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Dr. Bob is Robert Hsiung, MD,
bob@dr-bob.orgShown: posts 1 to 10 of 10. This is the beginning of the thread.
Posted by Pfinstegg on February 13, 2006, at 18:25:20
in the dopamine reward pathways of the brain are altered in depression, PTSD and social withdrawal. (Science, Vol 311, 10 February, 2006).
This article describes how "bullied mice" (those subjected to a larger, aggressive mouse) developed symptoms of social defeat, mediated by BDNF in the dopaminergic mesolimbic pathways- the "reward system". The presence of BDNF was essential for this learned defeat and social withdrawal. Either knocking out BDNF in this pathway, or administering fluoxetine, prevented this from happening. Up until now, attention has focussed on preserving BDNF and serotonin in the hippocampus and other nearby areas, in the treatment of these symptoms, which many antidepressants, including fluoxetine, are thought to do.
I thought it was interesting that the dopaminergic pathways are emerging as important areas in depression and PTSD, and also that while BDNF is considered important in maintaining a healthy hippocampus, and is vital to memory and new learning, it could be one of the neurotransmitters in learned social defeat and depression
I have always been aware that absence of a sense of reward is one of the biggest difficulties when one is depressed. But I've also noticed, from personal experience and from many posts here, that long-term use of SSRIs and SNRIs can make that symptom even worse, even though, according to this article, it is supposed to preserve the sense of reward in social interactions despite social stress.
Posted by jrbecker on February 13, 2006, at 18:30:00
In reply to Interesting article in Science about how changes, posted by Pfinstegg on February 13, 2006, at 18:25:20
> in the dopamine reward pathways of the brain are altered in depression, PTSD and social withdrawal. (Science, Vol 311, 10 February, 2006).
>
> This article describes how "bullied mice" (those subjected to a larger, aggressive mouse) developed symptoms of social defeat, mediated by BDNF in the dopaminergic mesolimbic pathways- the "reward system". The presence of BDNF was essential for this learned defeat and social withdrawal. Either knocking out BDNF in this pathway, or administering fluoxetine, prevented this from happening. Up until now, attention has focussed on preserving BDNF and serotonin in the hippocampus and other nearby areas, in the treatment of these symptoms, which many antidepressants, including fluoxetine, are thought to do.
>
> I thought it was interesting that the dopaminergic pathways are emerging as important areas in depression and PTSD, and also that while BDNF is considered important in maintaining a healthy hippocampus, and is vital to memory and new learning, it could be one of the neurotransmitters in learned social defeat and depression
>
> I have always been aware that absence of a sense of reward is one of the biggest difficulties when one is depressed. But I've also noticed, from personal experience and from many posts here, that long-term use of SSRIs and SNRIs can make that symptom even worse, even though, according to this article, it is supposed to preserve the sense of reward in social interactions despite social stress.
>
>
yes, here's another article from 2003 that also underlines the fact that neurogenesis in the VTA >negatively< impacts mood..Biol Psychiatry. 2003 Nov 15;54(10):994-1005.
Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression.
Eisch AJ, Bolanos CA, de Wit J, Simonak RD, Pudiak CM, Barrot M, Verhaagen J, Nestler EJ.
Department of Psychiatry, The University of Texas Southwestern Medical Center, Texas, Dallas 75390-9070, USA.
BACKGROUND: Previous work has shown that brain-derived neurotrophic factor (BDNF) and its receptor, tyrosine kinase receptor B (TrkB), are involved in appetitive behavior. Here we show that BDNF in the ventral tegmental area-nucleus accumbens (VTA-NAc) pathway is also involved in the development of a depression-like phenotype. METHODS: Brain-derived neurotrophic factor signaling in the VTA-NAc pathway was altered in two complementary ways. One group of rats received intra-VTA infusion of vehicle or BDNF for 1 week. A second group of rats received intra-NAc injections of vehicle or adeno-associated viral vectors encoding full-length (TrkB.FL) or truncated (TrkB.T1) TrkB; the latter is kinase deficient and serves as a dominant-negative receptor. Rats were examined in the forced swim test and other behavioral tests. RESULTS: Intra-VTA infusions of BDNF resulted in 57% shorter latency to immobility relative to control animals, a depression-like effect. Intra-NAc injections of TrkB.T1 resulted in and almost fivefold longer latency to immobility relative to TrkB.FL and control animals, an antidepressant-like effect. No effect on anxiety-like behaviors or locomotion was seen. CONCLUSIONS: These data suggest that BDNF action in the VTA-NAc pathway might be related to development of a depression-like phenotype. This interpretation is intriguing in that it suggests a role for BDNF in the VTA-NAc that is opposite of the proposed role for BDNF in the hippocampus.
PMID: 14625141 [PubMed - indexed for MEDLINE]
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Posted by Pfinstegg on February 13, 2006, at 19:08:34
In reply to Re: BDNF in the reward pathway » Pfinstegg, posted by jrbecker on February 13, 2006, at 18:30:00
That's so interesting! And you found it so quickly! (you must have an excellent folder) I see that article is mentioned in the bibliography. i guess the only new part in this article is the action of fluoxetine in lowering BDNF-regulated stress genes in the meso-limbic pathway. It's good to see the complexity of these illnesses becoming increasingly recognized, even if treatment necessarily lags behind.
Posted by linkadge on February 13, 2006, at 20:03:24
In reply to Interesting article in Science about how changes, posted by Pfinstegg on February 13, 2006, at 18:25:20
Note, that BDNF expression in the hippocampus and BDNF expression the neucleus accumbens assert two totally different behavioral effects.
