Oxidative stress has been implicated in a wide range of illnesses, but what is it exactly? Our bodies use the oxygen we breathe to burn the fuel we get from food, and while this is a natural process, it produces byproducts known as free radicals, which are unstable molecules that can strip electrons from other molecules in a process called oxidation. Antioxidants (such as vitamin C) act as a source of electrons, helping keep other cells stable and healthy. Oxidative stress refers to the stress on our bodies from the normal effects of free radicals combined with environmental stressors like tobacco smoke or radiation.
In work presented at the 2013 meeting of the Society of Biological Psychiatry, Anna Andreason showed that over-activity of neurons increases oxidative stress through the production of reactive oxygen species (ROS). These are a type of free radicals that can damage cells in two ways: nitrosylation of proteins (adding nitric oxide to a thiol molecule), and oxidation, which results in more lasting effects on synaptic structures. The chemical compound rotenone damages mitochondria by producing ROS, and Andreason found that lithium was able to reverse this production and reverse the adverse effects of oxidative stress.
Lithium Has an Amazing Array of Positive Effects
Editor’s Note: The ability of lithium to protect mitochondria (the energy storehouse of a cell) adds to an increasingly long list of lithium’s neurotropic and neuroprotective benefits. Lithium increases cell survival factors BDNF and Bcl-2, increases markers of neuronal integrity such as N-Acetylaspartic acid (NAA), increases the volume of the hippocampus and cortex, and now helps protect mitochondria from oxidative stress. Lithium also increases the length of telomeres, which cap the ends of chromosome and protect them from damage during the DNA replication that occurs each time a cell divides. Short telomeres are associated with many kinds of medical and psychiatric diseases, as well as shorter life spans. No wonder that in addition to preventing mania and depression it has other clinical benefits, such as preventing memory deterioration, medical mortality, and suicide.
Elizabeth Blackburn (who won the Nobel Prize for medicine in 2009) gave a spectacular plenary lecture at the 2013 meeting of the American Psychiatric Association, in which she described the role of telomeres in psychiatric and other medical disorders. Telomeres are the strands of DNA at the end of each chromosome that protect the integrity of the DNA each time the cell replicates. The end is capped to prevent damage, degeneration, and genetic instability. A minimum length must be maintained for the protection of the cells.
Telomeres shorten with aging and with each cell replication. They also shorten as a function of childhood adversity, stressors in adulthood, and number of episodes of depression. When a cell’s telomeres get too short, the cell enters a period of senescence, meaning it no longer replicates. Senescence is associated with a variety of adverse events, including the possibility of apoptosis (cell death), pro-inflammatory effects, and pro-tumor effects. The cell can begin to resemble a rotten apple that spreads its ill effects to others nearby. These effects can predispose a person to diseases such as diabetes, depression, attention deficit hyperactivity disorder (ADHD), anxiety disorders, pulmonary fibrosis, aplastic anemia, cardiovascular disorders (stroke and heart attack), osteoarthritis, immune abnormalities, dementia (in women), and premature aging.
Certain lifestyle alterations can increase telomere length, such as mindfulness/yoga training, exercise, sleep, omega-3 fatty acids, and having a positive purpose or meaning in life. Telomeres can also be lengthened by a synthetic enzyme called telomerase.
Other lifestyle factors can shorten telomeres or make telomerase less effective. Chronic stress can decrease the activity of telomerase by 50%. For people serving as the caregiver of a loved one, the longer the duration of this stress, the shorter the length of telomeres. High levels of what Blackburn described as cynical hostility also decrease telomere length.
Editor’s Note: Here we have more evidence that stress can affect our genes. We have written before about epigenetics, the study of the process by which environmental events such as stress can leave behind methyl and acetyl groups on DNA and histones that affect how easily DNA is turned on or off. Now it seems that stress can also have profound effects on the telomeres that cap each strand of DNA and keep it stable. An overly high proportion of short chromosomes is associated with a range of psychiatric and medical illnesses. This type of non-hereditary influence on genes could mediate some of the long-term effects of the environment on health. The good news for patients with bipolar disorder is that M. Schalling et al. found that treatment with lithium lengthened telomeres. Perhaps the bottom line of this whole collection of fascinating data is: Take good care of your telomeres, and they will take care of you.
