Biopsych seminar 2020

March 30 Papers (Holly et. al, Vassoler et. al) Holly et. al’s 2012 paper explores the sex differences in neural and behavioral cross-sensitization to cocaine following social defeat stress in rats. The study found that while both sexes develop this cross-sensitization, the effect is larger and lasts longer in females, possibly due to estrogens and their role in modulating mesocorticolimbic dopaminergic function. Additionally, female rats consumed more cocaine than male rats after undergoing the social defeat stress paradigm.  These findings could have great clinical relevance in developing treatments for drug addiction in humans, particularly for women who have a heightened vulnerability to cocaine addiction, use the drug more often than men, and are more likely to relapse. Perhaps the development of treatments for drug addiction in men and women should be carried out separately if it isn’t already, and should focus on mesocorticolimbic dopaminergic function, with special ...

Studying sex differences in response to the same stimuli is a particularly interesting topic to me. In the case of the Holly and Vassoler papers, the stimulus is cocaine. Holly et al report that cocaine binges in response to social defeat stress causes female rats to "binge" cocaine significantly more than stressed males. Also, they reported that stressed females, but not males, saw a prolonged increase of extracellular dopamine in the Nucleus Accumbens. Vassoler et al report that ingesting cocaine can have trans-generational effects on the behavior of male cocaine-users' offspring, but not female.  Teasing apart the differences between the effects of cocaine in males and females is challenging. I think the most important thing that we can take away from the Holly and Vassoler papers is that cocaine certainly has differential effects on both sexes, both directly and trans-generationally. However, to what degree those effects are seen can vary widely depending on the org...

Holly et. Al (2012) used an episodic social defeat stress paradigm to understand the differences between male and female rats as well as the effect of the female estrous cycle in behavioral and dopaminergic cross-sensitization to cocaine. The results indicate that episodically stressed females have significantly greater behavioral sensitization than controls as well as stressed male counterparts. This behavioral sensitization of increased locomotion activity in response to cocaine was also longer-lasting in the females, with higher levels seen in estrous females. There were no obvious group differences in neural sensitization, but the authors noted this limitation may be due to small sample size, and that more subjects might show statistically significant numbers. I’d be curious to see a follow-up study specifically built around the idea of stress exposure and circulating estradiol on dopaminergic function in females. In terms of its clinical usage and applications, I thought about ho...

I was very excited to read these two papers because they closely relate to my final paper topic – sex differences of addiction and how prenatal conditions affect offspring susceptibility to addiction. The first paper, Holly et al, (2012) explores cross-sensitization to cocaine in rodents that have undergone the social defeat stress paradigm. The paper analyzes the sex differences in behavior and neurobiology, particularly comparing NaC DA levels, in addition to exploring the effect of the estrous cycle. I enjoyed this paper because the interplay of addiction and stress was not something I was going to particularly focus on in my paper, but after reading this study and doing some further research, I realize that stress is indeed a very important factor to discuss. I liked this model for the social defeat stress paradigm and how they modified it to include an aggressor of equal magnitude in females compared to males. I believe the concept of using lactating dams as female aggressors was...

As I started reading Vassoler et al 2013, I first assumed that the behavioral results were in opposition to each other. As I thought more about the difference between their statistical analysis, I realized that Holly et al 2012 did something more to analyze sex differences. In addition to look at within sex differences, Holly et al looked at between sex differences of the same conditions. This is something that Vassoler appeared to not do. They have the data for both sex cohorts in their research, but I don’t think they compared the different sexes of the same conditions, only within sex. I’d be curious to see if they did a statistical analysis between sexes on their paper. Specifically, I noticed that for their first experiment on cocaine intake it looked as though the cocaine infusions for CocSired females increased over time while the males didn’t. It looks as though they could be statistically significant and might indicate a variable effect between males and females. Similarly, i...

