DAN discharge. Conversely, enhancing the activity of these neurons in young mice restored novelty-seeking behavior and increased spontaneous DAN discharge. The study concluded that the number of dopaminergic neurons decreases with age. In humans, 6% of medial and 2% of lateral neurons are lost every decade, and this loss is directly proportional to the reduction in dopamine availability.

In essence, healthy young DAN can fire action potentials in the absence of excitatory synaptic input, demonstrating relatively regular autonomous regulation of spontaneous firing. In contrast, aged DAN discharges at a significantly lower frequency, with reduced basal activity directly linked to the decline in curious behavior, as if the aging brain has dimmed the lights of curiosity. However, by enhancing the activity of dopaminergic neurons and subsequent dopamine release, interventions may offer new opportunities to prevent, delay, and improve the decline in cognitive ability and curiosity caused by aging or Alzheimer’s disease. These are potential ways to reignite curiosity.

In the 1950s, when Einstein was 63, he penned a letter to a friend, reflecting, “People like you and me, though mortal like everyone else, will never grow old no matter how long we live… We never stop being like curious children.” While it may seem that few can maintain the boundless curiosity of Einstein, inspiring exploration, learning, and scientific innovation, we now understand that the neural mechanisms behind curiosity are intimately linked to the chemical dopamine and the ever-inquisitive dopaminergic neurons (DAN).

With these new insights, perhaps the Sherlock Holmes residing in each of our brains will not retire prematurely. Instead, we might find ourselves not only aging gracefully but also aging with an enduring sense of curiosity. This newfound understanding offers the promise that our inner detective will continue to seek out the novel and the unknown, allowing us to grow old not just with wisdom, but with wonder.

Fig 3: Different representative signals of dopamine, in addition to happiness, desire, motivational goals, etc., there is also curiosity

 

 

 

 

 

 

 

 

 




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