Increasing evidence have highlighted significant sex-related differences in animal physiology and behavior, both in health and disease. Despite that, most neuroscience research involving animal models is still conducted using males only. Estrogen (E2) is known to have a protective role in females, mainly by preventing inflammation, however, when hormone levels decline, females become more prone than males to metabolic, cardiovascular and psychiatric diseases. Thanks to our established conditional knockout mouse model (Npy1rrfb mice), in which the gene encoding for the main NPY receptor Y1 is specifically inactivated in forebrain principal neurons, we have demonstrated that female gonadal hormones and the NPY-Y1 receptor system functionally interact in the arcuate nucleus of the hypothalamus in regulating neuroinflammation and susceptibility to obesity and associated disorders. We also discovered the presence of a possible functional link between NPY-Y1R transmission and key regulators of neuroplasticity, perineuronal nets (PNNs), for maintaining the correct E/I balance in the hippocampus, important for cognitive processes. PNNs are extracellular matrix structures that envelop types of neurons, mostly parvalbumin positive interneurons (PVI), to regulate neuroplasticity. In this study we show that Npy1rrfb females, ovariectomized and exposed to a high fat diet, exhibit an anxious-like phenotype and cognitive deficits typical of menopause, associated with neuroinflammation and PNN expression alterations in other brain areas important for metabolic and behavioral control, such as the anterior cingulate and the prelimbic areas of the prefrontal cortex. These results further support our findings relating to sex-dependent modulation of the NPY-Y1R system.Perineuronal nets enveloping neurons