Biology subjects

Azevedo, E.

Publications and source records attributed to Azevedo, E..

4 recordsLinked to original sources

bioRxiv2026

A Neurotensin Brake on Exploratory Drive under Persistent Threat

Avoidance behavior is an adaptive response that delays exploration to promote survival. Avoidance is enhanced by psychological stress and is a hallmark of many neuropsychiatric disorders. Neural circuits that control avoidance by integrating stressful stimuli and modulating exploratory behavior remain underexplored. Elucidating the functional dynamics of this highly conserved phenomenon and the underlying neural mechanism of avoidance is an important open-ended question, with relevance to understanding both innate behaviors and neuropsychiatric disorders. Using predator odor as an innate, chronic stressor to increase avoidance behaviors in mice, we identified a neural population in the lateral septum (LS) that integrates threat information and modulates latency to explore. Calcium recordings in freely exploring mice combined with activity-based transcriptomics revealed that predator-responsive LS neurons are GABAergic and express neurotensin (LSNT). Further, single nuclei RNA-seq analysis revealed that among predator-responsive neurons, NT-enriched inhibitory clusters are predominant. Chronic activation of LSNT neurons induces avoidance behaviors in the absence of predator odor, while synaptic silencing of this population abrogates predator-enhanced avoidance. Using transgenic mouse models to indelibly tag predator-responsive neurons, we defined the downstream circuit that connects the encoding of predator odor information to the lateral hypothalamus. Projection-specific activation of LSNT[->]LHA neurons recapitulate stress-induced avoidance behaviors in mice. Finally, we showed that deletion of neurotensin from LS neurons prevented the effects of predator odor on exploration. Together, these findings offer a genetically-and projection-defined, top-down circuit linking the limbic neurotensinergic system to chronic psychological stress and avoidance behaviors in mice.

neuroscience↗

bioRxiv2021

A Developmental Role for Microglial Presenilin 1 in Memory

Microglia, the macrophages of the brain, are increasingly recognized to play a key role in synaptic plasticity and function; however, the underlying mechanisms remain elusive. Presenilin 1 (PS1) is an essential protein involved in learning and memory, through neuronal mechanisms. Loss of Presenilin function in neurons impairs synapse plasticity and causes cognitive deficits in mice. Surprisingly, here we show memory enhancement in mice by deleting PS1 selectively in microglia. We further demonstrate increased synapse transmission and in vivo neuronal activity in mice by depleting PS1 during microglial development, but not after microglial maturation. Remarkably, conditional deletion of PS1 in microglia during development increased memory retention in adulthood and was dependent on the NMDA receptor subunit GluN2B. In vivo calcium imaging of freely behaving mice revealed increased amplitude of neuronal Ca2+ transients in the CA1 hippocampus of PS1 cKO mice compared to control mice, suggesting a greater CA1 engagement during novel object exploration. Finally, loss of PS1 in microglia mitigated synaptic and cognitive deficits in a mouse model of Alzheimers disease. Together our results reveal a novel mechanism and function of PS1 in microglia in which modulation can enhance neuronal activity, learning and memory in mice.

neuroscience↗

bioRxiv2019

Lateral septum neurotensin neurons link stress and anorexia

Stress and anxiety are precipitating factors for eating disorders, but the neural basis linking stress to alterations in feeding is not well understood. Here we describe a novel population of stress-responsive neurons in the lateral septum (LS) of mice that express neurotensin (LSNTS) in a sexually dimorphic, estrous cycle-dependent manner. We used in vivo imaging to show that LSNTS neurons are activated by stressful experiences when flight is a viable option, but not by a stressful experience associated with freezing or immobility. LSNTS activation leads to a decrease of food intake and body weight in mice, without altering locomotion or other behaviors associated with anxiety. Molecular profiling of LSNTS neurons showed that these neurons co-express Glp1r (glucagon-like peptide 1 receptor), and both pharmacologic and genetic manipulations of Glp1r signaling in the LS recapitulates the behavioral effects of LSNTS activation. Finally, we mapped the outputs of LSNTS neurons and show that activation of LSNTS nerve terminals in the lateral hypothalamus (LH), a well-established feeding center, also decrease food intake. Taken together, these results show that LSNTS neurons link stress and anorexia via effects on hypothalamic pathways regulating food intake.

neuroscience↗

bioRxiv2019

A molecularly defined insular cortex --> central amygdala circuit mediates conditioned overconsumption of food.

Feeding is a complex motivated behavior that is controlled not just by metabolic and homeostatic factors, but also by environmental factors such as emotion and the hedonic nature of the food itself. Yet, little is known about how brain regions involved in cognition and emotion might contribute to overeating, and therefore, obesity. We used a recently developed behavioral task in which learned contextual cues induce feeding even in sated mice to investigate the underlying neural mechanisms. Using viral tracing, molecular profiling and chemo/optogenetic techniques, we discovered that an insular cortex projection to the central amygdala is required for conditioned overconsumption but not homeostatic feeding. The projection neurons express nitric oxide synthase-1 and activation of this population suppresses satiety signals in the central amygdala. The data thus indicate that the insular cortex provides top down control of homeostatic circuits to promote overconsumption in response to learned cues.\n\nOne Sentence SummaryNitric oxide synthase-1 neurons in the insular cortex promote overconsumption by projecting to the central amygdala to suppress a homeostatic satiety signal.

neuroscience↗