2019 Biopsych Seminar Thursdays

        The two articles studying the role of mesolimbic dopaminergic neurons on depressive behavior published in the same issue of Nature are an important of why interpretations of results cannot easily be done beyond the scope of the models and methods being directly tested.         Generally, results in the two papers show exactly directionality for the effects of mesolimbic DA neurons on depressive like symptoms. In short, Chaudhury et. al (2012) found that activation of VTA neurons induces depressive behavior and that inhibiting the VTA-NAc dopaminergic pathway induces resilience to depressive behavior. Tye et. al (2012) shows that inhibition of VTA neurons induces depressive symptoms and that inhibiting dopaminergic input into the NAc resulted in a more depressive behavior. These results indicate that there is a bidirectional effect of this pathway on depressive like behavior. Notably, the effects described by Tye et. al (2012) are observe...

Here are two papers that use similar methods, that mainly focus on the same disease treatment and same areas of the brain, but that seemingly found opposite results. Chaudbury  et al.  found that stimulating the ventral tegmental area (VTA) of mice resistant to a social-defeat paradigm induced depressive-like symptoms, while Tye  et al.  found that stimulating the VTA of mice exposed to chronic mild stress (CMS) instantly reversed behaviors from depressive-like to normal. The main difference between the methods used in each study, is how they induced the depressive-like behavior in the mice. Chaudbury  et al.  utilized a social-defeat paradigm that differed greatly from the CMS used by Tye  et al.  Both papers utilized nearly the same optogenetics method to selectively target VTA dopamine neurons.  I found the papers interesting, and I agree with Tye  et al.  that the difference in stressors, as well as the general complexity of ...

First and foremost, I was impressed with the agreement of the results reported in both Tye et al. and Chaudhury et al. published in the same volume of nature. Although each group took to differing methods of inducing depressive phenotypes, one primarily using repeated social-defeat stress while the other using chronic mild stress, each was able to produce highly similar yet unique insights into the circuitry of dopamine neurons in the VTA and their projections and how it relates to depression models in rodents. Each group was able to show the necessity of the VTA-NAc pathway bidirectionally in certain depressive phenotypes such as anhedonia during sucrose preference testing (used by both groups), yet each group also took their own approach to investigating the underlying circuitry involved in this effect. I was fascinated with the direction taken near the end of the Tye et al. paper where the researchers were able to measure extremely temporally precise firing of individual NAc neuro...

The mesolimbic pathway is a dopaminergic pathway involved in the reward response. This pathway is suspected to be involved with anhedonia in depression. Chaudhury et al. and Tye et al. both used optogenetic techniques to selectively stimulate DA neurons projecting from the VTA to the NAc, however they found opposing results. Chaudhury et al. concluded that high frequency phasic stimulation of DA neurons projecting from VTA to the NAc induced the depressive symptoms in mice resilient to the social defeat stress test and inhibition of the VTA neurons induced the resilient phenotype in those who previously were susceptible based on the sucrose preference test and social interaction test. Tye et al, concluded that inhibition of VTA neurons after chronic mild stress (CMS) for 12 weeks reversed depressive symptoms and phasic activation of the neurons reversed the effects of CMS also using sucrose preference as the behavioral assay. The difference may lie in the implication that ...

Tye et al. and Chaudhury et al. both focused on the different roles of dopamine neurons in the VTA and how they affect depressive behaviors, but their varying methods presented differing results. Both also packed numerous experiments into one publication. Tye’s study manipulated VTA neurons expressing TH with eNpHR3.0/eYFP to hyperpolarize neurons upon illumination, as well as with ChR2/eYFP to excite them. Mice were either exposed or not exposed to a chronic mild stress (CMS) paradigm over 8-12 weeks. They found that phasic inhibition of VTA DA neurons resulted in an increase in depressive-like symptoms in the CMS group, and firing of these same neurons reversed these effects. Next, they collected recordings of the NAc and observed increased kicks during the forced swim task (FST) while stimulating VTA neurons. However, the role of these neurons can vary, as some responded to and some were inhibited by light. Chaudhury took a slightly different approach. They only used ChR2, but...

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...

I was intrigued by Tye et Al.'s discussion point towards the end where they begin to discuss the possible sources of variance between their paper and other papers in the past that demonstrated that phasic activation of ontogenetically induced light stimulation of VTA-Nacc circuit increases susceptibility to depressive behavior. They discuss the fact that different stressors may attenuate or increase responses to this neural circuit depending on the severity of the stressor. Could for example, a severe stressor require activation of dopaminergic cells projecting to the nucleus accumbens, due to the degree of harshness, while a more mild stressor may not need this added dopaminergic response? Chaudhury et al., showed that phasic activation of the VTA-Nacc circuit attenuates sucrose preference, and social interaction in ChR2 mice. This did not happen with tonic activation which is a surprising find. Why would phasic, and not tonic activation of this dopaminergic circuit increase sus...

Both Chaudhury et al. and Tye et al. explored the role of the mesolimbic dopamine (DA) neuron system in depression, as this system has been linked to reward, motivation, and stress. Despite many similarities in their approaches, the two groups diverged in their selection of depression-inducing models: Chaudhury et al. chose a 10-day repeated social defeat stress model (in conjunction with subthreshold defeat), while Tye et al. opted for 8-12 week chronic mild stress (CMS). Right off the bat, the groups report opposite results in response to phasic activation of VTA DA neurons. When Chaudhury et al. exposed mice to subthreshold social defeat and then stimulated channelrhodopsin 2 (ChR2)-expressing VTA DA neurons, they saw that phasic activation increased susceptibility to depressive behavior in the social interaction test. Conversely, when Tye et al. exposed mice to CMS and then stimulated ChR2-expressing VTA DA neurons, they observed reduction in depressive behavior, restoring sucros...