Increasing BDNF in the hippocampus asserts an antidepressant effect, whilest increasing BDNF in the reward centres of the brain asserts a behavioral depressant effect. Its slightly counterintiuitive, but this effect has been repeated in a number of studies.
Antidepressants are thought to work by increasing hippocampal BDNF, not BDNF in the NAA.
Linkadge
Posted by linkadge on February 13, 2006, at 20:05:46
In reply to A note, posted by linkadge on February 13, 2006, at 20:03:24
Sorry jrbecker, I should have read your post. I had remembered reading similar articles, but you beat me to the post.
Linkadge
Posted by jakeman on February 13, 2006, at 20:39:20
In reply to Interesting article in Science about how changes, posted by Pfinstegg on February 13, 2006, at 18:25:20
This article describes how "bullied mice" (those subjected to a larger, aggressive mouse) developed symptoms of social defeat, mediated by BDNF in the dopaminergic mesolimbic pathways- the "reward system"
Sounds a bit like the US job market.
~Jake
Posted by Phillipa on February 13, 2006, at 20:45:02
In reply to Re: Interesting article in Science about how changes » Pfinstegg, posted by jakeman on February 13, 2006, at 20:39:20
Maybe I shouldn't respond to this but I think Jakeman is right it does remind me of the US jobmarket. Fondly, Phillipa ps be careful or this will end up on politics
Posted by SLS on February 13, 2006, at 23:24:14
In reply to Re: BDNF in the reward pathway » Pfinstegg, posted by jrbecker on February 13, 2006, at 18:30:00
Location, location, location!
The brain is a gestalt of chemistry and circuitry. Utlitmately, this is the only way it can be understood.
- Scott
Posted by SLS on February 14, 2006, at 6:46:11
In reply to Re: BDNF in the reward pathway, posted by SLS on February 13, 2006, at 23:24:14
> Location, location, location!
>
> The brain is a gestalt of chemistry and circuitry. Utlitmately, this is the only way it can be understood.Well, maybe not the *only* way. I'm sure Eastern medicine has its own model of how things work...
- Scott
Posted by jrbecker on February 28, 2006, at 13:05:58
In reply to Re: BDNF in the reward pathway, posted by SLS on February 14, 2006, at 6:46:11
On the flip side of the case for BDNF detrimental actions in the Ventral Tagmental Area (VTA), the belief that neurogenesis [BDNF] in the hippocampal region is >integral< to the antidepressant response was recently bolstered. A new study shows that cell death in this region correlates with depressive behavior. Moreover, the study reported that the antidepressant they tested made only a limited impact in restoring cellular growth...
Public release date: 28-Feb-2006
[ Print Article | E-mail Article | Close Window ]Contact: Jules Asher
NIMHpress@nih.gov
301-443-4536
NIH/National Institute of Mental HealthDepression model leaves mice with molecular scar
In addition to triggering a depression-like social withdrawal syndrome, repeated defeat by dominant animals leaves a mouse with an enduring "molecular scar" in its brain that could help to explain why depression is so difficult to cure, suggest researchers funded by the National Institutes of Health's (NIH) National Institute of Mental Health (NIMH).
In mice exposed to this animal model of depression, silencer molecules turned off a gene for a key protein in the brain's hippocampus. By activating a compensatory mechanism, an antidepressant temporarily restored the animals' sociability and the protein's expression, but it failed to remove the silencers. A true cure for depression would likely have to target this persistent stress-induced scar, say the researchers, led by Eric Nestler, M.D., The University of Texas Southwestern Medical Center, who report on their findings online in Nature Neuroscience during the week of February 26, 2005."Our study provides insight into how chronic stress triggers changes in the brain that are much more long-lived than the effects of existing antidepressants," explained Nestler.
Mice exposed to aggression by a different dominant mouse daily for 10 days became socially defeated; they vigorously avoided other mice, even weeks later. Expression of a representative gene in the hippocampus, a memory hub implicated in depression, plummeted three-fold and remained suppressed for weeks. However, chronic treatment with an antidepressant (the tricyclic imipramine) restored expression of the gene for brain derived neurotrophic factor (BDNF) to normal levels and reversed the social withdrawal behavior. BDNF in the hippocampus has been linked to memory, learning and depression, but Nestler said social defeat stress probably similarly affects other genes there as well.
The researchers pinpointed how social defeat changes the BDNF gene's internal machinery. They traced the gene expression changes to long-lasting modifications in histones, proteins that regulate the turning on-and-off of genes via a process called methylation. Methyl groups, the silencer molecules, attach themselves to the histones, turning off the gene. Notably, imipramine was unable to remove these silencer molecules, suggesting that they remained a latent source of vulnerability to future depression-like responses to stress.
Imipramine reversed the suppressed BDNF gene expression by triggering a compensatory mechanism, acetylation, in which molecular activators attach themselves to the gene and overcome the silencer molecules. Imipramine turned off an enzyme (Hdac5) that degrades the activators, allowing them to accumulate.
"The molecular scar induced by chronic stress in the hippocampus, and perhaps elsewhere in the brain, can't be easily reversed," said Nestler. "To really cure depression, we probably need to find new treatments that can remove the silencer molecules."
###
Tsankova NM, Berton O, Renthal W, Kumar A, Neve R, Nestler EJ. Sustained hippocampal chromatin regulation in a mouse model of depression and antidepressant action. Nature Neuroscience. Published online, 2/26/2006.
NIMH is part of the National Institutes of Health (NIH), the Federal Government's primary agency for biomedical and behavioral research. NIH is a component of the U.S. Department of Health and Human Services.
http://www.eurekalert.org/pub_releases/2006-02/niom-dml022806.php
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