Tag: Dopamine

Gut-friendly psychobiotics could brighten moods and fight depression
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In a recent review published in the journal Nutrients, researchers investigated the psychobiotic treatment of depression by restoring microbial balance and regulating the microbiome-gut-brain (MGB) axis.

Depression is a global health concern that causes pain, lost productivity, higher healthcare expenditures, and a high risk of suicide. Dysbiosis, a disruption in gut microbiome homeostasis, can affect the gut-brain axis (GBA), resulting in microbial alterations. Psychobiotics, which have favorable effects on the gut barrier, immunological responses, cortisol expression, and the hypothalamic-pituitary-adrenal (HPA) axis, might be used as a supportive treatment for depression, particularly in treatment-recalcitrant depression (TRD) cases.

The Power of Psychobiotics in Depression: A Modern Approach through the Microbiota–Gut–Brain Axis: A literature Review. Image Credit: T. L. Furrer / Shutterstock

About the review

In the present review, researchers presented clinical evidence and elucidated the underlying mechanisms of psychobiotic therapies for depression via their effects on gut-brain communication.

Association between the gut-brain axis and depressive disorders

Depression is a complex biological disorder influenced by a variety of molecular mechanisms, such as neurotransmitter reduction, a decrease in brain-derived neurotrophic factor (BDNF), an abnormally stressed HPA axis, an increase in pro-inflammatory gut microbial responses, and vagus nerve interaction between gut microbiota and brain. The GBA and intestinal microbes are inextricably linked, with MGB influencing neurobehavioral outcomes via endocrine, neuronal, and immunological mechanisms. Dysbiosis, or a disruption in the GBA axis, can alter the intestinal microbiome, influencing neuronal function, immunology, and gut inflammation.

Chronic stress impairs intestinal homeostasis and changes gut microbial composition, increasing Faecalibaculum and Clostridium in individuals while decreasing Lactobacillus and Bifidobacterium. Recent animal models have demonstrated a relationship between the gut-brain axis and stress sensitivity and resilience. The intestinal microbiome influences inflammatory responses and brain states and is associated with psychiatric conditions such as major depressive disorder, bipolar disorder, psychosis, schizophrenia, anorexia nervosa, anxiety disorders, obsessive-compulsive disorder, post-traumatic stress disorder, and attention-deficit hyperactivity disorder (ADHD).

Graphical Abstract

Gut microbial metabolites involved in antidepressant actions

The gut microbiome is a vital metabolite source, facilitating communications between the gut and the central nervous system. These metabolites consist of tryptophan, gamma-aminobutyric acid (GABA), serotonin, histamine, 5-hydroxytryptamine (5-HT), short-chain fatty acids (SCFAs), acetylcholine, and dopamine (DA). Microbial metabolites impact various mechanisms important for mental health, such as immunological and neuroendocrine system development, nutrition metabolism modulation, and xenobiotic transformation. They also help to maintain gut barrier function, strengthen the intestinal mucosa, and keep dangerous infections and poisons out of circulation. SCFAs are necessary for emotional states and cognition, impacting the host’s brain via G-protein-coupled receptors. They supply energy to colonocytes, protect the intestinal barrier, regulate inflammatory responses, and regulate hunger hormones. Increased SCFAs can reduce neuroinflammation and boost BDNF synthesis, boosting brain neuroplasticity.

Impact of probiotic gut microbes on depression

Psychobiotics are probiotic bacteria that boost mental health by improving the intestinal barrier and modifying the immune response in the gut-associated lymphoid tissue (GALT), which plays a role in inflammation development. The gut microbiota is crucial in the pathophysiology of depression since it regulates inflammatory processes. Bifidobacterium breve boosts BDNF levels, lowers interleukin-6 (IL-60) and TNF-alpha (TNF-α) levels, and enhances cognitive function.

Lactic acid bacteria (LAB) reduce neuroinflammation, lower kynurenine levels, and promote tight junction (TJ) expression. Lactobacillus plantarum 299v boosts dopamine levels and helps with selective serotonin reuptake inhibitor (SSRI) therapy, resulting in better cognitive performance and lower kynurenine levels. Akkermansia muciniphila suppresses inflammatory cytokines in microglial cells, which lowers depressive-like behavior. Clostridium butyricum protects against neurological dysfunction, whereas Faecalibacterium prausnitzii lowers corticosterone and C-reactive protein (CRP) levels while boosting IL-10 levels and lowering cognitive impairment in Alzheimer’s disease rats.

Clinical evidence highlighting the psychobiotic features of bacterial strains

Postbiotics such as Bacillus coagulans MTCC 5856 and Bifidobacterium longum 1714 can help with irritable bowel syndrome (IBS) symptoms and depression. Probiotics such as Bifidobacterium longum 1714 and NCC3001 help to decrease stress and enhance memory. When coupled with antidepressants, these probiotics can effectively cure TRD. Probiotics such as Lactobacillus casei Shirota and Lactobacillus gasseri CP2305, at 2.5 × 109 CFU/g, enhance general health and lower mood disorders. Multi-strain probiotic medication also boosts general health, alleviates anxiety symptoms, and reduces inflammation. Lactobacillus gasseri fermented black soybean beverage helps healthy individuals sleep better and feel less stressed. Probiotic milk drinks and fermented soybean seed paste improve cognitive performance in individuals with moderate cognitive impairment and Alzheimer’s disease.

