Gender Impacts the Relationship between Mood Disorder Symptoms and Effortful Avoidance Performance.

We must often decide how much effort to exert or withhold to avoid undesirable outcomes or obtain rewards. In depression and anxiety, levels of avoidance can be excessive and reward-seeking may be reduced. Yet outstanding questions remain about the links between motivated action/inhibition and anxiety and depression levels, and whether they differ between men and women. Here, we examined the relationship between anxiety and depression scores, and performance on effortful active and inhibitory avoidance (Study 1) and reward seeking (Study 2) in humans. Undergraduates and paid online workers ([Formula: see text] = 545, [Formula: see text] = 310; [Formula: see text] = 368, [Formula: see text] = 450, [Formula: see text] = 22.58, [Formula: see text] = 17-62) were assessed on the Beck Depression Inventory II (BDI) and the Beck Anxiety Inventory (BAI) and performed an instructed online avoidance or reward-seeking task. Participants had to make multiple presses on active trials and withhold presses on inhibitory trials to avoid an unpleasant sound (Study 1) or obtain points toward a monetary reward (Study 2). Overall, men deployed more effort than women in both avoidance and reward-seeking, and anxiety scores were negatively associated with active reward-seeking performance based on sensitivity scores. Gender interacted with anxiety scores and inhibitory avoidance performance, such that women with higher anxiety showed worse avoidance performance. Our results illuminate effects of gender in the relationship between anxiety and depression levels and the motivation to actively and effortfully respond to obtain positive and avoid negative outcomes.

Androgen synthesis inhibition increases behavioural flexibility and mPFC tyrosine hydroxylase in gonadectomized male rats.

Behavioural flexibility is essential to adapt to a changing environment and depends on the medial prefrontal cortex (mPFC). Testosterone administration decreases behavioural flexibility. It is well known that testosterone is produced in the gonads, but testosterone is also produced in the brain, including the mPFC and other nodes of the mesocorticolimbic system. It is unclear how testosterone produced in the brain versus the gonads influences behavioural flexibility. Here, in adult male rats, we assessed the effects of the androgen synthesis inhibitor abiraterone acetate (ABI) and long-term gonadectomy (GDX) on behavioural flexibility in two paradigms. In Experiment 1, ABI but not GDX reduced the number of errors to criterion and perseverative errors in a strategy set-shifting task. In Experiment 2, with a separate cohort of rats, ABI but not GDX reduced perseverative errors in a reversal learning task. In Experiment 1, we also examined tyrosine hydroxylase immunoreactivity (TH-ir), and ABI but not GDX increased TH-ir in the mPFC. Our findings suggest that neurally-produced androgens modulate behavioural flexibility via modification of dopamine signalling in the mesocorticolimbic system. These results indicate that neurosteroids regulate executive functions and that ABI treatment for prostate cancer might affect cognition.

Effects of aging on testosterone and androgen receptors in the mesocorticolimbic system of male rats.

As males age, systemic testosterone (T) levels decline. T regulates executive function, a collection of cognitive processes that are mediated by the mesocorticolimbic system. Here, we examined young adult (5 months) and aged (22 months) male Fischer 344 × Brown Norway rats, and measured systemic T levels in serum and local T levels in microdissected nodes of the mesocorticolimbic system (ventral tegmental area (VTA), nucleus accumbens (NAc), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC)). We also measured androgen receptor (AR) immunoreactivity (-ir) in the mesocorticolimbic system. As expected, systemic T levels decreased with age. Local T levels in mesocorticolimbic regions - except the VTA - also decreased with age. Mesocorticolimbic T levels were higher than serum T levels at both ages. AR-ir was present in the VTA, NAc, mPFC, and OFC and decreased with age in the mPFC. Taken together with previous results, the data suggest that changes in androgen signaling may contribute to changes in executive function during aging.

Effects of aging on executive functioning and mesocorticolimbic dopamine markers in male Fischer 344 × brown Norway rats.

Aging is associated with changes in executive functioning and the mesocorticolimbic dopamine system. However, the effects of aging on different forms of behavioral flexibility are not fully characterized. In young (∼5 months) and aged (∼22 months) male Fischer 344 × brown Norway rats, we assessed spatial working memory and different forms of behavioral flexibility using operant tasks: strategy set-shifting (study 1) or probabilistic reversal learning (study 2). We also assessed dopaminergic markers using immunohistochemistry. Compared with young rats, aged rats displayed impairments in working memory. Aged rats also showed nonperseverative impairments in set-shifting, with a subset also showing impairments in initial discrimination learning. In probabilistic reversal learning, aged rats completed more reversals, driven by an increased sensitivity to recent reward and negative feedback. Tyrosine hydroxylase (TH) showed region-specific changes with aging and was correlated with several measures of behavioral flexibility. These data suggest that age-related changes prefrontal cortical function and dopamine synthesis contribute to changes in executive functioning during aging.

Testosterone and Corticosterone in the Mesocorticolimbic System of Male Rats: Effects of Gonadectomy and Caloric Restriction.

Steroid hormones can modulate motivated behaviors through the mesocorticolimbic system. Gonadectomy (GDX) is a common method to determine how steroids influence the mesocorticolimbic system, and caloric restriction (CR) is often used to invigorate motivated behaviors. A common assumption is that the effects of these manipulations on brain steroid levels reflects circulating steroid levels. We now know that the brain regulates local steroid levels in a region-specific manner; however, previous studies have low spatial resolution. Using ultrasensitive liquid chromatography tandem mass spectrometry, we examined steroids in microdissected regions of the mesocorticolimbic system (ventral tegmental area, nucleus accumbens, medial prefrontal cortex). We examined whether GDX or CR influences systemic and local steroids, particularly testosterone (T) and steroidogenic enzyme transcripts. Adult male rats underwent a GDX surgery and/or CR for either 2 or 6 weeks. Levels of T, the primary steroid of interest, were higher in all brain regions than in the blood, whereas corticosterone (CORT) was lower in the brain than in the blood. Importantly, GDX completely eliminated T in the blood and lowered T in the brain. Yet, T remained present in the brain, even 6 weeks after GDX. CR decreased both T and CORT in the blood and brain. Steroidogenic enzyme (Cyp17a1, 3ß-hydroxysteroid dehydrogenase, aromatase) transcripts and androgen receptor transcripts were expressed in the mesocorticolimbic system and differentially affected by GDX and CR. Together, these results suggest that T is synthesized within the mesocorticolimbic system. These results provide a foundation for future studies examining how neurosteroids influence behaviors mediated by the mesocorticolimbic system.