Functional Role of Adult-Born Neurons in Stress Vulnerability and Resilience
Involvement of Hippocampal Neurogenesis in Fear Memory Overgeneralization Following Exposure to Traumatic Stress
The importance of adult hippocampal neurogenesis may be revealed under conditions of environmental stress exposure.
Posttraumatic stress disorder (PTSD) is unique among stressor-related neuropsychiatric illness in that exposure to a traumatic event is an essential element of the diagnosis. PTSD may ensue following a life-threatening event (war, natural disaster, crime victimization, etc.) and is characterized by 4 symptom clusters: intrusive recollection of traumatic memories, hyperarousal, avoidance behavior, and negative alterations in cognition and mood. Other symptoms of PTSD include generalized anxiety and aberrant sleep patterns.1
The diagnosis of PTSD has retained the majority of symptoms including recurrent, involuntary, and intrusive memories, and avoidance of trauma-related thoughts, feelings, or external reminders. Some of the relatively recent changes, however, include shifting PTSD from an anxiety disorder to trauma- or stressor-related disorder. Moreover, DSM-5 added a new cluster of symptoms representing cognitive and mood disturbances, and it pays more attention to the behavioral symptoms that accompany PTSD.1
Human genetic studies reveal a heritability of PTSD of approximately 30%.2 The prevalence of PTSD among females is roughly twice that of males, yet studies that utilize female nonhuman animal models are limited. The examination of the putative sex-specific neuroendocrinologic mechanisms underlying PTSD and other trauma- and stressor-related disorders is therefore warranted.3
Neuropsychiatric disorders such as PTSD are caused by a combination of complex genetic and environmental factors. Genome-wide association studies and epidemiological analyses are unable to detect causative neurobiological mechanisms that underlie the development of PTSD. Consequently, nonhuman animal models are essential to address the physiologic basis of psychiatric illness.2-4 It is worth noting that fear conditioning is widely used in rodent models of PTSD as an environmental stressor due to its predictive, etiologic, and ethologic validity.4
Dynamics of Adult Hippocampal Neurogenesis in Stress-Related Neuropsychiatric Illness
Researchers have begun to illuminate the neurocircuitry that underlies fear processing and regulation, and are identifying potential genetic, neural, behavioral, and environmental markers of PTSD.4,5
Based on data from preclinical and clinical research, the “neurogenic hypothesis” originated as an effort to explain the nature of, and to help combat, stress-related psychiatric illnesses such as major depressive disorder (MDD) and PTSD.6 In humans, depression and anxiety are often comorbid, and thus the neurogenesis hypothesis might apply to both affective and anxiety disorders.7
One of the known neurogenic regions in the adult brain is the subgranular zone of the dentate gyrus in the hippocampus, and adult-born granule cells that functionally integrate into the dentate gyrus circuit impact cognitive and affective processing. The ventral hippocampus regulates emotional processing, whereas the dorsal hippocampus is involved in learning and memory processing.8 Hence, ventral and dorsal hippocampal neurogenesis may also differentially impact mood or cognition, respectively.9
The ablation of hippocampal neurogenesis was shown to negatively affect learning and memory processes that rely on proper functioning of the hippocampal formation, including contextual fear conditioning, long-term spatial memory, and working memory. Also, conditional suppression of adult hippocampal neurogenesis results in an exaggerated hypothalamic-pituitary-adrenal (HPA) axis response following exposure to a stressful situation.10
It is known that adult hippocampal neurogenesis is required for some of the behavioral effects of antidepressants,11 and also that certain categories of antidepressants increase neurogenesis selectively in the ventral dentate gyrus.12 It is worth noting that treatments that promote neurogenesis may enhance overall stress resilience.13