The review highlights probiotics’ involvement in lowering depressive symptoms and their importance in mental health. The gut microbiota is crucial for digestion, food absorption, and psychiatric concerns such as stress reduction and anxiety. With a shift in the emphasis in modern life from infectious disorders to more common mental illnesses such as depression, good dietary habits and optimal intestinal function are critical for mental well-being, with probiotics playing an important role.
Journal reference:

Dziedzic, A.; Maciak, K.; Bliźniewska-Kowalska, K.; Gałecka, M.; Kobierecka, W.; Saluk, J. The Power of Psychobiotics in Depression: A Modern Approach through the Microbiota–Gut–Brain Axis: A literature Review. Nutrients 2024, 16, 1054. DOI: 10.3390/nu16071054, https://www.mdpi.com/2072-6643/16/7/1054
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April 8, 2024
Study reveals obesity’s link to increased risk of multiple sclerosis and ischemic stroke

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In a recent study published in Scientific Reports, researchers from China used Mendelian randomization (MR) to assess the genetic relationship between body mass index (BMI) and multiple neurological diseases.

They found that BMI shows a genetic causal relationship with multiple sclerosis (MS) and ischemic stroke (IS), but not with Parkinson’s disease (PD), Alzheimer’s disease (AD), amyotrophic lateral sclerosis (ALS), and epilepsy (EP).

Study: Genetic causal role of body mass index in multiple neurological diseases. Image Credit: New Africa/Shutterstock.com

Background

BMI is widely used for obesity assessment owing to its simplicity and sensitivity. Economic changes and lifestyle shifts have increased obesity risk globally. Elevated BMI is linked to various diseases and higher mortality rates, including type 2 diabetes, hypertension, coronary heart disease, musculoskeletal disorders, and neoplastic growth.

Neurological diseases cover a broad spectrum of nervous system conditions, including neurodegenerative, cerebrovascular, infectious, oncological, and hereditary disorders.

While PD is characterized by dopamine concentration changes and Lewy body presence, AD is linked to β-amyloid deposition and tau protein phosphorylation. ALS affects motor neurons, while MS is a demyelinating disease mediated by the immune system.

IS is associated with various risk factors like hypertension and diabetes, and EP arises from synchronized neuronal discharges due to genetic or structural abnormalities.

MR is a method to assess causal relationships between exposures and outcomes using genetic instrumental variables, including single nucleotide polymorphisms (SNPs). The method is robust against the effects of confounders and reverse causation.

Therefore, researchers in the present study investigated the genetic links between BMI and neurological diseases using MR analysis, aiming to inform disease management strategies.

About the study

The present study used SNPs from a genome-wide association study (GWAS) dataset as instrumental variables to explore genetic causality between exposure and outcome factors.

The study followed stringent criteria for MR studies, ensuring robust correlations between instrumental variables and exposure factors while controlling for potential confounders.

Data on BMI indicators were obtained from the Integrative Epidemiology Unit (IEU) database, comprising nearly one million participants of European ancestry, with measurements for over seven million SNPs.

Data for various neurological diseases were sourced from the IEU database, including PD, AD, MS, ALS, IS, EP cases, and respective control groups.

The participants were predominantly of European origin, except for ALS and EP, which comprised individuals of multiple races and regions.

Quality control procedures were implemented for all disease data. SNPs significantly associated with BMI were subjected to cluster analysis to exclude redundant effects. SNPs causally linked to PD, AD, MS, ALS, IS, EP, and those related to disease confounders were excluded.

Two-sample MR analysis was employed, with inverse variance weighting (IVW) as the primary analytical approach, supported by weighted median, MR Egger, simple mode, and weighted mode. Further, the sensitivity analysis employed the MR-Egger method, Cochran Q test, and leave-one-out method to assess horizontal pleiotropy, heterogeneity, and robustness of the causal relationship between BMI indicators and neurological diseases.

Results and discussion

As per the study, significant genome-wide associations were found between BMI indicators and SNPs for PD (42), AD (42), MS (39), ALS (42), IS (42), and EP (31). The IVW analysis showed no genetic causality between BMI and PD, AD, ALS, and epilepsy (P > 0.05).

However, a positive genetic causality was found between BMI and MS (P = 0.035) and IS (P = 0.000). The findings suggest that a higher BMI is associated with increased risk for MS and IS.

Further, the weighted median analysis showed causal relationships between BMI and MS, IS, while the simple mode suggested a relationship with IS alone. Interestingly, MR Egger and weighted mode analyses showed no causal relationship between BMI and the studied diseases.

Results of the sensitivity analysis corroborated with the main findings. No significant heterogeneity or pleiotropy was found, and the findings were confirmed to be stable and reliable.

The findings are strengthened with the use of robust instrumental SNPs derived from the most comprehensive GWAS database so far.

However, the study is limited by its focus on patients of European ancestry, potential incomplete control of all neurological disorder risk factors, and reliance solely on BMI, without considering other body composition metrics.

Future studies involving waist circumference, waist-to-hip ratio, body fat percentage, and bioelectrical impedance could potentially reduce the bias in the results.

Conclusion

In conclusion, the study demonstrates MR analysis’s utility in exploring genetic causal links between BMI and neurological diseases.

While no causal relationship was found with PD, AD, ALS, or EP, a genetic causal association of BMI was identified with MS and IS, suggesting that an increased BMI may increase the risk of MS and IS.

These findings highlight obesity’s potential role as a risk factor in neurological disorders, paving the way for prevention and treatment strategies for improved health outcomes.

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March 29, 2024
Antipsychotic use during pregnancy not linked to childhood neurodevelopmental disorders or learning difficulties

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The use of antipsychotics during pregnancy isn’t linked to childhood neurodevelopmental disorders or learning difficulties, UNSW Sydney-led study shows – giving assurance to those concerned about continuing their medications during pregnancy.

Antipsychotics – a branch of medication designed to treat schizophrenia and bipolar disorder – are important tools for mental health care management. They work by blocking the effect of dopamine, which can help reduce psychotic symptoms such as hallucinations or delusions.

These versatile medications are also widely used for other mental health conditions and developmental disorders, like anxiety, depression, autism spectrum disorder, and insomnia.

But many women and pregnant people using these medications may feel concerned about the potential risks they pose to their unborn baby.

A new international study led by UNSW Sydney, published today in eClinicalMedicine, tracked the long-term risk of a child developing neurodevelopmental disorders and learning difficulties after being exposed to antipsychotics in the womb.

