Neurogenesis and Anti-Depression Actions - Annissa DeSilva



         Santarelli et al. and Bessa et al. both explore the neurogenic theory in the pathophysiology of depression. This theory proposes that diminished neurogenesis in the hippocampus may underlie the neural basis of depression. This theory is supported by a large body of research that has found that chronic anti-depressant (AD) treatment elicits neurogenesis in the hippocampus.
            The findings of Santerelli et al. further supported the neurogenic hypothesis finding that treatment with AD’s after 28 days decreased latency to feed in the novelty suppressed feeding (NSF) test and an increase of neurogenesis in the dentate gyrus (determined by an increase in the number of BrDU labelled cells). They conversely found that ablation of neurogenesis for 28 days through x-irradiation in vehicle treated mice did not produce any depressive like behavior evidenced by the NSF and chronic unpredictable stress (CUS) test (vehicle mice showed no effect in latency to feed or groom). Santerelli et al. concluded that this finding was still in line with the neurogenic hypothesis, speculating that a longer period of ablation would produce behavioral deficits or that the neurons created due to AD’s are different than cells produced before the introduction of AD’s. This conclusion seems vague and highlights one of the main criticisms of the neurogenesis hypothesis; decreased neurogenesis does not lead to depressive like behavior. Other studies have come to similar conclusions, Surget, et al., 2008 found that treatment of hippocampal irradiation had no effect on mice’s behavior in CUS test. Jayatissa, et al., 2009 found similar results and concluded that the lack of neurogenesis in irradiated mice is independent to the development of an anhedonia like state. This data suggests that the deficits in neurogenesis observed in depression model mice may be the result of a depressive state and not necessarily involved in the etiology of the disorder.
Both papers, to some extent, agree that in regard to the neurogenesis hypothesis that AD treatment increases neurogenesis in the SGZ of the hippocampus, however Santerelli et al. makes broad assumptions about the requirement of neurogenesis in AD action. However, it is unclear how proliferation of new cells is specifically involved in the pathology of depression. Bessa et al. linked the therapeutic effects of AD treatment to specific neural remodeling not neurogenesis.
The Bessa et al. findings paired with the findings of Jayatissa et al., 2009 and Surget et al., 2008 suggest that neurogenesis although effected by AD’s may not be implicated in depressive like behavior or treatment of it. It would be interesting, if possible, to examine if AD’s have therapeutic effects when different types of synaptic remodeling/plasticity is blocked. This would allow for  further examination of what exact neural changes are producing therapeutic effects, if any, or if synaptic plasticity is a “bi-product” of AD treatment similarly to neurogenesis.





Citations:
Surget, A., Saxe, M., Lemen, S., Ibarguen-Vargas, Y., Chalon, S., Griebel, G., . . . Belzung, C. (2008). Drug-dependent requirement of hippocampal neurogenesis in a model of depression and of antidepressant reversa. Biological Psychiatry,64(4), 293-301. doi:10.1016/j.biopsych.2008.02.022

 Jayatissa, M. N., Henningsen, K., Nikolajsen, G., West, M. J., & Wiborg, O. (2009). A reduced number of hippocampal granule cells does not associate with an anhedonia-like phenotype in a rat chronic mild stress model of depression. Stress,13(2), 95-105. doi:10.3109/10253890902951786

Comments

  1. Sierra Smith23 January 2019 at 20:32

    This comment has been removed by the author.

    ReplyDelete
  2. Sierra Smith23 January 2019 at 20:37

    Sierra Smith- Research methods discrepancy and unanswered questions in Santarelli et al 2003

    I think it's a very good catch that you highlight how x-irradiation in the Santarelli paper may have produced greater behavioral deficits following longer periods of ablation. Bessa et al 2009 draws attention to the fact that x-irradiation is a poor method for ablation due to the fact that it potentially causes significant inflammation effects, and may require an extended recovery period for reduced inflammation and lingering effects prior to beginning antidepressant treatment. This was the criteria that ultimately lead Bessa et al to use MAM as a means of chemically reducing neurogenesis without any confounding variables that may otherwise lead to hasty conclusions on the affects of antidepressant-treated ablated brains. Unfortunately, Santarelli et al do not seem to highlight any significant rest period of x-irradiated rodents prior to 28-day treatment course of antidepressants. I am concerned that the suppressed behavioral response to antidepressant treatment following x-ray ablation may be due to lingering inflammatory effects on the hippocampal connectivity instead of a true effect on the modulation of behavior through neurogenesis and antidepressant treatment.

