Campart, C. | Search bioRxiv

bioRxiv2021

The prostate cancer therapy enzalutamide compared with abirateroneacetate/prednisone impacts motivation for exploration, spatial learning andalters dopaminergic transmission in aged castrated mice

Cognitive side effects after cancer treatment, threatening quality of life (QoL) and adherence to treatments, now constitute a major challenge in oncology. Abiraterone acetate plus prednisone (AAP) and enzalutamide (ENZ) are next generation therapy (NGT) administered with androgen deprivation therapy to metastatic castration-resistant prostate cancer (mCRPC) patients. NGT significantly improved mCRPC overall survival but neurological side effects such as fatigue and cognitive impairment have been recently reported. We developed a behavioral 17 months-aged and castrated mouse model receiving per os AAP or ENZ during 5 days per week for six consecutive weeks. After behavioral tests, brain and plasma were collected for immunohistochemical studies. The objective was to elucidate the impact of NGT on spontaneous activity, cognitive functions and emotional reactivity, as well as neurobiological functions. ENZ exposure reduced spontaneous activity and exploratory behavior associated with a decreased tyrosine hydroxylase (TH)-dopaminergic activity in the substantia nigra pars compacta and the ventral tegmental area. A decrease in TH+-DA afferent fibers and Phospho-DARPP32-related dopaminergic neuronal activities in the striatum and the ventral hippocampus, highlighted ENZ-induced dopaminergic regulation whithin the nigrostriatal and mesolimbocortical pathways. ENZ and AAP treatments did not substantially modify spatial learning and memory or behavioral flexibility performances, but ENZ led to a thygmotaxis behavior impacting the cognitive score, and reduced c-fos-related activity of NeuN+-neurons in the dorsal hippocampus. These results establish the consequences of the mCRPC treatment ENZ in aged castrated mouse motivation to exploration and cognition, of particular importance for future management of patients elderly postrate cancer patients and their QoL.

animal behavior and cognition↗

bioRxiv2017

Social interactions impact on the dopaminergic system and drive individuality

Individuality is a ubiquitous and well-conserved feature among animal species. The behavioral patterns of individual animals affect their respective role in the ecosystem and their prospects for survival. Even though some of the factors shaping individuality have been identified, the mechanisms underlying individuation are poorly understood and are generally considered to be genetics-based. Here we devised a large environment where mice live continuously, and observed that individuality, measured by both social and individual traits, emerged and settled within the group. Midbrain dopamine neurons underwent neurophysiological adaptations that mirrored this phenotypic divergence in individual behaviors. Strikingly, modifying the social environment resulted in a fast re-adaptation of both the animals personality and its dopaminergic signature. These results indicate that individuality can rapidly evolve upon social challenges, and does not just depend on the genetic or epigenetic initial status of the animal.

neuroscience↗