Applying to a Doctoral Degree in Neuroscience

I will be completing my first (and hopefully the only) application process to get into a Ph.D. program in neuroscience. As a foreigner in the USA and the only person in my family aspiring to an advanced degree, I lacked much guidance and support in the process. My salvation was a handful of online resources from people who have already gone through the process. I would like to help others out there as well, so I will be releasing a couple of posts describing my over all experience as a prospective student for Fall 2020. Here I cover the “fundamentals” and the new GRE policies for most Ph.D programs in neuroscience.

The Fundamentals

GPA

The GPA is used in most programs to filter applicants. A really low GPA (less than 3.0) will put you in disadvantage and probably prevent the admissions committee from taking a look to your application. A solid GPA is higher than 3.5.

Research Experience

One of the most important factors to determine your potential to be a Ph.D. candidate is your research experience. Having a lab name on your resume is not enough. You should demonstrate your ability to carry independent work and understand the science behind your work. You are not required and certainly do not need a publication to be a strong candidate. What really matters is what you learned both technically and intellectually as well as the recommendation from your supervisor. Ideally, you want a recommendation from a PI/faculty member, so if you work in a big lab under a postdoc’s supervision, make sure you can also have interactions with your PI and obtain a letter from them.

I would recommend asking your lab colleagues to provide papers/literature background for you to learn more once you join the lab. Participating in lab meetings and journal clubs is also a great opportunity! Take advantage of the expertise and support of other lab members. In addition, rather than going around multiple labs, you should consider staying in a single lab and work in one project so you can be fully immersed in that experience. Of course, that is only realistic if you already know what type of research you want to do. Otherwise, do try different labs and narrow down your research interests. The best research environment for you is that in which you have good mentors and you love the ideas and the process involved in your work.

In my case, I had five major research experiences. The first two helped me realize I did not like doing molecular work only. The last three reassured my desired to do research in systems/behavioral neuroscience. One of those research experiences was full-time after I finished college.

Letters of Recommendation

Be sure you have at least three professors/investigators who can provide STRONG letters of recommendation for you. I would suggest having an additional recommender in case something happens to your other recommenders. One of my recommenders submitted his letter on the deadline. If I had had an additional recommender, I would not have spent days stressed out about this issue.

Personal Statement

I will write a single post on this important aspect of the application.

 

New GRE Policies (GRExit)

Starting 2018, many programs have dropped the GRE requirement. If you are somewhat poor like I am, this is great news! You do not have to spend over $200 in a meaningless test plus $27 for each school that requires the GRE. I did not submit my GRE to my dream school and I still got an interview.

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For more information in this matter, please visit:

https://www.sciencemag.org/careers/2019/05/wave-graduate-programs-drop-gre-application-requirement

For a list of Bio/Biomedical Graduate Programs Dropping GRE Requirement, please visit:

https://docs.google.com/spreadsheets/d/1MYcxZMhf97H5Uxr2Y7XndHn6eEC5oO8XWQi2PU5jLxQ/edit#gid=0

 

In the next few weeks, I will share information on how to write a good personal statement, interviews, and the results from my current cycle application.

 

The link between Herpes and Alzheimer’s Disease

One of the distinctive features of Alzheimer’s disease (AD) is the accumulation of a group of insoluble protein fibrils (Amyloid-β peptide fibrilization) as β-amyloid plaques . In the past, scientists thought that amyloid-β peptide (Aβ) was just a useless secondary product of biochemical pathways that was eventually eliminated in healthy cells. This assumption, however, was inconsistent when considering the high genetic conservation of Aβ across different species. Recently, researchers have discovered that this apparently annoying protein is not as worthless as it was once thought. In fact, Aβ seems to be an immune system super hero that fights against the bad guys in our body. Formally speaking, Aβ is an antimicrobial peptide (AMP) that starts to agglutinate (Aβ oligomerization) when it detects certain pathogens. As a result of the Aβ deposition in cells, the brain has a neuroinflammatory response. Apparently, this immune response leads to neural death in order to prevent the infection from spreading to other brain regions. Aβ oligomerization can end up protecting our brain if the neuroinflammatory response is controlled, otherwise, the accumulation of Aβ oligomers will lead to more neuronal death, which is the underlying pathology for multiple human diseases, including Alzheimer’s disease.

