Doctor of Philosophy in Zoology (PhD)
Local regulation of glucocorticoids in the nervous and immune systems
Kiran K. Soma is a Professor at the University of British Columbia in Vancouver, Canada and a member of the Djavad Mowafaghian Centre for Brain Health and Psychology Department. Dr. Soma joined UBC in 2004. He received his BA from Stanford University, his PhD from the University of Washington, and his postdoctoral training at the University of California, Los Angeles. He has published over 130 papers on neural circuits, hormones, behaviour, and immune function. His laboratory is focused on local steroid production in the nervous and immune systems.
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Glucocorticoids are steroid hormones primarily produced by the adrenal glands and released into the bloodstream to coordinate animal development and a myriad of physiological processes. Adrenal glucocorticoid production greatly increases in response to stressors, except during a period in early development in altricial species, termed the stress hyporesponsive period. During the stress hyporesponsive period, blood glucocorticoid levels are very low and have a blunted response to some stressors. Glucocorticoids are also locally produced by organs such as the bone marrow, thymus, spleen, and brain. Within such organs, glucocorticoids can be synthesized from precursors or regenerated from the inactive metabolite; however, it is not known which route is more important. Local glucocorticoid production allows organs to independently regulate glucocorticoid levels based on demand and this may be of particular importance during the stress hyporesponsive period when blood glucocorticoid levels are low. In this dissertation, I present a series of studies examining production of glucocorticoids in lymphoid organs and brain across development and in response to an acute stressor. Briefly, I report that 1) glucocorticoids are locally elevated in lymphoid organs and specific brain regions in neonatal mice, but not adolescent or adult mice, 2) within the brain, glucocorticoid levels are more modular during early development and more coupled between regions during adulthood, 3) local glucocorticoid production increases greatly in response to a stressor during the stress hyporesponsive period, but less afterwards. Altogether, lymphoid organs and specific brain regions produce glucocorticoids. Local glucocorticoid production is of increased importance during the stress hyporesponsive period as it allows tissues to independently regulate local levels, provides benefits of high glucocorticoid levels where needed, and helps avoid the deleterious effects of glucocorticoids where they are not required.
Glucocorticoids are steroid hormones that circulate in the blood to coordinate organismal physiology. They have pleiotropic effects, regulating metabolic, cardiovascular, neural, and immune function. While glucocorticoids are classically thought to be secreted exclusively by the adrenal glands, evidence suggests that different organs may be able to autonomously regulate their local glucocorticoid levels via local production. Local production may be important when circulating glucocorticoids are low or absent, such as in early life of altricial young, which are unable to care for themselves. Immune (lymphoid) organs are particularly interesting candidates for tissue-specific regulation of glucocorticoid levels, as glucocorticoids are necessary for early-life immune development in altricial young. In this dissertation, I present a series of studies using birds and mice to examine whether tissue- specific regulation of glucocorticoids occurs in lymphoid organs. In brief, I report that a) glucocorticoids are locally elevated in lymphoid organs of newly-hatched altricial but not precocial birds, b) glucocorticoids are locally elevated in lymphoid organs of neonatal altricial mice, and c) lymphoid organs of both neonatal and adult mice synthesize glucocorticoids from other steroid precursors. Local glucocorticoid production in lymphoid organs may function to ensure production of functional lymphocytes, and factors that alter lymphoid glucocorticoid levels may play a role in programming the overall immune reactivity.
Understanding affiliative behavior is critical to understanding social organisms. While affiliative behaviors are known to exist across taxa and a wide range of contexts, the bulk of what is known about the physiological regulation of affiliation comes from studies of mammals. The zebra finch (Taeniopygia guttata) is a good model to further our understanding of the neuroendocrine regulation of affiliative behaviors. Zebra finches form sexually monogamous pair bonds, which they actively maintain throughout the year. Thus, in this system we can examine the regulatory mechanisms of affiliation associated with long-term pair maintenance both within and outside of a breeding context. In this dissertation, I present a series of studies using the zebra finch to examine the hypothesis that sex steroids regulate pair-maintenance behavior differently depending on breeding condition. In brief, I report that, (a) zebra finches have distinct sex steroid profiles based on breeding condition, (b) levels of testosterone and estradiol levels are maintained in behaviorally-relevant regions of water-restricted (i.e. non-breeding) zebra finches, (c) aromatase inhibition rapidly increases pair-maintenance behavior (proximity time), (d) chronic male-testosterone treatment decreases pair-maintenance behavior (proximity time under stressed conditions), and (e) sex steroid profiles and pair-maintenance behavior are not correlated in wild-caught zebra finches. Taken together, this work suggests that sex steroids have breeding-specific and social-context-specific regulatory effects on pair-maintenance behavior. Finally, this research shows the importance of controlling for breeding condition in all behavioral neuroendocrinology research on zebra finches and it highlights the role of seasonality in the expression and regulation of affiliative behaviors.