    Santarelli et al also choose to highlight data that seem to show little evidence to undeniably support their claim that hippocampal neurogenesis is required for the behavioral effects of antidepressants. Most of the evidence presented shows that either A. neurogenesis is actually occurring as a result of antidepressant treatment as shown by the increase in the number of BrdU-positive cells following at least 11 days of fluoxetine treatment, or B. antidepressants are effective in combating traditional behavioral symptoms of depression such as in latency to feed. Other than the x-irradiation study, which, as discussed, may incorporate flawed methodology, there seems to be a lack of evidence that there is actually a requirement of hippocampal neurogenesis for the behavioral effects of antidepressants. Bessa et al have a much stronger argument for neuroplasticity and synaptic remodeling being an essential component for these effects, as their chemical ablation method seems to be much more reliable in addition to the presentation of a more comprehensive and multi-faceted story. Their finding that the shift in types of dendritic spines from mushroom to thin spine under chronic mild stress conditions is particularly intriguing; it could be valuable to investigate this even further by using a radioactive or fluorescence tagged agent to visualize this shift in dendritic spine type under chemical ablation and antidepressant treatment conditions to build a more comprehensive story as to how synaptic remodeling may modulate these effects.

    ReplyDelete

Post a Comment

Popular posts from this blog

Microbiotic effects on stress and social behavior in mice- Sierra Smith

For the final week of paper discussions, we dove into the fascinating and very new topic of the gut microbiome, and the influence of microbiotic composition on mice either under chronic subordinate colony housing situations or the offspring of dames fed a high-fat diet. In the first paper I read, Reber et al, there were fascinating findings that although supplementation with heat-killed Mycobacterium vaccae did not prevent all microbiotic changes induced by stressful housing conditions, it did have a significantly protective effect on the development of spontaneous colitis and stress-induced aggravation of pre-existing inflammatory bowel disease (colitis in mice). There was also a profound effect on proactive defensive behaviors in mice housed in CSC conditions, whereas they became defeated less easily and displayed significantly more proactive behaviors when faced with an aggressor. I was particularly excited to read about the increased Iba1 immunostaining in fear-regulato...
Read more

ACC-BLA Connections and Observational Learning- Annissa DeSilva

            Observational fear learning is an innate social behavior, Allsop et al. 2018 outlines the neural circuit underlying how the brain encodes emotionally salient (fear) behavior with neutral cues associated through observational fear learning. Allsop et al, found that projections from the Anterior cingulate cortex (ACC) to the Basolateral Amygdala (BLA) are essential in encoding observational learning. Specifically observing distress causes basal changes in the ACC neurons (encoding of the observed behavior through social cues) which enables the acquisition of the predictive nature of the aversive cue by BLA neurons. When ACC - BLA projections were optogenetically inhibited while mice were observing fear conditioning a reduced freezing response was seen when conditioned fear response was tested. Interestingly when the ACC - BLA projections were inhibited during testing of observational fear conditioning the...
Read more

Two sides of the same coin?: the bidirectional effects of VTA-NAc DA neurons - Emily Jones

Papers like the ones assigned this week reminded of the reasons I opted to take this class. Research into the biological nuances of complex clinical disorders really reinforces the idea that everything psychological is simultaneously biological. And in these papers, optogenetics amazingly gives us a fast and efficient way to explore these nuances. Interestingly, both papers demonstrated a bidirectional effect of dopamine neurons in the VTA-NAc pathway on depression phenotypes using phasic photoactivation. However, it seemed that these effects were flipped. In other words, when Chaudhury et al. inhibited the neurons, a resilient phenotype was induced in previously susceptible mice (indicated by a high preference for sugar water and decreased social avoidance compared to control mice); when Tye et. al. use the same opsin to inhibit the same kind of neurons, depression phenotypes were induced. Indeed the differences may be due in large part to the different stress conditions the mice we...
Read more