In a plenary lecture at the Collegium Internationale Neuro-Psychopharmacologicum (CINP) in Istanbul in 2012, Pasco Rakic, professor of neuroanatomy at Yale University, may have debunked a myth of modern medicine, one that we have cited in many previous BNNs. Despite what has been written by famous neuroscientists and published in the most prestigious journals, including Science, Cell, and PNAS, based on data in rodents, Rakic presented evidence that neurogenesis does not occur to any substantial extent in adult primates.
Two decades ago, data in rodents and other species clearly indicated that neurogenesis, the creation of new neurons, occurred in adult animals, especially in the dentate gyrus of the hippocampus. Thousands of papers were written on the subject, and neurogenesis was understood to be possible in adult humans as well. It was even suggested based on data in rodents that the mechanism of action of antidepressants was dependent on neurogenesis. However, Rakic argues that most of the research on neurogenesis was based on faulty data.
Rakic found that while rats do have neurogenesis into adolescence, it diminishes greatly in older adult animals. In primates, neurogenesis in the cortex ends before birth. In the primate dentate gyrus of the hippocampus, there is some postnatal neurogenesis, but it rapidly drops toward zero in the first months of life. Rakic concludes: “We are as old as our neurons…or slightly younger.”
Why should primates have permanent stores of neurons when rodents and other lower animal species get new ones further into their lifespan? Rakic postulates that for primates, neurons must hold experience-dependent memories necessary for the survival of the species, and turning them over would endanger the permanence of this memory. Whatever the reason, it is disappointing to find out that the revolutionary discovery of adult neurogenesis in rodents so widely presumed to also occur in adult primates and humans may not be correct.
This has clinical implications. If we don’t get replacement hippocampal neurons like rats do, it is even more important to protect the billions of neurons that we do have. There are many things that endanger neurons, including inflammation, oxidative stress, high cortisol, poor diet, psychosocial adversity, and episodes of depression and mania. Greater numbers of mood episodes are associated with increasing degrees of cognitive dysfunction because of these many factors. A startling statistic from Denmark by Lars Kessing is that having four or more hospitalizations for depression (either unipolar or bipolar) doubles the risk for a diagnosis of dementia in late life. Thus, it looks like too many episodes hurt the brain.
However, on the positive side, the mood stabilizers (lithium, lamotrigine, valproate, and carbamazepine) and some atypical antipsychotics prevent episodes and increase the neuroprotective factor BDNF, or brain-derived neurotrophic factor, which facilitates synaptogenesis and helps protect neurons. BDNF is produced in selected neurons in the brain and decreases with stress and affective episodes, further endangering neurons. Since many effective treatments both prevent episodes and their associated decreases in BDNF and also directly increase BDNF, they may be having a dual positive benefit. The evidence is best for lithium having neuroprotective effects that can be directly observed in humans. Thus a not unreasonable mantra for patients with recurrent mood disorders is: “Prevent Episodes, Protect the Brain.”
The brain consists of 12 billion neurons and four times as many glial cells. Neurons conduct electrical activity, and it is thought that changes in neural activity and synaptic activity (where neurons meet) underlie most behaviors. It was once thought that glia were just fluff, but new research shows that they may play a role in depression.
There are three types of glia: astrocytes, oligodendrocytes, and mico-glia. Researcher Mounira Banasr had previously shown that neuronal lesions in the prefrontal cortex of mice did not produce depressive-like behaviors, but glial lesions did.
In a new study presented at a recent scientific meeting, Banasr reported that destroying astrocytes in the prefrontal cortex of mice induced depressive- and anxiety-like deficits. Using a virus that specifically targeted astrocytes, the researchers documented that the depressive behavior was specifically related to loss of astrocytes and not loss of other glial cell types, such as oligodendrocytes or micro-glia.
