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Decision-making is a complex process essential to daily adaptation in many species. Risk is an inherent aspect of decision-making and it is influenced by gonadal hormones. Testosterone and 17β-estradiol may modulate decision making and impact the mesocorticolimbic dopamine pathway. Here, we explored sex differences, the effect of gonadal hormones and the dopamine agonist amphetamine on risk-based decision making. Intact or gonadectomised (GDX) male and female rats underwent to a probabilistic discounting task. High and low doses of testosterone propionate (1.0 or 0.2 mg) and 17β-estradiol benzoate (0.3 µg) were administered to assess acute effects on risk-based decision making. After 3-days of washout period, intact and GDX rats received high or low (0.5 or 0.125 mg/kg) doses of amphetamine and re-tested in the probabilistic discounting task. Results showed that males made more risk-based choices during the probability discounting task than female rats, but GDX did not influence risky choices. The high dose, but not the low dose, of testosterone reduced risky decision making in GDX male rats. However, 17β-estradiol had no significant effect on risk-based decision making regardless GDX status in either sex. Lastly, the high dose of amphetamine enhanced risky decision making in both intact males and females, with no effect in GDX rats. These findings demonstrated sex differences in risk-based decision making, with males making more risky choices. GDX status influenced the effects of amphetamine, suggesting different dopaminergic regulation in risk-based choices among males and females. Highlights Male rats made more risky choices in the probability discounting task than females. Gonadectomy (GDX) did not influence risk-based decision making in both sexes. A high dose of testosterone reduced risky choices in GDX male rats. A high dose of amphetamine enhanced risky choices in intact male and female rats. 17β-estradiol did not affect risk-based decision making in male or female rats.

Depression is a devastating neuropsychiatric disease that has profound effects on neural structure and function, however the pathogenesis and modes of effective treatment remain poorly understood. Stress is the primary preceding factor in depression, leading to profound deficits in neurophysiology, particularly in the hippocampus. Depressed patients show reduced hippocampal neuroplasticity, while antidepressant treatment enhances both neurogenesis and the expression of proteins that mediate plasticity such as the polysialylated form of the neural cell adhesion molecule (PSA-NCAM). Interestingly, men are half as likely as women to develop depression, where androgens appear to confer resiliency in males, as hypogonadal men are more likely to develop depression and supplementation of testosterone shows antidepressant efficacy. Little is known about the neurological underpinnings of this profound sex difference, however androgens influence the stress response and enhance hippocampal neurogenesis. The experiments in this thesis aimed to examine the role of androgens in the pathogenesis and treatment of depression using an animal model, with a specific eye toward the impact on hippocampal neurogenesis and neuroplasticity, and whether neuroplasticity mediated through PSA-NCAM is essential to antidepressant efficacy. In Chapter 2, surgically-induced hypogonadism potentiates the expression of depressive-like endophenotypes in male rodents within a chronic unpredictable stress (CUS) model of depression. Hypogonadal males showed potentiated behavioural, endocrine, and neurophysiological depressive-like phenotypes, including reductions in hippocampal neurogenesis and the expression of PSA-NCAM, compared to intact males. In Chapter 3, the hypogonadism-induced susceptibility to depressive-like phenotypes following CUS is largely inhibited by supplementation with testosterone. Testosterone treatment ameliorated physiological and endocrine phenotypes while showing independent antidepressant-like effects and facilitating the efficacy of an antidepressant drug in some measures. In Chapter 4, the enzymatic cleavage of the polysialic acid moiety from NCAM completely inhibits the behavioural efficacy of antidepressant treatment, while also serving to attenuate the survival of newly generated hippocampal neurons. Collectively, this body of research demonstrates the protective effects of androgens against the development of depression in males, coinciding with enhanced hippocampal neuroplasticity, and delineates an essential role for neuroplasticity mediated through PSA-NCAM in antidepressant action.

Depression is a devastating and prevalent disease, with profound effects on neural structure and function; however the etiology and neuropathology of depression remain poorly understood. Though antidepressant drugs exist, they are not ideal, as only a segment of patients are effectively treated, therapeutic onset is delayed, and the exact mechanism of these drugs remains to be elucidated. Several theories of depression do exist, including modulation of monoaminergic neurotransmission, alterations in neurotrophic factors, and the upregulation of adult hippocampal neurogenesis, and are briefly mentioned in the review. However none of these theories sufficiently explains the pathology and treatment of depression unto itself. Recently, neural plasticity theories of depression have postulated that multiple aspects of brain plasticity, beyond neurogenesis, may bridge the prevailing theories. The term “neural plasticity” encompasses an array of mechanisms, from the birth, survival, migration, and integration of new neurons to neurite outgrowth, synaptogenesis, and the modulation of mature synapses. This review critically assesses the role of adult hippocampal neurogenesis and the cell adhesion molecule, PSA-NCAM (which is known to be involved in many facets of neural plasticity), in depression and antidepressant treatment.