Necessity of Hippocampal Neurogenesis for the Therapeutic Action of Antidepressants in Adult Nonhuman Primates

Department of Psychiatry, College of Physicians and Surgeons, Columbia University Medical Center and New York State Psychiatric Institute, New York, New York, United States of America.
PLoS ONE (Impact Factor: 3.23). 04/2011; 6(4):e17600. DOI: 10.1371/journal.pone.0017600
Source: PubMed


Rodent studies show that neurogenesis is necessary for mediating the salutary effects of antidepressants. Nonhuman primate (NHP) studies may bridge important rodent findings to the clinical realm since NHP-depression shares significant homology with human depression and kinetics of primate neurogenesis differ from those in rodents. After demonstrating that antidepressants can stimulate neurogenesis in NHPs, our present study examines whether neurogenesis is required for antidepressant efficacy in NHPs. MATERIALS/METHODOLOGY: Adult female bonnets were randomized to three social pens (N = 6 each). Pen-1 subjects were exposed to control-conditions for 15 weeks with half receiving the antidepressant fluoxetine and the rest receiving saline-placebo. Pen-2 subjects were exposed to 15 weeks of separation-stress with half receiving fluoxetine and half receiving placebo. Pen-3 subjects 2 weeks of irradiation (N = 4) or sham-irradiation (N = 2) and then exposed to 15 weeks of stress and fluoxetine. Dependent measures were weekly behavioral observations and postmortem neurogenesis levels.
Exposing NHPs to repeated separation stress resulted in depression-like behaviors (anhedonia and subordinance) accompanied by reduced hippocampal neurogenesis. Treatment with fluoxetine stimulated neurogenesis and prevented the emergence of depression-like behaviors. Ablation of neurogenesis with irradiation abolished the therapeutic effects of fluoxetine. Non-stressed controls had normative behaviors although the fluoxetine-treated controls had higher neurogenesis rates. Across all groups, depression-like behaviors were associated with decreased rates of neurogenesis but this inverse correlation was only significant for new neurons in the anterior dentate gyrus that were at the threshold of completing maturation.
We provide evidence that induction of neurogenesis is integral to the therapeutic effects of fluoxetine in NHPs. Given the similarity between monkeys and humans, hippocampal neurogenesis likely plays a similar role in the treatment of clinical depression. Future studies will examine several outstanding questions such as whether neuro-suppression is sufficient for producing depression and whether therapeutic neuroplastic effects of fluoxetine are specific to antidepressants.

