Psychiatric Revolution: Changes in Behavior Are Associated with Dendritic Spine Shape and Number
Neuron cell
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.
Cocaine
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
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.
An Animal Model of Poor Judgment in Adolescence: Previous Learning Suppressed
As young mice transition into adolescence, they experience a “sensitive” period in which their context-based fear memories are temporarily suppressed. In a recent study, young animals learned to avoid an environment associated with a mild shock. Later, when they entered adolescence, this learning was temporarily forgotten or suppressed. However, when the same mice aged into adulthood, they reacquired this learned fear memory and began to again avoid the environment associated with the earlier shock. This temporary loss of fear memory differs in mice depending on their genes.
At the 2012 meeting of the Society of Biological Psychiatry, researcher Francis S. Lee reported that mice with a certain genetic variation display an impairment of this fear memory process. There are several common variants of the gene responsible for the production of brain-derived neurotrophic factor (BDNF), which protects neurons and is necessary for long-term memory. Mice with the poorer functioning variant known as Val66Met (as opposed to the better functioning Val66Val) fail to recall the earlier fear-related events not only in adolescence, but also in adulthood when the fear memory is usually retrievable again.
Editor’s Note: In mice and humans, Val66Val is the most frequently occurring allele in the population, but Val66Met is also a fairly common variation of the BDNF gene. It is this Val66Met allele that is associated with not retaining earlier learned experience about a “dangerous” environment that should be avoided.
These data suggest an intriguing explanation for some of the “wild” behavior and poor judgment to which even the smartest adolescents are prone. This kind of behavior may be based in part on the temporary forgetting in adolescence of earlier learning about which situations or environments are safe versus which ones are dangerous. Read more
Amygdala Size Linked to Manic Symptom Severity
In two posters presented at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry, a research group led by Kiki Chang reported that increased severity of manic symptoms is associated with increased size of the amygdala (especially the right amygdala) in adolescents who are at high risk for developing bipolar disorder.
The amygdala is a crucial area for emotion regulation. The increasing size, either with more manic symptoms or as patients with bipolar disorder age into adulthood compared to normal volunteer controls (as we describe in the article on brain imaging at far left) could reflect increased use of the amygdala in bipolar disorder.
The increased amygdala size could be linked to increased emotion dysregulation, or it could be a compensatory mechanism in which the amygdala works harder to exert better emotion control.
Experience-dependent neuroplasticity describes a phenomenon in which the volume of a brain area increases as it gets more use (like a muscle that grows when it gets more exercise). One interesting example in which this may occur is London taxi drivers, who have larger hippocampi than the general public. (The hippocampus is responsible for some of the brain’s spatial recognition abilities.) This could be explained in two different ways. The discrepancy in size between the hippocampi of taxi drivers and of the general population may exist because the taxi drivers’ brains change over the course of their careers via experience-dependent neuroplasticity, or it may exist because those with excellent spatial recognition abilities and bigger hippocampi choose to become taxi drivers.
White Matter Abnormalities in the Brain Predict Onset of Psychosis
At the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP), Carrie E. Bearden presented data from a study that predicted conversion to psychosis in at-risk youth (those who have prodromal symptoms or a particular genetic mutation that leads to psychosis) by observing white matter abnormalities.
Bearden found that the degree of white matter abnormality seen during magnetic resonance imaging (MRI) was proportional to the degree of cognitive deficit in patients who subsequently developed a first episode of psychosis. The white matter abnormalities were seen particularly in the superior longitudinal fasciculus (SLF) and were associated with increased severity of symptomatology. The overall degree of white matter alteration was also significantly related to clinical outcome 15 months later.
Editor’s Note: The SLF is a major neuronal conduit between prefrontal cortical systems, which are responsible for cognition and planning, and the parietal cortex, which is responsible for spatial abilities. Disruption of this fiber track has been related to difficulties in social cognition and “theory of mind” concepts, like inferring what others might be thinking.
Brain Imaging Finds Abnormalities that Appear Over the Course of Childhood-Onset Bipolar Illness
There is considerable evidence that children with bipolar disorder have smaller amygdalas, and the amygdala also appears to be hyper-reactive when these children perform facial emotion recognition tasks. A symposium on longitudinal imaging studies in pediatric bipolar disorder was held at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry to shed light on other brain abnormalities in these children.
Researcher Nancy Aldeman reported that there is some evidence children with bipolar disorder have decreased gray matter volume in parts of the brain including the subgenual cingulate gyrus, the orbital frontal cortex, and the superior temporal gyrus, as well as the left dorsolateral prefrontal cortex and amygdala. At the same time there is evidence of increased size of the basal ganglia. These abnormalities do not appear to precede the onset of the illness.
Some changes occur over the course of the illness. The basal ganglia seem to increase in volume in patients with bipolar disorder, but decrease in volume in those with severe mood dysregulation and comorbid ADHD. Moreover, parietal cortex and precuneus cortex volumes appeared to increase in children with bipolar disorder while decreasing or staying the same in normal volunteer controls.
