Research

Research Methods: Model Organisms in Neuroscience

Jacob Umans, Meenu Johnkutty


     In the previous issue of the YNCA Journal, we discussed how neuroscientists have studied human patients to learn about the brain. Despite the progress that can be made in human studies, such studies are very limited in scope due to the moral issues involved in human experimentation.  Due to these ethical barriers, scientific often turn to animals to perform research. In all fields of biology, animals commonly used in research, or “model organisms”, are critical to experimentation. For this reason, the research team decided to place an emphasis on understanding the importance of model organisms in neuroscience in this edition of the YNCA Journal.

 

Caenorhabditis Elegans

     Caenorhabditis Elegans, more commonly known by the abbreviated name C. Elegans, is perhaps the simplest model organism in neuroscience. Since Dr. Sydney Brenner proposed its use as a model organism in 1963, C. Elegans has vastly aided scientific progress. It is a one millimeter long nematode that can feed on bacteria such as E. Coli in laboratory settings.

     There are many advantages to using C. Elegans as a model organism. First, C. Elegans has a relatively short life cycle (about 2-3 weeks). Owing to this, researchers can analyze several generations of C. Elegans in a relatively short period of time. Furthermore, its relative simplicity (with hermaphrodites—which make up the majority of C. Elegans—having only 302 neurons) has allowed scientists to make a complete map of its nervous system, allowing for incredibly precise studies of its anatomy (“A short history,” n.d.). Though its nervous system is small, C. Elegans does exhibit complex behaviors, such as locomotion and chemotaxis, which can be analyzed in depth by researchers. Furthermore, analyzing neural circuits is simple in C. Elegans models (when compared to studying circuits in other organisms), as individual neurons can be experimentally ablated with lasers.

     The same simplicity that makes C. Elegans such a good model organism is also its primary limitation. As it lacks a brain, C. Elegans cannot be used in many studies analyzing complex cognitive phenomena.
 

Drosophila Melanogaster

     The fruit fly Drosophila Melanogaster is another very well-known model organism in the sciences. Its genetic amenability, or its conduciveness to testing, has made it a valuable model for Alzheimer’s Disease and Parkinson’s - two genetically-linked neurodegenerative disorders. Alongside its use for gene research, studies investigating proteopathies (diseases resulting from the misfolding of proteins) such as Alzheimer’s Disease and Parkinson’s show Drosophila Melanogaster’s invaluability in the investigation of chemical compounds which can prevent or ameliorate disease. Furthermore, its relatively short lifespan allows for relatively fast analysis of many generations. Drosophila is also cheap and easy to maintain in the laboratory. Its offspring is genetically identical and its sophisticated brain and associated behaviors make the Drosophila a rather commendable research model (Hirth, 2010).

     Thomas Hunt Morgan popularized the use of the fruit fly after having early successes with his research and experiments with chromosomes and heredity. After teaching at Bryn Mawr for over 13 years, he established his famous “Fly Room” at Columbia University. Morgan’s early chromosomal experiments with the fruit fly confirmed the chromosomal theory of inheritance, which states that a)genes are located on chromosomes and b)some genes are linked. The ease at which his genetic experiments were conducted make them classics for undergraduate genetics education even today. In his honor, the map unit (a unit measuring genetic distance) was given an alternate name: the centimorgan  (“Thomas Hunt Morgan: The Fruit Fly Scientist,” n.d.).

     The contributions of Drosophila Melanogaster to the field of genetics and neuroscience are great and many. From its use in the investigation of proteopathies, such as Alzheimer’s and Parkinson’s, to its predominance in Morgan’s early genetic experiments, the fruit fly has established itself as a crucial ally in neuroscience research.

 

Aplysia Californica

     With just 20,000 neurons—compared to the billions of neurons within the average human— Aplysia Californica’s simple nervous system allows it be a prime animal model for the study of learning and memory. Its rather large neurons  range from 0.1 mm to 1mm in diameter (The Broad Institute). The Aplysia Californica is also commonly used in the study of defense mechanisms. Similar to withdrawing one’s hand from a hot stove, the sea slug withdraws its sensitive appendages, the siphon and the gill, when touched. Aplysia also exhibit a form of learning known as habituation. Similar to a goldfish becoming desensitized to a child tapping on its fishbowl, the Aplysia shows a reduced response to repeated stimuli of the same degree (“The Machinery of Memory”).

     A neuroscientist known for his research with the Aplysia Californica is Eric Kandel. Some of his most famous work focuses on Long Term Potentiation (LTP), or the cellular mechanism by which memories form. Kandel chose to focus on the hippocampus, a structure in the brain responsible for the storage of memories, and he needed a simpler organism with which he could study at the cellular level. Since the Aplysia contained the simplified nervous system and rather large neurons, Kandel, much to the surprise of his colleagues who preferred to use vertebrates, chose the sea slug as his model for study. Today, Kandel continues to research the molecular mechanisms behind different types of memory with the aid of the Aplysia. One recent discovery of his is that one isoform of the protein cytoplasmic polyadenylation element–binding protein (CPEB) “regulates this synaptic protein synthesis in an activity-dependent manner” (Cell and Molecular Biological Studies of Memory Storage, n.d., Para. 3). In other words, CPEB is a molecule critical to synaptic changes in response to neuronal activity  (The machinery of memory, 2010).

