Does Short-Form Content Cause Neurodegenerative Diseases?

Exploring the Long-Term Impact of Short-Form Content on Neurodegenerative Disease Development

Since 1990, disability and death from neurodegenerative diseases, such as Parkinson’s Disease (PD), have increased by 18% [1]. PD is characterized by dopamine  dysregulation, oxidative stress, neuroinflammation, and Lewy bodies (deposits of the protein alpha-synuclein) [2, 3]. New behavioral factors, such as the consumption of short-form video content on social media platforms like TikTok prompt concerns about their effect on neurodegeneration. These platforms encourage users to engage in repetitive short-form video consumption, triggering frequent DA releases. Dopamine (DA) is a neurotransmitter that regulates reward-related behavior through the mesolimbic DArgic pathway [4]. Over time, constant DA stimulation leads to receptor desensitization, requiring more stimulation to achieve the same rewarding effect, resulting in DA ‘crashes’ [5].  Chronic DA fluctuations may contribute to PD development. 

Despite the growing popularity of short-form content such as TikTok, Reels, research on its long-term effects is scarce. This study investigates how excessive DA stimulation from repetitive reward cycles influences dopamine-activated (DAergic) neuron loss in the substantia nigra, neuroinflammation, oxidative stress, and protein aggregation in a rodent model. Using Enzyme-Linked Immunosorbent Assay (ELISA) and immunohistochemistry (IHC) on rats, biomarkers will be quantified and localized in brain tissue after exposure. The findings aim to provide novel insights into the link between DA dysregulation and neurodegenerative diseases like PD, providing new evidence to inform prevention and treatment strategies.

Introduction

Neurodegenerative diseases such as PD are characterized by loss of DAergic neurons, oxidative stress, neuroinflammation, and protein aggregation [2, 3]. A hallmark of PD is the degeneration of DA-producing neurons in the substantia nigra, resulting in motor and cognitive symptoms due to insufficient DA [2]. While genetics  can contribute to PD, environmental and behavioral factors may accelerate its progression. The proposed study will explore a behavioral factor’s contribution to PD, specifically short-form social media content consumption. 

Short-form social media content poses several unique risks to brain health. First, short-form content disrupts and exploits the brain’s DAergic reward system by delivering quick and repetitive stimulation to the mesolimbic pathway, which governs reward processing [5, 6]. This content overstimulates the ventral tegmental area (VTA) and nucleus accumbens (NAc), leading to excessive DA release [7]. Over time, chronic overstimulation desensitizes DA receptors, particularly D1 and D2 receptors, and disrupts normal signaling, resulting in DA “crashes” and chronic fluctuations in DA levels [8]. This dysregulation is hypothesized to disrupt normal functioning in the mesocortical pathway (critical for decision-making and executive functions), and potentially contribute to neurodegeneration [9]. Although this behavior has been linked to cognitive effects like reduced attention spans, its long-term impact on DAergic neurons remains unclear. Constant stimulation of reward pathways such as the mesolimbic pathway poses a research question- Does excessive dopamine-induced stimulation accelerate the death of DAergic neurons? 

Second, DAergic system dysregulation and defects are linked to neuroinflammation. Excess DA, when metabolized, generates reactive oxygen species (ROS), which can activate microglia, the brain’s immune cells, and initiate inflammation [10]. 

Third, DA metabolism generates ROS that damage cellular components, including lipids, proteins, and DNA. A study found that DA exposure reduced neuronal cell viability and increased ROS production, resulting in cellular stress [10, 11]. This finding suggests oxidative stress as a harmful consequence of DA metabolism [10, 11]. Oxidative stress can also lead to mitochondrial dysfunction, which is found in PD [12]. Furthermore, cellular stress caused by ROS may result in protein misfolding, a hallmark of neurodegenerative diseases [12]. These effects are particularly detrimental in the nigrostriatal pathway, which controls motor function [13].

