This blog started as me debunking a study but the study was legit. The problem with it was that it used an intestine bacteria to try and use oxytocin as a treatment for autistic behavior by comparing mice tissue to human tissues.
Autistics are not mice.
How Mice Models Started
When Dr. Jill Silverman graduated from her graduate program where she studied sex differences in rodent brains, she joined a mouse behavior lab at the National Institute of Mental Health (NIMH) in Bethesda, Maryland. She was excited to study autism.
In 2007, researchers started to identify strong candidate genes for autism. They genetically engineered mice with mutated genes that were common in autistic people. They relied on mouse behaviorists to identify the mice could be “furry proxies” for autistic people.
How “Autism” Mice are Chosen
The “ideal” autism mouse should show all the traits that characterize autism in people. They are language and social issues and restricted and repetitive behaviors.
There are some “mutant” mice make fewer vocalizations than the control mice do. These are mice with gene mutations. Many animal behaviorists equated this to language issues. Other mice groom, jump or bury marbles excessively. To them this is autism in mice.
The rationale was if the mice displayed autism traits, according to them, they could design drugs to treat autistic behaviors.
Studies Involving “Autism” Mice
In 2011 one mouse made the headlines in Nature. The mice lacked part of the SHANK3 gene that mutated in 1% of autistic people. The first study they participated in said they “display autistic-like behaviors.”
Translation: The mice showed little interest in seeking out another mouse in a three chambered enclosure. In this test, researchers placed a mouse in a Plexiglas box that had three rooms in a row.
The mouse has a choice:
- It can spend time in the first room, where another mouse is trapped in a small wire cage
- It can stay in a back room that has an empty cage
Most mice went over to the other mouse but the “autistic” mouse moved in slowly, pausing frequently to groom. They groom so compulsively, that they have bald spots (usually this is indicative of allergies or anxiety). They sniffed the empty cage and the cage with the other mouse but showed no real preference for the mouse.
A study in 2017 looked at two male and two female groups of the same mice in the same three-chambered enclosure. They found something different. The mice showed behavior that was “mostly normal.” Only now one group of mice showed “social deficits.”
At the same time, another team said that it was unable to replicate the 2011 results. Any “social deficits” in the “autism mice” were significantly “milder” than previously reported.
News confirmed what many scientists started to suspect.
I felt like I was very naive. The models were coming out and we were like,’Oh we have models now, and we’ve developed these essays, and now we’re really going to start to clear up and have answers. And then we realized it’s not so simple.
Silverman, who runs her own lab at the University of California at Davis
Excitement of the “Autism Mice” Faded
The original reports of “social deficits” in mice have not been consistent when tested in independent labs, including Silverman’s, or in different strains of mice.
These inconsistent findings have plagued more than just Silverman’s mouse studies. The genes affected in this are CHD8, NLGN3, NLGN4 and CNTNAP2 and others. This makes scientists wonder whether mice can ever emulate complex in humans such as autism.
To get all those things in a nice, neat package with a bow- we’re not going to get that.”
Valarie Bolivar, the director of Mouse Behavioral Phenotype Analysis Core at the Wadsworth Center in Albany, New York
A more productive approach may be to focus on only behaviors that are reproducible in mice. These are quantitative measures of how the animals learn. If researchers do want to get “social deficits” they may need to methodically catalog mouse behavior.
Their mice are not scientific. The mice cannot be autistic.
Much of the inconsistency in the reports of social behavior in “autism mice” may originate from the fundamental misunderstandings of the three-chamber enclosure. Crawley developed the test in 2003. This was a few years after NIMN had a meeting that brought experts on mouse and human behavior to design screens for autism features in mice.
Mice cannot be autistic.
Cawley says that the three-chambered enclosure was intended to deliver a binary result:
- Does the mouse prefer another animal over an object? This is similar to a child choosing a playmate or a toy
This test is not sensitive enough to quantify the amount of time the mutant mice spend with the other mice and compare it with the control group.
Many teams use this scenario and report the mice to have autism-like social behavior. This gets contradicted later in observations from other labs.
Silvermans biggest concern with the enclosure is that unrelated features common in many “autism mice.” This makes the test impossible to interpret.