 

Danio Rerio

     Native to Southeast Asia, the Danio Rerio, or zebrafish, is a  popular model organism in biomedical research. Like Drosophila Melanogaster, Danio Rerio is genetically amenable and cheap. The zebrafish responds to behaviors tested in the lab quite well, such as aggression, novelty exploration, and anxiety responses. But what makes Danio Rerio quite exceptional is the transparency of its larva (Stewart, Braubach, Spitbergen, Gerlai & Kalueff, 2014, p. 264).

     Joseph Fetcho, a neurobiologist at Cornell University, pioneered the use of brain-circuit research in fish with the aid of the Danio Rerio. After getting frustrated with goldfish brains, Fetcho made the switch to zebrafish after noticing the ease at which its embryonic cells divided over a short period of time to form organs and limbs. Fetcho, in his first paper, used a green calcium-sensitive dye to track the activity of motor neurons during a predator-escape reflex. Using another approach with the Danio Rerio, Florian Engert and his postdoctoral students utilized a two photon microscope and virtual environments in order to study the circuitry of the zebrafish. Compared to the use of rodents or flies, during which the scientists must cut through animals’ heads to expose the parts of the brain they desire, the zebrafish can be manipulated in a virtual environment in which its movements can be tracked using a computer. In addition, its neurons can be analyzed using a two-photon microscope.

     Though many researchers are still hesitant to use the zebrafish in their studies due to its complex behaviors and lack of communication, its contributions to the fields of developmental and circuitry research cannot be discounted (Hughes, 2013).

 

Mus Musculus

     Mus Musculus, or the house mouse, is another common organism used in neuroscience. Analysis of congenic mice, or strains that differ at only one genetic locus, is especially valuable to research—this allows researchers to focus on individual genes when studying animals. As it is a mammal, this organism shares many more traits with humans than the other organisms on this list; thus, it is a very useful model in studying the pathophysiology of disease because “evolutionary conservation of large linkage groups within the mouse and human genomes with respect to the nature of the encoded genes and their linear order along chromosomes has been a great asset in the identification of potentially corresponding homologous mutations and disease genes.” (Nguyen & Xu, 2008, p. 56). In other words, mouse and human genetics are similar enough that researchers can extrapolate their discoveries on the mouse model to human research. Obtaining mouse embryonic stem cells and transforming them with specific mutations allows researchers to conduct functional research on these genes and elucidate both normal brain function and the effects of these mutations on the pathology of disease, among other things. Alternatively, transposons can be used to create and analyze mutations.

     Mus Musculus serves as a key model organism in Parkinson’s disease: the use of the MPTP neurotoxin allows researchers to simulate and study the disease outside of human patients. MPTP causes damage to dopaminergic neurons in the substantia nigra; in doing so, it imitates the normal neurodegenerative effect of Parkinson’s disease. Even the topographic characteristics of the neurodegeneration, both in the striatum (caudate nucleus, putamen) and midbrain mimics the decline in humans. One weakness to this specific model is that Parkinson’s is normally progressive, whereas MPTP application does not replicate this (Meredith & Rademacher, 2012).


References


  1. Cell and Molecular Biological Studies of Memory Storage. (n.d.). Retrieved from: https://www.hhmi.org/research/cell-and-molecular-biological-studies-memory-storage

  2. Stewart A.M., Braubach O., Spitbergen J., Gerlai R., Kalueff, A. V. (2014). Zebrafish models for translational neuroscience research: from tank to bedside, Trends Neurosci, Volume 37 (Issue 5), 264–278. doi:10.1016/j.tins.2014.02.011.Stewart

  3. Thomas Hunt Morgan, The Fruit Fly Scientist. (n.d.). Retrieved From: http://www.nature.com/scitable/topicpage/thomas-hunt-morgan-the-fruit-fly-scientist-6579789

  4. The Machinery of Memory. (2010). Retrieved from: http://www.brainfacts.org/sensing-thinking-behaving/learning-and-memory/articles/2010/the-machinery-of-memory/

  5. Hirth, F. Drosophila melanogaster in the Study of Human Neurodegeneration (2010). NS Neurol Disord Drug Targets. Volume 9 (Issue 4). 504-523. Doi: 10.2174/187152710791556104

  6. Nguyen D., Xu T. (2008). The expanding role of mouse genetics for understanding human biology and disease. Dis Model Mech, Volume 1. 56–66. doi: 10.1242/dmm.000232

  7. Meredith, G. E., & Rademacher, D. J. (2012). MPTP Mouse Models of Parkinson ’ s Disease: An Update. J Parkinsons Dis, 1(1), 19–33. doi:10.3233/JPD-2011-11023.MPTP

  8. Hughes, V. (2013). Mapping Brain Networks: Fishbowl Neuroscience. Retrieved From: http://www.nature.com/news/mapping-brain-networks-fish-bowl-neuroscience-1.12272

  9. A Short History of C. elegans Research. (n.d.) Retrieved from: http://wormclassroom.org/short-history-c-elegans-research

Jacob Umans

Jacob Umans


Jacob Umans is an aspiring physician-scientist in the Stanford University Class of 2020. As a cofounder of the IYNA, he is passionate about science education and hopes to share his excitement about all subfields of neuroscience -- especially glial biology and neuroimmunity -- with students around the world. He hopes to go on to earn an MD/Ph.D. after graduating from Stanford and to use his clinical experience develop a research focused on developing a better understanding of and improved therapies for neurodegenerative diseases. Outside of neuroscience, Jacob is an avid fan of puns, table tennis, and reading.

Meenu Johnkutty

Meenu Johnkutty


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