Editor’s Note: There is evidence of glial abnormalities in patients with mood disorders. Banasr’s research raises the possibility that glial deficits (rather than neuronal alterations) could be crucially involved in depression. In this study, the depressive- and anxiety-like behaviors persisted for 8 days following the astrocyte ablation, but by day 14 the animals had recovered, possibly with the production of a new supply of astrocytes. These data also raise the possibility that targeting the mechanisms of glial dysfunction could be a new avenue to pursue in the therapeutic approaches to depression.
In articles published in Science in 2007 and 2009, Han et al. showed that about 20% of neurons in the lateral amygdala of mice were involved in the formation of a fear memory, and that selective deletion of these neurons could erase the fear memory. Using the same methodology, Josh Sullivan et al. identified neurons that were active in the mouse brain during cocaine conditioning. Amygdala activity showed that the mice preferred an environment where they received cocaine to an environment where they didn’t. The researchers noticed increased cyclic AMP, a messenger that led to increased production of calcium responsive element binding protein (CREB). When the researchers targeted the neurons in the lateral amygdala that were overexpressing CREB, they found that selective destruction of the overexpressing neurons disrupted the cocaine-induced place preference.
The research team further documented this effect by temporarily, rather than permanently, knocking out neuronal function. They could reversibly turn off neurons with an inert compound that promotes neuronal inhibition. Silencing the neurons that were overexpressing CREB before the conditioned place preference testing also limited cocaine-induced place preference memory.
Editor’s Note: While this type of intervention is not feasible in humans with cocaine addiction, these data do shed more light on the mechanisms behind cocaine conditioning.
We have written before that if extinction training to break a cocaine habit or neutralize a learned fear is performed within the brain’s memory reconsolidation window (five minutes to one hour after memory recall), it can induce long-lasting alterations in cocaine craving or conditioned fear.
It is possible that properly timed extinction of cocaine- or fear-conditioned memories might work similarly to the selective silencing of neurons that was carried out in the mice using a drug that inhibited CREB-activated neurons. Determining the commonalities between these ways of eliminating conditioned memories could lead to a whole new set of psychotherapeutic approaches to anxiety disorder, addictions, and other pathological habits.
At a recent scientific meeting, Jennifer E. Murray et al. presented findings about the amygdala’s role in habitual cocaine seeking. The amygdala is the part of the brain that makes associations between a stimulus and a response. When a person begins using cocaine, a signal between the amygdala and the ventral striatum (also known as the nucleus accumbens), the brain’s reward center, creates a pleasurable feeling for the person. The researchers found that in mice who have learned to self-administer cocaine, as an animal progresses from intermittent use to habitual use, the amygdala connections shift away from the ventral striatum toward the dorsal striatum, a site for motor and habit memory. If amygdala connections to the dorsal striatum are severed, the pattern of compulsive cocaine abuse does not develop.
Editor’s Note: These data indicate that the amygdala is involved in cocaine-related habit memory, and that the path of activity shifts from the ventral to the dorsal striatum as the cocaine use becomes more habit-based—automatic, compulsive, and outside of the user’s awareness.
As we’ve reviewed before, the amygdala also plays a role in context-dependent fear memories, such as those that occur in post-traumatic stress disorder (PTSD). The process of retraining a person with PTSD to view a stimulus without experiencing fear is called extinction training. A study by Agren et al. published in Science in 2012 demonstrated that when extinction training of a learned fear took place within the brain’s memory reconsolidation window (five minutes to one hour after active memory recall), the training was sufficient to not only “erase the conditioned fear memory trace in the amygdala, but also decrease autonomic evidence of fear as revealed in skin conductance changes in volunteers.”
The preclinical data presented by Murray and colleagues suggest the possibility that amygdala-based habit memory traces could also be revealed via functional magnetic resonance imaging (fMRI) in subjects with cocaine addiction. Attempts at extinction of cocaine craving, if administered within the memory reconsolidation window, might likewise be able to erase the cocaine addiction/craving memory trace, as Xue et al. reported in Science in 2012.
MDMA, better known as the drug ecstasy, has been found to reduce serotonin axons in animals. A small study by Di Iorio et al. published in the Archives of General Psychiatry in 2012 suggests that the drug also has detrimental effects on serotonin signaling in humans.
