Hypothalamic control of physiological responses to seasonality

Dr Perry Barrett

In temperate zones of the planet, light & dark cycles vary over the course of the year and create the seasons we experience. For mammals living in a natural environment this has implications for availability of food resources which are less abundant in winter months. Furthermore, the ambient temperature may decrease substantially in winter, so both food scarcity and lower temperatures impose challenges for survival. However, mammals have adapted to these challenges by interpreting the daily variation in daylength over the course of the year to make appropriate changes in physiology and behaviour.

Physiological and behavioural adaptions include a change in appetite, energy balance, reproduction, immunity, and in some mammals adopting energy saving mechanisms such as torpor or hibernation. These adaptations are controlled centrally by the brain, but which areas of the brain are involved and what are the mechanisms by which these changes are brought about? The Siberian hamster has been an excellent model to investigate the basis of seasonal adaptations which include decreased appetite, cessation of reproduction, altered immune status and torpor.

The hypothalamus is a key area of the brain which is involved in behavioural and physiological adaptations such as appetite control, thermogenesis and reproduction behaviour, it is also the principal gateway for communication for neural control of pituitary hormone secretion and peripheral hormone feedback. Using the Siberian hamster, our work identified several genes in the hypothalamus which changed in response to exposure of seasonal daylengths (ie longer daylength of summer verses short daylength of winter).

Among the genes that changed were genes for the enzyme DIO2 which synthesises the bioactive form of thyroid hormone (T3) from the precursor thyroxine (T4); and the enzyme DIO3 which degrades T3 to an inactive form (T2). These were regulated in opposing manner with DIO2 elevated in summer photoperiod and DIO3 in winter photoperiod. Implants releasing T3 showed this hormone was key to promoting physiological adaptations for long daylengths.

Surprisingly, DIO2 and DIO3 were found to be altered in a layer of cells (known as tanycytes) that forms the interface between the cerebrospinal fluid (CSF) and neurons of the hypothalamus. Other laboratories have subsequently identified tanycytes as an important source of stem cells for neurogenesis and a gateway for peripheral hormones which feedback to the hypothalamus to control behavioural and physiology, including appetite and reproduction.

Seasonal variation in neurogenesis are also likely to occur. Our work has identified other genes varying with seasonal daylength in tanycytes, including a gene for the receptor Gpr50. This receptor has been identified to be involved in energy balance regulation, including torpor.

Although we have made some significant advances toward understanding seasonality, many questions remain. What is the mechanism of thyroid hormone action? How are DIO enzymes regulated in tanycytes? What is the extent and mechanism of involvement of Gpr50 in energy balance and what is the temporal relationship over the course of a year between the genes responsible for adaptations?

Understanding the mechanisms of seasonal physiological adaptations will be important going forward as we now appreciate annual rhythms of physiology are important in human health and wellbeing, which includes disease susceptibility and immunity. Furthermore, it is particularly relevant to seasonal mammals in an environment impacted by climate change.

This work has been, funded by the BBSRC, RESAS and the British Society for Neuroendocrinology with the involvement of many collaborators.

 

Linking early life vulnerability of the brain reward system with the emergence of food-related disorders

Dr Fabien Naneix

Control of food intake in a dynamic environment requires complex cognitive processes integrating internal and external information. Increasing evidence demonstrates that highly palatable foods (e.g. soft drinks, sweets, cafeteria diet) can dysregulate food intake and induce maladaptive behaviours (overconsumption, craving…). To date, most studies investigating the impact of palatable foods have looked at the effects of consumption during adulthood. However, early postnatal life like childhood and adolescence are critical periods for the correct development of food behaviours. It therefore might represent a vulnerability window for the deleterious effects of palatable food consumption and, in turn, the emergence of dysfunctional feeding behaviours.

The so-called “reward system” is a group of brain regions involved in the processing of rewarding stimuli, including palatable foods, and controlling motivated responses. Interestingly these circuits show a late maturation between birth and adulthood. Combining behavioural analyses, in vivo recordings of brain activity and post-mortem measures of brain function in rodent models, our previous works demonstrated that the exposure to specific diets (high sugar, high fat, or low protein) during adolescence differentially alters the functioning of the dopamine system, a central actor of the reward system. Moreover, changes in the composition of diet have a greater effect on adolescents than adults, highlighting adolescence as a vulnerability window for the deleterious impact of an unbalanced diet.

                                         

Many questions still remain: 1) how do early-life diet changes impact other parts of the reward system? (especially the prefrontal cortex, involved in decision making processes) 2) how might specific alterations underlie pathological development like juvenile obesity or eating disorders?