Using ELISA and IHC on rat models, biomarkers of neuroinflammation and  oxidative stress such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-6 (IL-6), Superoxide Dismutase (SOD1), and alpha-synuclein will be quantified [14, 15]. Also, protein aggregates and DAergic neurons in the substantia nigra will be quantified. 

This study offers a novel approach by exploring the following research question- Does excessive dopamine-induced stimulation cause DAergic neuron loss, neuroinflammation, oxidative stress, and protein aggregation, ultimately leading to neurodegenerative diseases like PD? By exploring the impact of DA dysregulation on DAergic neuron loss, neuroinflammation, oxidative stress, and protein aggregation, the research could provide new insights into the mechanisms behind neurodegenerative diseases. The innovative aspect of linking modern digital behaviors with PD development could open doors to targeted prevention and treatment strategies that address the effects of excessive DA stimulation. This would bridge the gaps in current research, offering a new perspective on neurodegenerative disease prevention in the digital age. 

Hypothesis

Excessive DA release induced by short-form social media use combined contributes to DAergic neuron loss, neuroinflammation, oxidative stress, protein aggregation and neurodegeneration in rat models. Rats exposed to DA-inducing stimuli will have less DAergic neurons in the substantia nigra, increased neuroinflammation markers, increased  oxidative stress markers, and more protein aggregation. 

Methods 

The study will use animal models of adult male Wistar rats to simulate the neuropathological effects of DA dysregulation. There will be two forms of DA inducing stimuli, and the study will utilize 3 distinct groups of rats. 

• Group 1 will be a control group and will not have any exposure to unnatural DA-inducing stimuli. 

• Group 2 will be exposed to DA inducing stimuli using a lever and food pellets.

• Group 3 will be exposed to sensory stimuli from dynamic screens and auditory cues, simulating short-form content consumption.

Group 2 rats will be exposed to rapid DA reward cycles. The stimuli will be generated using chambers equipped with a lever and a feeder. Following a variable-ratio reward system (VRRS), rats will sometimes receive a small food pellet when they press the lever [16]. The reward and its intensity will be randomized, following VRRS [16]. The number of lever presses required to earn a treat, and the size of the treat, will change randomly and unpredictably. These lever pressing sessions will last 2 hours a day, for a 3 week period. 

Group 3 rats will be exposed to the sensory effects of watching short-form social media content. To simulate sensory stimuli and induce rapid DA reward cycles, we will create  touch-screen based chambers for the rats. The screen will display colorful, dynamic, and continuous visual stimuli. These stimuli will include animations, like spirals and moving shapes; bright colors; and abstract patterns. Visual stimuli will also be paired with auditory stimuli, like chimes and dings. The rats will be exposed to the visual and auditory stimuli for 2 hours a day, over a 3 week period. 

Following the 3 week period, the rats will be euthanized through CO₂ asphyxiation [17]. Brain tissue from all rats will be extracted, specifically the prefrontal cortex, hippocampus, basal ganglia, and substantia nigra.

Data Collection

Biomarkers related to DAergic neuron loss, neuroinflammation, oxidative stress, and protein aggregation will be quantified from the brain tissue.

DAergic neurons: To assess the impact of excessive DA stimulation on DAergic neurons, the substantia nigra will be analyzed for neuronal loss. Brain tissue will be homogenized in ice-cold PBS with protease inhibitors, and then centrifuged to isolate the supernatant for further analysis [18]. IHC will be used to visualize DAergic neurons by staining for tyrosine hydroxylase (TH), a marker for DAergic neurons [19]. Brain sections will be incubated with anti-TH antibodies and visualized using DAB staining [18, 19]. The number of TH-positive neurons in the substantia nigra will be quantified to determine the extent of DA-induced neurodegeneration. Statistical analysis will compare the number of DAergic neurons between experimental groups to assess potential neuronal loss due to DA dysregulation.

