We previously demonstrated that Npy1r^rfb mice, which carry the conditional inactivation of the Npy1r gene in forebrain principal neurons, display a sexually dimorphic phenotype, with male mice showing metabolic, hormonal and behavioral effects and females being only marginally affected. Moreover, exposure of Npy1r^rfb male mice to a high-fat diet (HFD) increased body weight growth, adipose tissue, blood glucose levels and caloric intake compared to Npy1r^2lox male controls. We used conditional knockout Npy1r^rfb and Npy1r^2lox control mice to examine whether forebrain disruption of the Npy1r gene affects susceptibility to obesity and associated disorders of cycling and ovariectomized (ovx) female mice in a standard diet (SD) regimen or exposed to an HFD for 3 months. The conditional deletion of the Npy1r gene increased body weight and subcutaneous white adipose tissue weight in both SD- and HFD-fed ovx females but not in cycling females. Moreover, compared with ovx control females on the same diet regimen, Npy1r^rfb females displayed increased microglia number and activation, increased expression of Neuropeptide Y (NPY)-immunoreactivity (IR) and decreased expression of proopiomelanocortin-IR in the hypothalamic arcuate nucleus (ARC). These results suggest that in the ARC NPY-Y1R reduces the susceptibility to obesity of female mice with low levels of gonadal hormones and that this effect may be mediated via NPY-Y1R ability to protect the brain against neuroinflammation.

NPY and its Y1 cognate receptor (Y1R) have been shown to be involved in the regulation of stress, anxiety, depression and energy homeostasis. We previously demonstrated that conditional knockout of Npy1r gene in the excitatory neurons of the forebrain of adolescent male mice (Npy1r^rfb mice) decreased body weight growth and adipose tissue and increased anxiety. In the present study, we used the same conditional system to examine whether the targeted disruption of the Npy1r gene in limbic areas might affect susceptibility to obesity and associated disorders during adulthood in response to a 3-week high-fat diet (HFD) regimen. We demonstrated that following HFD exposure, Npy1r^rfb male mice showed increased body weight, visceral adipose tissue, and blood glucose levels, hyperphagia and a dysregulation of calory intake as compared to control Npy1r^2lox mice. These results suggest that low expression of Npy1r in limbic areas impairs habituation to high caloric food and causes high susceptibility to diet-induced obesity and glucose intolerance in male mice, uncovering a specific contribution of the limbic Npy1r gene in the dysregulation of the eating/satiety balance.

Anxiety- and depression-related disorders are frequently associated with deficits in social behavior, including excessive aggression and violence, which may arise from disruptions in the neural circuits regulating emotions and social interactions. Sex differences play a crucial role in modulating emotional and social behaviors, particularly aggression and anxiety. Neuropeptide Y (NPY) and its Y1 receptor (Y1R) are involved in regulating various physiological functions, including emotional behavior and stress response. We previously demonstrated that conditional knockout of Npy1r gene in the forebrain excitatory neurons (Npy1r^rfb mutant mice) increased anxiety-like behavior and hypothalamus-pituitary-adrenocortical axis reactivity and decreased body weight growth in a sex-dependent manner. In the present study we investigated how the depletion of the Npy1r gene in limbic areas might affect male and female mice by using a test battery aimed at assessing anxiety-like, social and aggressive behavior as well as response to novelty. Our results showed reduced exploratory behavior and increased anxiety in response to a novel environment in Npy1r^rfb mice, with females exhibiting more pronounced effects. In contrast, only Npy1r^rfb males showed reduced neophobia and increased impulsivity in response to a novel palatable food. Moreover, reduced limbic Npy1r expression decreased territorial aggression and increased defensive behaviors only in males. These findings reveal that limbic Y1R modulates anxiety, social interaction, and aggression in a sex-dependent manner. Moreover, they uncover a novel role for Y1R in regulating intermale aggression and suggest sex-specific links between NPY-Y1R signaling and the modulation of motivational and emotional responses.

Ultimate and proximate levels of analysis offer synergistic explanations can improve the search for causes of disease and their cures. Here we review how several principles of evolutionary biology such as historical contingencies, mismatches, trade-offs, sexual selection and genomic conflict are applied to problems in medicine and psychiatry. The application of evolutionary principles to many other domains of medicine, among them mental disorders, have not received the same reception from preclinical and clinical researchers. The lack of a well-coordinated interdisciplinarity may be one reason for the slow application of evolutionary principles to biomedicine and psychiatry. This is exemplified by the case of ethopharmacology, an evolutionary approach to psychopharmacology strongly proposed and applied by ethologists but apparently unknown to many evolutionary minded scholars. Another reason has to do with the lack of efforts from many medical schools to integrate evolution and its principles in their curriculum studiorum. Interestingly, this Darwinian approach is generating an important evolutionary epistemology for the study of body and human mind health and diseases.

Age-dependent cognitive decline is associated with a downregulation of the cyclic nucleotide cascade. Through their regulation of the cGMP pathway, phosphodiesterase 5 inhibitors have been proven to enhance episodic memory in rodents and mice and have been proposed as drugs with the potential to counteract aging-dependent cognitive and neurodegenerative disorders. One caveat of this line of research is that these studies have been carried out in male rodents, leaving unknown their effects on female cognition. With the present study, we aim to fill this methodological gap. Twenty-four-month-old female mice were exposed to a continuous 33-day treatment with 2 mg/kg of Vardenafil and tested in the object recognition test, the elevated plus maze, and the open field test. The results show that, compared to females from the control group, Vardenafil-exposed females showed higher discrimination between familiar and novel objects compared to controls both at 1 h and 24 h delays, indicating that Vardenafil enhances episodic memory. No effects of Vardenafil on anxiety-like behaviors were found.