Our very own Professor Mathew Campbell, of the Neurovascular Genetics Laboratory in Trinity College, Dublin, is leading the way in understanding the blood brain barrier (BBB) and how it functions in health and disease. Dysfunction of the BBB has long been associated with multiple diseases, including Epilepsy, Multiple Sclerosis, Ischemic Stroke and even more complex neurodegenerative diseases like Alzheimer’s disease.
Where things get really interesting is recently BBB dysregulation has been implicated in neuropsychiatric conditions specifically Major Depressive Disorder (MDD). The idea that the BBB can affect cognition, brain function and stress is a relatively new concept that Professor Campbell has lately explored. Right now, evidence remains elusive and much of the current knowledge regarding the BBB and its impact on cognition comes from neurodegenerative disorders like Alzheimer’s disease. However, studies researching the dysregulation of the BBB and its correlation with neuropsychiatric disorders appear promising.
Think of the blood brain barrier like the brain’s security system, protecting it from pathogens and ensuring the right things stay in and the wrong things stay out.
So, what is the BBB? Think of it like the brain’s security system, protecting it from pathogens and ensuring the right things stay in and the wrong things stay out. The BBB refers to a set of unique characteristics in the blood vessels of the brain and central nervous system. It is a complex system of cell properties that provide control over the extracellular movement in neural tissues. Endothelial cells form the lining of blood vessels and are held together by junctions; small adhesions that bind cells together. In the brain, these junctions are highly selective, regulating the passive diffusion of ions and solutes and are referred to as tight junctions. Tight junctions help the BBB ensure the central nervous system keeps functioning normally. The claudin genes encode for a family of proteins important in tight junction formation, especially claudin-5 (CLDN-5).
Dysregulation of the BBB has been implicated in Major Depressive Disorder. Chronic stress is a huge risk factor for major depression and also affects memory. Short term (acute) stress can actually facilitate learning while long term (chronic) stress does the opposite; harming memory leading to impairment. The tight junction protein CLDN-5 functions in memory and is affected by stress. When mice and humans were exposed to stress it caused CLDN-5 levels to drop. CLDN-5 loss correlates with stress and furthermore is associated with major depressive disorder. This compromises the BBB making it ‘leaky’ allowing harmful substances into the central nervous system. This includes neuroinflammation-causing molecules like immune cells and cytokines. Neuroinflammation is very common in many psychiatric disorders including post-traumatic stress disorder, bipolar disorder and major depressive disorder.
Acute stress can increase vigilance and make us more alert which is good. However, chronic stress contributes to anxiety making it harder to concentrate and motivate ourselves to do tasks.
Stress doesn’t just affect memory but also our cognitive flexibility; this is our ability to adapt and think. Acute stress can increase vigilance and make us more alert which is good. However, chronic stress contributes to anxiety making it harder to concentrate and motivate ourselves to do tasks. Again, in mouse models a loss of CLDN-5 was associated with impaired cognition and emotional regulation, further linking BBB dysregulation to neuropsychiatric disorders. Interestingly, significant changes in brain cells called astrocytes were also linked to attention issues in mice. Astrocytes are responsible for the communication between neurons and they help support the BBB. When stress causes astrocytes to malfunction they weaken the stability of the BBB, permitting neuroinflammation which intensifies cognitive impairments and mental health issues like anxiety and depression.
When it comes to stress, a little can actually be beneficial but with everything too much of a good thing never ends well, especially when it starts to affect your cognitive function. Chronic stress is a major environmental risk factor for psychiatric disorders. Chronic stress exerts our mental effort and negatively impacts our memory, our ability to think and our ability to act. The stress-induced loss of CLDN-5 and astrocyte impairments weakens the BBB and raises the question as to whether BBB dysfunction may directly cause depression-related symptoms. Overall, such research is vitally important and thanks to the work of academics like Professor Campbell and others at the Neurovascular Genetics Laboratory we may soon have a better understanding into how the BBB contributes to mental health and what we can do to keep it functioning at its best.