Holly et al. (2012) and Vassoler et al. (2013) were both fairly straightforward reads and discussed two aspects of sex differences in the development of cocaine addiction in rodents. The former focused on the effects of social defeat stress while the latter was concerned with paternal epigenetic inheritance of a cocaine-resistance phenotype.   One question I had for both articles concerned their use of ketamine as an anesthetic drug. It caught my attention in the methods as it was recently discussed in another course of mine for its role as an antidepressant. Briefly, we know ketamine is an NMDA receptor antagonist which preferentially binds to receptors on GABA neurons. It is also known that clinical depression and addiction are highly co-morbid and have circuitry involving many overlapping regions, such as the nucleus accumbens and prefrontal cortex as studied here. Unsurprisingly, GABA inhibition via ketamine could increase glutamate release from excitatory neurons and theo...

The first of the two papers, Holly et al. (2012), is an interesting look into the effects of stress at different stages in the estrogen cycle on behavioral and neural sensitization as well as self-administration of cocaine. Although the paper was compelling, it left me with a lot of questions. Why in Figure 2 is their increased walk duration with cocaine administration in the non-stressed females-estrus? I feel like the authors just kind of moved passed this and never addressed it. Additionally, the entire paper I could not stop thinking about how maybe this study could lead to an additional study looking into immune responses linked to stress and how that might vary in different stages of the estrogen cycle and effect behavioral and neural sensitization as well self-administration of cocaine, as I learned in Brain, Behavior, and Immunity that there are studies that show how immune responses can impact addiction. A final thought I had with this paper is if be defeated by a lactating d...

Holly (2012) paper I am still a bit confused by the concept of cross-sensitization. By definition, it means the sensitization of one stimulus is generalized to a related stimulus but that it is non-associative. In this paper, I interpreted the cross-sensitization here as the sensitization of stress is generalized to the sensitization of cocaine so that stress causes the response to cocaine to be amplified and stronger (not entirely confident that’s what cross-sensitization means here). If this is what cross-sensitization refers to, I’m confused about how stress and cocaine response are related without any explicit association and why increased stress would increase the cocaine response. One thought I have is that the rewarding effects of cocaine help combat or mitigate the harmful effects of stress and so the brain adapts to stress and copes with it by amplifying any incoming rewarding stimulus. If this is the case, I wonder if other rewarding stimuli (e.g. food, sex) have similar ef...

Increasing our understanding of susceptibility to drug addiction disorders is critical for preventing and reducing risk of developing such disorders. Holly et al. (2012) and Vassoler et al. (2013) both consider the effects of sex on susceptibility to increased cocaine use as well as the impacts of stress and paternal experience with cocaine, respectively. While these studies both address important concerns in regard to susceptibility to stimulant addiction, they leave many questions unanswered and introduce additional questions.  One question I had while reading these papers, especially Holly et al., was what aspects of sex differences between male and female rats might have led to the behavioral and neurochemical differences seen in response to cocaine exposure. Because females in estrus/proestrus had more robust differences from males in locomotion, it would seem that sex hormones are involved, but I am interested in the extent to which they impact cocaine sensitization. It ...

Both of these papers aimed to examine the sexual dimorphisms that contribute to cocaine addiction susceptibility, either through the lens of social defeat stress or paternal cocaine use. The first paper, published by Holly et al. in 2012, not only examined the differences between male and female rats, but also addressed the variation within the female group as a result of the estrous cycle. One aspect of this paper that I found particularly interesting was the difference in increase in dopamine in the NAc from baseline across the male and female groups. The data showed that while there was a greater increase in local dopamine in the stressed groups of both sexes, the dopamine levels returned to baseline within 60 minutes in the male group, but stayed elevated for much longer in the female (35-45 minutes longer than in the males). I found this data very compelling, but it did lead me to wonder what developmental steps are at play that would make female rats more susceptible to this pro...