Neuroinflammation: Standardly available ELISA kits will be used to quantify levels of pro-inflammatory cytokines like Tumor Necrosis- alpha (TNF-α) and Interleukin-6 (IL-6) [14]. Brain regions (prefrontal cortex, hippocampus, basal ganglia) will be homogenized in ice-cold PBS with protease inhibitors, centrifuged at 10,000 × g for 10 minutes at 4°C, and the supernatant will be analyzed [18]. For localization, immunohistochemistry will be used to examine the distribution of SOD1 and MDA in paraffin-embedded brain sections using primary antibodies specific to each marker and DAB staining.

Oxidative Stress Markers: ELISA will also be used to measure oxidative stress markers, including Superoxide Dismutase 1 (SOD1) and Malondialdehyde (MDA) [15]. SOD1 is an oxidative enzyme that protects cells from ROS and oxidative damage [20]. Brain regions (prefrontal cortex, hippocampus, basal ganglia) will be homogenized in ice-cold PBS with protease inhibitors, centrifuged at 10,000 × g for 10 minutes at 4°C, and the supernatant will be analyzed [18]. To understand the localization, immunohistochemistry will be used to examine the distribution of SOD1 and MDA in paraffin-embedded brain sections using primary antibodies specific to each marker and DAB staining.

Protein Aggregation: Protein aggregation in the brain tissues will be assessed using ELISA kits, quantifying amyloid-beta (Aβ) and alpha-synuclein levels in the prefrontal cortex, hippocampus, and basal ganglia [3]. The brain tissue will be homogenized in ice-cold PBS containing protease inhibitors, centrifuged at 10,000 × g for 10 minutes at 4°C, and the supernatant will be analyzed [18].  To assess localization, IHC will be performed on paraffin-embedded brain sections. Primary antibodies specific to amyloid-beta and alpha-synuclein will be used, with DAB staining for visualization of protein aggregates. Aggregation will be confirmed by identifying distinct deposits in the brain regions under a microscope [3].

Hypothesized Results

We hypothesize that chronic exposure to dopamine-inducing stimuli, mimicking the overstimulation from short-form social media content, will lead to the following outcomes in rat models:

• A reduction in DAergic neurons in the substantia nigra.

• Increased markers of neuroinflammation (e.g., TNF-α, IL-1β).

• Elevated oxidative stress markers (e.g., MDA, SOD1)

• More protein aggregation, (α-synuclein) and beta amyloid)

Previous studies found that rat models exposed to dopamine-induced stress showed α-synuclein aggregation in dopaminergic neurons, a hallmark feature of Parkinson’s disease [21]. This aggregation correlates with neurodegeneration. Another study found that DA exposure reduced neuronal cell viability and increased ROS production, resulting in cellular stress [10, 11].

Discussion and Conclusion

The quantified DAergic neurons in the substantia nigra, neuroinflammation levels, oxidative stress markers, and protein aggregation in the brain tissues will provide novel insight into the effects of DA dysregulation. The expected findings reiterate the hypothesis that DA dysregulation from short-form social media content consumption accelerates the pathogenesis of neurodegenerative diseases like PD. The findings link back to the research question by indicating that DA dysregulation contributes to neurodegeneration. The findings would enhance understanding of how digital media affects brain health and lead to treatments for DAergic neuron loss, neuroinflammation, oxidative stress, and protein aggregation from DA dysregulation.

Although this study is a valuable asset for new research regarding neurodegeneration, some limits should be addressed. First, the use of rat models may not fully simulate the complexities of the human brain. Also, the range of biomarkers and neurodegenerative markers quantified and evaluated in the study is relatively narrow. In future studies, a broader examination of molecular pathways such as neurotrophic factors and neuroplasticity should be examined. Future research may also use non-human primate animal models, to find outcomes more similar to humans. These studies should be longer-term, exploring what happens to the brain over time. This study will assess the specific neuropathologic changes in the brain when exposed to unnaturally high DA- inducing stimuli. These conditions are increasingly common in today’s society, and this study hopes to provide novel insights to how digital factors impact brain health and pave the way to future research and treatments to mitigate the negative effects of  short-form content.

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Written by Ivy Datta

References

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