Research indicates that the proliferation of granule cells precursors and the production of new granule cells depend on the levels of circulating glucocorticoids and consequently are altered by stress exposure.14 More specifically, glucocorticoids negatively regulate neurogenesis,15,16 and basal levels of glucocorticoids are inversely correlated with the rate of cell proliferation in the dentate gyrus.17 Also, the exposure to environmental stress significantly diminishes the proliferation of granule cell precursors in the dentate gyrus.18
It has been proposed that the importance of neurogenesis may be revealed under conditions of environmental stress,7 and that stress-induced inhibition of neurogenesis may contribute to the onset or exacerbate stress-related disorders like PTSD.19 In preclinical models of PTSD, decreased hippocampal cell proliferation and survival were reported following stress exposure.6 In one study, behavioral recovery following a traumatic experience correlated with enhanced hippocampal cell proliferation in mice20, while ziprasidone (atypical antipsychotic drug) treatment ameliorated anxiety-like behaviors and promoted neurogenesis in rats.21 In another study, following exposure to inescapable shocks, rats exhibited avoidance behavior, which is a clinically relevant symptom of PTSD,1 coupled with reductions in the proliferation and survival rate of newly generated cells in the hippocampus.22
Promoting Hippocampal Neurogenesis to Reduce Excessive Generalization of Fear Memory
An overgeneralization of fear responses to emotional stimuli is common in anxiety disorders as well as stress-related disorders such as PTSD. It is hypothesized that deficits in pattern separation, the inability to transform related experiences into distinct inputs (ie, memories), may be an underlying mechanism.23 Studies performed in both humans and rodents indicate that the process of pattern separation occurs in the dentate gyrus. More specifically, the dorsal dentate gyrus supports spatial and contextual pattern separation, whereas the ventral dentate gyrus supports odor pattern separation.24
It is important to note that an increase in adult hippocampal neurogenesis is sufficient to facilitate pattern separation,25 whereas ablation of neurogenesis leads to a significant deficit in tasks designed to test pattern separation.26
Environmental enrichment, physical exercise, cognitive stimulation (eg, learning), and antidepressants stimulate neurogenesis as well as promote pattern separation. Conversely, stress, aging, and sensory depravation diminish neurogenesis, impair pattern separation, and favor pattern completion that results in overgeneralization.27
Taken together, evidence indicates that exposure to traumatic stress causes deficits in pattern separation, which is a neurogenesis-dependent computation. Although the exact mechanisms remain elusive,23 it is becoming evident that facilitation of neurogenesis to enhance pattern separation, and thus restrict overgeneralization, may prove beneficial in treating psychiatric illness including affective, anxiety, and stress-related disorders.28
In addition to clinical research with humans, genetic models provide insight into cellular and molecular mechanisms that underlie stress vulnerability (and resilience), and greater understanding of basic neurobiology of PTSD will possibly facilitate the development of novel behavioral or pharmaceutical approaches and methodologies to treatment of stress-related psychiatric illness.
1. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013.
2. Mehta D, Binder EB. Gene x environment vulnerability factors for PTSD: the HPA-axis. Neuropharmacology. 2013;62:654-662.
3. Cohen H, Yehuda R. Gender differences in animal models of posttraumatic stress disorder. Dis Markers. 2011;30:61-65.
4. Daskalakis NP, Yehuda R, Diamond DM. Animal models in translational studies of PTSD. Psychoneuroendocrinology. 2013;38:1895-1911.
5. Johnson LR, McGuire J, Lazarus R, Palmer AA. Pavlovian fear memory circuits and phenotype models of PTSD. Neuropharmacology. 2012;62:638-646.
6. DeCarolis NA, Eisch AJ. Hippocampal neurogenesis as a target for the treatment of mental illness: a critical evaluation. Neuropharmacology. 2010;58:884-893.
7. Petrik D, Lagace DC, Eisch AJ. The neurogenesis hypothesis of affective and anxiety disorders: are we mistaking the scaffolding for the building? Neuropharmacology. 2012;62:21-34.