Holly et al. 2012 and Vassoler et al. present an interesting look not only into the susceptibility to drug abuse and addiction but how sexual dimorphisms may alter this behavioral response to drug administration. Holly et al. 2012 closely examines how sex and differences in hormonal levels may affect the likelihood of rats to “binge” or are more likely to develop behavioral responses to prolonged drug use when faced with social defeat stress. Interestingly, social defeat stress along did cause a heightened effect in both sexes but had a much more profound effect on the dopaminergic response to cocaine in female rats. One shortcoming is the mechanism by which estrogens may affect this heightened sensitization. In the first assay, it is clear that female estrous cycle socially stressed rats have the higher behavioral response of walk duration when  administered  cocaine as compared to non-estrous. But, in the second and third experiments the estrous condition is collapsed to on...

Both Holly et al. and Vassoler et al. examined neurobiological and behavioral sex differences in cocaine use in rats. However, that is the extent of the similarities between the two paradigms. Holly and colleagues used a social defeat stress method in which male and female rats were defeated by a rat of their respective sex—either a larger male rat or a lactating dam—using the resident-intruder method of social defeat. This is the first instance of female social defeat stress we have seen this semester, which was really exciting! The rats then underwent one of three experiments to examine behavioral sensitization to cocaine (increased locomotion), neural sensitization to cocaine (microdialysis of DA in the NAcc), or cocaine binge (unlimited access to cocaine). Stressed rats were compared with non-stressed controls of the same sex. I really appreciated how thorough the experimental setup was, but I think the unrestricted cocaine availability was probably not the most accurate model of...

            I have always thought that if one of your parents was an addict, that you were more likely to become one as well. I’m not sure if that preconceived notion was based in something scientific that I had read or if I just heard it somewhere, but I’m really happy that the Vassoler paper addressed it in the discussion. Apparently, there are data that show that cocaine addiction is heritable. Since this conflicted with their conclusion, the authors then went on to say that there are so many other aspects of addiction that could contribute to this data we see in humans. Since both genetics and environment come into play, I would really like to see them do an experiment in which they also alter the environment. I’d be curious to see if they raised the F1 generation of both cocaine sired rats and saline sired rats in a neutral environment, an enriched environment, and a negative environment. I wonder if being raised in a negative environment, with c...

Addiction is a very interesting topic to me and I believe there is so much progress to be made in this field, making it very exciting in terms of research. I have done some clinical research in addiction during one of my co-ops at MGH in the pediatric psychopharmacology department. The clinical study was based on the comorbidity of mood disorders and substance use disorders in young adults and the effects of treating this mood disorder on the subject's substance use. While this correlation of improved substance use post-treatment of an underlying mood disorder seemed obvious to me, it is not a very well studied area. I was excited to dive into the Holly paper and learn about the effects of stress on addiction and drug response. The Holly et al. paper published in 2012 investigates the effects of episodic social defeat stress on cross-sensitization to cocaine. The central theme within this investigation were the sex differences among these effects and how the estrous cycle further c...

The two papers were very interesting to read, especially as they both discuss sex differences in addiction (a very interesting topic in my opinion)  and show how findings can be across male and female rodents can vary.  Holly et al, in 2012, presents a paradigm of social defeat stress and its relation to drug addiction. The experimental rats used in investigating social defeat stress model are same sex resident. However, I would be curious to know how opposite sex experimental rats would have an effect on the stress response. Would the response be even greater if a male rat was causing social defeat stress of a female rat? Although the paper represents a throughout approach towards addiction and sex differences, I would also like to learn more about how drug tolerance and withdrawal are affected in regards to both stress and addictive behavior.   From previous neuroscience classes, I have constantly encountered the topic of hormones’ role in behavioral responses...

Holly et al. 2012 studied the sex differences in rats associated with cocaine usage in repeated social defeat stress episodes. This paper was particularly interesting to me as it took major variables that affect human functioning into account. First off, as we have discussed in class, looking at sex differences in animal model research is very important for later clinical applications. Women are the majority of diagnosed cases of disorders such as mood disorders and PTSD and therefore more attention to research should be done in both sexes. Secondly, Holly et al. look at the effect of stress on the usage of cocaine. They drew this directly from human clinical data and this research could propagate a deeper understanding of the relationship between stressed individuals and drug usage. Lastly, a part I found quite engaging with this paper was their use of a 3 pronged approach to studying the effects of cocaine on stressed and unstressed rats. They used behavioral sensitization, in viv...

