2019 Biopsych Seminar Thursdays

This week's two papers both addressed understudied issues surrounding cocaine addition in a rat model, with the Holly group examining the influence of sex differences, including different stages of the estrous cycle for female rate and the Vassoler group unpacking sex-specific paternal epigenetic influence on F1 acquired cocaine addiction. I was disappointed while reading the Holly paper to discover that the only significant effects of estrous cycle in female rats was related to increased locomotion (walk duration) and not on actual dopamine levels in the nucleus accumbans or measures of a cocaine binge. Essentially, it seems that estrous cycle does not actually significantly impact the severity of a cocaine addiction on a neural system or behavioral level, but only heightens the response to the same dose of cocaine. The effect of stress, however, on both males and females but particularly on female cocaine addiction is quite shocking, but not surprising. Drug abuse is more frequ...

 This week’s paper investigated sex differences in addiction behavior. Sex differences always reveal hard to probe as there are usually many confounding factors. Holly et. al (2012) looked at differences in stress induced increased addictive behavior in response to cocaine. One of the most important factors accounted for in this paper was the phase of the estrous cycle in females. This allowed for the observation that females in the estrous phase of the cycle respond differently to cocaine when compared to both males and females in the diestrus cycle. Specifically, cocaine addiction is facilitated in this phase. Cycle specific DA levels in the NAcc were, unfortunately, not probed. This limits the conclusions that can be taken from the correlational observations made. Those effects should be investigated, along with direct manipulation of estradiol levels to determine if there is cause-effect relationship by which estradiol facilitates cocaine addiction by inducing DA signaling ch...

I found it unsurprising that female rats would have dopaminergic tone mediated by the presence of estradiol, and that this was not the case for castrated males. Recent studies show that females have a harder time dealing with chronic stress. This goes in line with the idea that the neuro-endocrine and neurobehavioral changes associated with female rats take place on a longer time scale. This explains the sustained dopamine elevation after stress since this might be a compensatory mechanism to prevent the negative symptoms of long lasting and chronic stress. This model might make sense from an evolutionary perspective. Males, having aggressive phenotypes and presence of testosterone, may be unlikely to feel chronic stress since they have a means of protecting themselves, while females do not. Thus males encounter acute stress and as such their baseline dopamine elevation after stress and cocaine administration spike for shorter duration but with great intensity.

Even as society learns to accept people with physical disabilities and other mental illnesses, drug addicts and their addiction are still too often stigmatized and trivialized. This is especially pertinent to women, who, at all stages of addiction, display more severe behaviors compared to men. To examine this gender difference, experimenters turn to rats. Holly et al. (2012) sought to find sex differences in behavioral and neural cross-sensitization, and cocaine binging behavior, as a result of episodic social defeat stress. It was interesting to see their implementation of a social defeat paradigm on female rats since  studies that study only male aggression (like the ones we’ve seen in past papers) lacked generalizability. In previous class discussions, the possibility of taking advantage of innate maternal drives to model female aggression. So, I thought it was a pleasant surprise to see this current study use lactating dams as the “resident” in the paradigm. The researchers a...

            The papers this week seem to be less directly connected than most of the previous pairings. While Vassoler  et al.  (2012) explored paternal epigenetic inheritance, Holly  et al.  (2012) focused on sex differences in behavior as a result of stress. The main similarities between these papers was their use of cocaine, their use of rats (different types, I might add), and the examination of some sex differences. Each paper made for interesting reading. As I mentioned before, Vassoler  et al.  examined the effects of chronic cocaine exposure to male rats on their offspring. They did this by exposing male rats to unlimited cocaine (or saline) for 60 days, then allowing them to mate. The offspring (F1 generation) were then allowed to grow and tested for cocaine resistance, learning deficits, and changes in neurochemistry. Vassoler  et al.  found that cocsired males seemed to exhibit a resistance to cocaine...

In the articles this week Holly et al. and Vassoler et al. investigated how environmental exposure to stress and genetic predisposition may lead to enhanced susceptibility to cocaine addiction. Interestingly both studies separated the mice by sex to observe sex specific differences in cocaine addiction. Holly et al found that episodic stress exerted a larger effect on female mice versus male mice. Compared to the stressed male stressed mice the female mice had a greater locomotor response to cocaine and longer cocaine binges than males. What I found most interesting about this paper was the discussion of gonadal hormones, specifically estradiol’s implication in enhancing susceptibility to addiction. The researchers took vaginal smears before each task, however concluded that only duration walking after cocaine administration was affected by estrous cycle. Holly et al suggest that in terms of cocaine binging, effects may not have been seen due to the fact that the binge spa...

These two articles, published in the same year, take slightly different approaches to studying sex differences in behaviors resulting from cocaine in mice. Holly and colleagues built on research on social defeat and cocaine use in male mice, as well as established gender differences in cocaine sensitivity, and adds circulating ovarian hormones as a factor. They proposed that females, especially those in estrus/proestrus, would show a greater effect of behavioral and dopaminergic cross-sensitization to cocaine. Males and females underwent social defeat stress or control handling, and estrous cycle was measured. They were then divided into one of three experiments (behavioral sensitization, in vivo microdialysis, and cocaine self-administration.) For experiment 1, both stressed and non-stressed females in estrus walked for longer than other stressed or non-stressed groups. Stressed females showed increased walk duration 25-30 min after injection, while males had returned to baseline ...