You are probably wondering now what the relevance of the herpes viruses is in this story. Let me begin by saying that all of us have at least a herpes virus. Yes, herpes, which in Greek means “to creep” but don’t freak out! Genital herpes is not the only type of herpes virus. There are multiple herpes viruses and they are known as the herpesviridae family. Nine herpes viruses affect humans and five of them are present in around 90% of the human population. In the case of Alzherimer’s disease, herpes simplex virus 1 (HSV1) has been shown to be correlated to an increase in Aβ deposition. This is why a group of scientists in Harvard decided to explore the question of whether Aβ oligomerization in the brain had a protective role against herpes virus infection.

To answer this question, the researchers investigated three herpes viruses (HSV1, HHV6A, and HHV6B, the latter two standing for human herpesvirus 6A and 6B, respectively) in vivo and in vitro. For the in vivo experiments, they used a transgenic mouse model used in AD research known as 5XFAD. These animals have high levels of Aβ protein in their first weeks of life, which allows the researchers to explore whether more Aβ protein can protect the brain from herpes virus infection. They injected wild type (WT) and 5XFAD mice’s brains with a high dose of HSV1 only (no HHV6A/B were used because mice lack homologous receptors for these human viruses in their neurons). Subsequently, the researchers observed how long it took mice to die. Of course, the researchers had a control group of mice that went through surgery but did not get a lethal injection of HSV1. The results indicated that 5XFAD had a higher survival rate than WT animals (see fig.1). This increase in survival rate was, presumably, due to the protective effects of Aβ protein against HSV1 in 5XFAD mice.

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Fig 1. Higher survival rate in 5XFAD mice over expressing Aβ42 after being infected with HSV1. Image taken from https://doi.org/10.1016/j.neuron.2018.06.030

The next piece of evidence that supports the interpretation of this result was the examination of brain sections from 5XFAD and WT mice that were infected with HSV1. The authors used antibodies to visualize the location of HSV1 and Aβ protein in the hippocampus of these mice. The results showed that HSV1 and Aβ were co-localized in the brain of 5XFAD (see fig.2). More specifically, the presence of Aβ proteins in 5XFAD brains led to agglutination of Aβ around the herpes virus, apparently as a form of protection against viral infection.

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Fig.2. Co-localization of Aβ oligomers and HSV1 in 5XFAD brain sections using fluorescent markers. Image taken from https://doi.org/10.1016/j.neuron.2018.06.030

The in vitro experiments were in line with the findings in vivo. The researchers found that those cell cultures where Aβ protein was expressed showed a lower percent of infection by HSV1 than those where Aβ was eliminated (immunodepleted: reducing a protein by means of antibodies). Similarly, the authors performed transmission electron micrographs (TEMs which is a very powerful form of microscopy) and found that cells infected with HSV1, HHV6A, or HHV6B, and expressing Aβ protein presented fibrilization(the formation of protein fibers) around the virus (see Fig. 3).

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Fig. 3. Formation of Aβ protein around the viral envelops of HSV1 and HHV6A/B. Image taken from https://doi.org/10.1016/j.neuron.2018.06.030

Taken together, these results suggest that Aβ protein might have a protective role against herpes viruses in the brain. These findings do not directly demonstrate a relationship between AD and herpes virus, but they are strong evidence that Aβ protein oligomerization can be triggered by pathogens such as herpes virus. Because this is one of the major underlying pathologies of Alzheimer’s disease, it is logical to think that the exposure of the brain to herpes virus might lead to a higher risk of developing AD. As we get older, the brain blood barrier (our friendly bouncer of undesired substances in the brain) gets leaky, so our brain gets exposed to a wider set of substances, including pathogens. It is possible that this is one of the events triggering Aβ protein agglutination in aging populations because herpes viruses are now able to move from the peripheral system to the central nervous system.

 

For more information:

Eimer WA, Vijaya Kumar DK, Navalpur Shanmugam NK, Rodriguez AS, Mitchell T, Washicosky KJ, Gyorgy B, Breakefield XO, Tanzi RE, Moir RD (2018)Alzheimer’s Disease-Associated beta-Amyloid Is Rapidly Seeded by Herpesviridae to Protect against Brain Infection. Neuron 99:56-63 e53.

Nature and Nurture

In chapter 11 of Animal Behavior, John Alcock postulates that the dichotomy of nature or nurture is a misconception. According to his view, the idea of a purely environmentally determined behavior makes no sense because ultimately,  in order for the environment to affect our behavior, there must be a change in our genetic material. Otherwise, what would the link between environment and our behavior be? Behavior has its substrates in our brain, so there must be a regulation of genes if we argue that the environment can affect our behavior.