There is also interference with other behavioral tests, according to Silverman. Researchers may tune into ultrasonic vocalizations for clues to mice levels of social interest. These are the inaudible squeaks of male mice near a female in heat or those of pups separated from their mother.
A mouse’s background strain can also affect behavior. The genetic background of the SHANK3 mice published in the 2011 study changed over time. This may help explain the differences between the original report and later subsequent reports.
The conflicting results also came from mice missing other parts of SHANK3. Also, mice are finicky.
They behave differently depending on:
- whether they live with other mutants or controls
- whether they are anxious from a prior test
- whether they are male or female
- whether their handlers are male or female
- whether the scientists observing them stay in the room or set up a camera and sneak out
The biggest problem with using mice in these studies may be that mice aren’t especially social to begin with.
The area of the mammalian brain that controls social behaviors, the prefrontal cortex, is smaller in mice than in people. In the wild, male mice are solitary and may only come into contact with a mate and their young, according to Mu Yang. Yang directs a mouse behavioral facility at Columbia University.
“Let me sit next to you; what’s going on? Not necessarily what mice will do.”
Mu Yang, Director of a mouse behavioral facility at Columbia University
“They are not solitary in the sense that they kill each other if they come too close or something. They’re not nearly as social as most rats.”
Caroline Blanchard, a rodent behavioralist at the University of São Paulo, Brazil, has spent almost 40 years scrutinizing mice as they do mice things in large enclosures that mimic their natural habitat.
Whether the brains of mice and the behavioral repertoires of mice are sophisticated enough to sufficiently monitor autism and its primary symptoms – that, I think, is a very logical question to ask. I think about this al the time and I don’t have an answer.
Crawley
I think that defining an autism mouse is folly
Valerie Bolivar
Are Mice Viable for Autism Studies?
Many behaviorists are rethinking whether mice can mimic “social deficits” at all as far from obvious from the literature. Top journals still publish studies that describe “social deficits” in “autism mice.” This is often based on inexperienced interpretations of the three-chambered enclosure. “It’s annoying when you see the words ‘autism mouse;’ in the title of five Nature papers,” says Silverman.
Only a portion of these are based on genes highly associated with ASD (others are based on environmental exposure or those with low or no association to evidence-based risk).
Silverman, in a peer reviewed paper
However, many behavioral assays are rudimentary, do not engage similar neural circuitry as in humans, and lack translational face validity. Given behaviors in a model system with apparent face validity to symptoms of ASD (specifically social communication deficits together with the presence of restrictive and repetitive behaviors) are never going to look the same as those displayed in a human.
Silverman, in a peer reviewed paper
Researchers feel pressure from journal reviewers to demonstrate an “autism mouse” has “social deficits” that seem to emulate autism. This is according to Gouping Feng, a professor of brain and cognitive sciences at the Massachusetts Institute of Technology. Feng led the 2011 study that showed the “social deficits” in the SHANK3 mice. He mainly looked at the effects of a mutation in SHANK3 on the brain. In order for these experiments to be meaningful, he understood that the mice needed to show autism-like behaviors.
Results from our analysis revealed: clear omissions in some parameters from behavioral assays, fair to insistently report background strains and/or breeding schema, scarce level of detail in testing protocols. . . Findings observed included: a lack of adequate statistical power, differing reporting practices, varying procedures for testing, variability in assays to assess different types of social or repetitive behaviors, utilization of behavioral assays for broad interpretations of complex behavior and other sources of variability which which undoubtedly influence and results fairs to reproduce
Gouping Feng, professor of brain and cognitive sciences at Massachusetts Institute of Technology
Using mice to represent autistics in these are very flawed.
In 2014, there was the same pressure on at least five other teams to look at social behavior in mice with the mutations CHD8, which was the top candidate gene for autism.
In 2016, one team announced in Nature that they had a CHD8 model showing “autism like phenotypes” even thought those mice prefer a playmate over an object for the three chamber enclosure.
At the same time, Silverman and her collaborators were characterizing a mouse with another mutation of CHD8. Findings from both teams were similar. Silverman’s team interpreted the mice as having normal social interactions.
The journals the teams approached were hesitant to publish results that contradicted the other group’s paper. In order to convince the reviewers, Silverman’s team needed to replicate their behavioral experiments. This was six months worth of work before they were even able to publish their findings.
