The kynurenine pathway describes the steps that turn the amino acid tryptophan (the ingredient in turkey that might make you sleepy) into nicotinamide adenine dinucleotide. This pathway might be a connection between the immune system and neurotransmitters involved in schizophrenia.
A recent autopsy study by researcher Thomas Weickert and colleagues explored this link by determining that in the brains of people with schizophrenia and high levels of inflammation, messenger RNA for Kynurenine Aminotransferase II (KATII, a step on the kynurenine pathway) was elevated in the dorsolateral prefrontal cortex compared to the brains of people who died healthy and those with schizophrenia but low levels of inflammation.
The KATII mRNA levels also correlated with mRNA levels of inflammatory markers such as glial fibrillary acidic protein and interleukin-6.
Blood measures related to the kynurenine pathway also differentiated people with schizophrenia from healthy controls. People with schizophrenia had lower levels of tryptophan, kynurenine, and kynurenic acid in their blood. The low levels of kynurenic acid in the blood were correlated with deficits in working memory and smaller volume of the dorsolateral prefrontal cortex.
Weickert and colleagues suggest that blood levels of kynurenic acid might provide a measurable indicator of the degree to which people with schizophrenia are experiencing problems with executive functioning (planning and decision-making) and loss of brain volume.
Suicide and depression have both been linked to elevated levels of inflammatory cytokines in the blood and cerebrospinal fluid. A recent study finds that these inflammatory markers are also elevated in the brains of teens and depressed adults who died from suicide.
In autopsy studies, researcher Ghanshyam N. Pandey measured levels of the inflammatory cytokines interleukin-1beta, interleukin 6, and TNF-alpha in the brains of teen suicide victims, and compared these to the brains of teens who died from other causes. Pandey also measured levels of interleukin-1beta, interleukin 6, interleukin 8, interleukin 10, interleukin 13, and TNF-alpha in the prefrontal cortex of depressed adult suicide victims and compared them to levels in adults who died of other causes.
There were abnormalities in the inflammatory markers in the brains of those who died from suicide compared to their matched controls. The suicide victims had higher levels of interleukin-1beta, interleukin 6, and TNF-alpha than the controls. Among the adults, levels of the anti-inflammatory cytokine interleukin 10 were low in the suicide victims while levels of Toll-like receptors (TLR3 and TLR4), which are involved in immune mechanisms, were high.
Brain inflammation has also been observed in positron emission tomography (PET) scans of depressed patients, where signs of microglial activation can be observed. Elevated inflammatory cytokines are also found in the blood of some people with bipolar disorder, depression, and schizophrenia.
Pandey presented this research at the 2016 meeting of the Society of Biological Psychiatry.
Evidence is mounting that certain behaviors by parents can leave marks on their sperm or eggs that are passed on to their offspring in a process called epigenetics. In a recent study by researcher Mathieu Wimmer and colleagues, male rats that were exposed to cocaine for 60 days (the time it takes for sperm to develop fully) had male offspring who showed diminished short- and long-term spatial memory compared to the offspring of male rats that were not exposed to cocaine. Female offspring were not affected in this way.
The spatial tasks the offspring rats completed depended heavily on the hippocampus. Wimmer and colleagues believe that cocaine use in the fathers decreased the amount of a brain chemical called d-serine in the offspring. D-serine plays a role in memory formation and the brain’s ability to form synaptic connections. Injecting the offspring of rats who were exposed to cocaine with d-serine before the spatial memory tasks normalized the rats’ performance.
A recent study clarified how cognitive behavioral therapy improves symptoms of depression and post-traumatic stress disorder (PTSD). The participants were 62 adult women. One group had depression, one had PTSD, and the third was made up of healthy volunteers. None were taking medication at the time of the study. The researchers, led by Yvette Shelive, used functional magnetic resonance imaging (fMRI) to analyze participants’ amygdala connectivity.
At the start of the study, participants with depression or PTSD showed diminished connectivity between the amygdala and brain areas related to cognitive control, the process by which the brain can vary behavior and how it processes information in the moment based on current goals. The lack of connectivity reflected the severity of the participants’ depression. Twelve weeks of cognitive behavioral therapy improved mood and connectivity between the amygdala and these control regions, including the dorsolateral prefrontal cortex and the inferior frontal cortex. These regions also allow for executive functioning, which includes planning, implementation, and focus.
People with post-traumatic stress disorder (PTSD) often experience fearful memories of the trauma they witnessed. Researchers are working to determine the neurobiological basis for these persistent fear memories in order to better treat PTSD. Current treatments mainly target the central nervous system. Because many people with PTSD have elevated levels of pro-inflammatory immune molecules in their blood, there has been a recent push to determine whether targeting that inflammation may be another way of treating PTSD.
