Decidualization potential of endometrial mesenchymal stem cells and their role in reproductive health.

Diabetes mellitus (DM) is a common chronic metabolic disorder with a worldwide increasing prevalence. DM comprises a group of heterogeneous disorders characterized by an increase in blood glucose concentrations resulting from defects in insulin secretion, insulin action, or both. DM stems from the progressive failure of the body to manage circulating blood glucose, resulting in a wide array of comorbidities, from traditional micro- and macrovascular complications, such as stroke, nephropathies, retinopathies, and peripheral neuropathies, to recently acknowledged liver diseases. Recent evidence also indicates that DM is associated with complications affecting the central nervous system. For example, DM has lately emerged as a risk factor for neurodegenerative diseases. Moreover, DM can affect superior brain domains (e.g., cognition) and can possibly alter the emotional state. This is suggested by the evidence that diabetic patients may display behavioural abnormalities, such as heightened aggressivity and agitation, that may depend on underlying alterations in the emotional state, often occurring in patients with chronic illnesses such as DM. Progress in understanding how DM affects the emotional state could come from studies in animal models that allow investigating the effects of long-term hyperglycaemia on neurocircuits that regulate reward and aversion, as well as the behavioural correlates of those effects. Indeed, earlier studies in rodent models of DM have demonstrated the manifestation of altered responses in the elevated plus maze and the forced swim test, two experimental paradigms classically used to study in rodents the presence of anxious/depressive-like phenotypes that may stem from the presence of a negative emotional state (reviewed in. Moreover, a recent study of our group has demonstrated the occurrence of altered social behaviour in rats exposed to long-term (i.e., 5 months) diabetic hyperglycaemia, which could possibly depend on the presence of modifications in the emotional state. Indeed, in rats an interplay may exist between social behaviour and emotional states, as demonstrated by other data showing differences in social approach behaviour and in aggressivity towards conspecifics in rats with low or high levels of anxiety, as well as in putative rat models of depression. To further investigate the effects that long-term hyperglycaemia has on the emotional state, we deemed interesting to evaluate the emission of ultrasonic vocalizations (USVs) in our model of long-term (i.e., 5 months) HG rats. In fact, USVs are regarded as a behavioural marker that may express the state of arousal, motivation, as well as the presence of positive or negative emotional states in rats. USVs emitted by adolescent/adult rats can be broadly categorized in two families, the “22-kHz USVs” and the “50-kHz USVs”, based on their average frequency and supposed behavioural significance. The so-called “22-kHz USVs” possess low maximum frequency (up to 35 kHz), long duration (more than 300 ms), and lack significant frequency modulation. Rats emit 22-kHz USVs in response to aversive stimuli; accordingly, these calls are considered behavioural markers of negative emotional states. Conversely, the so-called “50-kHz USVs” possess high maximum frequency (up to 120 kHz), short duration (less than 150 ms) and may display substantial frequency modulation within individual calls. Rats emit 50-kHz USVs in response to appetitive stimuli; accordingly, these calls are considered behavioural markers of positive emotional states. On these bases, evaluating the emission of USVs could provide valuable information on the possible changes affecting the emotional state in rat models of DM. Measuring the emission of USVs allows disclosing the occurrence of both positive and negative emotional states of rats, as well as the fluctuation between and intensity of emotional states. Conversely, other experimental paradigms that have been so far used to characterize the behavioural phenotype of rat models of DM, such as the elevated plus maze and forced swim test, allow disclosing only behavioural responses that may be related to negative emotional states. Therefore, measuring the emission of USVs as a behavioural marker is a valuable approach to increase the amount of information that can be obtained in preclinical studies about the changes affecting emotional states in experimental models of central and peripheral diseases, including models of chronic diseases as DM.