Fernandez Ugidos, I. | Search bioRxiv

bioRxiv2025

Preserved synaptic architecture but impaired ketamine-induced synaptic plasticity of layer 5 pyramidal neurons in the aged frontal cortex

Healthy aging is accompanied by a gradual decline in higher-order cognitive functions, including working memory, attention, and cognitive flexibility, processes that critically rely on intact frontal cortical circuits. While neuronal loss is minimal during aging, whether there are changes in functional plasticity in this region remains unexplored. In this regard, dendritic spines, the primary postsynaptic structures of excitatory synapses, act as key hubs for experience-dependent synaptic remodeling. Using longitudinal in vivo two-photon imaging in Thy1-eGFP-M mice, we examined age-related changes in dendritic spine density and dynamics in layer 5 pyramidal neurons of the secondary motor area (MOs), a frontal cortical region essential for strategy switching and cognitive flexibility, and that was assessed using an operant conditioning paradigm. We found that aged mice (18-22 months) exhibited significant impairments in cognitive flexibility relative to young mice (3-5 months) in the four-odor choice discrimination and reversal task. Analysis of dendritic spine plasticity revealed that baseline spine density, turnover, and morphology were largely preserved in aged mice. Sex differences were evident, with females displaying higher spine density and a greater fraction of stable spines, a feature maintained across aging. Importantly, despite preserved baseline architecture, aged mice showed impaired ketamine-induced spinogenesis and reduced stabilization of newly formed spines, in contrast to the robust structural plasticity observed in young mice. These results indicate that healthy aging selectively impairs activity-dependent synaptic remodeling without affecting steady-state spine architecture in frontal cortical circuits. By linking deficits in induced synaptic plasticity to age-related impairments in cognitive flexibility, our study highlights the critical need to target plasticity mechanisms as a therapeutic strategy to restore executive function and cognitive adaptability in the aging brain.

neuroscience↗

bioRxiv2025

Estradiol treatment enhances neurovascular coupling independent of metabolic health status in a mouse model of menopause

The loss of ovarian estrogen during the menopause transition has been identified as a risk factor for increased cardiometabolic and neurovascular dysfunction, age-related cognitive decline, and Alzheimers disease. A wealth of studies using rodent models of menopause have highlighted the cardio- and neuroprotective effects of 17{beta}-estradiol (E2) treatment when administered within a critical period, though these have yet to be successfully translated to human populations in clinical trials of hormone therapy. A proposed explanation for this mismatch in results is the "healthy cell bias," where estrogen is only beneficial when initiated in physiologically intact systems. Our study investigates whether pre-existing metabolic dysfunction attenuates the effects of E2 on neurovascular coupling (NVC) in a rodent model of menopause. Female mice were fed a high-fat diet (HFD) or control diet (CD) for 11 weeks to induce metabolic dysfunction, followed by ovariectomy (OVX) and subsequent E2 or vehicle (Veh) treatment. NVC was assessed in awake mice using two-photon laser scanning microscopy of penetrating arterioles (PAs) in the somatosensory cortex, barrel field. Mice developed glucose intolerance and increased adiposity yet displayed intact NVC following 11 weeks of HFD exposure. Following ovariectomy, E2 treatment enhanced NVC responses regardless of diet. Interestingly, in HFD-fed mice, E2 appeared to reduce basal PA diameter relative to Veh, suggesting health status-specific mechanisms of action. These results indicate that PAs retain functional sensitivity to estrogen treatment in the face of metabolic impairment, which has implications for the use of hormone therapy in women that arrive at the menopause transition with varied pre-existing cardiometabolic disorders.

neuroscience↗