8. Kheirbek MA, Hen R. Dorsal vs ventral hippocampal neurogenesis: implications for cognition and mood. Neuropsychopharmacology Rev. 2011;36:373-374.
9. Sahay A, Hen R. Adult hippocampal neurogenesis in depression. Nat Neurosci. 2007;10:1110-1115.
10. Schloesser RJ, Manji HK, Martinowich K. Suppression of adult neurogenesis leads to an increased hypothalamo-pituitary-adrenal axis response. Neuroreport. 2009;20:553-557.
11. Santarelli L, Saxe M, Gross C, et al. Requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Science. 2003;301:805-809.
12. Banasr M, Soumier A, Hery M, et al. Agomelatine, a new antidepressant, induces regional changes in hippocampal neurogenesis. Biol Psychiatry. 2006;59:1087-1096.
13. Lehman ML, Brachman RA, Martinowich K, et al. Glucocorticoids orchestrate divergent effects on mood through adult neurogenesis. J Neurosci. 2013;33:2961-2972.
14. Gould E, Tanapat P. Stress and hippocampal neurogenesis. Biol Psychiatry. 1999;46:1472-1479.
15. Sapolsky RM, Krey LC, McEwen BS. Prolonged glucocorticoid exposure reduces hippocampal neuron number: implications for aging. J Neurosci. 1985;5:1222-1227.
16. Cameron HA, Gould E. Adult neurogenesis is regulated by adrenal steroids in the dentate gyrus. Neuroscience. 1994;61:203-209.
17. Gould E, Wooley CS, Cameron HA, et al. Adrenal steroids regulate postnatal development of the rat dentate gyrus: II. Effects of glucocorticoids and mineralocorticoids on cell birth. J Comp Neurol. 1991;313:486-493.
18. Tanapat P, Galea LA, Gould E. Stress inhibits the proliferation of granule cell precursors in the developing dentate gyrus. Int J Dev Neurosci. 1998;16:235-239.
19. Kitayama N, Vaccarino V, Kutner M, et al. Magnetic resonance imaging (MRI) measurement of hippocampal volume in posttraumatic stress disorder: a meta-analysis. J Affect Disord. 2005;88:79-86.
20. Hendriksen H, Prins J, Olivier B, Oosting RS. Environmental enrichment induces behavioral recovery and enhanced hippocampal cell proliferation in an antidepressant-resistant animal model for PTSD. PLoS ONE. 2010;5:e11943.
21. Peng Z, Zhang R, Wang H, et al. Ziprasidone ameliorates anxiety-like behaviors in a rat model of PTSD and up-regulates neurogenesis in the hippocampus and hippocampus-derived neural stem cells. Behav Brain Res. 2013;244:1-8.
22. Kikuchi A, Shimizu K, Nibuya M, et al. Relationship between post-traumatic stress disorder-like behavior and reduction of hippocampal 5-bromo-2'-deoxyuridine-positive cells after inescapable shock in rats. Psychiatry Clin Neurosci. 2008;62:713-720.
23. Kheirbek MA, Klemenhagen KC, Sahay A, Hen R. Neurogenesis and generalization: a new approach to stratify and treat anxiety disorders. Nat Neurosci. 2012;15:1613-1620.
24. Kesner RP. An analysis of the dentate gyrus function. Behav Brain Res. 2013;254:1-7.
25. Sahay A, Scobie KN, Hill AS, et al. Increasing adult hippocampal neurogenesis is sufficient to improve pattern separation. Nature. 2011;472:466-470.
26. Clelland CD, Choi M, Romberg C, et al. A functional role for adult hippocampal neurogenesis in spatial pattern separation. Science. 2009;325:210-213.
27. Sahay A, Wilson DA, Hen R. Pattern separation: a common function for new neurons in hippocampus and olfactory bulb. Neuron. 2011;70:582-588.
28. Besnard A, Sahay A. Adult hippocampal neurogenesis, fear generalization, and stress. Neuropsychopharmacology. 2016;41:24-44.