The findings show there’s little to no increased risk of the exposure leading to intellectual disability, poor academic performance in maths and language, or learning, speech and language disorders.

The findings are really reassuring for both women managing these psychiatric conditions during pregnancy and their providers.”

Dr. Claudia Bruno, pharmacoepidemiologist at UNSW’s School of Population Health and lead author of the study

“There’s no increased risk when taking the medication during pregnancy, not only for the specific neurodevelopmental disorders that we looked at, but also ADHD and autism as shown in our team’s previous studies.”

This research is the most comprehensive study on antipsychotics and neurodevelopmental outcomes to date: it pulls together nationwide data from Denmark, Finland, Iceland, Norway, and Sweden into a large sample size of 213,302 children born to mothers with a diagnosed psychiatric condition, 5.5 per cent (11,626) of which were prenatally exposed to antipsychotics.

These five Nordic countries all have similar health and education systems and keep detailed data on birth records, filled prescriptions, and diagnoses from inpatient and outpatient specialist care, as well as antenatal care. The researchers teamed these data with results from the children’s first standardised national school test (similar to Australia’s NAPLAN tests), which happens between the ages of 8-10.

“It’s reassuring that everything points to the same ‘no major indication’ of increased risks overall,” says Scientia Associate Professor Helga Zoega, senior author of the study and pharmacoepidemiologist, also based at UNSW’s School of Population Health.

“The study builds on our team’s previous work that looked at birth outcomes, including serious congenital malformations, where we’ve seen similar null results.

“I think it’s important to get excited about null results because this is essential information for the management of serious mental health conditions in pregnancy. It’s as equally important as finding an increased risk of outcomes.”

A gap that big health data is trying to fix

While this study is part of a growing body of research about medication safety in pregnancy, there’s still a lot left in this field to discover, says A/Prof. Zoega.

“This is a hugely understudied area,” she says. “Unfortunately, we know way too little about medication safety during pregnancy.”

One of the reasons so little is known about medicines and pregnancy is that it’s simply not feasible – or in many cases, ethical – to conduct randomised clinical trials on pregnant women. The potential risks of testing or withholding treatment to the unborn child and mother or pregnant person is often too great.

That’s where harnessing big data can step in – although the research isn’t as simple as looking at the raw data alone.

For example, women treated with antipsychotics during pregnancy were more likely to smoke, have higher BMIs, lower education levels, to be older (35 years or more) and use other medications during pregnancy compared to women who didn’t take antipsychotics during pregnancy – all of which are risk factors that can potentially impact birth outcomes.

These circumstances – called ‘confounding factors’ – are accounted for in observational research using careful study design and complex adjusted risk models to make sure the results show the impact of the medication alone.

“These types of studies are methodologically tricky, and can take a long time to do,” says A/Prof. Zoega. “This study has been in the making for almost 10 years now.

“We already know these women are dealing with psychiatric conditions, and by genetic default, their children would be more likely to have psychiatric or neurodevelopmental outcomes. But we’re focused on the risks and benefits of the medication treatment in pregnancy, so we use methods to make the comparison groups as similar as possible.”

The researchers also strengthened their findings by slicing up the data to take a closer look at whether individual medications, trimesters of exposure, and siblings carried higher risk levels.

While one antipsychotic, chlorpromazine, showed potential increased links to language and speech delays, these findings were based on small sample sizes of 8-15 children, so more research is needed to investigate this potential link.

Other than this anomaly, the results supported the finding that there was little to no increased risk of children prenatally exposed to antipsychotics developing neurodevelopmental disorders or learning difficulties.

Looking ahead

Dr Bruno is currently involved in two related studies on prenatal medication use and pregnancy outcomes. One explores if there is a relationship between the use of antiseizure medications during pregnancy and child school performance, and the other examines whether taking ADHD medication use and discontinuation during pregnancy on child health outcomes.

But she sees many avenues for future research to build on this work, including harnessing more Australian big health data.

“There’s so much to learn about medication safety in pregnancy,” says Dr Bruno. “These women are typically excluded from clinical trials, so there’s a real lack of data or evidence.

“While these results are highly generalisable to women in Australia, we now have real-world linked Australian data that can start contributing to large-scale international studies like this one which we’re very excited for.”

A/Prof. Zoega co-leads an international research collaboration called International Pregnancy Drug Safety Study (InPreSS), which investigates the safety of medication in pregnancy. She says there’s plenty to do in this space.

“Antipsychotics are only one class of medications, and we already know that up to 80 per cent of women use at least one prescription medicine during pregnancy. Most often, there’s little or no guidance on safety.

“There are so many unanswered questions that there’s enough for a lifetime of research.”

Source:

University of New South Wales

Journal reference:

Bruno, C., et al. (2024) Antipsychotic use during pregnancy and risk of specific neurodevelopmental disorders and learning difficulties in children: a multinational cohort study. eClinicalMedicine. doi.org/10.1016/j.eclinm.2024.102531.

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March 18, 2024
Innovative Levodopa infusion pump trial shows promise for reducing Parkinson’s symptoms

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An international, multisite phase 3 trial co-led by a University of Cincinnati researcher found Parkinson’s disease medication delivered through an infusion pump is safe and effective at reducing symptoms for longer periods of time.

These results, published March 15 in the Lancet Neurology journal, could lead to additional treatment options for patients with the condition.

Parkinson’s symptoms such as tremors, slowness and stiffness are caused by low levels of dopamine in the body. For decades, doctors have treated Parkinson’s by giving patients levodopa, the inactive substance in the brain that once converted makes dopamine.

“Levodopa is a replacement strategy. We all make levodopa, but Parkinson’s patients make less of it,” said Espay, co-principal investigator of the trial, James J. and Joan A. Gardner Family Center for Parkinson’s Disease Research Endowed Chair in UC’s Department of Neurology and Rehabilitation Medicine and a physician at the UC Gardner Neuroscience Institute.

