Exercise increases brain-derived neurotrophic factor (BDNF), a protein that protects neurons and is important for learning and memory. In a study of mice who were trained to find objects, sedentary mice could not discriminate between familiar object locations and novel ones 24 hours after receiving weak training, while mice who had voluntarily taken part in exercise over a 3-week period could easily distinguish between these locations after the weak training.
Mice who received sodium butyrate (NaB) after training behaved similarly well to those who had exercised. Sodium butyrate is a histone deacetylase (HDAC) inhibitor, meaning it helps keep acetyl groups on histones, around which DNA is wrapped, making the DNA easier to transcribe. In this case the easy transcription of DNA enables learning under conditions in which it might not usually take place.
Both sodium butyrate and exercise promote learning through their effects on BDNF in the hippocampus. They make the DNA for BDNF easier to transcribe, suggesting that exercise can put the brain in a state of readiness to create new or more lasting memories.
Residue from Nuclear Bomb Testing Shows That Contrary to Earlier Reports, Neurogenesis Occurs in the Brains of Adults
In 2013 we reported that according to Pasco Rakic, professor of neuroanatomy at Yale University, neurogenesis (the production of new neurons) occurs only in rodents, and not in any significant amount in the brains of adult primates. However, a new carbon-dating procedure shows that the adult human brain does actually continue to create new neurons.
According to an article by Spalding et al. published more recently in the journal Cell, such neuroplasticity occurs to a much greater degree than previously thought. The authors base their research on levels of carbon isotope 14 (14C) that were released into the atmosphere during aboveground nuclear bomb tests between 1945 and 1963. Dividing cells require carbon, so the 14C released into the atmosphere during the era of nuclear testing made its way into the cells of people who were alive at the time. Levels of 14C that were incorporated into the DNA of dividing cells correlate with levels of 14C in the atmosphere at the time the cells divided, and since carbon levels have declined at a predictable rate since the nuclear tests, measuring the 14C in cells can show how old they are.
Spalding et al. show that neurogenesis in humans occurs only in the hippocampus. They found evidence that a subpopulation of hippocampal neurons continually renews itself at a rate of about 700 new neurons per day, while other hippocampal cells are non-renewing. The annual turnover rate of about 1.75% is the same for men and women and declines slightly with age.
The researchers were able to determine that the renewing cells play an important role in certain types of brain function. Long-term potentiation, the process by which learning and memory can occur, depends heavily on new cells produced in the part of the hippocampus knows as the dentate gyrus.
Sherman Brown of the University of Texas Southwestern reports that the neurosteroid allopregnanolone has positive effects in bipolar depression. Patients in Brown’s study received doses of 100mg capsules twice daily during the first week, then one capsule in the morning and two capsules in the evening during the second week, and two capsules in the morning and three capsules in the evening during the third week.
Neurosteroids can change the excitability of neurons through their interactions with the neurotransmitters that carry signals from neurons across synapses. Among the various types of neurotransmitters, GABA plays an inhibitory role, while glutamate is responsible for excitability. Allopregnanolone, which is naturally produced in the body, has positive effects on GABA receptors and inhibitory effects on glutamate NMDA receptors, so that it increases the balance of inhibition (GABA) over excitation (glutamate).
Research has shown a link between inflammation and mental illness. Inflammation leads to a series of chemical changes that can overexcite neurons and interfere with the protection of neurons.
Inflammation increases the production of indoleamine-pyrrole 2,3-dioxygenase (IDO), an enzyme that breaks down the amino acid tryptophan into kynurenic acid and quinolinic acid. They in turn increase glutamate, the main excitatory neurotransmitter, and decrease brain-derived neurotrophic factor (BDNF), which keeps neurons healthy.
Kynurenic acid stimulates microglia, which clean up the central nervous system as a form of immune defense, to produce inflammatory cytokine proteins.
Quinolinic acid directly stimulates glutamate receptors and encourages glutamate release from astrocytes. Quinolinic acid also blocks glutamate removal that would normally occur through reuptake into the astrocytes, leading to more stimulation of extrasynaptic glutamate receptors and decreases in BDNF.