Holly et al’s paper focuses on sex differences in stress and the effects of cocaine on each stressed vs non-stressed male and female rats. Ultimately, it was determined that female stressed mice are more prone to cocaine use than stressed males. Additionally, estrous cycle did not have an effect other than increased walking (a measure of stress) after the social defeat paradigm and cocaine administration in females in estrus. There was also a general trend towards females having more dopaminergic tone. First, I want to address the stress paradigm, a social defeat model using the same sex as the perpentrator. For males, it was a larger dominant male, and for females it was a lactating dame. The study tried to keep the stressful experience as close as possible for males and females, monitoring corticosterone hormone levels, weight gain, and behavior. They observed no drastic differences. I thought that this was clever and indicated that the experiences were somewhat the same in terms of...

The gut brain axis has recently been studied and indicated within multiple neurologic and psychiatric disorders. While the biome has traditionally been thought to have its effects limited to the gut and digestive tracts, new research suggests a very different story. The bacterial colonies within our guts appear to play critical roles in neurological functioning, diseases such as Autism, depression, anxiety, and even Parkinson’s. For my opinion review, I am hoping to examine the different ways the biome affects the brain both on a granular mechanistic level, and within different diseases. Ultimately, I hope to pose an argument that this should be an area of focus for further research and potential treatment. Listed below are 5 research articles indicating an interesting relationship between the brain and gut:  1.       Neufeld, K.M., Kang, N., Bienenstock, J. and Foster, J.A. (2011), Reduced anxiety‐like behavior and central neurochemical change in ge...

For my final paper, I would like to focus on the intersection between the Hypothalamic-Pituitary Thyroid Axis (HPT Axis) and the Hypothalamic-Pituitary Adrenal Axis (HPA Axis), specifically as it relates to the role of thyroid hormones in fear learning, anxiety, and depression. I've been interested in this topic since my freshman year of college when I first learned about fear in a research setting and began to learn about behavioral endocrinology and how hormones can affect behavior. Since then, I've noticed a gap in research on connecting the dots between thyroid hormones and their mechanistic action affecting anxiety, depression, and other fear learning behaviors. This interests stems from not only the symptomatology of thyroid disorders like hyper- and hypothyroidism. Two majors symptoms of both disorders are anxiety and depression. Additionally, research shows an increased incidence of PTSD, depression, and anxiety with thyroid disorders. Additionally, thyroid disorders...

Blog Post #7: Final Paper Proposal I am interested in writing my final paper on the neurodevelopmental factors that contribute to the onset of schizophrenia. Perhaps I’d also like to tie this in with a closer study of the neural mechanisms behind the sensory disruptions experienced by those affected by schizophrenia. This disorder has been of great interest to me for a long time, and I found the last papers we read about it to be fascinating, which motivated me to write my final paper about this.  1. How Schizophrenia Develops: Cognitive and Brain Mechanisms Underlying Onset of Psychosis: https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=26493362 2. Stress during critical periods of development and risk for schizophrenia: https://www.sciencedirect.com/science/article/abs/pii/S0920996419300209 3. Schizophrenia and the neurodevelopmental continuum:evidence from genomics: https://www.ncbi.nlm.nih.gov/pmc/a...

One topic that has particularly fascinated me is the effects of endocrine disrupting compounds (EDC) on the brain. Chemicals that are prevalent in people's everyday lives, like Bisphenol-A (BPA) and phthalates, found in canned goods and plasticizers, respectively, can have profound impacts on brain function. Though BPA and phthalates are some of the most common EDC's, many others exist in products such as pesticides, herbicides and cosmetics. Interestingly, these effects can persist across multiple generations, altering the neurodevelopment of offspring that were never exposed to these EDC's first-hand. However, robust effects are also seen in animal models where the first generation were directly exposed to a specific EDC. The reason I find EDC's so interesting is because the dysfunction they cause is a direct result of environmental exposure. Not only do these exogenous chemicals have detrimental consequences for the organism that is exposed to them, but for their o...