Early-life and chronic exposure to high-fat diet alters noradrenergic and glutamatergic neurotransmission in the male rat amygdala and hippocampus under cognitive challenges.

Childhood obesity increases the risk of health and cognitive disorders in adulthood. Consuming high-fat diets (HFD) during critical neurodevelopmental periods, like childhood, impairs cognition and memory in humans and animals, affecting the function and connectivity of brain structures related to emotional memory. However, the underlying mechanisms of such phenomena need to be better understood. This study aimed to investigate the neurochemical profile of the amygdala and hippocampus, brain structures involved in emotional memory, during the acquisition of conditioned odor aversion in male rats that consumed a HFD from weaning to adulthood. The rats gained weight, experienced metabolic changes, and reduced insulin sensitivity and glucose tolerance. Rats showed enhanced odor aversion memory, contrary to the expected cognitive impairments. This memory enhancement was accompanied by increased noradrenergic and glutamatergic neurotransmission in the amygdala and hippocampus. Importantly, this upregulation was specific to stimuli exposure, as basal neurotransmitter levels remained unaltered by the HFD. Our results suggest that HFD modifies cognitive function by altering neurochemical signaling, in this case, upregulating neurotransmitter levels rendering a stronger memory trace, demonstrating that metabolic dysfunctions do not only trigger exclusively detrimental plasticity processes but also render enhanced plastic effects depending on the type of information.

Underlying Mechanisms of the Protective Effects of Lifestyle Factors in the Prevention of Age-Related Diseases.

The rise in life expectancy has significantly increased the occurrence of age-related chronic diseases, leading to escalating expenses for both society and individuals. Among the main factors influencing health and lifespan, lifestyle takes a forefront position. Specifically, nutrition, mental activity, and physical exercise influence the molecular and functional mechanisms that contribute to the prevention of major age-related diseases. Gaining deeper insights into the mechanisms that drive the positive effects of healthy lifestyles is valuable for creating interventions to prevent or postpone the development of chronic degenerative diseases. This review summarizes the main mechanisms that underlie the positive effect of lifestyle factors in counteracting the major age-related diseases involving brain health, musculoskeletal function, cancer, frailty, and cardiovascular diseases, among others. This knowledge will help to identify high-risk populations for targeted intervention trials and discover new biomarkers associated with healthy aging.

Understanding Sociodemographic Factors among Hispanics Through a Population-Based Study on Testicular Cancer in Mexico.

Testicular cancer (TCa) is a rare malignancy affecting young men worldwide. Sociodemographic factors, especially socioeconomic level (SEL) and healthcare access, seem to impact TCa incidence and outcomes, particularly among Hispanic populations. However, limited research has explored these variables in Hispanic groups. This study aimed to investigate sociodemographic and clinical factors in Mexico and their role in health disparities among Hispanic TCa patients. We retrospectively analyzed 244 Mexican TCa cases between 2007 and 2020 of a representative cohort with diverse social backgrounds from a national reference cancer center. Logistic regression identified risk factors for fatality: non-seminoma histology, advanced stage, and lower education levels. Age showed a significant trend as a risk factor. Patient delay and healthcare distance lacked significant associations. Inadequate treatment response and chemotherapy resistance were more likely in advanced stages, while higher education positively impacted treatment response. Cox regression highlighted non-seminoma histology, below-median SEL, higher education, and advanced-stage survival rates. Survival disparities emerged based on tumor histology and patient SEL. This research underscores the importance of comprehensive approaches that integrate sociodemographic, biological, and environmental factors to address health disparities improving outcomes through personalized interventions in Hispanic individuals with TCa.

Voluntary physical activity improves spatial and recognition memory deficits induced by post-weaning chronic exposure to a high-fat diet.

Childhood and adolescent exposure to obesogenic environments has contributed to the development of several health disorders, including neurocognitive impairment. Adolescence is a critical neurodevelopmental window highly influenced by environmental factors that affect brain function until adulthood. Post-weaning chronic exposure to a high-fat diet (HFD) adversely affects memory performance; physical activity is one approach to coping with these dysfunctions. Previous studies indicate that voluntary exercise prevents HFD's detrimental effects on memory; however, it remains to evaluate whether it has a remedial/therapeutical effect when introduced after a long-term HFD exposure. This study was conducted on a diet-induced obesity mice model over six months. After three months of HFD exposure (without interrupting the diet) access to voluntary physical activity was provided. HFD produced weight gain, increased adiposity, and impaired glucose tolerance. Voluntary physical exercise ameliorated glucose tolerance and halted weight gain and fat accumulation. Additionally, physical activity mitigated HFD-induced spatial and recognition memory impairments. Our data indicate that voluntary physical exercise starting after several months of periadolescent HFD exposure reverses metabolic and cognitive alterations demonstrating that voluntary exercise, in addition to its known preventive effect, also has a restorative impact on metabolism and cognition dysfunctions associated with obesity.