Santarelli et al.(2003) and Bessa et al. (2009) both look into the importance of hippocampal neurogenesis for the behavioral effects of antidepressants. At a first glance it might seem like the most recent article contradict the conclusions of the earlier one, in fact it replicate the earlier results. Both studies demonstrate that hippocampal neurogenesis is required for antidepressant facilitated improvement of anxiety like behavior in rats. This is evident in figure 5A of Santarelli et al.(2003) and figure 3 C of Bessa et al. (2009). Both figures show that without neurogenesis antidepressants do not improve latency to feed. There are, however, important differences to note in the methodologies and results of these 2 studies with regards to the anxiety paradigm. Santarelli et al.(2003) studies mice at basal level, while Bessa et al. (2009) utilizes a chronic mild stress paradigm to induce anxiety and depressive symptoms in the mice. In fact, the use of CMS results in increased baselin...

The previous posts bring up a really good point in criticizing the generalizability of Santarelli and colleagues’ results. Bessa et al. (2009) looked at multiple dimensions of depression while Santarelli et. al. (2003) only examined anxiety-like feeding behavior and then generalized their findings. Intuitively, it seems that the later 2009 paper contains more conclusive results: that it is neuronal remodeling that is necessary for the behavior improving actions of antidepressants. However, I think Bessa and colleagues’ do not necessarily refute, but adds onto the work of Santarelli et al., helping readers to evaluate the 2003 article in a new way. Bessa and colleagues’ findings corroborate the need for neurogenesis but also, by examining different behavioral manifestations of depression, makes for a more generalizable result when discussing the pathogenesis of depression.  Although the research done by Bessa et al. suggests that behavioral homeostasis is restored by an...

Santarelli  et al. (2003) and Bessa  et al . (2009) both present new research related to determining the mechanism of action for antidepressants (AD) in mice models. The mechanism for action is still not well understood, despite ADs being available for many decades and a multitude of hypotheses. These authors both examine one of the hypotheses; that neurogenesis within the hippocampus causes the behavioral effects of AD treatment.  Santarelli  et al.  suggests that hippocampal neurogenesis, specifically in the SVZ and SGZ, is required for the behavioral effects of antidepressants to occur. Santarelli  et al.  lacks a Materials and Methods section, which makes it more difficult (if not impossible) to completely assess the validity of the research and the findings. I was extremely surprised by this, and I had difficulty comparing this paper to others partially because it was missing that entire section (though some information that would normally be...

          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 chr...

         An interesting find in the Santarelli paper was that the effects of imipramine administration on 5HTA-KO mice still had an effect while fluoxetine did not ( This is intriguing as there are many explanations that are possible for this phenomena. The first is that the nature of these two antidepressant drugs is different entirely. Flueoxetine is an SSRI, causing a block of re-uptake of serotonin alone, while the TCA imipramine causes an increase in not only blocking re-uptake of serotonin, but norepinephrine as well, suggesting that perhaps the increase in cell proliferation arising in KO mice with imipramine administration is coming from the activation of Norepinephrine receptors. Another explanation draws support from the fact that imipramine causes increase in the acetylation pattern at the BDNF promoter, possibly causing a neurotrophic factor induced neurogenic response, as imipramine has been shown to increase level of BDNF.       ...

Separately, Santarelli et al.’s 2003 article and Bessa et al.’s 2009 article provide scientifically supported views on the effects of antidepressants on the hippocampus; specifically, how they impact hippocampal neurons to result in behavioral improvements. Santarelli and colleagues propose hippocampal neurogenesis is required for antidepressants to have any effect. They subjected mice to low-dose x-irradiation, effectively blocking 5-HT1A receptors and reducing neurogenesis in the subgranular zone by 85%. These affected mice, when treated with antidepressants, failed to show the same decreased latency to feed as sham mice. These mice also showed smaller improvements following a chronic unpredictable stress paradigm and subsequent fluoxetine treatment. The authors suggested a potential causal relationship between the deletion of the 5-HT1A receptor and failure of antidepressants to improve symptoms, citing their finding that disrupting hippocampal neurogenesis blocked the effects of ...

Both Santarelli et al. and Bessa et al. concur that hippocampal atrophy is central in the behavioral manifestations of depression, and that the hippocampus is a major substrate for antidepressant drug (AD) action. However, it seems (at first) that these two papers are otherwise at odds with each other: Santarelli et al. posit that ADs act primarily via neurogenesis, while Bessa et al. contend that they act primarily via neuronal plasticity and also target the prefrontal cortex (PFC).  Santarelli et al. demonstrated that ADs increased hippocampal neurogenesis and decreased latency in the novelty-suppressed feeding (NSF) test from baseline in WT mice, as did the 5HT1A receptor agonist 8-OH-DPAT. 5HT1A knockout (KO) mice still responded to TCAs but not to the SSRI fluoxetine or to 8-OH-DPAT, indicating that fluoxetine likely interacts with this receptor to mediate neurogenesis and anti-depressive effects. They also show that ADs didn’t decrease feeding latency in mice who receiv...