Espay said oral levodopa is effective and typically helps people regain normal motor function, but its benefits tend to last less than a few hours after a few years, requiring increases in doses or its frequency.

Levodopa is most commonly administered orally, but this trial tested continuous, 24-hour levodopa delivery through a subcutaneous infusion pump. A total of 381 patients with Parkinson’s disease in 16 countries enrolled in the trial and were randomized to receive levodopa through the infusion pump or through traditional oral medication.

The researchers found levodopa delivered through the infusion pump was safe and led to almost two hours of day (1.72) of additional “on time,” or the time when the medication is working and symptoms are lessened, compared to taking levodopa orally.

Espay said the results of this trial pave the way for this specific infusion pump delivery system to be approved by the Food and Drug Administration and other countries’ respective governing bodies.

Once approved, this will become an important treatment strategy to consider for patients with Parkinson’s disease experiencing motor fluctuations not adequately controlled with medication. Future studies will need to determine the durability of the long-term benefits and whether any safety issues could emerge, as well as how it might compare with deep brain stimulation.”

Prof Alberto J Espay, James J and Joan A Gardner Center for Parkinson’s Disease and Movement Disorders, University of Cincinnati

Two additional subcutaneous delivery systems are also expected to be approved this year, Espay said, and researchers are continuing to study how to improve levodopa formulations and delivery to optimize its effect for patients.

“Levodopa delivery systems are expected to continue to improve over time,” he said. “This is a thriving area of research for the benefits of our patients.”

Source:

Journal reference:

Espay, A. J., et al. (2024). Safety and efficacy of continuous subcutaneous levodopa–carbidopa infusion (ND0612) for Parkinson’s disease with motor fluctuations (BouNDless): a phase 3, randomised, double-blind, double-dummy, multicentre trial. The Lancet Neurology. doi.org/10.1016/s1474-4422(24)00052-8

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March 15, 2024
Research provides insight into how the brain translates motivation into goal-oriented behavior

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Hunger can drive a motivational state that leads an animal to a successful pursuit of a goal -; foraging for and finding food.

In a highly novel study published in Current Biology, researchers at the University of Alabama at Birmingham and the National Institute of Mental Health, or NIMH, describe how two major neuronal subpopulations in a part of the brain’s thalamus called the paraventricular nucleus participate in the dynamic regulation of goal pursuits. This research provides insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.

For the study, mice first had to be trained in a foraging-like behavior, using a long, hallway-like enclosure that had a trigger zone at one end and a reward zone at the other end, more than 4 feet distant.

Mice learned to wait in a trigger zone for two seconds, until a beep triggered initiation of their foraging-like behavioral task. A mouse could then move forward at its own pace to the reward zone to receive a small gulp of strawberry-flavored Ensure. To terminate the trial, the mice needed to leave the reward zone and return to the trigger area, to wait for another beep. Mice learned quickly and were highly engaged, as shown by completing a large volume of trials during training.

The researchers then used optical photometry and the calcium sensor GCaMP to continuously monitor activity of two major neuronal subpopulations of the paraventricular nucleus, or PVT, during the reward approach from the trigger zone to the reward zone, and during the trial termination from the reward zone back to the trigger zone after a taste of strawberry-flavored food. The experiments involve inserting an optical fiber into the brain just about the PVT to measure calcium release, a signal of neural activity.

The two subpopulations in the paraventricular nucleus are identified by presence or absence of the dopamine D2 receptor, noted as either PVT^D2(+) or PVT^D2(–), respectively. Dopamine is a neurotransmitter that allows neurons to communicate with each other.

We discovered that PVT^D2(+) and PVT^D2(–) neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVT^D2(+) neuronal population mirrored motivation parameters such as vigor and satiety.”

Sofia Beas, Ph.D., assistant professor in the UAB Department of Neurobiology and co-corresponding author of the study

Specifically, the PVT^D2(+) neurons showed increased activity during the reward approach and decreased activity during trial termination. Conversely, PVT^D2(–) neurons showed decreased activity during the reward approach and increased activity during trial termination.

“This is novel because people didn’t know there was diversity within the PVT neurons,” Beas said. “Contrary to decades of belief that the PVT is homogeneous, we found that, even though they are the same types of cells (both release the same neurotransmitter, glutamate), PVT^D2(+) and PVT^D2(–) neurons are doing very different jobs. Additionally, the findings from our study are highly significant as they help interpret contradictory and confusing findings in the literature regarding PVT’s function.”

For a long time, the thalamic areas such as the PVT had been considered just a relay station in the brain. Researchers now realize, Beas says, that the PVT instead processes information, translating hypothalamic-derived needs states into motivational signals via projections of axons -; including the PVT^D2(+) and PVT^D2(–) axons -; to the nucleus accumbens, or NAc. The NAc has a critical role in the learning and execution of goal-oriented behaviors. An axon is a long cable-like extension from a neuron cell body that transfers the neuron’s signal to another neuron.

Researchers showed that these changes in neuron activity at the PVT were transmitted to the NAc by measuring neural activity with an optical fiber inserted where the terminals of the PVT axons reach the NAc neurons. The activity dynamics at the PVT-NAc terminals largely mirrored the activity dynamics the researchers saw at the PVT neurons -; namely increased neuron activity signal of PVT^D2(+) during reward approach and increased neuron activity of PVT^D2(–) during trial termination.

“Collectively, our findings strongly suggest that motivation-related features and the encoding of goal-oriented actions of posterior PVT^D2(+) and PVT^D2(-) neurons are being relayed to the NAc through their respective terminals,” Beas said.

