Neocortex enters a ‘low battery mode’ during food scarcity

Dietary measures, particularly reducing calorie intake, are among the most common and effective weight loss measures. It is also an effective way to prevent or even reverse certain metabolic disorders. However, reduced calorie intake also comes with certain risks like malnutrition. Although the risks and benefits of reduced calorie intake on physical health are well-studied, it appears that the impact of low-calorie intake on the most energy-hungry organ that is the human brain, remains unclear. Pound for pound, the brain consumes vastly more energy than other organs; The human brain is just 2% of the body mass, and yet it spends more than 20% of energy. Thus, it is vital to understand the impact of restrictive calorie intake on brain functioning.

Studies using animal models are essential for understanding the impact of dietary energy intake on the brain at the molecular and cellular levels and, importantly, data obtained from animal experiments directs the design of clinical studies in humans. In a new research study published in Journal Neuron focused mainly on findings from animal studies which have elucidated the effects of dietary energy restriction on brain function. Scientists from the University of Edinburgh, Dr. Zahid Padamsey, Dr. Danai Katsanevaki, Dr. Nathalie Dupuy, and led by Dr. Nathalie Rochefort studied the influence of calorie restriction on the performance of the brain of vertebrates. They hypothesized that since the energy intake is not constant, the brain may have some way to save energy while maintaining core functions, during periods of energy deficiency. Additionally, there is already evidence from studies on invertebrates. For example, the brain of food-deprived Drosophila may inactivate long-term memory pathways. However, if these pathways are artificially stimulated in experiments, it results in reduced lifespan of the fly. However, there are no studies regarding how the mammalian brain saves energy in times of food scarcity.

The researchers analysed energy consumption of the cortical neurons, using whole-cell patch clamp recordings and two-photon imaging of excitatory neurons in the visual cortex of awake male mice. They used a control mouse that was fed as usual and an experimental mouse on calorie restriction that caused a 15% body weight reduction. They found that calorie restriction that was enough to cause a 15% body weight reduction also reduced the neurons’s energy use by almost 30%. This was due to the fact that food restriction reduced excitatory synaptic currents, caused by a reduction in AMPA receptor conductance. Additionally, it caused an increase in specific compensatory mechanisms to preserve neuronal excitability such that spike rate was maintained. One of the most exciting findings in their study was that they noticed that reduced calorie intake impaired fine visual discrimination in an experimental mouse model. Moreover, they also reported that reduced calorie intake and weight loss caused a reduction in serum leptin levels. Interestingly, leptin supplementation restored neuronal function. Therefore, precision coding which is defined as the rich signaling information transmitted in the brain was reverted back in the animals by simple administration of leptin.

The key finding of this study is that, similar to previous findings in the invertebrates, certain mental functions are compromised in mammals to conserve energy during food scarcity. Thus, this ability to reduce brain function to save energy is an evolutionary feature. However, researchers also mention that this decline in mental ability during energy scarcity depends on multiple factors like age, sex, and severity of calorie restriction. For example, moderate calorie restriction that does not cause significant weight loss may boost certain mental abilities. This is consistent with the understanding that mild stressors may help optimize physiological function. Additionally, researchers noticed that their study demonstrated the particular role of leptin in these changes. They think that it is quite likely that leptin plays a vital role in these changes, as it can cross the blood-brain barrier and leptin receptors are present in the brain, such as in the cortex and in the hypothalamus. Another possible way leptin may influence the brain’s metabolism is through other hormonal pathways, e.g. by influencing thyroid hormones. Indeed many studies address leptin as a potential pharmacological therapy in the control of weight gain and obesity. However, the complexity of leptin actions in the brain, requires a deeper understanding of the physiology of leptin signaling pathways.

The new findings improve our understanding of how the brain reacts during periods of severe calorie restrictions. In addition, the vulnerability of the brain to the disruption of its fuel supply is a major problem in neurology, and metabolic deficiencies have been noted in a host of common brain diseases including Alzheimer’s and Parkinson’s disease. This line of investigation ultimately could help solve important medical puzzles and suggest new treatments.