Both of week’s papers examined how nature versus nurture can affect one’s vulnerability to cocaine addiction, with a focus on sex-specific differences. The latter part is important given that women tend to engage in cocaine usage younger and more extensively than males, and that maternal versus paternal cocaine exposure produce differential effect in male and female offspring. Holly et al. focused on “nurture” with stress as a key factor for females, while Vassoler et al. explored “nature” with epigenetic reprogramming of cocaine sensitivity in males. Holly et al. cite findings that stress increases vulnerability to drug abuse, implementing an episodic social defeat stress paradigm in rats. This model was previously shown to increase male response to cocaine, with elevated behavioral and neural cross-sensitization. I was surprised that the male and female aggressor rats exhibited equal fight frequency and duration, and it’s cool that they had qualitatively distinct fight tactics....

This week we looked at two papers focused on how changes in gene expression influence the phenotype expressed in two genetic models of schizophrenia. The first paper (Ayhan et. al, 2011) focuses on the DISC1 model of schizophrenia, and looks at differential expression of the mutated gene over different stages of development. This study showed that expression of the DISC1 gene during specific periods (i.e. pre or post-natal) is critical for certain changes to take place. Interestingly, results also showed that some alterations require expression of the gene to occur exclusively during either the pre-natal or the post-natal phase. Such a result reveals how the expression of this gene will not only have differing effects depending on when it is expressed, but that expression at a certain time can influence the phenotype resulting from expression at another, different time.                 The second study, by Bu...

This week we look at two paradigms of observational learning in mice. The first paradigm, by Sial et. al, demonstrated that mice can effectively learn by observing physical defeat of other mice, providing a chronic instead of physical model of stress. Importantly, the results showed that the effects of emotional stress are not unlike those of physical stress in many aspects. This demonstrates the value of this paradigm as an approximation for a model of PTSD which comes as a consequence not only of physical but also emotional stress. Furthermore, a recent publication by Iñiguez and colleagues (2018) making use of the same stress model demonstrated that emotional stress can be effectively induced in female mice. The physicals stress paradigm is not applicable to females because male mice will not attack them, and this paradigm provides a novel manner for research into stress in females to be conducted, which is severely lacking due to the limitations of previous paradigms.  ...

Burrows et al. (2015) and Ayhan et al. (2011) emphasize that idea that the neurological pathology of schizophrenia is complex and nuanced. While Ayhan’s team focused on the effect of temporal expression on mutant human DISC1 expression on schizophrenic phenotypes, Burrows and colleagues put forth the idea that environment mediates glutamatergic pathways responsible for schizophrenic phenotypes. Both papers brought forward interesting human parallels and potential future directions in animal models in schizophrenia research. One finding of note in the paper by Ayhan et al. was prefaced by the fact that “lateral ventricle enlargement is one of the most consistent abnormalities of the brain of patients with schizophrenia.” The team found no significant gender effects on ventricle enlargement after performing MRIs on the mice. The study also found that the Pre&Post and Post-Only groups had significantly larger ventricles and smaller cortical volume compared to the NO group. At the sa...

The two papers we explored for this week, Ayhan et al and Burrows et al, took two very different approaches for modeling schizophrenia, and each of these two methods were different again from the previous schizophrenia mouse models we have seen to date. I believe this truly speaks to the complexity of modeling schizophrenia in rodents and how little we still know as a community about the exact molecular underlying of schizophrenia. I quite immediately took a preference to the research done by the Ayhan group, which focused on using a mutant DISC1 model regulated by a system we are already familiar with: Tet-off. It was theorized by this research group that when expression of the mutant form of DISC1 was on (when the animals were being fed normal food to maintain mutant gene expression), this mutant form would bind to endogenous DISC1 and negatively regulate it in a dominant matter, rendering the protein nonfunctional. There were many things I liked about the research presented in thi...

It was interesting to find differential effects between the Post and Pre induction of the Disc-1 mutant. Since there were many more negative changes associated with post induction than pre-induction (i.e, DA levels decreased, volumetric reductions in cortex, decrease in PV+ cells). This however may suggest that the changes that lead to schizophrenia are indeed gradually accumulating over time. There are obviously negative changes associated with pre -induction as well, suggesting an inherited component of the disorder, however since more negative changes are associated with the post induction of the mutant protein, this may suggest that the pathological process of schizophrenia is less deterministic, and more so dynamic and sensitive to environmental factors. It was not surprising to find  decrease in Gabbaergic tone within the hippocampus (decreased PV+ neurons), s this may explain the positive symptoms of schizophrenia, hallucinations and the like; since this lack of inhibitory t...

   Schizophrenia has a heritability of about 80%, and numerous of candidate genes have been identified as “risk” genes of schizophrenia. Ayan et al, selectively expressed mutated human DISC-1 (hDISC-1) in mice during embryonic development, postnatally, or during both embryonic development and postnatally. In humans DSIC-1 encodes for a synaptic protein and is crucial for neuronal development in both pre and post-natal development, there is also evidence to suggest that those with mutated DSIC-1 are at higher risk to develop schizophrenia. What I found the most interesting about this paper is the separation of behavioral tests by gender based on the difference of schizophrenia symptomology seen between males and females (something that we have not seen in any of the previous models presented). Ayan et al found that female mice with the hDISC-1 mutation in the pre+post group had decreased mobility in the TST and the post hDISC-1 group had significantly more tim...