Intro_to_Human_Brain

020.312 | Term Paper 1. What idea are the authors testing' It has been previously shown that D2R (dopamine receptors) in the striatum have been decreased levels of expression in obese rats and humans. The researchers have hypothesized that obese subjects tend to compensate for the hyposensitivity in the reward circuit by increasing the intake of high-energy foods, which raises dopamine levels in the brain, and contributes largely to obesity. Thus, the researchers will test for the effects of extended consumption of high-energy foods and the addictive behavior of this food consumption in rats. 2. What are their one or two principal experimental methods' The authors tested the rats by a brain-stimulation reward (BSR) procedure where they were trained for 10-14 days to run on a cycle that shocks the brain of the rat which rewards them for the behavior. The BSR sets the reward threshold, which is the level of stimulation at which the rats will continue to run, and this level remains stable at baseline conditions. Then, the rats (which measure 300-350g) were divided into 3 groups, one with only lab chow access, one with lab chow access and limited (1 hr) access to palatable energy-dense foods, and the third with lab chow access and extended (18-23 hr) access. The test ran for 40 days measuring their weight and BSR reward threshold. Afterwards, they were killed and brains were sliced and immunoblotted to test for D2R density. In continuation with the experiment, the researchers injected rats with lentiviral vector to deliver a short hairpin interfering RNA in the striatum of each brain hemisphere to knock down D2R. Daily BSR threshold assessment continued for 33 days after virus injections to ensure maximal striatal D2R knockdown. Another group of rats were injected with empty lentivirus vector as a control group. These two groups were divided as previously with chow only, restricted, and extended access, and were tested for BSR and reward threshold. 3. What are their key results' The key results of this experiment was that the extended access group gained significantly more weight than the other two, with elevated BSR reward threshold, which equates to deficit in brain function, similar to addiction-like deficits in the brain. The first two groups actually have a similar caloric intake with the limited access group getting 66% of their calorie intake from the fatty meal, which shows their binge-eating in one hour. The extended access group had almost double the caloric intake. After 40 days, all rats were fed only chow and were tested for BSR, and the extended group showed continued elevated levels of BSR for two weeks. At the end of 14 days’ abstinence, the brains were tested for D2R levels in the striatum. The extended access rats had a significantly lower density than the other two groups. With rats whom have had D2R knocked down by the lentivirus, the development of addiction like reward deficits were rapid as shown by almost immediate increase in reward threshold in rats with extended access, whereas reward threshold remained unaltered in rats with empty lentivirus with extended access. Reward thresholds were also unaltered in rats treated with lentivirus or lenti-control with restricted or no access to fatty foods, showing that these rats were vulnerable to reward hypofunction only after extended access. 4. How shall their findings change our understanding of the problem' That is, recap the author’s interpretation of their data. This finding shows that like food addiction is in some ways similar to drug addiction. BSR is a good way to test for addiction and brain function and the results show that the reward threshold for extended access group had a significant change in brain function similar to drug addiction such as with cocaine and heroin. However, the BSR of these drug-addicted rats went down rather quickly whereas food-addicted rats’ BSR was continually elevated. With the observance of lowered density of D2R, this experiment shows that neurophysical changes in rats, especially in the reward circuitry, can cause behavioral changes in rats to lose sensitivity to rewards and become compulsory to the thing of addiction, even at the sight of a fear-inducing cue. 5. Attempt to give another interpretation of the results. Another way that these results can be viewed is that the BSR reward threshold is elevated due to the increased weight and size. When these rats become big and fat, they are less motivated to move around and run because they may have become lazy and it takes more energy to move around because of this increased size. This conclusion is based on the thinking that these rats have changed behavior not solely based on the factor of dopamine receptors but some other psychological or physiological factor that would decrease their motivation to exercise. 6. Propose a significant and feasible follow up experiment using essentially the same methods employed by the authors that might decide between the interpretations in #4 and #5 above. Don’t pretend you will invent an entirely novel methodology to conduct this one experiment. To test this idea, we must design an experiment with five groups: fat rats with dopamine receptor KO (DRKO), lean rats with DRKO, fat rats with up-regulated dopamine receptor, lean rats with up-regulated dopamine receptor, and regular rats with extended access to energy-dense foods. The methods will still be mainly similar with BSR training and regular measurement for 40 days but with only regular chow except the last group, to compare the reward threshold levels and motivation of the different groups. By this way, we will be able to test if dopamine receptor is the key factor in changes in the reward threshold. If there are significant changes in reward threshold of DRKO rats to up-regulated DR rats, this would prove that dopamine receptor and therefore the reward circuitry is the cause for the elevated threshold. However, if the changes in reward threshold are bigger in fat rats versus lean rats, it might be that the size and weight of rats could be an important factor in motivation and reward. Also, if there is a significant difference between fat DRKO rat with regular rat with extended access, it might be that the energy-dense foods causes other physiological changes to the rat that causes brain function deficits. 7. What new ideas did you learn from reading this paper' From this paper, I learned that drugs and food can cause changes rewards system that leads to lack of motivation and insensitivity to imminent punishment (fear cue). Although this food-addiction is not the sole reason of America’s obesity, it shows that the energy-dense fatty fast foods that are prevalent in any city can cause problems in the brain that lasts longer than cocaine or heroin usage. In order to battle this problem, society must face this fact and eat a proper diet that the body can handle. http://www.nature.com/neuro/journal/v13/n5/abs/nn.2519.html#/ http://www.nature.com/neuro/journal/v13/n5/full/nn0510-529.html#/