A Brain Pathway That Regulates Eating

Post by Rebecca Hill

The takeaway

Overeating leading to obesity can be caused by mutations in brain signaling molecules. One neural circuit in the hypothalamus regulates this overeating behavior.

What's the science?

The brain regulates eating by taking signals from our body about our internal state and processing them into behavioral responses such as eating. Brain-derived neurotrophic factor (BDNF) is a signaling molecule in the brain expressed in the hypothalamus, the brain area responsible for regulating hunger, and other bodily functions. This week in Nature, Kosse and colleagues studied which specific pathway in the brain controls our eating and jaw movements.

How did they do it?

Using optogenetics, a technique that uses light to control the activity of certain cells in the brain, the authors activated or inhibited the activity of BDNF cells in the hypothalamus of mice. The authors fasted mice before the experiment to make sure the mice would be hungry enough to eat. They then measured how much food mice ate to determine how this affected the feeding behavior controlled by these cells. The authors also specifically examined this effect in obese mice to determine if feeding behavior changed after BDNF cell activity was inhibited.

What did they find?

When the authors activated BDNF cells in the hypothalamus, fasted mice did not increase feeding behavior. This means that even though mice had a drive to eat, BDNF cell activity prevented them from feeding. When the authors inhibited BDNF cells in the hypothalamus, mice ate more due to more jaw movements triggered by this neural pathway. When BDNF cell activity was inhibited in obese mice, mice continued feeding behavior despite not needing to eat. This means that the BDNF cell pathway in the hypothalamus processes input about the energy state of an animal and outputs feeding behavior from it. 

What's the impact?

This study is the first to find a neural pathway linked to feeding behavior in which its breakdown leads to obesity. Obesity is a widespread issue, with many struggling to overcome eating behaviors. With the information found in this study, we may be able to develop more effective treatments for overeating behaviors.

Access the original scientific publication here

Current Treatment Options for Multiple Sclerosis

Post by Meredith McCarty

The takeaway

MS is a degenerative disease that affects millions of people worldwide. Over the past several years numerous treatment options have emerged that can alleviate many MS symptoms and slow the progression of this disease significantly. 

What is Multiple Sclerosis (MS)?

MS is a neurological condition that affects the central nervous system (CNS), including the spinal cord and the brain. What makes this disease so complex is that individual outcomes can be unpredictable, with varying phases of disease progression and relapse among individuals. MS is commonly diagnosed in individuals experiencing cognitive problems, vision loss, numbness, or weakness, though the severity of symptoms vary greatly1. Most individuals with MS will experience periods of remission and relapse of symptoms, with different treatments that target the immune system offering therapeutic benefits. 

The hypothesized sources of the acute symptoms of MS are not only focal changes in brain pathology but also diffuse changes throughout the CNS. Focal changes include inflammation of the meninges (tissues that cover the surface of the brain and include arteries, veins, and lymphatic network), demyelination (destruction of the protective sheath surrounding neurons), and changes in the blood-brain barrier1,2. More widespread diffuse changes include neuron loss and overactivation of microglia (which support neurons in the brain)1,2. 

Current disease-modifying therapies

Most approved treatments for MS target the immune system. This is based on evidence that the acute symptoms of inflammation seen in MS are due to atypical immune system functioning. While various immune cells typically circulate through the bloodstream and target invasive or damaged cells for destruction, in MS, neuroinflammation within the CNS can lead to the accumulation of immune cells that instead attack otherwise healthy brain cells. Previously, this immune dysfunction has been thought to be caused by T-Cell action, however, treatments that target B-Cells have been found to have greater therapeutic benefit3. 

There are several disease-modifying therapies (DMTs) currently FDA-approved for MS treatment that have been shown to delay the progression of acute MS symptoms4. The mechanism of action of these DMTs is targeting B-cells for downregulation. Essentially, this is thought to slow the progression of damage to the CNS by directly targeting the immune system. These DMTs are administered either orally, intravenously (via an IV) directly and quickly, or into the hypodermis (the innermost layer of the skin), which leads to a slower absorption rate. Some research suggests different mechanisms of administration may alleviate some side effects due to the speed of the DMT reaching circulation, and the cost of treatment is also a consideration (whether it must be administered in a clinical setting4). These DMTs have been found to reduce the formation of new brain lesions, as well as MS relapse rates in many patients. They remain the most effective treatment method for MS.  

Progress in MS research

There is much current research into the underlying cause of MS, to uncover a cure for this disease. Interestingly, recent research has found that the Ebstein-Barr virus (EBV) is associated with an increased risk of developing MS. EBV is a B-Cell virus that may cause long-standing changes in B-Cells post-infection that could cause chronic inflammation in the CNS5. In healthy individuals, the number of EBV-infected cells is kept low via action by cytotoxic T-Cells that can identify these EBV-infected cells and eliminate them. If there is a deficit in the action of these cytotoxic T-Cells, this could lead EVC-infected cells to accumulate in the CNS. Indeed, a recent human study found clinical improvement in individuals with MS who were treated with cytotoxic T-Cells targeted against EBV-infected cells5.

Interestingly, research into the gut microbiome may offer clues into the cause of MS. Prior work has shown the gut microbiome (the bacteria and other microbes in the gut) plays an important role in immune regulation6. Some researchers theorize that an imbalance in the gut microbiome may lead to inflammation throughout the immune system, potentially playing a role in MS development and progression. Therapeutic strategies to regulate gut microbiome homeostasis may illuminate alternative treatments for MS. 

