On the face of it, humans and other vertebrates enjoy a more sophisticated behavioral repertoire than clams, crabs, worms and most other invertebrates. We're much better equipped to live in different environments and cope with changing circumstances. But until now, no one has shown why those of us with spines have so much more cognitive sophistication and versatility in our actions than invertebrate organisms.
Two papers published in the January issue of Nature Neuroscience help answer this riddle. In a two-part study, scientists in the United Kingdom demonstrated that a genetic event 550 million years ago that led to the duplication of certain genes fostered the evolution of complex nervous systems and behaviors in humans, mice and other vertebrates. That event, however, also led to a downside for vertebrates: the development of mental illnesses.
To glean the evolutionary story of our complexity, the team spent three years testing the cognitive and behavioral aspects of a family of genes called Dlg genes, chosen because they control fundamental signaling properties within nerve synapses. Scientists already knew that these gene families arose from two mutation events, called whole genome duplications, which occurred in the lineage of animals that gave rise to vertebrates around 550 million years ago.
The first accidental copying of an extra genome is thought to have occurred in an ancient marine invertebrate, and it happened again later in one of the organism's descendants, resulting in a total of four copies of invertebrate ancestral genes. These duplication events explain how vertebrates expanded their sets of genes: Over the millennia following the duplications, the extra gene copies accumulated smaller mutations, which in turn diversified their DNA sequences and function. The events gave vertebrates a much larger molecular toolbox to perform biological functions.
These insights led the British scientists to wonder if these genomic evolutionary events were responsible for generating vertebrates' more sophisticated behavioral repertoire — the first time anyone has examined the effects of these events on learning, memory, cognitive flexibility and attention.
In the first part of the study, the researchers genetically engineered mice to remove each of the four diversified vertebrate Dlg genes. They had them do tasks on an iPad-like touch screen that involved, for example, learning to associate objects with locations, and detecting and responding to targets briefly displayed on the screen, which they did by nose-poking stimuli on the screen to obtain rewards. Compared with normal mice, the mice lacking the Dlg4 gene had a very difficult time doing more advanced tasks; those lacking the Dlg2 gene performed worse on many tests; and those lacking the Dlg3 gene actually performed better on some tasks, the team found.
The results prove for the first time that the evolution of the four Dlg genes "produced distinct and sometimes complementary functions," says genetic researcher Seth Grant, MD, of Edinburgh University, who led the studies.
"In turn, that evolution had the overall effect of increasing the complexity in the way vertebrates regulate their behavior," he says.
In the second part of the study, the team set out to test whether the function of the Dlg genes was the same in mice and humans — an important question given that scientists routinely apply findings on mice and other rodents to humans.
First, the team compared the DNA sequences and RNA expression maps of the brain in mice and humans, and found a high degree of similarity in Dlg genes between the two species. But they also wanted to test that similarity on a functional level since human brains are much larger than mouse brains, and therefore the genes controlling their behavior might manifest very differently.
The researchers gave touch-screen tasks testing the same cognitive functions to both mice and people with known mutations in the Dlg2 gene. The human participants — three of whom had been diagnosed with schizophrenia, one who had not — had difficulty in the same domains of cognition as the impaired Dlg2 mice, including visual discrimination and cognitive flexibility, visuo-spatial learning and memory, and attention.
The findings demonstrate that the role of Dlg2 in regulating specific cognitive functions has been "conserved," or remained essentially the same since it first arose. The results also show how mutations in those genes might lead to mental illness. As such, the research provides an important evolutionary insight into the way the fundamental molecular mechanisms of human cognitive complexity and mental illness arose deep in our ancestry, says Grant.
"The price we pay for our amazing behavioral complexity and flexibility is that we're also susceptible to deleterious mutations that can cause mental disorders," he says.
The findings may also pave the way for practical applications, by identifying some of the genes and proteins involved in higher cognitive functioning as well as in mental illness, adds study co-author Tim Bussey, PhD, of the University of Cambridge. The study also shows how humans and rodents can be tested on highly comparable cognitive tasks, thereby highlighting the possibility of improved cognitive translation between preclinical and clinical research, says Bussey, who developed the touch-screen technology.
"I think this more accurate translation can only help with drug discovery and other medical advances," he says.
Tori DeAngelis is a writer in Syracuse, N.Y.
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