The researchers used positron emission tomography (PET) scans to identify serotonin receptors in the brains of 10 women who had never used ecstasy and 14 who had used the drug at least five times before and then abstained for at least 90 days. The team found significantly greater cortical serotonin2A receptor nondisplaceable binding potential (serotonin2ABPND, an indicator of serotonin receptors) in abstaining MDMA users than in those women who had never used the drug.
The increase in serotonin receptors observed in these ecstasy users could be a sign of chronic serotonin neurotoxicity. Loss of serotonin nerve terminals decreases serotonin levels and secondarily results in the production of more serotonin receptors. Thus, one explanation for the receptor increase is that it is prompted by the decrease in serotonin transmission that MDMA is known to cause.
The higher levels of serotonin2ABPND were found in several regions of the MDMA users’ brains: occipital-parietal, temporal, occipito-temporal-parietal, frontal, and frontoparietal. Lifetime use of the drug was associated with serotonin2ABPND in the frontoparietal, occipitotemporal, frontolimbic, and frontal regions. There were no regions in which the MDMA users had lower levels of receptors than women in the control group. The duration of the ecstasy users’ abstinence from using the drug had no effect on levels of serotonin2ABPND observed, suggesting that the effects might be long-lasting, if not permanent.
Editor’s Note: Given serotonin’s importance in brain function and the drug’s popularity for recreational use, this finding has implications both for ecstasy users and for research on serotonin signaling. Ecstasy is supposed to be a “love drug,” but people should show their serotonin nerve terminals some love and look after them by avoiding the drug.
New research shows that regular meditation in the form of mindfulness training improves both mood and measures of white matter (axon tract) integrity and plasticity in the anterior cingulate cortex (a key node in the brain network modulating self-regulation).
This research by Tang et al. published in the Proceedings of the National Academy of Sciences in 2012 was a continuation of the same research group’s investigation of integrative mind-body training (IMBT), a type of mindfulness training that incorporates increased awareness of body, breathing, and attention to external instructions meant to induce a state of balanced relaxation and focused attention. In a previous Tang et al. study comparing participants who received IMBT training with a control group who spent the same amount of time doing relaxation training, the participants who practiced IMBT for five days (20 minutes/day) had better scores on measures of attention, anxiety, depression, anger, fatigue, and energy. In another study the researchers found that four weeks of IMBT (30 minutes/day) increased fractional anisotrophy (FA) in white matter areas involving the anterior cingulate cortex, while four weeks of relaxation training did not bring about any effect on white matter. Decrease in FA is a part of aging. The four weeks of IMBT also decreased axial and radial diffusivity, suggesting better alignment of axons along white matter tracts.
In the most recent study, two weeks of IMBT (30 minutes/day) produced a reduction in axial diffusivity, but not effects on fractional anisotrophy or radial diffusivity, suggesting that the reduced axial diffusivity leads to the other changes seen with longer IMBT.
Editor’s Note: In those with unresolved problems with anxiety and depression, regular 20-30 minutes/day mindfulness practice may have beneficial effects not only on mood, but also on central nervous system structures. Mindfulness training involves focused attention on sequentially different parts of the body leading to exclusive focus on the physical aspects of breathing in and out. Intruding thoughts are recognized, but let go as trivial, passing interruptions, and focus is returned to the body and breathing. The aim is to clear the mind of its usual ideas, thoughts, and worries by continually refocusing on breathing. It takes practice to achieve, but regular mindfulness training can be a helpful addition to pharmaco- and psychotherapy.
It is also noteworthy that mindfulness training is one of the processes that helps elongate the ends of each strand of DNA, called telomeres. Telomeres shorten with aging, stress, and episodes of depression, and short telomeres lead to a variety of adverse medical consequences.
Studies have indicated that lithium increases gray matter and the volume of the cortex and hippocampus in patients with bipolar I disorder. A poster presented by S. Selek et al. at the 5th Biennial Conference of the International Society for Bipolar Disorders described a longitudinal study of fronto-limbic brain structures in patients with bipolar I disorder during lithium treatment.