Quinolinic acid’s effects are opposite to those of the antidepressant ketamine, which blocks glutamate NMDA receptors and increases BDNF. When people are given interferon protein for the treatment of cancers, quinolinic acid increases in cerebrospinal fluid, inducing depression. The severity of depression induced is correlated with the patient’s levels of quinolinic acid.
It appears that ketamine has indirect anti-inflammatory effects through its ability to block glutamate receptors and increase BDNF.
The brain contains neurons, which transmit electrical impulses, and glia, which protect and support neurons. New evidence suggests that some types of glia also play a role in pruning back overabundant neurons that are produced as the brain develops in utero.
Researcher Beth Stevens reports that astrocytes secrete a protein called transforming growth factor beta (TGF-beta). TGF-beta is a cytokine, or regulating protein, that activates brain microglia to initiate a complement cascade (C1 to C3), a series of chemical changes that destroy unnecessary neurons and synapses.
The various proteins involved in a complement cascade are numbered. This complement cascade starts with C1q and is continued by C4, C2, and C3, which initiate phagocytosis (or eating up) of the axon terminals of the underutilized neurons, sparing those that are active.
Inflammation and other changes in glia could cause either deficient or excess pruning of neurons, which has been thought to occur in neuropsychiatric disorders such as autism or schizophrenia.
Prairie voles, which form monogamous bonds for life, are often studied as a source of information about social attachment. New findings indicate that these mating choices are regulated by epigenetics.
Epigenetics refers to changes in genes that do not affect the inherited sequence of DNA, but affect how easily the DNA is transcribed to produce proteins. Environmental events such as stress or exposure to chemicals can bring about epigenetic changes by adding or subtracting acetyl or methyl groups from strands of DNA or the histones around which it is wound.
When prairie voles mate naturally, levels of oxytocin, often thought of as the “bonding hormone,” increase in the reward area of the brain, the nucleus accumbens. When voles are given a drug that increases histone acetylation, their behavior mimics natural partner preference. The drug, known as a histone deacetylase (HDAC) inhibitor, blocks the removal of acetyl groups, and researchers Wang et al. reported in the journal Nature Neuroscience in 2013 that oxytocin levels increase in the nucleus accumbens. The voles receive the drug and mate for life, suggesting that social bonding is epigenetically regulated.
Similar epigenetic alterations may play a role in human social bonding and vulnerability to depression. Depressed mothers and their offspring have low levels of oxytocin in their blood, and maternal depression is a risk factor for depression in the offspring, as reported by Apter-Levy et al. in the American Journal of Psychiatry in 2013.
Editor’s Note: Perhaps depressed moms who show reduced physical and verbal interactions with their newborns should receive special training in holding, cuddling, cooing, and other social bonding activities that could increase their infants’ oxytocin levels and potentially also decrease their own anxiety and depression.
Brain-derived neurotrophic factor (BDNF) keeps neurons healthy and is critical for long-term memory and synapse formation. BDNF levels increase in the nucleus accumbens (the brain’s reward center) and decrease in the hippocampus during clinical depression and chronic cocaine use. In rodents, the same changes in BDNF levels occur during defeat stress (which resembles human depression).
Rodents who are repeatedly defeated by a larger rodent exhibit behaviors such as social withdrawal, lethargy, and decreased interest in sucrose. The increases in BDNF in the nucleus accumbens of these rodents could reflect the learning that takes place during the repeated defeat stress and the depression-like behaviors that follow it. Blocking the BDNF increases in the nucleus accumbens prevents these behaviors from developing.
Chadi Abdallah and other researchers at Yale University recently found that the left nucleus accumbens of patients with treatment-resistant depression is enlarged compared to normal controls, and the drug ketamine, which produces rapid-onset antidepressant effects, rapidly decreases the volume of the nucleus accumbens in the depressed patients. The mechanism by which it does so is unknown, but could reflect some suppression of the depressive learning.
