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    • In mice the Tfm mutation increased the anxiety

    2023-10-16

    In mice, the Tfm mutation increased the anxiety-state assessed in the novel object and in light/dark box tests, whereas no changes were detected in the open field or elevated plus maze tasks (Zuloaga et al., 2008). As for Tfm rats, this seemed to be related to an increased HPA response to stress. The same group showed that global AR knock-out male mice exhibit similar behavioral deficiencies and HPA dysregulation (Chen et al., 2014). An elevated anxiety-state, in particular during the light phase, was seen in the open field, novel object and elevated plus maze tests, but not in the light/dark box and corticosterone levels remained high after mild stress. In contrast, neural AR invalidation did not affect androgenic regulation of anxiety or HPA activity (Chen et al., 2016, Raskin et al., 2009, Picot et al., 2016). It has been suggested that in neural AR mutant male mice, this lack of effect may be due to residual AR expression in the amygdala and hypothalamus, but not in the hippocampus or cortex (Chen et al., 2016). Alternatively, AR-expressing sites other than neurons and glial cells may be involved in such effects. Indeed, novel data suggest the involvement of the immune system including microglia cells in the development of anxiety in response to stress (reviewed in Reader et al., 2015).
    Other dl 473 functions Recent reviews nicely summarize the role of expanded polyQ chain within the first exon of the AR in spinal and bulbar muscular atrophy and recent views on the development of this neurodegenerative disease (Giorgetti and Lieberman, 2016, Pennuto and Rinaldi, 2017). Otherwise, several studies documented the implication of androgens in neuroprotection. Pharmacological studies addressing the mechanisms underlying androgen-induced effects showed that pre-treatment of hippocampal neurons with testosterone or DHT, but not with estrogens, reduces cell death induced by different insults (Nguyen et al., 2010). In agreement with these data, the SARM RAD140 exerted a neuroprotective effect in both primary hippocampal cells and the hippocampus of kainite lesioned males (Jayaraman et al., 2014). Flutamide counteracted testosterone-induced improvement of dendritic spine density in the hippocampal CA1 region of an Alzheimer's disease mouse animal model (Jia et al., 2016). The AR was also reported to mediate DHT-induced suppression of neuronal injury in rat organotypic hippocampal slice cultures as shown by flutamide treatment (Ishihara et al., 2016). However, in a male mouse model of cerebral ischemia, the AR was found to be involved in both neuroprotective and deleterious effects of androgens (Uchida et al., 2009). In CNS lesions induced by chronic treatment with toxic agents, testosterone was effective in stimulating the formation of new myelin and in reversing myelin damage in the brain (Hussain et al., 2013). In the ventral spinal cord, it favored astrocyte recruitment and spontaneous oligodendrocyte-mediated re-myelination (Bielecki et al., 2016). Both types of glial cell express the AR. Interestingly, testosterone failed to induce these effects in Tfm mutants and neural AR knock-out mice, indicating a main role of this receptor (Bielecki et al., 2016, Hussain et al., 2013). Although less documented than the other CNS effects of androgens, a regulatory role of circadian responses has been suggested. This hypothesis was based on high AR expression in the mouse suprachiasmatic nucleus, the brain clock controlling circadian rhythms in physiology and behavior (Iwahana et al., 2008). Hypothalamic implants of testosterone in this nucleus increases AR expression and restores locomotor activity in gonadectomized male mice (Model et al., 2015).
    Conclusions and future directions Information from in vitro and in vivo models is progressively allowing a more precise view of the neural role of AR in rodents. This helps to open and consider new perspectives in human studies since androgens are also suggested to modulate several brain functions related to reproduction, cognition, anxiety or neuroprotection in man. However, much remains to be discovered and many questions still need to be addressed. For instance, although the effects of androgens are widely studied in the brain, the mechanisms underlying their effects in each brain area or nucleus still remain to be identified. In particular, AR targets and mediators remain largely unknown. A better knowledge of AR signaling pathways would be of particular relevance in studies of the physiological regulation of reproductive and non-reproductive functions as well as in physio-pathological situations such as exposure to anabolic androgenic steroids or endocrine disrupters with anti-androgenic activities. Furthermore, AR is expressed not only in neurons but also in glial cells including astrocytes, oligodendrocytes and microglia, which play a key role in brain physiology and behavior. Models targeting AR expression in each of these cell types would be of great help. Finally, more studies are needed in females. Although expressed to a lesser extent than in males, AR is present in the female brain, but its role in female brain physiology is not yet clear.