This is an example of what’s been happening in the literature with mouse models of autism. The first paper that comes out has incorrectly interpreted findings or done the wrong experiment sometimes, and their findings get popularized in the community and sometimes in the press- and then the next papers that come out have done things right get lost in the shuffle.
Crawley
In order to break this cycle, researcher should work with mouse behaviorists to help interpret their studies, according to Crawley.
A logical solution might be to move away from the pressure to show autism features, say some researchers.
We need to loosen the standard of framing mouse models using the mouse version of [a diagnostic manual]. When that happens, people can stop trying too hard to shop their data to look like the cardinal symptoms of autism.
Yang
“I am not sure how necessary it is going to be to try to recapitulate exactly the same symptoms in the animals as you see in the human”
Patricia Kabitzke
Mice are Not Neurologically the Same as Humans
The mouse brain and human brain are drastically different. It’s laughable that researchers use mice to try to prove different aspects of autism. It is pseudoscience.
The only similarities are that they have approximately the same number of cell types. The outer layer of the brain handles complex jobs. They are planning, decision making and consciousness, according to neuroscientist Rebecca Hodge at Allen Institute for Brain Science in Seattle. This comes from comparing the behavior of genes in single mouse cells with the behavior of genes in single nuclei human cells.
A big difference was the behavior of genes that hold instructions on how cells sense serotonin. The type of cell that senses serotonin in mice is different than in humans, according to lab tests. This means laboratory mice aren’t good models for conditions that involve serotonin such as depression.
Mouse neurons are also more resilient to oxidative stress than humans. A damaging imbalance is a mechanism behind neurological disorders. A lack of oxygen triggers molecular repair in mice that humans lack.
Microgila, the brains immature cells gene behavior is different between humans and mice.
The mouse brain is much smaller than the human brain. By volume, its less than one thousandth the size of the human brain.
Not counting size, mouse brains are organized differently than human brains. The proportion of a brain is composed of the neocortex. This is the region most associated in human brains with consciousness. This is much greater in humans than mice.
Neuroscientists believe that it is the architecture of the brain that produces consciousness, not the nature of the neurons (brain cells) that make it up.
In other words, architecture determines whether a building is a cathedral or a garage, not whether the bricks used are red or grey. A mouse brain made up entirely of human neurons would still be a mouse brain, in size and in architecture. Its impossible to have human attributes, including consciousness.
Due to this, humans make too much of findings in mice. There are a number of studies that have compared mouse and human brain circuits and these studies have revealed key differences.
Many researchers use the rationale that it is difficult to get human brain tissues so animals are the next best thing, even thought animal brains are much different than human brains.
PETA Actually Got Something Right
In a clinical study on oxytocin, it was tested on mice. Oxytocin promotes social bonding in humans. It was found to have “no meaningful impact” on autistic children.
The study was called a “major setback” but it was set up for failure because children are not mice.
For more than a decade of experiments on annals has shown that mice cannot replicate unique traits of autism in humans. The scientific community is very aware, as stated above, that using them in experiments does not advance understanding of autism.
There have been numerous failed attempts to replicate autism in mice. There were researchers genetically modifying mice ignorer to have them make fewer social interactions and produce unusual vocalizations. These mice are NOT AUTISTIC and mice do not make good models for humans in general.
There are some laboratories that sell these animals to different researchers in order to “treat” autistic traits.
Human Relevant Research is the Answer for Understanding Human Health
There are numerous human research methods that can help autistic people. Many human clinical trials have led to advances in early diagnosis, uncovering and addressing health co-morbidities in autistic people and understanding how autism is in adults.
Say it with me: Autistics are not mice. Let’s see what other animals they will compare us to because neurotypical researchers see us as subhuman.
Aviva Seigler, Fierceautie.com
sources
https://www.spectrumnews.org/features/deep-dive/why-studying-autism-in-mice-may-be-doomed-to-fail/
https://onlinelibrary.wiley.com/doi/full/10.1111/gbb.12803
https://elifesciences.org/articles/90017
https://www.sciencedaily.com/releases/2021/06/210625173158.htm
Aviva Seigler 
2 thoughts on “Quackery Myth: Mice Make Good Models for Autism Studies”