Australasian Science Magazine

Ingestion of a meal rich in carbohydrate is associated with improved mood and increased cognitive performance.

By Jayanthi Maniam and Margaret Morris

Stressful experiences during childhood can affect brain development, leading to increased anxiety and depression-like behaviours in adults, but this process can be reversed with diet and exercise.

Early childhood experiences can have long-lasting impacts on behaviour later in life. Several studies have shown that children who are abused or neglected have a higher risk of developing psychological disorders such as depression and anxiety during adulthood. In addition, animal studies have demonstrated similar effects using a model of stress induced by separating pups from their mothers.

Extensive data both from human and animal studies demonstrate the stress-reducing effects of certain kinds of food, specifically those foods that are rich in sugar, fat and carbohydrate. Work from Prof Mary Dallman’s lab at the University of California, San Francisco showed that rats consuming such “palatable” food during a stressful period not only consumed more but had lower stress hormone levels compared with rats given no access to such food during the same stressful period.

A study from the Netherlands reported that human ingestion of a meal rich in carbohydrate increases the availability of tryptophan, which is the precursor of serotonin. This was associated with improved mood and increased cognitive performance.

Likewise, consumption of chocolate has positive effects on mood according to a range of studies, including one from Prof Gordon Parker from the University of New South Wales.

We know that stress alters signals to the brain via the dopaminergic and serotonergic systems to promote the intake of a more palatable diet. Research by A/Prof Tracy Bale from the University of Pennsylvania found that palatable food acts as a natural reinforcer in rodents: withdrawal from a high-fat diet reduced reward-related markers in the brain and increased stress markers, thus suggesting that palatable food has reward-related properties similar to drugs of addiction.

So far no animal studies have examined whether a palatable diet or exercise can ameliorate deficits in behaviour and stress responses induced by adversity experienced in early life.

Our research has modelled early life stress by separating pups from their mother shortly after birth. This classic model of early life stress was first reported in the 1950s.

We separated rat pups from their mother for 3 hours daily for 12 days, commencing 2 days after birth. During periods of separation the pups remained with their peers on a heating pad maintained at 32°C.

A control group of pups was only separated for 15 minutes daily from their mother. This separation is not considered a stressor because normally rats in the wild leave their pups for periods throughout the day to forage for food.

This model of early life stress in rodents has been shown in several studies to alter neurodevelopment and reprogram physiological and endocrine responses during adulthood. Thus exposure to early life stress does have detrimental long-term effects, and this is evidenced in human epidemiological studies where adults who were diagnosed with psychosocial disorders have a history of maltreatment or adverse experiences during childhood.

Behavioural Measures
After maternal separation our rat pups were assessed for hedonic-like behaviour using the sucrose preference test, which indicates the ability to sense pleasure, and compared with control pups that were separated for 15 minutes. When exposed to sugar for the first time, rats normally show a preference for sugar solution over water, and the ratio of sugar to water drunk is used as an index of hedonic behaviour.

This was followed by the porsolt swimming test. This classic test measures depression-like behaviour, and is routinely used to test depression-modifying activity of new drugs. In this short swimming test, the length of time spent either swimming or remaining immobile is documented. Increased immobility and decreased swimming time indicates greater depression-like behaviour – akin to increased helplessness.

Another test we used as a marker of anxiety-like behaviour observed whether rats choose to spend time in a brightly lit area or a dark area in two arms of a maze. We measured the time spent and the number of times the animals entered the two arms.

In our study, the pups that were separated for 3 hours daily drank less sucrose, which indicates less ability to sense pleasure – a symptom of depression-like behaviour. In addition, these rats spent more time immobile and less time swimming, which indicated that they have increased depression-like behaviour compared with control rats. They also showed increased anxiety, choosing to spend less time in the brightly lit part of the maze.