A meta-analysis of brain imaging studies indicated that in general, the size of the amygdala appears to increase from childhood to adulthood in bipolar patients, starting out smaller than that of similarly-aged normal volunteers, but becoming larger than that of adult normal volunteers as the patients age into adulthood.
Lithium treatment increases gray matter volume in a variety of cortical areas and in the hippocampus in multiple studies. In contrast, treatment with valproate for 6 weeks appears to decrease hippocampal volume.
Neuronendocrine Function in Sexually Abused Adolescent Girls
Brooks R. Keeshin from a research group led by Frank Putnam presented a poster at the 2012 meeting of the American Academy of Child and Adolescent Psychiatry (AACAP) on neuroendocrine function in recently sexually abused adolescent girls with and without post-traumatic stress disorder (PTSD). Average age of the girls was 15 and they had experienced the sexual abuse six months to one year before the study. The researchers found that morning cortisol awakening response was flattened in the girls, and this was associated with PTSD severity and the severity of intrusive symptoms. Increased adversity prior to the sexual abuse experience was also associated with flattening of the cortisol awakening response.
The researchers suggest that alterations in the hypothalamic pituitary adrenal axis (HPA) appear around the time of the abuse and are associated with the severity of PTSD symptomatology in sexually abused adolescent girls.
Parental Nurturing Linked to Greater Hippocampal Volume in Young Children
An article published by Medscape reports that in a recent study by Dr. Joan Luby of Washington University School of Medicine in St. Louis, non-depressed preschool children whose parents showed more nurturing behaviors during a mildly stressful task were found to have hippocampal volume almost 10% greater than their peers whose parents showed fewer nurturing behaviors. The hippocampus affects cognitive functioning and emotion regulation.
Unfortunately, parental nurturing did not effect the hippocampal volume of children with early-onset depression.
Dr. Luby and colleagues think their findings could have “profound public health implications and suggest that greater public health emphasis on early parenting could be a very fruitful social investment.”
“The finding that early parenting support, a modifiable psychosocial factor, is directly related to healthy development of a key brain region known to impact cognitive functioning and emotion regulation opens an exciting opportunity to impact the development of children in a powerful and positive fashion”.
Exercise Good for Learning and Memory in Children and the Elderly
Another article in the Telegraph today suggests that aerobic exercise can increase the size of the hippocampus in elderly people and lead to improvements in memory, attention, and ability to multi-task. Children who were more fit were also better at multitasking. Art Kramer of the Beckman Institute for Advanced Science and Technology at the University of Illinois said,
“It is aerobic exercise that is important so by starting off doing just 15 minutes a day and working up to 45 minutes to an hour of continuous working we can see some real improvements in cognition after six months to a year.
“We have been able to do a lot of neuroimaging work alongside our studies in the elderly and show that brain networks and structures also change with exercise.
More Support for the Connection Between Exercise and Cognition
We recently wrote about a study that suggested exercise may improve cognition function in depression. In today’s New York Times, an article suggests that in mice, exercise expanded the brain’s capacity to store energy, a process known as supercompensation.
While a brain with more fuel reserves is potentially a brain that can sustain and direct movement longer, it also “may be a key mechanism underlying exercise-enhanced cognitive function,” says Hideaki Soya, a professor of exercise biochemistry at the University of Tsukuba and senior author of the studies, since supercompensation occurs most strikingly in the parts of the brain that allow us better to think and to remember. As a result, Dr. Soya says, “it is tempting to suggest that increased storage and utility of brain glycogen in the cortex and hippocampus might be involved in the development” of a better, sharper brain.
BDNF Related to Cognition and Fitness in Men with Coronary Artery Disease
At the 51st Annual Meeting of the National Institute of Mental Health’s New Clinical Drug Evaluation Unit (NCDEU) in 2011, Walter Swardfager and colleagues from Toronto, Ontario presented a study indicating that brain-derived neurotrophic factor (BDNF) concentrations in blood are associated with cognitive performance and cardiopulmonary fitness in people with coronary artery disease.
In 88 mostly male subjects with a mean age of 63 years, cardiopulmonary fitness was directly correlated with BDNF in blood as well as higher scores of cognition on two tests, the mini mental status exam and the digit symbol coding task. The investigators concluded that better fitness, psychomotor processing speed, and overall cognition were consistent with a hypothesis that BDNF protects midbrain dopaminergic neurons against inflammatory neurodegenerative processes.
Blood levels of interleukin 6, a measure of inflammatory cytokines, were associated with lower mini mental status scores in a multivariate analysis that controlled for BDNF levels.
Editor’s note: BDNF appears to be necessary for long-term learning and memory. Meta-analyses indicate that BDNF levels are low in depression and improve with euthymia. Many mood stabilizers including lithium, valproate, carbamazepine, and lamotrigine and most types of antidepressants are able to increase BDNF. The current findings linking BDNF with better cardiopulmonary fitness and cognition continue to emphasize the potential importance of BDNF beyond its role as a marker for depression.
In BNN Volume 12, Issue 3 from 2008, we reported on the data of Schmidt and Duman, which indicated that BDNF administered in a subcutaneous minipump is able to reverse many depressive-like behaviors in an animal model of depression, suggesting that even peripheral BDNF may have a role in the central nervous system.