Stress increases adrenal glucocorticoid secretion, and chronic elevation of glucocorticoids can have detrimental effects on the brain. Dehydroepiandrosterone (DHEA) is an androgen precursor synthesized in the adrenal glands, gonads or the brain and has anti-glucocorticoid properties. However, little is known about the role of DHEA in the stress response, particularly in the brain. In Chapter 2, I validated a solid phase extraction technique for extracting steroids from lipid-rich brain tissue and plasma of songbirds. In Chapter 3, I demonstrated that acute stress had statistically significant effects on plasma corticosterone and DHEA in wild adult male song sparrows that were season and vein specific. For corticosterone, acute stress increased jugular levels more than brachial levels during the molt. For DHEA, acute stress did not affect brachial DHEA but decreased jugular DHEA during the breeding season and increased jugular DHEA during the molt. These results suggest that corticosterone and DHEA are locally synthesized in the brain during molt. In Chapter 4, I measured the effects of acute stress and season on corticosterone and DHEA in brain tissue and jugular plasma. Compared to jugular plasma, corticosterone levels were up to 10Ã lower in brain, whereas DHEA levels were up to 5Ã higher in brain and were highest in the hippocampus. Acute stress increased corticosterone levels in jugular plasma and brain, except during molt, when stress decreased corticosterone levels in the hippocampus. In Chapter 5, I tested the effects of corticosterone and DHEA treatments on the brain. Corticosterone and DHEA had additive effects on the volume, neuron number and recruitment of new cells into HVC. Elsewhere in the brain, DHEA increased BrdU+ cells only in the absence of corticosterone suggesting that corticosterone can interfere with the action of DHEA. Together, these studies demonstrate that acute stress and season have distinct effects on corticosterone and DHEA in plasma and brain. Furthermore, I demonstrate that corticosterone and DHEA can have additive effects on cell survival and recruitment in the adult brain and that, in some cases, corticosterone can inhibit the actions of DHEA in the brain.
Androgens regulate sexual and aggressive behaviour in males. However, little attention has focused on the effects of androgens on executive function. Androgens are produced in the gonads but are also produced in the brain, which might be important when systemic androgen levels are low. Here, we examined the effects of gonadectomy (GDX) and/or an androgen synthesis inhibitor (abiraterone acetate, ABI) on different forms of behavioural flexibility in adult male Long-Evans rats. Rats received either GDX or Sham surgeries and then were housed for 5 weeks, to allow for upregulation of local androgen synthesis after GDX. Five days prior to the commencement of behavioural training, rats received daily treatments of either Vehicle or ABI (40 mg/kg, p.o.), an androgen synthesis inhibitor that crosses the blood-brain barrier. Behavioural flexibility was assessed on an operant based strategy set-shifting task or a spatial reversal learning task. The strategy set-shifting task required rats to disengage from a previously correct (but now incorrect) visual-cue based discrimination strategy, and acquire and maintain a new egocentric spatial response strategy. During the set-shift to an egocentric response strategy, ABI treatment (but not GDX) caused an improvement in behavioural flexibility, by reducing the number of errors made before reaching criterion. In a separate group of rats trained on a reversal learning task, we found a similar effect, in that only ABI reduced perseverative-type errors during the reversal. During the set-shift and the response reversal, there were no effects of GDX, suggesting that GDX+Vehicle subjects maintain or upregulate neural androgen synthesis to maintain baseline flexibility. Using liquid chromatography tandem mass spectrometry, we measured testosterone (T) in the medial prefrontal cortex (mPFC) and the dorsomedial striatum (DMS). Neural T was only detectable in the Sham+Vehicle rats, suggesting that GDX+Vehicle rats may have neural T synthesis occurring in other brain regions important for behavioural flexibility. Taken together, these data suggest that neural T synthesis may serve to increase persistence of behaviour, which can in some instances suppress behavioural flexibility.
Androgens, such as testosterone (T), are steroid hormones that exert effects on several tissues, including the brain, through interaction with androgen receptors (ARs). In the brain, androgens are traditionally known for modulation of reproductive behaviors mediated by classical regions rich in ARs. However, there is growing recognition of androgen involvement in higher-order cognitive processes, such as executive functions, which are mediated by non-classical brain regions like the prefrontal cortex (PFC), nucleus accumbens (NAc), and ventral tegmental area (VTA), which are part of the mesocorticolimbic system. In males, executive functions and serum T levels decline with age, but it is unclear how age impacts mesocorticolimbic ARs, and also mesocorticolimbic T levels. In these regions, ARs are present, but often at lower abundances per cell, and are difficult to detect immunochemically. Given the lack of information about mesocorticolimbic ARs and T, and how both may be altered by age, the main goals of this thesis were to: (1) improve immunochemical visualization of ARs, (2) phenotype prefrontal AR-expressing cells, and (3) examine how aging affects levels of ARs and neural T. In brief, we use a male rat model to demonstrate superior detection of ARs through application of tyramide signal amplification (TSA), confirm that prefrontal AR-expressing cells are neuronal and not glial, and show region-dependent reductions in ARs and neural T levels with age. More specifically, we show an age-associated decline in serum T and neural T, but an increase in the ratio of neural T: serum T, suggesting partially compensatory T production may occur in the aging brain. We also show an age-associated decrease in the amount of ARs in the PFC, but not the NAc or VTA. We conclude that the observed declines in T and AR levels may contribute to age-related impairment in executive functions. Furthermore, our results also contribute to improved visualization and examination of mesocorticolimbic ARs, and ultimately, a better understanding of the role they play in cognitive processes.