Posted by: Neurobites | January 20, 2011

Early life protein restriction alters dopamine circuitry

Gestational development represents a time in which the organism is at its peak vulnerability for developing lifelong changes. Consequently, an aberrant fetal environment can permanently shape the organization of the individual. We recognize things such as alcohol and other drugs, endocrine disrupting compounds such as bisphenol-A, and vitamin deficiency (to name a few) as possible ways normal development can be disrupted. But it turns out that gross nutrition, be it too much or too little food is also capable of bringing about such changes.

Our concern for the obesity epidemic, and the role of developmental influences in the prevalence of obesity (yes there will be a post about that soon) may blind us to the other side of the coin. While it is true that over-nourishment is the reality for an ever-increasing number of infants, the issue of under-nourishment must not be forgotten. By the estimates given in this paper, roughly 10% of American children experience some degree of under-nourishment during gestation. This figure is no doubt even larger among poorer nations.

Children born smaller than average end up being at higher risk for a number of neurodevelopmental disorders including ADHD, as well as other adverse neurobehavioral outcomes including depression, antisocial personality disorder, and even addiction. The dopamine circuitry, as it turns out, is implicated in each of those conditions to some degree. So the question becomes: does growth restriction impact dopamine function?

In this study the researchers fed pregnant female mice one of two diets. The control diet was simply ordinary lab chow, nutritionally complete and quite healthy. The other diet was nutritionally and compositionally identical to the first with the exception of its protein content being substantially lower than usual. After the offspring were weaned, they were all fed ordinary lab chow for the rest of the experiment.

All of the pups were born weighing roughly the same, but by weaning those pups in the protein restricted groups came to weigh less than those whose mothers were eating the control diet. Nursing is an extremely demanding state of affairs for a mouse mom. A litter of mice can quickly grow to exceed the mom’s weight, yet still require a constant supply of milk. Not surprisingly, diminished nutrition during these trying times took its toll on the pups. Once the pups were weaned and returned to the ordinary diet, they quickly rebounded and came to weigh roughly the same as those who were never growth restricted.

It turned out that these mice had significantly altered dopamine systems. The mesocorticolimbic dopamine system is involved in reward processing, learning, and other such matters. People who study drug addiction are quite interested in this system, because a common property of addictive drugs is their ability to increase the dopaminergic activity of this system. The ventral tegmental area, the root of this system, reaches upward throughout the brain making connections with a number of important areas including the nucleus accumbens and prefrontal cortex. These and other areas play important roles in addiction, as well as the other disorders listed earlier. It seems that these animals had greater expression of enzymes concerned with dopamine production, as well as dopamine reuptake in the aforementioned areas of this system.

These neurochemical changes have a certain appeal in and of themselves. But what makes them truly relevant is the extent to which they correlate with a behavioral change. Here, the authors carried out a simple experiment wherein the acute locomotor response to a cocaine injection was measured in growth restricted and control animals. As it happens, the protein-restricted animals had a greater locomotor response to acute cocaine. The authors also tested the animal’s preference for sugar sweetened water. When given the choice between tap water and lightly sweetened water, it’s typical of normal animals to show a strong preference for sweetened water. The protein-restricted animals, on the other hand, showed a decreased preference for sugar water. This is not to say that they suddenly found it aversive – they still did drink it more than tap water, just not to the same extent as control animals.

It seems, then, that these animals somewhat under-value the so called “natural” rewards like sugar, and yet are more responsive to high powered rewards such as cocaine. These characteristics are believed to underlie some cases of human drug addiction; normal pleasures won’t cut it for certain people so they turn to drugs.

So what does this tell us? Well it’s already established that growth-restricted offspring tend to have health and behavioral problems. But the causal mechanism of these tendencies has yet to be revealed. Here it is suggested that some manner of permanent reprogramming of the mesocorticolimbic dopamine system and the genes expressed therein is to blame.

Vucetic Z, Totoki K, Schoch H, Whitaker KW, Hill-Smith T, Lucki I, & Reyes TM (2010). Early life protein restriction alters dopamine circuitry. Neuroscience, 168 (2), 359-70 PMID: 20394806


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