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Arango-Lievano, M.

Publications and source records attributed to Arango-Lievano, M..

3 recordsLinked to original sources
bioRxiv2025

Feeding-fasting cycle of obesogenic food determines glucocorticoid neuromodulation of cortico-hippocampal activities sustaining long-term memory

BackgroundHighly caloric food consumed around the clock perturbs the metabolism and cognitive functioning. We hypothesized that obesogenic food could alter neuronal representations of memory depending on the feeding-fasting cycle. MethodsWe tracked memory performance, dendritic spine dynamics and neuronal representations of memory in C57Bl6J mice fed obesogenic food ad libitum from peri-adolescence. We aimed to correct energy rich diet-induced plasticity deficits and cognitive impairment with time-restricted feeding in males and females. We further used chemogenetics, pharmacology and knock-in mice to investigate functional correlates underlying diet-induced neurocognitive impairments. ResultsWe find that changes in the feeding-fasting cycle reverted the effects of ad libitum obesogenic food on memory impairment in both sexes (n=55, p=0.003). Concurrently, it also corrected the increased dendritic spine maintenance and neuroactivity in hippocampus and the decreased spine maintenance and activity in parietal cortex (n=48, p<0.005). Bi-directional effects in cortex and hippocampus mediated by glucocorticoid signalling are causal to behavioural changes (n=91, p=0.0008), and scaling hippocampal with cortical activities restored memory in mice fed obesogenic food (n=44, p=0.02). ConclusionThese results indicate that meal scheduling is a promising approach to confront glucocorticoid signalling bias and memory deficits caused by obesogenic food. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSWhat and when we eat contributes to our health. This is particularly worrisome for kids and adolescents because of the lifelong effects that unrestricted snacking on highly caloric food could cause on brain maturation. A variety of school policies and nutritional programs have emerged to prevent poor nutritional habits. But obesity is on the rise and a major cause of neurological disabilities difficult to detect and treat. Human studies are limited by the size and duration of sampling with low resolution metrics to prove causality between nutritional habits and cognitive health trajectory. Animal studies showed that all-day snacking on highly caloric food disrupts innate biological rhythms that influence hormonal secretions, neuronal structure and function in brain regions that encode, store and retrieve memories. It isnt known if, like adipocytes and hepatocytes, the brain in obesity can develop glucocorticoid resistance -a state that would prevent the robust but complex effects of this hormone on memory- to the point that researchers still question whether glucocorticoids are a cause or solution to obesity related-brain comorbidities. Added value of this studyLongitudinal sampling of several metrics at multiple timepoints in mice fed highly caloric food since peri-adolescence up to adulthood showed that the trajectory of obesity-related brain comorbidities is corrected when reinstating the feeding/fasting cycle, albeit consuming highly caloric food. Glucocorticoid resistance -manifesting as receptor phosphorylation deficits impeding coincidence detection between glucocorticoid and neuronal activities -was reversible when reinstating the feeding/fasting cycle, albeit consuming highly caloric food. Studies in receptor mutant mice lacking a phosphorylation site-independent of glucocorticoids showed it is required to reinstate neuroplasticity to changes of feeding/fasting cycle, albeit consuming highly caloric food. Fos-trapping experiments showed less engagement of pyramidal neurons in the cortex when activity-dependent phosphorylation of glucocorticoid receptor was low, and more in the hippocampus of mice fed obesogenic diet, which reinstating the feeding/fasting cycle reverted, albeit consuming highly caloric food. Finally, chemogenetic experiments confirmed the requirement for the co-engagement of cortical and hippocampal pyramidal neurons to fully remember, despite poor nutritional habits. Implications of all the available evidenceThe cortico-hippocampal activities necessary for remembering are uncoupled by obesogenic food consumed ad libitum but not on meal scheduling, extending neuroimaging correlation studies in obese adolescents. Poor nutritional habits cause glucocorticoid resistance in the brain as previously suggested, with altered neuronal representation of memory that meal scheduling corrected. This result should transform school policies and familial nutritional habits to promote cognitive health. Future research will develop allosteric ligands targeting phosphorylation motifs in the glucocorticoid receptor as more specific alternative to orthosteric ligands for the treatment of obesity-related brain comorbidities.

neuroscience↗
bioRxiv2019

Cerebellar dopamine D2 receptors regulate preference for social novelty

The cerebellum, a primary center involved in the control of sensorimotor tasks, also contributes to higher cognitive functions including reward, emotion and social interaction. The regulation of these behaviors has been largely ascribed to the monoaminergic system in limbic regions. However, the contribution of cerebellar dopamine signaling in the modulation of these functions remains largely unknown due to the lack of precise characterization of cerebellar dopaminoceptive neurons. By combining cell type-specific transcriptomic and histological analyses, 3D imaging and electrophysiology we demonstrate that cerebellar dopamine D2 receptors (D2R) in mice are preferentially expressed in Purkinje cells (PCs). While activation of D2R regulate synaptic efficacy onto PCs, their deletion or overexpression in PCs bidirectionally controls preference for social novelty without affecting motor functions. Altogether, these findings demonstrate novel D2Rs roles in PC function and causally link cerebellar D2R levels of expression to social behaviors.

neuroscience↗
bioRxiv2019

Persistence of learning-induced synapses depends on neurotrophic-priming of glucocorticoid receptors

Stress can either promote or impair learning and memory. Such opposing effects depend on whether synapses persist or decay after learning. Maintenance of new synapses formed at the time of learning upon neuronal network activation depends on the stress hormone activated glucocorticoid receptor (GR) and neurotrophic factor release. Whether and how concurrent GR and neurotrophin signaling integrate to modulate synaptic plasticity and learning is unknown. Here we show that deletion of the neurotrophin BDNF-dependent GR phosphorylation sites (GR-PO4) impairs long-term memory retention and maintenance of newly formed postsynaptic dendritic spines in the mouse cortex after motor skills training. Chronic stress and the BDNF polymorphism Val66Met disrupt the BDNF-dependent GR-PO4 pathway necessary for preserving training-induced spines and previously acquired memories. Conversely, enrichment living promotes spine formation but fails to salvage training-related spines in mice lacking BDNF-dependent GR-PO4 sites, suggesting it is essential for spine consolidation and memory retention. Mechanistically, spine maturation and persistence in the motor cortex depend on synaptic mobilization of the glutamate receptor GluA1 mediated by GR-PO4. Together, these findings indicate that regulation of GR-PO4 via activity-dependent BDNF signaling is important for learning-dependent synapses formation and maintenance. They also define a new signaling mechanism underlying these effects.\n\nSIGNIFICANCE STATEMENTSignal transduction of receptors tyrosine kinase and nuclear receptors is essential for homeostasis. Phosphorylation is one of the currencies used by these receptors to support homeostatic reactions in learning and memory. Here we show that consolidation of learning-induced neuroplasticity is made possible via stress activated glucocorticoid nuclear receptor phosphorylation through the brain-derived neurotrophic tyrosine kinase pathway. Crosstalk between these pathways is specific of cell types and behavioral experience (e.g. learning, stress and enrichment living). Disruption of this response may contribute to the pathophysiology of stress-related disorders and treatment resistance.

neuroscience↗