A recent study by researchers Matthew Young and Leonard Howell used an animal model to learn more about the link between trauma, inflammation, and fear memories. The researchers exposed mice to a trauma that produced both a persistent fear response and an increase in inflammatory molecules in the blood. Some of the mice were also given antibodies to neutralize the inflammatory immune response. When the mice were exposed to a cue meant to remind them of the trauma, levels of the inflammatory molecule IL-6 spiked again. When the mice were given antibodies to neutralize IL-6 just before being exposed to the cue, they produced less of a fear reaction.
The researchers, who presented their work at a scientific meeting in December, concluded that traumatic experiences produce not only persistent fearful memories, but also an immune reaction. They believe that the spike in IL-6 following trauma plays a role in the persistence of those memories, and that elevated IL-6 in the blood may explain symptoms of PTSD and other disorders that involve fear learning (such as phobias).
Many studies have found links between levels of inflammatory molecules in the blood and depression or depressive symptoms. There has been less research about inflammation in the brain and its possible role in depressive illness. Improvements in positron emission topography (PET) scan technology now allow for better brain imaging that can reveal when microglia are activated. (Microglia serve as the main immune responders in the central nervous system.)
A study by researcher Jeffrey Meyer found evidence of microglial activation in several brain regions (including the prefrontal cortex, the anterior cingulate cortex, and the insula) in people in an episode of depression who were not receiving any treatments. Participants with more microglial activation in the anterior cingulate cortex and insula had more severe depression and lower body mass indexes.
Meyer, who presented this research at a scientific meeting in December, called it strong evidence for brain inflammation in depressive episodes, and suggested that treatments that target microglial activation would be promising for depression.
However, at the same meeting, researcher Erica Richards reported that she had not been able to replicate Meyer’s results. Her research, which included depressed participants both on and off medication and non-depressed participants, found that depressed participants did show more inflammation in the two brain regions she targeted, the anterior cingulate and the subgenual cortices, but this difference did not reach statistical significance, particularly when patients taking antidepressants were included in the calculations. Richards hopes that with a greater sample size, the data may show a significant difference in brain inflammation between depressed and non-depressed participants.
One-fifth of children in America grow up in poor families. Poverty can affect development, health, and achievement, and new evidence shows it even affects brain structure.
New unpublished research suggests that early poverty can affect the brain’s structure into adulthood. At a 2015 scientific meeting, researcher James Swain reported that socio-economic status at age 9 was associated with the integrity of white matter in several regions of the brain, including the hippocampus, parahippocampal gyrus, dorsolateral prefrontal cortex, ventrolateral prefrontal cortex, corpus collosum, and thalamus at age 23–25, regardless of income at that time.
The brain regions affected by childhood poverty support executive function (planning and implementation skills), social cognition, memory, and language processing. White matter provides the physical connections between parts of the brain, so damage to white matter may lead to problems with functional connectivity of the brain.
Scientists have known for some time that heightened activity of dopaminergic neurons (neurons in the midbrain that contain the neurotransmitter dopamine) can make people vulnerable to depression. New research in animals suggests for the first time that noradrenergic neurons (those that contain the neurotransmitter norepinephrine) control the activity of dopaminergic neurons and that these noradrenergic neurons can make the difference between vulnerability to depression or resilience to stress. The research, published by Elsa Isingrini and colleagues in the journal Nature Neuroscience in 2015, showed that animals that cannot release norepinephrine are vulnerable to depression following chronic stress, but increasing the production of norepinephrine increases the animals’ resilience and reduces depression.
These findings may open up new avenues to treatment that target norepinephrine rather than or in addition to dopamine or serotonin, which is targeted by SSRI antidepressants, or selective serotonin reuptake inhibitors.
A gene that plays a role in the pruning of synapses has been linked to schizophrenia. The gene encodes an immune protein called complement component 4 (C4), which may mediate the pruning of synapses, the connections between neurons. Researchers led by Aswin Sekar found that in mice, C4 was responsible for the elimination of synapses. The team linked gene variants that lead to more production of C4A proteins to excessive pruning of synapses during adolescence, the period during which schizophrenia symptoms typically appear. This may explain why the brains of people with schizophrenia have fewer neural connections. The researchers hope that future therapies may target the genetic roots of the illness rather than simply treating its symptoms.
In a 2015 article in Nature Neuroscience, Stefan Bonn and André Fischer reported that when mice were prompted to use their long-term memory to recognize a specific environment, epigenetic changes occurred in their neurons and glia. Epigenetic changes refer to chemical alterations in DNA or histones (which give DNA structure) that increase or decrease the expression of certain genes. Sometimes environmental factors lead to a methyl or acetyl group joining a strand of DNA or histones, changing how easily the genes are turned on or off.
When the mice used their long-term memory, the main change that occurred was DNA methylation in their neurons. There were also changes to histones that were linked to memory acquisition but resulted in few changes in gene expression. The DNA methylation changes, on the other hand, changed neural pathways, leading to “rewiring” of the brain.