Kiran Soma

Exercise is beneficial for the body, including the brain. Despite extensive research on the benefits of exercise, the neural and endocrine mechanisms controlling the motivation to exercise remain largely unknown. Wheel running is inherently rewarding for rodents and can be used to model voluntary exercise. Steroid hormones such as corticosterone, testosterone, and 17β-estradiol influence wheel running. Previous rodent studies have assessed wheel running performance, but this measure fails to distinguish between physical ability and motivation. The primary objective of this study was to validate a novel operant task for specifically measuring the motivation to run in rats. Females run more than males, and calorie restriction increases wheel running in rats. Here, adult female rats were calorie restricted (CR) or fed ad libitum (AL), and their motivation to exercise was assessed using a novel progressive ratio task in which lever pressing was paired with the opportunity to wheel run for 1 min. CR rats ran significantly more and reached a significantly higher breakpoint (i.e., last ratio not completed) than AL rats, indicating that calorie restriction increased both running performance and the motivation to run. A secondary objective was to explore whether steroids in the brain modulate the motivation to exercise. A panel of steroids including corticosterone, testosterone, and 17β-estradiol were measured in blood and microdissected brain regions after the end of the behavioural experiment using liquid chromatography tandem mass spectrometry (LC-MS/MS). Levels of testosterone and the less potent androgen androstenedione in the brain were altered by calorie restriction in a region-specific manner. Given that androgens have previously been shown to increase wheel running and calorie restriction increased the motivation to run in the current study, these results suggest that the motivation to exercise may be modulated by androgen signaling in the brain. To our knowledge, this study is the first to directly investigate the neuroendocrine mechanisms of the motivation to exercise. This work establishes a simple, specific, and effective operant task for assessing the motivation to exercise in rats and provides insight into potential neurosteroidal mechanisms modulating this behaviour.

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Behavioural flexibility, the ability to adapt behaviour in response to environmental changes, is regulated by the mesocorticolimbic system. Strategy set-shifting is one form of behavioural flexibility, where subjects initially learn one rule to receive a reward (e.g., select the lever illuminated by a visual-cue, or the “light rule”), but then must switch to a novel rule (e.g., select the lever in one position, regardless of visual-cue, or the “side rule”). Androgens, such as testosterone (T), are produced locally within the mesocorticolimbic system, and T treatment impairs set-shifting. Decreasing androgens with the androgen synthesis inhibitor abiraterone acetate (ABI) improves performance of male rats on the strategy set-shifting task using the light-side shift. However, the effect of ABI treatment was small. In this study, we assess different set-shifting procedures to make the strategy set-shifting task more difficult and examine whether this may increase the effect size of ABI treatment. In the first study, rats were assigned to one of six different set-shifting tasks, which required them to perform either the light-side shift or side-light shift, with variable numbers of minimum learning trials for the initial discrimination and with or without 20 reminder trials prior to the set-shift. The side-light shift was significantly more difficult than the light-side shift, as indicated by rats making a greater number of errors to criterion, perseverative errors, regressive errors, and never-reinforced errors on the set-shift and requiring a greater number of trials to criterion to complete the task. In the second study, rats were assigned to (1) ABI or vehicle treatment and (2) the light-side or side-light shift. We replicated our previous findings showing that the side-light shift was significantly more difficult. However, we found no effect of ABI on either type of shifts. These data demonstrate one version of the strategy set-shifting task that is more difficult and provide more insight into the potential role of androgens in behavioural flexibility in male rats.

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Adult male song sparrows (Melospiza melodia) display territorial aggression year-round. Territoriality is supported by gonadal sex steroids during the breeding season but might be supported by brain-derived sex steroids during the non-breeding season. Juvenile (hatch-year) male song sparrows also defend territories during the non-breeding season despite having immature testes and low plasma testosterone levels. Juvenile males therefore represent an excellent model to investigate the modulatory role of neurosteroids on aggression. Here, free-living non-breeding juvenile males experienced a 10-min simulated territorial intrusion (STI) or control condition. Blood and brain were collected, and steroids were quantified in blood and microdissected brain regions via liquid chromatography-tandem mass spectrometry (LC-MS/MS). Juveniles were robustly aggressive during an STI. Juveniles were equally as aggressive or more aggressive than non-breeding adults. Androgens and estrogens were low or non-detectable in blood and brain regardless of social context. After an STI, progesterone and glucocorticoids were elevated in the blood and brain in a region-specific manner. Together, these data suggest that juvenile non-breeding aggression might be rapidly modulated by adrenal-derived or brain-derived progestogens and glucocorticoids. These rapid changes in steroid levels might impact behaviourally relevant neural circuits and mobilize energy stores from peripheral organs. To our knowledge, we are the first to investigate the interplay between developmental life-stage and social context at the behavioural and steroidal level in an avian model. This work provides insight into distinct endocrine and neuroendocrine mechanisms of social behaviour in a juvenile songbird that might extend to other vertebrates.

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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.

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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.

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