During each mouse recording session, the researchers recorded eight to 10 data samples per second, resulting in a very big dataset. In addition, these types of recordings are subject to many potential confounding variables. As such, the analysis of this data was another novel aspect of this study, through use of a new and robust statistical framework based on Functional Linear Mixed Modeling that both account for the variability of the recordings and can explore the relationships between the changes of photometry signals over time and various co-variates of the reward task, such as how quickly mice performed a trial, or how the hunger levels of the animals can influence the signal.

One example of how researchers correlated motivation with task performance was separating the trial times into “fast” groups, two to three seconds to the reward zone from the trigger zone, and “slow” groups, nine to 11 seconds to the reward zone.

“Our analyses showed that reward approach was associated with higher calcium signal ramps in PVT^D2(+) neurons during fast compared to slow trials,” Beas said. “Moreover, we found a correlation between signal and both latency and velocity parameters. Importantly, no changes in posterior PVT^D2(+) neuron activity were observed when mice were not engaged in the task, as in the cases where mice were roaming around the enclosure but not actively performing trials. Altogether, our findings suggest that posterior PVT^D2(+) neuron activity increases during reward-seeking and is shaped by motivation.”

Deficits in motivation are associated with psychiatric conditions like substance abuse, binge eating and the inability to feel pleasure in depression. A deeper understanding of the neural basis of motivated behavior may reveal specific neuronal pathways involved in motivation and how they interact. This could lead to new therapeutic targets to restore healthy motivational processes in patients.

Co-authors with Beas in the study, “Dissociable encoding of motivated behavior by parallel thalamo-striatal projections,” are Isbah Khan, Claire Gao, Gabriel Loewinger, Emma Macdonald, Alison Bashford, Shakira Rodriguez-Gonzalez, Francisco Pereira and Mario Penzo, NIMH, Bethesda, Maryland. Beas was a post-doctoral fellow at the NIMH before moving to UAB last year.

Support came from National Institutes of Health award K99/R00 MH126429, a NARSAD Young Investigator Award by the Brain and Behavior Research Foundation, and NIMH Intramural Research Program award 1ZIAMH002950.

At UAB, Neurobiology is a department in the Marnix E. Heersink School of Medicine.

Source:

University of Alabama at Birmingham

Journal reference:

Beas, S., et al. (2024). Dissociable encoding of motivated behavior by parallel thalamo-striatal projections. Current Biology. doi.org/10.1016/j.cub.2024.02.037.

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March 15, 2024
Gut bacteria and tryptophan diet can play a protective role against pathogenic E. coli

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Gut bacteria and a diet rich in the amino acid tryptophan can play a protective role against pathogenic E. coli, which can cause severe stomach upset, cramps, fever, intestinal bleeding and renal failure, according to a study published March 13 in Nature.

The research reveals how dietary tryptophan – an amino acid found mostly in animal products, nuts, seeds, whole grains and legumes – can be broken down by gut bacteria into small molecules called metabolites. It turns out a few of these metabolites can bind to a receptor on gut epithelial (surface) cells, triggering a pathway that ultimately reduces the production of proteins that E. coli use to attach to the gut lining where they cause infection. When E. coli fail to attach and colonize the gut, the pathogen benignly moves through and passes out of the body.

The research describes a previously unknown role in the gut for a receptor, DRD2. DRD2 has otherwise been known as a dopamine (neurotransmitter) receptor in the central and peripheral nervous systems.

It’s actually two completely different areas that this receptor could play a role in, which was not appreciated prior to our findings. We essentially think that DRD2 is moonlighting in the gut as a microbial metabolite sensor, and then its downstream effect is to help protect against infection.”

Pamela Chang, associate professor of immunology in the College of Veterinary Medicine and of chemical biology in the College of Arts and Sciences

Samantha Scott, a postdoctoral researcher in Chang’s lab, is first author of the study, “Dopamine Receptor D2 Confers Colonization Resistance via Microbial Metabolites.”

Now that Chang, Scott and colleagues have identified a specific pathway to help prevent E. coli infection, they may now begin studying the DRD2 receptor and components of its downstream pathway for therapeutic targets.

In the study, the researchers used mice infected with Citrobacter rodentium, a bacterium that closely resembles E. coli, since certain pathogenic E. coli don’t infect mice. Through experiments, the researchers identified that there was less pathogen and inflammation (a sign of an active immune system and infection) after mice were fed a tryptophan-supplemented diet. Then, to show that gut bacteria were having an effect, they gave the mice antibiotics to deplete microbes in the gut, and found that the mice were infected by C. rodentium in spite of eating a tryptophan diet, confirming that protection from tryptophan was dependent on the gut bacteria.

Then, using mass spectrometry, they ran a screen to find the chemical identities of tryptophan metabolites in a gut sample, and identified three such metabolites that were significantly increased when given a tryptophan diet. Again, based on pathogen levels and inflammation, when these three metabolites alone were fed to the mice, they had the same protective effect as giving the mice a full tryptophan diet.

Switching gears, the researchers used bioinformatics to find which proteins (and receptors) might bind to the tryptophan metabolites, and from a long list they identified three related receptors within the same family of dopamine receptors. Using a human intestinal cell line in the lab, they were able to isolate receptor DRD2 as the one that had the protective effect against infection in the presence of tryptophan metabolites.

Having identified the metabolites and the receptor, they analyzed the downstream pathway of DRD2 in human gut epithelial cells. Ultimately, they found that when the DRD2 pathway was activated, the host’s ability to produce an actin regulatory protein was compromised. C. rodentium (and E. coli) require actin to attach themselves to gut epithelial cells, where they colonize and inject virulence factors and toxins into the cells that cause symptoms. But without actin polymerization they can’t attach and the pathogen passes through and clears.

The experiments revealed a new role of dopamine receptor DRD2 in the gut that controls actin proteins and affects a previously unknown pathway for preventing a pathogenic bacteria’s ability to colonize the gut.

Jingjing Fu, a former postdoctoral researcher in Chang’s lab, is a co-author.