This study reported that patients whose illness failed to respond to lithium had smaller right amygdalas than euthymic bipolar I patients or healthy controls. After treatment with lithium, those who responded well to the drug showed significant enlargement of the left prefrontal cortex and the left dorsolateral prefrontal cortex, while those who responded poorly to lithium showed decreases in the volume of their left hippocampus and right anterior cingulate cortex.
Editor’s Note: This is one of several studies that suggest a relationship between volume of brain regions and degree of response to lithium. These data add to the remarkably consistent literature suggesting that lithium may have neurotrophic and neuro-protective effects, potentially because of the drug’s ability to increase neuroprotective factors such as BDNF and Bcl-2 while decreasing cell death factors such as BAX and p53.
New research shows that cocaine, defeat stress, the rapid-acting antidepressant ketamine, and learning and memory can change the size, shape, or number of spines on the dendrites of neurons. Dendrites conduct electrical impulses into the cell body from neighboring neurons.
Several researchers, including Peter Kalivas at the Medical University of South Carolina, have reported that cocaine increases the size of the spines on the dendrites of a certain kind of neurons (GABAergic medium spiny neurons) in the nucleus accumbens (the reward center in the brain). This occurs through a dopamine D1 selective mechanism. N-acetylcysteine, a drug that can be found in health food stores, decreases cocaine intake in animals and humans, and also normalizes the size of dendritic spines.
Depression in animals and humans is associated with decreases in Rac1, a protein in the dendritic spines on GABA neurons in the nucleus accumbens. Rac1 regulates actin and other molecules that alter the shape of the spines.
In an animal model of depression called defeat stress, rodents are stressed by repeatedly being placed in a larger animal’s territory. Their subsequent behavior mimics clinical depression. This kind of social defeat stress decreases Rac1 and causes spines to become thin and lose some function. Replacing Rac1 returns the spines to a more mature mushroom shape and reverses the depressive behavior of these socially defeated animals. Researcher Scott Russo has also found Rac1 deficits in the nucleus accumbens of depressed patients who committed suicide. Russo suggests that decreases in Rac1 are responsible for the manifestation of social avoidance and other depressive behaviors in the defeat stress animal model, and that finding ways to increase Rac1 in humans would be an important new target for antidepressant drug development.
Another animal model of depression called chronic intermittent stress (in which the animals are exposed to a series of unexpected stressors like sounds or mild shocks) also induces depression-like behavior and makes the dendritic spines thin and stubby. The drug ketamine, which can bring about antidepressant effects in humans in as short a time as 2 hours, rapidly reverses the depressive behavior in animals and converts the spines back to the larger, more mature mushroom-shape they typically have.
Learning and Extinction of Fear
Researcher Wenbiao Gan has reported that fear conditioning can change the number of dendritic spines. When animals hear a tone paired with an electrical shock, they begin to exhibit a fear response to the tone. In layer 5 of the prefrontal cortex, spines are eliminated when conditioned fear develops, and are reformed (near where the eliminated spines were) during extinction training, when animals hear the tones without receiving the shock and learn not to fear the tone. However, in the primary auditory cortex the changes are opposite: new spines are formed with learning, and spines are eliminated with extinction.
Editor’s Note: It appears that we have arrived at a new milestone in psychiatry. In the field of neurology, changes seen in the brains of patients with strokes or Alzheimer’s dementia have been considered “real” because cells were obviously lost or dead. Psychiatry, in comparison, has been considered a soft science because neuronal changes have been more difficult to see and illnesses were and still are called “mental.” Now that new technologies have made a deeper level of precision, observation, and analysis possible, we know that the brain’s 12 billion neurons and 4 times as many glial cells are exquisitely plastic–capable of biochemical and structural changes that can be reversed using appropriate therapeutic maneuvers.
The changes associated with abnormal behaviors, addictions, and even normal processes of learning and memory now have clearly been shown to correspond with the size, shape, and biochemistry of dendritic spines. These subtle, reproducible changes in the brain and body are amenable to therapeutic intervention, and are now even more demanding of sophisticated medical attention.