Download full-text


Available from: Christopher Lange, Oct 05, 2015
66 Reads
    • "For example, social isolation stress induced anhedonia and depression-like behavior in monkeys; this was alleviated by fluoxetine treatment, which also upregulated neurogenesis (Perera et al., 2011). However fluoxetine's behavioral antidepressant effect was abolished by focal hippocampal X-irradiation (Perera et al., 2011), which is highly toxic to immature neurons (Snyder et al., 2001; Winocur et al., 2006). Similarly, chronic unpredictable mild stress induced 0306-4522/Ó 2015 Published by Elsevier Ltd. on behalf of IBRO. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Chronic stress has a profoundly negative impact on the brain (1). Even acute stress exposure can markedly decrease neurogenesis (2), with significant implications for plasticity, memory, and mood (3). It is evident that the heightened plasticity of these newborn neurons makes them responsive to many environmental factors, which consequently affect behaviour. Some factors that robustly enhance neurogenesis and can mitigate the effects of stress and depression include antidepressant medications (4), dietary antioxidants (5) and exercise (6). At the physiological level, these factors are associated with biochemical processes and signaling pathways which are also altered in age-related cognitive decline, such as neurotrophin expression (7), cellular oxidative stress (5), inflammation (8) and mTOR regulation (9). A complex dietary supplement designed to counteract five potential mechanisms of ageing: inflammation, oxidative stress, mitochondrial dysfunction, insulin resistance and membrane integrity, has been shown to ameliorate physiological and cognitive decline in aged transgenic growth hormone mice (an accelerated aging model) and aged wild type control mice (10). We therefore predicted that this supplement combined with aerobic exercise would exert potent neuroprotective effects against chronic unpredictable stress in young adult mice. Four weeks of unpredictable mild stress strongly affected all stressed groups, as indicated by reduced saccharin preference and increased adrenal weights. Interestingly, the combination of dietary supplementation and aerobic exercise buffered the adverse effects of stress, as reflected in the number of doublecortin-positive immature neurons in the dentate gyrus, the sectional area of the dentate gyrus and CA1, and serum vascular endothelial growth factor levels. In contrast, these benefits were not observed in chronically stressed animals exposed to dietary supplementation or exercise alone. It is expected that RT-PCR analysis of hippocampal brain-derived neurotrophic factor mRNA, currently under investigation using samples from these animals, will reveal a similar pattern. Given the well-established effects of aerobic exercise (6) on neurogenesis in non-stressed animals, it is interesting that in stressed animals we observed no such benefit of either exercise or dietary supplementation alone, whereas the combination of diet supplementation and exercise exerted potent neuroprotective effects on hippocampal integrity. Our findings have important clinical implications for those suffering chronic stress-related psychiatric disorders such as major depression. (1) Gould, E.; McEwen, B. S.; Tanapat, P.; Galea, L. A.; Fuchs, E. J. Neurosci. 1997, 17, 2492–2498. (2) Gould, E.; Cameron, H. A.; Daniels, D. C.; Woolley, C. S.; McEwen, B. S. J. Neurosci. 1992, 12, 3642–3650. (3) Willner, P.; Towell, A.; Sampson, D.; Sophokleous, S.; Muscat, R. Psychopharmacology (Berl). 1987, 93, 358–364. (4) Malberg, J. E.; Eisch, A J.; Nestler, E. J.; Duman, R. S. J. Neurosci. 2000, 20, 9104–9110. (5) Valente, T.; Hidalgo, J.; Bolea, I.; Ramirez, B.; Anglés, N.; Reguant, J.; Morelló, J. R.; Gutiérrez, C.; Boada, M.; Unzeta, M. J. Alzheimers. Dis. 2009, 18, 849–865. (6) van Praag, H.; Kempermann, G.; Gage, F. H. Nat. Neurosci. 1999, 2, 266–270. (7) Sairanen, M.; Lucas, G.; Ernfors, P.; Castrén, M.; Castrén, E. J. Neurosci. 2005, 25, 1089–1094. (8) Goshen, I.; Kreisel, T.; Ben-Menachem-Zidon, O.; Licht, T.; Weidenfeld, J.; Ben-Hur, T.; Yirmiya, R. Mol. Psychiatry 2008, 13, 717–728. (9) Ota, K. T.; Liu, R.; Voleti, B.; Maldonado-Aviles, J. G.; Duric, V.; Iwata, M.; Dutheil, S.; Duman, C.; Boikess, S.; Lewis, D. A.; Stockmeier, C. A.; DiLeone, R. J.; Rex, C.; Aghajanian, G. K.; Duman, R. S. Nat. Med. 2014, 20, 531–535. (10) Aksenov, V.; Long, J.; Liu, J.; Szechtman, H.; Khanna, P.; Matravadia, S.; Rollo, C. D. Age (Dordr). 2013, 35, 23–33.
    Adult Neurogenesis: Evolution, Regulation and Function, Center for Regenerative Therapies, Dresden, Germany; 05/2015
  • Source
    • "It is therefore believed that the function of adult neurogenesis in primates is similar to that in rodents. For instance, the age-dependent decrease in hippocampal neurogenesis was correlated to reduced learning ability in aged animals (Aizawa et al. 2009), suggesting that hippocampal neurogenesis is important for learning ability in primates; the stress-induced decrease and antidepressant-induced increase in neurogenesis indicated that hippocampal neurogenesis might be a potential mechanism underlying the efficiency of antidepressants (Perera et al. 2011a), as shown in rodents (Yuan and Hou 2014; Yuan and Slotnick 2014). In addition, the upregulation of endogenous neurogenesis under brain injury and ischemic conditions implied the repairing function of endogenous neural stem cells in primate brains, as demonstrated in rodents (Carlen et al. 2009). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Adult neurogenesis in rodents has been extensively studied. Here we briefly summarized the studies of adult neurogenesis based on non-human primates and human postmortem brain samples. The differences between rodent, primate and human neurogenesis were discussed.
    Cell and Tissue Research 10/2014; 358(1). DOI:10.1007/s00441-014-1980-z · 3.57 Impact Factor
  • Source
    • "Recent studies with adult macaques have obtained similar results. Perera et al. (2011) found adult male bonnet macaques (M. radiata) displayed a depressive-like reaction of a slumped body posture accompanied by an apparent lack of interest in their surroundings following 13–15 week cycles of 2 days of separation from the social group interspersed with 5 days of reunion. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Social isolation is a major risk factor for the development of depressive illness; yet, no practical nonhuman primate model is available for studying processes involved in this effect. In a first study, we noted that adult male rhesus monkeys housed individually indoors occasionally exhibited a hunched, depressive-like posture. Therefore, Study 2 investigated the occurrence of a hunched posture by adult males brought from outdoor social groups to indoor individual housing. We also scored two other behaviors-lying on the substrate and day time sleeping-that convey an impression of depression. During the first week of observation following individual housing, 18 of 26 adult males exhibited the hunched posture and 21 of 26 displayed at least one depressive-like behavior. Over 2 weeks, 23 of 26 males showed depressive-like behavior during a total of only 20 min observation. Further, the behavior during the first week was positively related to the level of initial response to a maternal separation procedure experienced in infancy. In Study 3, more than half of 23 adult males of a new sample displayed depressive-like behavior during 10 min of observation each of Weeks 7-14 of individual housing. The surprisingly high frequency of depressive-like behavior in Studies 2 and 3 may have been due to recording behavior via camera with no human in the room to elicit competing responses. These results suggest that a common animal husbandry procedure might provide a practical means for examining effects of social isolation on depression-related endpoints in a nonhuman primate. The findings also suggest that trait-like differences in emotional responsiveness during separation in infancy may predict differences in responsiveness during social isolation in adulthood.
    Frontiers in Behavioral Neuroscience 09/2014; 8:309. DOI:10.3389/fnbeh.2014.00309 · 3.27 Impact Factor
Show more