The study was supported by the Arnold and Mabel Beckman Foundation, a President’s Council of Cornell Women Affinito-Stewart Grant, the National Institutes of Health and a Cornell Institute of Host-Microbe Interactions and Disease Postdoctoral Fellowship.

Source:

Journal reference:

Scott, S. A., et al. (2024). Dopamine receptor D2 confers colonization resistance via microbial metabolites. Nature. doi.org/10.1038/s41586-024-07179-5

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March 14, 2024
Study unveils role of dopamine and serotonin in social behavior

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In a study in today’s (Monday Feb. 26) Nature Human Behavior, scientists delve into the world of chemical neuromodulators in the human brain, specifically dopamine and serotonin, to reveal their role in social behavior.

The research, conducted in Parkinson’s disease patients undergoing brain surgery while awake, homed in on the brain’s substantia nigra, a crucial area associated with motor control and reward processing.

Led by Virginia Tech computational neuroscientist Read Montague, the international team revealed a previously unknown neurochemical mechanism for a well-known human tendency to make decisions based on social context -; people are more likely to accept offers from computers while rejecting identical offers from human players.

Insight from an ultimatum game

In the study, four patients receiving deep brain stimulation surgery for Parkinson’s disease were immersed in the “take it or leave it” ultimatum game, a scenario where they had to accept or reject varying splits of $20 from both human and computer players. For instance, one player may propose to keep $16, whereas the patient gets the remaining $4. If the patient rejects the split, then neither of them receives anything.

You can teach people what they should do in these kinds of games -; they should accept even small rewards as opposed to no reward at all. When people know they’re playing a computer, they play perfectly, just like mathematical economists – they do what they should do. But when they’re playing a human being, they cannot help themselves. They are often driven to punish the smaller bid by rejecting it.”

Read Montague, Montague, the Virginia Tech Carilion Mountcastle professor, Fralin Biomedical Research Institute at VTC and senior author of the study

Dopamine-serotonin dance

The idea that people make decisions based on social context is not a new one in neural economic games. But now, for the first time, researchers show the impact of the social context may spring from the dynamic interactions of dopamine and serotonin.

When people make decisions, dopamine seems to closely follow and react to whether the current offer is better or worse than the previous one, as if it were a continuous tracking system. Serotonin, meanwhile, appears to focus only on the current value of the specific offer at hand, suggesting a more case-by-case evaluation.

This fast dance happens against a slower backdrop, where dopamine is overall higher when people play other human beings – in other words, when fairness comes into play. Together, these signals contribute to our brain’s overall assessment of value during social interactions.

“We are shining a spotlight on various cognitive processes and finally receiving answers to questions in finer biological detail,” said study shared first author Dan Bang, associate professor of clinical medicine and Lundbeck Foundation Fellow at Aarhus University in Denmark, and an adjunct associate professor at the Fralin Biomedical Research Institute.

“Dopamine levels are higher when people interact with another human as opposed to a computer,” Bang said. “And here it was important that we also measured serotonin to give us confidence that the overall response to social context is specific to dopamine.”

Seth Batten, a senior research associate in Montague’s lab and shared first author of the study, built the carbon-fiber electrodes that were implanted in patients receiving Deep Brain Stimulation surgery and helped collect the data at the Mount Sinai Health System in New York.

“The unique twist with our method is that it allows us to measure more than one neurotransmitter at a time -; the impact of that should not be lost,” Batten said. “We’ve seen these signaling molecules before, but this is the first time we’ve seen them dance. No one has ever seen this dance of dopamine and serotonin in a social context before.”

Teasing out the meaning of the electrochemical signals recorded from patients in surgery was a major challenge that took years to solve.

“The raw data that we’re collecting from patients isn’t specific to dopamine, serotonin, or norepinephrine – it’s a mixture of those,” said Ken Kishida, a co-author of the study and an associate professor of translational neuroscience, and neurosurgery, at Wake Forest University School of Medicine. “We’re essentially using machine-learning type tools to separate what’s in the raw data, understand the signature, and decode what’s going on with dopamine and serotonin.”

In the Nature Human Behavior study, researchers showed how the rise and fall of dopamine and serotonin are intertwined with human cognition and behavior.

“In the model organism world, there is a candy store full of fantastical techniques to ask biological questions, but it’s harder to ask questions about what makes you, you,” said Montague, who is also the director of the Center for Human Neuroscience Research and the Human Neuroimaging Laboratory of the Fralin Biomedical Research Institute.

Addressing Parkinson’s

“At some point, after we have evaluated enough people, we’re going to be able to address the Parkinson’s disease pathology that’s given us this window of opportunity,” said Montague, who is also a professor in the Virginia Tech College of Science.

In Parkinson’s disease, a significant loss of dopamine-producing neurons in the brainstem is a key characteristic that usually coincides with the onset of symptoms.

This loss impacts the striatum, a brain region heavily influenced by dopamine. As dopamine diminishes, serotonin terminals begin to sprout, revealing a complex interaction, as observed in rodent models.

“Already there is pre-clinical evidence that the attrition of the dopamine system is telling the serotonin system, ‘Hey, we’ve got to do something.’ But we’ve never been able to watch the dynamics,” Montague said. “What we’re doing now is the first step, but one would hope that once we get up to hundreds of patients, we’d be able to relate this to symptomatology and make some clinical statements about the Parkinson’s pathology.”

In that respect, researchers said a window is opening to learn about a wide range of brain disorders.

“The human brain is like a black box,” Kishida said. “We have developed one more way to look inside and understand how these systems work and how they have become affected by various clinical conditions.”

Michael Friedlander, executive director of the Fralin Biomedical Research Institute and a neuroscientist who was not involved in the study, said, “This work is changing the entire field of neuroscience and our ability to query the human mind and brain -; with a technology that was just not even imagined not many years ago.”

Psychiatry is an example of a medical field that could benefit by this approach, he said.

