Conference Agenda

The pathological consequences of type 2 diabetes mellitus (T2DM) also involve the central
nervous system with learning and memory disabilities [1-2]; indeed, T2DM patients suffer
from a higher risk to develop dementia [3]. Although different causes have been proposed
as putative contributors, how neuroactive steroids and gut microbiota impact brain
pathophysiology in T2DM is still not well explored. On this basis, in male Zucker Diabetic
Fatty (ZDF) rats, we have investigated whether T2DM alters memory abilities by the novel
object recognition test, neuroactive steroid levels by liquid chromatography-tandem mass
spectrometry, hippocampal parameters by molecular assessments and gut microbiome by
16S next-generation sequencing. Data obtained reveal that T2DM worsens memory abilities
and that these are correlated with increased of plasma corticosterone levels and with a
decrease of allopregnanolone in the hippocampus, where neuroinflammation, oxidative
stress and mitochondrial dysfunction were reported. Interestingly, our analysis highlighted
a small group of taxa strictly related to both memory impairment and neuroactive
steroid levels. Overall, the data underline an interesting role for allopregnanolone and
microbiota that may represent candidates for the development of therapeutic strategies.

The conversion of testosterone by brain aromatase is necessary for the activation of several physiological responses and behaviors, including male sexual behavior. Brain-derived estrogens (neuroestrogens) are typically thought to participate to the long-term regulation of behavior by seasonal changes in circulating testosterone, while the moment-to-moment regulation of behavior in response to environmental/social cues would depend on neurotransmitter systems. Although this view fits with the transcriptional mode of action of sex steroids, it does not take into account their rapid actions initiated at the cell membrane. Using the Japanese quail as an animal model we have studied the dichotomy between these two modes of action of neuroestrogens and how they cooperate to the fine coordination of male sexual behavior within two distinct time frames. In parallel, we have contributed to show that brain estrogen production is also rapidly regulated by behaviorally relevant cues, thus providing a mechanism for fast and local regulation of estrogenic actions. More recently we have started to explore these questions in mice to map the circuits formed by aromatase expressing neurons.

Environmental factors throughout life can influence neural activity via epigenetic mechanisms, including DNA methylation/demethylation, as well as the activity of small regulatory non-coding RNAs like microRNAs (miRNA). These mechanisms play a crucial role in regulating neuronal plasticity and heavily influence the adaptive features of the central nervous system (CNS). Dysregulation of the epigenetic landscape is associated with neuroinflammatory diseases, characterized by changes in DNA methylation and miRNA expression. Neuroinflammatory cascades involve altered cross-talk between glial cells and neurons due to the activation of microglia and astrocytes. Additionally, sex differences in the neuroimmune response are reported, with gonadal hormones impacting neural circuit plasticity and exerting neuroprotective effects under neuroinflammatory conditions. Microglial cells, the primary resident immune cells in the CNS, influence brain sexual differentiation and display altered dynamics under the influence of gonadal hormones. Consequently, it is becoming a priority to comprehend the microglial, gonadal hormone-dependent modifications of the epigenetic landscape under neuroinflammatory conditions.

The massive DNA methylome study of rodent microglial shows differences in the epigenetic landscape between males and females, with over 80,000 sequences being differentially methylated and mainly related to steroid hormones and intracellular pathways. Inflammatory conditions modify the methylation profile of 18,000 sequences in males and 76,000 in females, mainly related to metabolic pathways, cytoarchitecture, cell adhesion molecules, and inflammatory mediators. Differential expression of specific DNA methyltransferases (Dnmts) and demethylases (Gadd45) is also correlated to sex, gonadal hormones, inflammatory state, and differential epigenetic landscape.

Therefore, investigating epigenetic landscape alterations in both sexes is essential for understanding neuroplasticity mechanisms in neuroinflammatory processes.

Fundings: UAM – CAM, Programa de estímulo a la investigación de jóvenes doctores, Project: SI3-PJI-2021-00508; Agencia Estatal de Investigación, Spain, and Fondo Europeo de Desarrollo Regional (FEDER) [PID2020-115019RB-I00; PID2021-125039NB-I00], Centro de Investigación Biomédica en Red Fragilidad y Envejecimiento Saludable (CIBERFES), Instituto de Salud Carlos III, Madrid.