We also tested the rats’ response to an acute stress to examine their ability to respond to an imposed stress, in this case a brief restraint where the animal is restricted from moving. We measured blood levels of the major peripheral stress hormone corticosterone, which is released in response to stress, both before and after the restraint stress. Interestingly we found that the rats that were separated for 3 hours daily had an increased stress response, with higher plasma corticosterone levels soon after the stressor and a slower return to normal compared with control rats.

In short, the early life stress of maternal separation for 3 hours daily had long-term detrimental effects on the behaviour of the pups during adulthood, leading to increased depression-like behaviour and an increased stress response.

Testing of Interventions
A major goal of our next experiment was to see whether diet or exercise could ameliorate the behavioural deficits we observed. From the age of weaning (3 weeks old) we offered half the pups a palatable cafeteria-style diet comprising a choice of different types of food with different textures, taste and smell, and the other half a low-fat regular chow. The different types of cafeteria-style food included cakes, biscuits, meat pies and potato fries.

In the same experiment we offered half the rats on each diet access to voluntary running wheels.

Interestingly, rats that had been separated from their mother during early development for 3 hours daily but were now given access to either the cafeteria diet or exercise demonstrated less anxiety- and depression-like behaviour compared with control rats. In addition, these rats had a decreased stress response with less plasma corticosterone after restraint stress and a more rapid return to baseline levels after the stressor.

Brain Mechanisms Involved
The next question we investigated was the possible mechanisms that may be contributing to the beneficial effects of diet or exercise following maternal separation. To this end we examined a region of the brain known as the hippocampus, and measured levels of the receptor that binds corticosterone, the glucocorticoid receptor (GR) and brain-derived neurotrophic factor (BDNF).

GRs play a principal role in negative-feedback response during stress to re-establish homeostasis by binding glucocorticoids and sending signals to the brain to reduce the further release of corticosterone.

BDNF is a member of the neurotrophin family of growth factors. It has a critical role in nerve growth, and is important in the response to antidepressant drugs. Most research has reported that stress leads to reductions in BDNF protein and mRNA in the hypothalamus, hippocampus and pituitary – regions involved in the regulation of stress responses.

Our data demonstrate that both GR and BDNF mRNA expression in the hippocampus declined in maternally separated rats, but this returned to control levels in rats that had access to a palatable diet or exercise from weaning. Increased GR mRNA in these rats following the restraint stress was in line with reduced corticosterone levels compared with rats that were only consuming standard chow. This finding further highlights that the diet or exercise interventions reduced stress sensitivity, which is in keeping with the improved behavioural profile observed in these rats.

The role of GR in ameliorating behavioural deficits through diet or exercise in our experiment is further supported by evidence from other researchers showing that pups who received naturally increased maternal care or an environment that was greatly enriched with toys and activities also had increased GR mRNA in the hippocampus.

In addition, reduced BDNF mRNA levels observed in the rats that were separated for 3 hours daily from their mother were restored through diet or exercise. While the effects of energy-rich diets on BDNF mRNA are variable, in our hands the palatable diet that we provided for almost 3 months from weaning was able to “rescue” the reduced BDNF levels in maternally separated rats.

However, further work is required to investigate whether a shorter period of this diet intervention will produce similar effects, which is an important question.

Our findings are also in line with other work demonstrating the effects of exercise on BDNF levels, and with the observation that exercise can have mood-elevating effects.

Conclusion
In summary, we think that a palatable diet or exercise modulate the behavioural and physiological deficits that manifest after prolonged maternal separation early in life through a number of proteins and genes. More work is required to fully uncover these.

We have also shown for the first time that the beneficial changes seen with a palatable diet or exercise were partly mediated through molecular changes in the hippocampal GR and BDNF mRNA.

While much work would be required to test whether the same mechanisms apply in humans, overall these findings may provide a clue about a different way to tackle a range of conditions that affect mood and behaviour.

But while there are beneficial effects of maintaining a high-fat diet to ameliorate behavioural deficits induced by early life stress, prolonged intake increases the risk for metabolic disorders such as obesity and related diseases such as diabetes and hypertension. Thus a healthier intervention such as exercise is recommended as it has similar beneficial effects on behavioural responses.