“We have an enormous number of people in the world who suffer from a variety of psychiatric conditions, and, in many cases, the pharmacological solutions do not work very well,” said Friedlander, who is also Virginia Tech’s vice president of health sciences and technology. “Dopamine, serotonin, and other neurotransmitters are in some ways intimately involved with those disorders. This effort adds real precision and quantitation to understand those problems. The one thing I think we can be sure of is this work is going to be extremely important in the future for developing treatments.”

More than a decade in the making

The effort to measure neurotransmitters in real-time in the human brain began more than 12 years ago when Montague assembled a team of experts who “think about thinking, a lot.”

In first-of-their-kind observations in the human brain the scientists published in Neuron in 2020, researchers revealed dopamine and serotonin are at work at sub-second speeds to shape how people perceive the world and take action based on their perception.

More recently, in a study published in October in the journal Current Biology, the researchers used their method of recording chemical changes in awake humans to gain insight into the brain’s noradrenaline system, which has been a longtime target for medications to treat psychiatric disorders.

And, in December in the journal Science Advances, the team revealed that fast changes in dopamine levels reflect a specific computation related to how humans learn from rewards and punishments.

“We’ve made active measurements of neurotransmitters multiple times in different brain regions, and we have now reached the point where we’re touching on crucial elements of what makes us human beings,” Montague said.

Source:

Journal reference:

Batten, S. R., et al. (2024). Dopamine and serotonin in human substantia nigra track social context and value signals during economic exchange. Nature Human Behaviour. doi.org/10.1038/s41562-024-01831-w.

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February 26, 2024
Study reveals pivotal insights into the progression of Parkinson’s disease

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Parkinson’s disease, the second most common type of progressive dementia after Alzheimer’s disease, affects nearly 1 million people in the U.S. and an estimated 10 million individuals worldwide. Each year, close to 90,000 new cases of Parkinson’s disease are diagnosed in the U.S.

In a new study, Jeffrey Kordower, director of the ASU-Banner Neurodegenerative Disease Research Center, and his colleagues unveil pivotal insights into the progression of Parkinson’s disease, presenting new hope for patients battling the severely debilitating disorder.

The research highlights the role of a critical protein called tau in the early stages of the disease. The results suggest that aggregates of the tau protein may jump-start processes of neuronal damage and death characteristics of the disease.

The findings challenge the conventional view of Parkinson’s disease pathology, which typically focuses on the protein alpha-synuclein as the classic diagnostic hallmark of the disease. The new study illustrates how tau pathology could be actively involved in the degeneration of dopamine-producing neurons in the brain, independent of alpha-synuclein. This revelation could shift the focus of Parkinson’s disease research, diagnosis and treatment.

Currently, a protein called alpha-synuclein is believed to be the main player in Parkinson’s disease pathogenesis. This study highlights that misfolded tau may be the first player in causing the cardinal motor symptoms in the disease.”

Jeffrey Kordower, Professor, ASU’s School of Life Sciences

The study appears in the current issue of the journal Brain.

Shattering progression

The progression of Parkinson’s disease involves distinct stages, and the timeline can vary significantly among individuals. The typical stages of Parkinson’s, as outlined by the Parkinson’s Foundation, can help patients understand the changes as they occur.

The disease impacts people in different ways, and not everyone will experience all the symptoms or experience them in the same order or intensity. Some may experience the changes over 20 years or more; for others, the disease advances rapidly.

The progression of the disease is influenced by a combination of genetic and environmental factors. Following a diagnosis, many individuals experience a good response to medications such as levodopa, and this optimal time frame can last for many years. Over time, however, modifications to medication are often needed and symptoms may intensify.

The prevalence of Parkinson’s has doubled in the past 25 years, which may be related to population growth, aging, genetic predisposition, lifestyle changes and environmental pollution.

A fresh perspective

The tau protein accumulates in two regions: the substantia nigra and putamen, both part of the basal ganglia in the brain. The substantia nigra is responsible for the production of dopamine, which is critical for modulating movement, cognitive executive functions and emotional limbic activity.

The putamen, a component of the dorsal striatum, is involved in movement initiation, selection and decision-making, as well as learning, memory, language and emotion. Dysfunction in the putamen can contribute to various disorders, particularly those related to motor function.

A wide range of physical and mental symptoms characterize Parkinson’s disease. These include: rhythmic tremors, often beginning in a limb, such as the hand or fingers; slowness of movement, which can lead to difficulty in performing simple tasks; muscle stiffness or rigidity; and difficulties with balance.

In addition to these physical symptoms, Parkinson’s disease can also cause various mental and emotional changes, including depression and anxiety, sleep disorders, memory difficulties, fatigue and emotional changes.

Brain traces of disease

The scientists conducted the study using postmortem brain tissue from older adults who had experienced different degrees of motor impairment. The research analyzed brain tissues from individuals with no motor deficits, mild motor deficits with and without Lewy pathology in the nigral region of the brain, and from individuals clinically diagnosed with Parkinson’s disease.

Lewy bodies are abnormal aggregates of the protein alpha-synuclein that accumulate in the brain, and they are a hallmark of several neurodegenerative disorders, including Parkinson’s and dementia with Lewy bodies.

In the case of Parkinson’s, Lewy bodies are primarily found in the substantia nigra, a region of the brain that is crucial for movement control, which leads to characteristic motor symptoms such as rigidity, tremors and bradykinesia (slow movement).

The study focused on a cohort of subjects with mild motor impairments -; not pronounced enough to diagnose Parkinson’s, but still significant. Dividing these subjects based on the presence or absence of α-synuclein, researchers found that tau pathology was a common denominator.

The researchers observed that the brain tissue associated with minimal motor deficit demonstrated similar accumulations of tau to those with advanced Parkinson’s, suggesting that tau’s role occurs early in the disease’s evolution. These findings open doors to earlier diagnosis and intervention, potentially slowing or altering the disease’s progression.

