Nearly a century before Charles Darwin published Origin of Species describing evolution and natural selection, French soldier and naturalist Jean-Baptiste Lamarck developed his own theory of inheritance. Lamarck detailed the process of inheritance of acquired traits or “soft inheritance.” For example, a mother giraffe who had to stretch her neck to reach tall leaves would pass a longer neck on to her offspring, according to Lamarckian genetics.

After the scientific advances of Darwin, Mendel, and others, Lamarck and soft inheritance were widely discredited. But recent research in mice and humans has once again brought Lamarck to the fore, with new evidence that a mother’s experiences can actually impact the gene expression of her offspring.

An example of one such breakthrough is a set of experiments conducted by Dr. Larry Feig and his team of researchers at Tufts University School of Medicine in Boston, MA. This research demonstrates the effects of a mother’s environment on the learning and memory of her offspring.

Dr. Feig never imagined that he would end up studying the subjects of learning and memory. His path to neuroscience was accidental and shows the interrelatedness and complexity of science and nature. Dr. Feig began his career in cancer research. He studied the molecular basis of cancer and unregulated cell growth that creates tumors. He focused on a family of proteins called Ras that, when activated, can promote cellular division. In normal situations, Ras proteins can only be activated through an outside stimulus. However, in cancer cells, Ras proteins are defective: they are always in the active state and cannot be deactivated. As a result, we see the rapid cell division characteristic of cancerous tumors.

Ras proteins can be activated when they receive signals from extracellular receptors known as N-methyl-D-aspartate (NMDA) receptors. NMDA receptors are protein receptors that are located on the outer membranes of neurons (nerve cells) and are responsible for receiving and transmitting messages to the inside of neurons.

Yeast as a Model

In order to better understand how Ras proteins normally become activated in cells, the researchers looked for proteins similar to Ras activators that had recently been discovered in a very simple model organism, yeast. They found one and called it Ras-GRF. However, to their surprise it was only found in neurons in the brain, which do not contribute to cancer. “At this point we had a decision to make,” Dr. Feig explained. “We could drop the Ras project in nerve cells and continue looking for the activator of Ras in cells that do cause cancer, or we could study this process in brain function.” Dr. Feig decided to pursue studying Ras proteins in the brain, and so began his research in neuroscience.

The first step for the team was to determine the role of Ras-GRF in neuron function. To do this, they developed a mouse model that lacked the Ras-GRF protein, known as a “knock-out” mouse, and then compared Ras-GRF knock-out mice to a control group of normal mice. Dr. Feig found that there were significant differences in learning and memory between the two groups. Specifically, the Ras-GRF knock-out mice had a defect in their ability to remember a certain task they had learned.

Both groups would learn the task equally well, but the knock-out mice forgot the task much more quickly than the controls. The researchers found that the nerve cells in the knock-out mice NMDA receptors could no longer activate Ras. NMDA receptors are involved in learning and memory. Dr. Feig concluded that in nerve cells Ras-GRF activated Ras causes something to happen that makes cells remember that they were stimulated. This is what many believe is the basis of memory. The mechanisms by which Ras allows for memory are still not well understood.

Memory Strengthening by Enrichment?

Dr. Feig and his team now had a mouse model with significant memory deficiencies. One of Dr. Feig’s research colleagues in his lab, post-doctoral fellow Dr. Shaomin Li, was curious about how these Ras-GRF deficient mice would react to a stimulating environment, known as an “enriched environment.” Laboratory animals are usually kept in nice cages with some things to explore, but they lack novelty and change. An enriched environment, on the other hand, includes exercise equipment and new toys that are rearranged often to stimulate the brain. Previous experiments have shown that such stimulating environments cause dramatic effects in the brain and increase the numbers of connections between nerve cells. Dr. Li wondered whether the genetic defects in the Ras-GRF deficient mice could be overcome by exposure to a stimulating environment. To find out, Dr. Li performed an initial memory test on these mice before placing the Ras-GRF deficient mice in an enriched environment. The mice lived in the enriched environment for 2 weeks, after which he gave them the memory test again. Dr. Li found that the mice that had been exposed to the enriched environment did indeed perform better on the second memory test.

Memory-Deficient Knock-Out Mice

Group In Enriched Environment	Control Group In A Conventional Environment
Adolescents perform better on the memory test. Older mice remained deficient.	No change in performance
Offspring of the adolescents performed better on the memory tests. [Note: only the female parent affects performance.]	Offspring also deficient in memory
Offspring of the offspring did NOT perform better on the memory test: thus, the benefit is a single-generation benefit

Environment Changed the Biochemical Pathway – Another Benefit of Youth

Next, Dr. Feig and Dr. Li investigated the biochemistry of how the Ras-GRF deficient mice had compensated for their genetic deficiencies. They found that the enriched environment had opened up a new biochemical pathway in the brain that circumvented the lack of the Ras-GRF pathway. (In normal mice, an enriched environment also opened up this pathway, which complements the Ras-GRF pathway). This was only true, however, for young, “adolescent” mice. Similar experiments in older, mature mice did not have the same result. These experiments demonstrated that a rich environment can have a profound impact on the adolescent brain which is known to be more “plastic” which means it changes more in response to its environment.