Susceptibility to GSK3ß-induced tau phosphorylation differs between the young and aged hippocampus after Wnt signaling inhibition.

The abnormal phosphorylation of the microtubule-associated protein tau is a prominent aspect of Alzheimer's disease (AD). Considerable evidence suggests that glycogen synthase kinase 3ß (GSK3ß) and the protein phosphatase 2A (PP2A) are involved in normal and pathological tau phosphorylation. However, the mechanisms underlying a shift of the phosphorylation/dephosphorylation balance that leads to abnormal tau phosphorylation remains unknown. The canonical Wnt pathway negatively regulates GSK3ß activity, and this signaling pathway has also been found to be dysregulated in the AD brain. Here, we report that the Wnt antagonist Dkk-1 selectively increases tau phosphorylation in the hippocampus of aged rats at Ser199/202, Ser396/404, and Ser214 sites. In the aged hippocampus, the inhibition of Wnt signaling is also accompanied by reduced PP2A activity. This study suggests that aging promotes tau hyperphosphorylation after Wnt inhibition, due to an imbalance between GSK3ß and PP2A activities.

Role of wnt signaling in the control of adult hippocampal functioning in health and disease: therapeutic implications.

It is well recognized the role of the Wnt pathway in many developmental processes such as neuronal maturation, migration, neuronal connectivity and synaptic formation. Growing evidence is also demonstrating its function in the mature brain where is associated with modulation of axonal remodeling, dendrite outgrowth, synaptic activity, neurogenesis and behavioral plasticity. Proteins involved in Wnt signaling have been found expressed in the adult hippocampus suggesting that Wnt pathway plays a role in the hippocampal function through life. Indeed, Wnt ligands act locally to regulate neurogenesis, neuronal cell shape and pre- and postsynaptic assembly, events that are thought to underlie changes in synaptic function associated with long-term potentiation and with cognitive tasks such as learning and memory. Recent data have demonstrated the increased expression of the Wnt antagonist Dickkopf-1 (DKK1) in brains of Alzheimer´s disease (AD) patients suggesting that dysfunction of Wnt signaling could also contribute to AD pathology. We review here evidence of Wnt-associated molecules expression linked to physiological and pathological hippocampal functioning in the adult brain. The basic aspects of Wnt related mechanisms underlying hippocampal plasticity as well as evidence of how hippocampal dysfunction may rely on Wnt dysregulation is analyzed. This information would provide some clues about the possible therapeutic targets for developing treatments for neurodegenerative diseases associated with aberrant brain plasticity.

GSK3 Function in the Brain during Development, Neuronal Plasticity, and Neurodegeneration.

GSK3 has diverse functions, including an important role in brain pathology. In this paper, we address the primary functions of GSK3 in development and neuroplasticity, which appear to be interrelated and to mediate age-associated neurological diseases. Specifically, GSK3 plays a pivotal role in controlling neuronal progenitor proliferation and establishment of neuronal polarity during development, and the upstream and downstream signals modulating neuronal GSK3 function affect cytoskeletal reorganization and neuroplasticity throughout the lifespan. Modulation of GSK3 in brain areas subserving cognitive function has become a major focus for treating neuropsychiatric and neurodegenerative diseases. As a crucial node that mediates a variety of neuronal processes, GSK3 is proposed to be a therapeutic target for restoration of synaptic functioning and cognition, particularly in Alzheimer's disease.

Spatial memory formation induces recruitment of NMDA receptor and PSD-95 to synaptic lipid rafts.

NMDA receptors (NMDARs) activation in the hippocampus and insular cortex is necessary for spatial memory formation. Recent studies suggest that localization of NMDARs to lipid rafts enhance their signalization, since the kinases that phosphorylate its subunits are present in larger proportion in lipid raft membrane microdomains. We sought to determine the possibility that NMDAR translocation to synaptic lipid rafts occurs during plasticity processes such as memory formation. Our results show that water maze training induces a rapid recruitment of NMDAR subunits (NR1, NR2A, NR2B) and PSD-95 to synaptic lipid rafts and decrease in the post-synaptic density plus an increase of NR2B phosphorylation at tyrosine 1472 in the rat insular cortex. In the hippocampus, spatial training induces selective translocation of NR1 and NR2A subunits to lipid rafts. These results suggest that NMDARs translocate from the soluble fraction of post-synaptic membrane (non-raft PSD) to synaptic lipid raft during spatial memory formation. The recruitment of NMDA receptors and other proteins to lipid rafts could be an important mechanism for increasing the efficiency of synaptic transmission during synaptic plasticity process.