He argues as well that not every environmental factor can affect our behavior. The reality is that we are sensitive to a specific range of stimuli. These environmental stimuli are the ones that we can detect using our sensory system. This idea implies that our genetic material “prepares” us to be shaped by certain environmental factors. The metamorphosis of bees is a clear example of this concept. Bees transition from being “nurses” (younger bees) to being “foragers” (older bees). Scientists discovered that nurse bees can be induced to become “foragers” if they are put in an environment where older foragers are absent. Later, it was discovered that the gene activity varies in the brains of nurse bees and foragers. Many of these genes were transcription factors, which code for proteins regulating the activity of other target genes.

Conversely, the higher the number of older foragers in a colony, the lower the number of young nurse bees that have an early transition into foragers. Scientists were puzzled by how the number of foragers in the environment could transform the behavior of younger bees. Eventually, it was discovered that foragers produce a chemical (ethyl oleate) that inhibits young bees from transitioning into foragers. Therefore, the more foragers in a colony, the less likely younger bees are to transition to foraging status because they are being inhibited by this chemical.

Alcock’s honey bee example shows that behavior, at least in this case, is not purely genetically determined because bees’ behavior is reshaped by the interaction of environmental chemicals and intrinsic genetic factors. It is important to notice that the genes that elicit the forager behavior in bees were activated only when the appropriate environmental factors were present. Gene Robinson summarized this idea by saying: “DNA is both inherited and environmentally responsive”.

In my opinion, this is an interesting concept, particularly coming from a school where I hear all the time that everything is a social construct. Is gender nothing but a purely environmentally determined behavior? What are the genetic factors that drive us here and there? The factors that make us respond in a way or another to our social experience? Will we ever find these neural substrates in our brain? What makes us female, male, or other? I share Alcock’s opinion and I think that we do not live in a mutually exclusive dichotomy of nature and nurture. Instead, we are the product of a beautiful balance of factors. Something unique that has come to be thanks to what we carry inside us and what we take from our environment. We are evolving all the time.

– H. C

Sex Steroid Receptors Cheat Sheet

This is a cheat sheet I made to understand the role of estrogen and progestin receptors in sexual behavior. If you are studying basic neuroendocrinology, this might be a useful resource.

 

SEX STEROID RECEPTORS

 

Receptor

Experiment

Results in rodents

 

ERa

Estrogen receptor (ER)

Knock-out (KO) ERa gene Completely eliminates hormonal induction of feminine sexual behavior
ERb KO ERb gene §  No apparent effect in ovariectomized (OVX) hormone-injected mice

§  Extends the period of behavioral estrus

§  Enhances receptivity in estrous-cycling mice

  abERKOs

double knockout

§  Infertile

§  Decreased levels of sexual receptivity

 

Receptor

Experiment

Results in rodents

PR-A

Progestin receptor (PR)

PRAKO mice §  Showed minimal progesterone (P) -facilitated lordosis in the presence of males

§  dominant PR-B isoform alone was incapable of mediating the effects of P on sexual behavior

 

§  Essential role in progesterone-facilitated sexual behavior

PR-B PRKBKO §  Improved PR-A-dependent receptivity with experience

§  Lesser role

 

 

  Experiment Result
Dopamine (DA) agonists DA agonist + P antagonists DA facilitates sexual behavior by indirectly activating PRs

(acts on both isoform)

8-Br-cAMP

(PKA activator)

 

8-Br-cAMP

Protein kinase A =cAMP-dependent protein kinase

Primarily mediated via PR-A isoform

Conclusion:

  • Each isoform of PR may be involved in signaling routes leading to facilitation of sexual behavior, but PR-A seems to have the dominant role in most situations, and PR-B involvement seems to depend upon the mode of activation of the receptor.
  • ER down regulates alpha-ER in most neuroanatomical areas
  • Downregulation of PRs leads to estrous termination and the refractory period
  • Progesterone downregulates its own receptors
  • Functional participation of both the isoforms is critical for P-mediated effects on sexual receptivity
  • Thus, both isoforms of PR, probably via heterodimerization, appear to be required in the RU38486 effects on ligand-independent PR-mediated lordosis.

 

Ligand-Independent Activation of PRs

  • DA agonists can also activate PRs== blocked by P antagonists
  • Facilitation by dopaminergic agonists was blocked by progesterone antagonists, antisense oligonucleotides directed at the PR mRNA or in PRKO mice
  • SKF 81297= DA agonist