There is some debate as to whether a longer-lasting increase in chronic inflammation may be the cause of progressive MS symptoms over time, while more acute symptoms may be caused by focal infiltration of the CNS leading to acute inflammatory damage2. Future research into the complex interaction between the CNS and the immune system following cortical injury will offer novel insight into the progression of acute and chronic MS. Especially as current DMTs cannot pass the blood-brain barrier directly if it is undamaged, novel methods to allow therapeutic intervention within the CNS via direct route may offer promising treatment alternatives. There are exciting research studies and clinical trials underway that will help clarify the cause of MS. Through a greater understanding of the interaction between the immune system and the CNS, researchers will continue to fill the gaps in understanding this complex disease.

References +

Magliozzi R., Howell O. W., Calabrese M., Reynolds R. Meningeal inflammation as a driver of cortical grey matter pathology and clinical progression in multiple sclerosis. Nature Reviews Neurology. 2023. https://doi.org/10.1038/s41582-023-00838-7

Zuroff L. R.; Benjamins J. A.; Bar-Or A.; Lisak R. P. Inflammatory mechanisms underlying cortical injury in progressive multiple sclerosis. Neurosciences. 2021, 8, 111. http://dx.doi.org/10.20517/2347-8659.2020.35

Gelfand J. M., Cree B. A. C., Hauser S. L. Ocrelizumab and Other CD20+ B-Cell-Depleting Therapies in Multiple Sclerosis. Neurotherapeutics. 2017. https://doi.org/10.1007/s13311-017-0557-4

Cotchett K. R., Dittel B. N., Obeidat A. Z. Comparison of the Efficacy and Safety of Anti-CD20 B Cells Depleting Drugs in Multiple Sclerosis. Multiple Sclerosis Related Disorders. 2021. https://doi.org/10.1016/j.msard.2021.102787

Pender M. P., Csurhes P. A., Smith C., Douglas N. L., Neller M. A., Matthews K. K., Beagley L., Rehan S., Crooks P., Hopkins T. J., Blum S., Green K. A., Ionnides Z. A., Swayne A., Aftab B. T., Hooper K. D., Burrows S. R., Thompson K. M., Coulthard A., Khanna R. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2018. https://doi.org/10.1172/jci.insight.124714

Altieri C., Speranza B., Corbo M. R., Sinigaglia M., Bevilacqua A. Gut-Microbiota, and Multiple Sclerosis: Background, Evidence, and Perspectives. Nutrients. 2023. https://doi.org/10.3390/nu15040942

Identifying Targets for Neuromodulation of PTSD

Post by Kelly Kadlec

The takeaway

In this study, the authors investigated the functional connectivity between brain regions of veterans with and without brain lesions to identify a neural circuit for Post-traumatic stress disorder (PTSD). They demonstrated the potential therapeutic benefits of targeting brain regions within this circuit using noninvasive neuromodulation.  

What's the science?

Post-traumatic stress disorder can result from the experience of a traumatic event or series of events and symptoms can include anxiety and depression. Despite its prevalence, traditional medication and psychotherapy treatments are often not effective, leading researchers to explore neuromodulation techniques such as transcranial magnetic stimulation (TMS). Unfortunately, one of the most commonly implicated regions in PTSD, the amygdala, is not accessible by TMS. Therefore, there is a need to identify alternative modulation targets. Recently in Nature Neuroscience, Siddiqi and colleagues investigated circuits involved in  PTSD in veterans and identified and demonstrated the medial prefrontal cortex (mPFC) as a potential target for TMS treatment of PTSD.

How did they do it?

First, the authors compared rates of PTSD in veterans with and without penetrating traumatic brain injury (TBI), and examined which lesioned brain areas were most associated with reduced rates of PTSD. Additionally, they used functional MRI (fMRI) to determine the functional connectivity (FC) of brain areas where lesions seemed to protect against PTSD. This connectivity was established by lesion network mapping, which relies on the connectome database of resting-state fMRI for 1,000 individuals. Then, they compared the patterns of FC found in veterans with TBI to those without TBI including a large cohort of veterans with PTSD.   

The authors then assessed whether neuromodulation of implicated brain regions resulted in changes in PTSD symptoms. First, they evaluated how TMS in regions identified by the connectivity results compared with TMS in other regions in terms of the ability to relieve PTSD symptoms. In addition, they evaluated how different types of modulation (i.e. inhibitory, excitatory) impacted PSTD symptoms.

What did they find?

First, the authors report that veterans with penetrative brain injuries had reduced rates of PTSD. In particular, individuals with damage to the amygdala were the most protected against developing PTSD. 

Next, the authors found that reduced functional connectivity between the mPFC, amygdala, and hippocampus, was associated with reduced PTSD symptoms. This ‘lesion-derived PTSD circuit’ was also validated in veterans without TBI by comparing FC in individuals with and without PTSD. They were able to further examine this circuit in individuals who had received TMS for PTSD in a previous study and found that, as hypothesized, a reduction in these patient’s symptoms was associated with a reduction in FC between the areas in this circuit. 

Finally, the authors validated the neural circuit they identified as a target for TMS-based treatment of PTSD by showing that TMS in regions within the circuit was more effective than TMS in other areas in reducing symptom severity. In addition, as predicted by the FC results, applying inhibitory modulation to these regions resulted in a decrease in PTSD symptom severity while applying excitatory modulation had the opposite effect.  

What's the impact?

PTSD can have a negative impact on the quality of life of individuals afflicted and current treatments are unfortunately limited in their efficacy. The findings in this study demonstrate the mPFC as a promising target for non-invasive neuromodulation and reduction of PTSD symptoms. Further, the results of this study present causal evidence for a critical neural circuit in PTSD.  

Access the original scientific publication here.