Primates Shed Light on the Neurobiology of Anxiety Disorders in Children
Studies of primates suggest that the amygdala plays an important role in the development of anxiety disorders. Researcher Ned Kalin suggested at the 2015 meeting of the Society of Biological Psychiatry that the pathology of anxiety begins early in life. When a child with anxiety faces uncertainty, the brain increases activity in the amygdala, the insula, and the prefrontal cortex. Children with an anxious temperament, who are sensitive to new social experiences, are at almost sevenfold risk of developing a social anxiety disorder, and later experiencing depression or substance abuse.
A study by Patrick H. Roseboom and colleagues presented at the meeting was based on the finding that corticotropin-releasing hormone (CRH) plays a role in stress and is found in the central nucleus of the amygdala (as well as in the hypothalamus). The researchers used viral vectors to increase CRH in the central nucleus of the amygdala in young rhesus monkeys, hoping to determine what impact increased CRH has on a young brain. Rhesus monkeys and humans share similar genetic and neural structures that allow for complex social and emotional functioning.
Roseboom and colleagues compared the temperaments of five monkeys who received injections increasing the CRH in their amygdala region to five monkeys who received control injections. As expected, the monkeys with increased CRH showed increases in anxious temperament. Brain scans also revealed increases in metabolism not only in the central nucleus of the amygdala, but also in other parts of the brain that have been linked to anxiety, including the orbitofrontal cortex, the hippocampus, and the brainstem, in the affected monkeys. The degree of increase in amygdala metabolism was directly proportional to the increase in anxious temperament in the monkeys, further linking CRH’s effects in the amygdala to anxiety.
The Myth of Neurogenesis in Adult Primates Debunked
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.”