Any relationship between the volume of the nucleus accumbens and its levels of BDNF is unknown, but ketamine’s effect on the size of this brain region could be linked to a decrease in the defeat-stress memories.
Colleen Hanlon, a researcher at the Medical University of South Carolina, has found that biofeedback can be used to decrease cocaine craving in people with substance abuse problems. In her research, patients were given real time feedback from functional magnetic resonance imaging (fMRI) and learned to decrease the activation of a part of the brain called the anterior cingulate when exposed to cocaine cues (reminders of their desire for cocaine). They were able to decrease drug craving as well as heart rate and skin conduction, which often accompany it.
Brain-derived neurotrophic factor (BDNF) is a protein in the brain that protects neurons and is necessary for long-term memory and learning. Different people have different genetic variations in BDNF depending on which amino acid the gene that codes for it inserts into the protein, valine or methionine. There are three possible combinations that vary in their efficiency. The Val66Val allele of BDNF is the most efficient for secreting and transporting BDNF within the cell body to synapses on dendrites, and is also a risk factor for early onset of bipolar disorder and rapid cycling. Twenty-five percent of the population has a Met variant (either Val66Met or Met66Met), which functions less efficiently. These people have mild decrements in some cognitive processing.
Increases in BDNF are necessary to the antidepressant effects of intravenous ketamine. In animals, ketamine also rapidly changes returns dendritic spines that had atrophied back to their healthy mushroom shape in association with its antidepressant effects. Depressed patients with the better functioning Val66Val allele of BDNF respond best to ketamine, those with the intermediate functioning Val66Met allele respond less well, and those with the poorest functioning Met66Met allele virtually do not respond at all.
Researcher Ronald S. Duman of Yale University recently found that increases in BDNF in the medial prefrontal cortex are necessary to the antidepressant effects of ketamine. If antibodies to BDNF (which block its effects) are administered to the prefrontal cortex, antidepressant response to ketamine is not observed.
Duman also found that calcium influx through voltage sensitive L-type calcium channels is necessary for ketamine’s antidepressant effects. A genetic variation in CACNA1C, a gene that codes for a subunit of the dihydropiridine L-type calcium channel, is a well-replicated risk factor for bipolar disorder. One might predict that those patients with the CACNA1C risk allele, which allows more calcium influx into cells, would respond well to ketamine.
Researchers have identified neurons responsible for remembering conditioned fear in the amygdala of rodents, and can turn them on and off. At the 2013 meeting of the Society of Biological Psychiatry, Sheena A. Josselyn gave a breath-taking presentation on this process.
When animals hear a tone they have learned to associate with the imminent delivery of a shock in a given environment, they learn to avoid that environment, and they reveal their learning of the tone-shock association by freezing in place. Josselyn was able to observe that 20% of the neurons in the lateral nucleus of the amygdala were involved in this memory trace. They were revealed by their ability to increase the transcription factor CREB, which is a marker of cell activation. Using cutting-edge molecular genetic techniques, the researchers could selectively eliminate only these CREB-expressing neurons (using a new technology in which a diphtheria toxin is attached to designer receptors exclusively activated by designer drugs, or DREADDs) and consequently erase the fear memory.
The researchers could also temporarily inhibit the memory, by de-activating the memory trace cells, or induce the memory, so that the animal would freeze in a new context. Josselyn and colleagues were able to identify the memory trace for two different tones in two different populations of amygdala neurons.
The same molecular tricks with memory also worked with cocaine cues, using what is known as a conditioned place preference test. A rodent will show a preference for an environment where it received cocaine. Knocking out the selected neurons would remove the memory of the cocaine experience, erasing the place preference.
The memory for cocaine involved a subset of amygdala neurons that were also involved in the conditioned fear memory trace. Incidentally, Josselyn and her group were eventually able to show that amygdala neurons were in competition with each other as to whether they would be involved in the memory trace for conditioned fear or for the conditioned cocaine place preference.