Signaling cascades that contribute to LTP induction depend upon the environment to which an animal is exposed. This phenomenon lasts for at least 3 months in enriched juvenile mice, whereupon it wanes and is absent by 6 months of age. Remarkably, this effect is passed on to the offspring of these enriched mice. [From the Feig Lab website: http://sackler.tufts.edu/Academics/Degree-Programs/PhD-Programs/Faculty-Research-Pages/Larry-Feig.aspx]

In addition to experiments on memory, Dr. Feig looked at the nerve cells themselves. When nerves are stimulated after a learning experience, they remember that they were stimulated by a process known as long-term potentiation, or LTP . Dr. Feig found that the Ras-GRF deficient mice had deficient LTP, which was consistent with the fact that they had reduced memory. However, young Ras-GRF deficient mice that were placed in an enriched environment for two weeks had normal LTP.

Is it Passed On to the Next Generation?...Epigenetics

Dr. Li had just shown that a genetic defect in mice causing deficient memory can be overcome through an enriched environment. Now he wondered how the exposure to an enriched environment during adolescence might affect the offspring of these mice. To do this, he allowed the mice to mature and then looked at their offspring. Not surprisingly, Ras-GRF deficient parents who were not exposed to an enriched environment as adolescents had offspring that were similarly memory deficient. These offspring had the same genetic defect as their parents that caused the memory problems. In contrast, the offspring of Ras-GRF deficient parents that had been exposed to an enriched environment had normal LTP and almost normal memory, even though they still lacked the Ras-GRF protein. Further experiments demonstrated that the inheritance of improved memory depended solely on the mother and not the father.

This is a remarkable result when you look at how genetic inheritance works. Normally we think that offspring inherit sequences of nucleotides that make every individual’s genes unique. Dr. Feig’s and Dr. Li’s experiments are consistent with the newly-appreciated idea that the genes of mice can be chemically modified to either turn them on or off for very long periods of time. This process, called epigenetics , occurs during animal development, when a single fertilized egg gives rise to many types of cells of the adult. All cell types contain a full set of genes, but epigenetics permanently turns on or off different sets of genes in different cell types.

In the present study, genes apparently get modified in response to the environment and these modifications can be passed on from mother to child in a somewhat Lamarckian fashion. The idea that behavioral modifications to genes can be passed down from one generation to the next is known as transgenerational epigenetic inheritance.

There are numerous other examples of transgenerational epigenetic inheritance now emerging. These effects are not always positive. For example, in the 1950’s pregnant mothers were given a chemical known as diethylstilbestrol, or DES, to prevent premature birth. It has now been shown that these chemicals have made the children and grandchildren of these mothers more susceptible to certain diseases, such as cancer. The mechanism for how genes can be modified in response to the environment is still not known.

The case of the mice in Drs. Feig and Li’s experiments are not quite so dramatic because the epigenetic changes can only be inherited for one generation. The offspring lose the positive effects inherited from their parents before they are sexually mature unless they too are exposed to an enriched environment. Thus the offspring of these mice cannot continue to pass the traits of their mothers down to the next generation. Dr. Feig hypothesizes that because the mother was exposed to the enriched environment, it gives the offspring a better chance at survival by inheriting some of the positive benefits of the mother’s experience. “But this is all high speculation,” he notes.

Future research for Dr. Feig is focused on figuring out how this new biochemical pathway gets opened up in the brains of enriched Ras-GRF deficient mice and in their offspring. Once this is done he will be able to figure out a way to block it in animals to test the consequence on adolescent behavior. “I never thought I would end up studying something like this,” remarks Dr. Feig. “It just goes to show how exciting science can be if you follow where it leads you.”

To learn more:

For more information:

Rebecca Kranz with Andrea Gwosdow, PhD at Gwosdow Associates

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Dr. Feig and his team

Dr. Larry Feig

Dr.Shaomin Li

The Feig Laboratory Team (left to right) Adam Sowalsky (graduate student), Anna Maione (graduate student), Dr. Feig, Harold Hatch (graduate student), Junko Arai (postdoctoral fellow), Richard Wong (graduate student), Shan-xue Jin (postdoctoral fellow), Chris Rombaoa (graduate student).

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