Neurosteroids

Sex steroids, such as testosterone, estradiol and progesterone, are secreted by the gonads into the blood and modulate diverse neural circuits and behaviours. More recent studies show that multiple brain regions locally produce sex steroids. How the production of neurosteroids is regulated remains unclear, as are the behavioural functions of neurosteroids. These are critical gaps in our knowledge.

One set of studies is exploring the role of neurosteroids in social behaviour. In particular, these studies aim to understand how neurosteroids regulate aggressive behaviour and also how aggressive interactions affect neurosteroid production. These studies employ an avian model, the song sparrow, because male song sparrows show robust aggression during the non-breeding season, when testosterone levels in the blood are very low. In addition, neurosteroid production is higher in the avian brain than in the mammalian brain, facilitating analyses of local steroid levels and brain steroidogenic enzymes. Moreover, these studies demonstrate natural seasonal fluctuations in neurosteroids and relevance for natural behaviours.

A second set of studies is focused on the role of neurosteroids in executive function and decision making. These studies aim to elucidate how neurosteroids regulate working memory, motivation, reward seeking, and behavioural flexibility. These studies use a rat model, because of the strong foundation of neuroanatomical studies and well-established operant conditioning tests. In particular, we are conducting steroid profiling using LC-MS/MS to measure multiple steroids in microdissected brain regions, especially within the mesocorticolimbic system (ventral tegmental area, nucleus accumbens, medial prefrontal cortex, orbitofrontal cortex). In addition, we perform gene expression profiling for steroidogenic enzymes using qPCR assays. We can then manipulate neurosteroid production in specific brain regions and measure behavioural changes in a variety of behavioural paradigms, as well as changes in dopamine neurotransmission. These studies are done in collaboration with Prof. Stan Floresco. The data are relevant for understanding how steroids are important in a variety of brain diseases, including depression.

A third set of studies is determining how diet affects neurosteroids and behaviour. We are investigating the effects of early exposure to sucrose (table sugar). During early development, the brain is particularly plastic, potentially allowing for robust effects of sucrose exposure on the brain and behaviour. In particular, we are examining the long-term effects of maternal sucrose intake on the offspring using a rat model. These studies are done in collaboration with Prof. Stan Floresco and Prof. Angela Devlin. These experiments are critical for understanding how exposure to sugar early in life produces long-term effects on metabolic health, brain health, and behaviour.

We welcome collaborations on these topics, especially for steroid analyses by ultrasensitive LC-MS/MS in microdissected brain tissue.

Specific studies on neurosteroids have been supported by various organizations, including CIHR, HHMI, NIH, MSFHR, NSERC, NSF, CFI and BCKDF.