The research also sheds light on parkinsonism, a condition that mimics Parkinson’s disease symptoms but is distinct in its underlying mechanisms. The study suggests that tau pathology in the nigrostriatal region of the brain is a shared characteristic, offering a new lens through which to view and treat various forms of parkinsonism.

The findings also underscore the potential of targeting tau pathology as a therapeutic approach in Parkinson’s disease. Because tau aggregation correlates with motor deficits and degeneration of dopamine-producing regions of the brain, interventions aimed at reducing tau accumulation could offer new hope for altering the disease’s trajectory.

Kordower is joined by researchers from Neurodegenerative Diseases Research Unit, Biogen, Cambridge, Massachusetts; Aligning Science Across Parkinson’s (ASAP) Collaborative Research Network, Chevy Chase, Maryland; Neurology, School of Medicine, Georgetown University Medical Center, Washington, D.C.; Department of Neurology, University of Alabama at Birmingham; and Pacific Parkinson’s Research Centre and Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver.

Source:

Journal reference:

Chu, Y., et al. (2023). Nigrostriatal tau pathology in parkinsonism and Parkinson’s disease. Brain. doi.org/10.1093/brain/awad388.

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February 24, 2024
How dopamine influences movement in Parkinson’s

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Dopamine, a chemical messenger in the brain, is mostly known for its role in how we experience pleasure and reward. However, new research from the Champalimaud Foundation (CF) shifts the spotlight towards dopamine’s critical involvement in movement, with implications for our understanding and treatment of symptoms in Parkinson’s Disease (PD).

Imagine the act of walking. It’s something most able-bodied people do without a second thought. Yet it is actually a complex process involving various neurological and physiological systems. PD is a condition where the brain slowly loses specific cells, called dopamine neurons, resulting in reduced strength and speed of movements. However, there’s another important aspect that gets affected: the length of actions. Someone with PD might not only move more slowly but also take fewer steps in a walking sequence or bout before stopping. This study shows that dopamine signals directly affect the length of movement sequences, taking us a step closer to unlocking new therapeutic targets for enhancing motor function in PD.

Dopamine is most closely associated with reward and pleasure, and is often referred to as the ‘feel-good’ neurotransmitter. But, for dopamine-deficient individuals with PD, it’s typically the movement impairments that most impact their quality of life. One aspect that has always interested us is the concept of lateralization. In PD, symptoms manifest asymmetrically, often beginning on one side of the body before the other. With this study, we wanted to explore the theory that dopamine cells do more than just motivate us to move, they specifically enhance movements on the opposite side of our body”.

Marcelo Mendonça, study’s first author

Shedding light on the brain

To this end, the researchers developed a novel behavioral task, which required freely-moving mice to use one paw at a time to press a lever in order to obtain a reward (a drop of sugar water). To understand what was happening in the brain during this task, the researchers used one-photon imaging, similar to giving the mice a tiny, wearable microscope. This microscope was aimed at the Substantia nigra pars compacta (SNc), a dopamine-rich region deep within the brain that is significantly impacted in PD, allowing the scientists to see the activity of brain cells in real-time.

They genetically engineered these mice so that their dopamine neurons would light up when active, using a special protein that glows under the microscope. This meant that every time a mouse was about to move its paw or succeeded in getting a reward, the scientists could see which neurons were lighting up and getting excited about the action or the reward.

Observing these glowing neurons, the discoveries were, quite literally, illuminating. “There were two types of dopamine neurons mixed together in the same area of the brain”, notes Mendonça. “Some neurons became active when the mouse was about to move, while others lit up when the mouse got its reward. But what really caught our attention was how these neurons reacted depending on which paw the mouse used”.

How dopamine chooses sides

The team noticed that the neurons excited by movement lit up more when the mouse used the paw opposite to the brain side being observed. For example, if they were looking at the right side of the brain, the neurons were more active when the mouse used its left paw, and vice versa. Digging deeper, the scientists found that the activity of these movement-related neurons not only signaled the start of a movement but also seemed to encode, or represent, the length of the movement sequences (the number of lever presses).

Mendonça elaborates, “The more the mouse was about to press the lever with the paw opposite the brain side we were observing, the more active neurons became. For example, neurons on the right side of the brain became more excited when the mouse used its left paw to press the lever more often. But when the mouse pressed the lever more with its right paw, these neurons didn’t show the same increase in excitement. In other words, these neurons care not just about whether the mouse moves, but also about how much they move, and on which side of the body”.

To study how losing dopamine affects movement, the researchers used a neurotoxin to selectively reduce dopamine-producing cells on one side of a mouse’s brain. This method mimics conditions like PD, where dopamine levels drop and movement becomes difficult. By doing this, they could see how less dopamine changes the way mice press a lever with either paw. They discovered that reducing dopamine on one side led to fewer lever presses with the paw on the opposite side, while the paw on the same side remained unaffected. This provided further evidence for the side-specific influence of dopamine on movement.

Implications and future directions

Rui Costa, the study’s senior author, picks up the story, “Our findings suggest that movement-related dopamine neurons do more than just provide general motivation to move – they can modulate the length of a sequence of movements in a contralateral limb, for example. In contrast, the activity of reward-related dopamine neurons is more universal, and doesn’t favor one side over the other. This reveals a more complex role of dopamine neurons in movement than previously thought”.

Costa reflects, “The different symptoms observed in PD patients could be perhaps related to which dopamine neurons are lost-; for instance, those more linked to movement or to reward. This could potentially enhance management strategies in the disease that are more tailored to the type of dopamine neurons that are lost, especially now that we know there are different types of genetically defined dopamine neurons in the brain”.

Source:

Champalimaud Centre for the Unknown

Journal reference:

Mendonça, M. D., et al. (2024). Dopamine neuron activity encodes the length of upcoming contralateral movement sequences. Current Biology. doi.org/10.1016/j.cub.2024.01.067.

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February 20, 2024