Marques-Morgado, I. | Search bioRxiv

bioRxiv2025

Chronic Circadian Disturbance Reshapes Hippocampal Connectivity and Cognitive Function

Circadian rhythms regulate a wide range of physiological and cognitive functions, yet the neural mechanisms linking circadian timing to memory remain poorly defined. Here, we identify a direct anatomical projection from the suprachiasmatic nucleus (SCN) to the dorsal hippocampus using complementary viral anterograde, retrograde, and monosynaptic tracing approaches, alongside established indirect pathways via septal and neuromodulatory regions. These findings revise prevailing models that restrict SCN influence on hippocampal function to polysynaptic routes. Functionally, chronic circadian disruption (CCD) induced region-specific metabolic alterations and widespread reorganization of brain-wide functional connectivity (FC). Hypometabolism emerged in the SCN, dentate gyrus, and perirhinal and entorhinal cortices, accompanied by loss of SCN- hippocampal connectivity and compensatory engagement of cortical and subcortical networks. In contrast, the serotonergic dorsal raphe nucleus showed selective hypermetabolism and increased connectivity with the SCN, prefrontal cortex, and hippocampus, suggesting altered neuromodulatory control under circadian misalignment. Behaviorally, CCD produced a selective impairment in object recognition memory, while spatial memory, working memory, cognitive flexibility, and hippocampal synaptic plasticity at the Schaffer collateral-CA1 synapse remained intact. Disrupted functional coupling within perirhinal-entorhinal- hippocampal and prefrontal-hippocampal circuits, together with altered SCN-medial septum- hippocampus connectivity, indicates that cognitive dysfunction arises from desynchronization of distributed brain networks rather than local synaptic failure. Together, these findings provide a new mechanistic framework linking circadian disruption to selective memory impairment and highlight network-level synchrony as a potential target for chronotherapeutic intervention.

neuroscience↗

bioRxiv2021

Glycation modulates glutamatergic signalling and exacerbates Parkinson's disease-like phenotypes

Alpha-synuclein (aSyn) is assumed to be a central player in the pathogenesis of synucleinopathies due to its accumulation in typical protein aggregates in the brain. However, it is still unclear how it contributes to neurodegeneration. Type-2 diabetes mellitus is a risk factor for Parkinsons disease and, one common molecular alteration among these disorders is an age-associated increase in protein glycation. Thus, we hypothesized that glycation-induced dysfunction of neuronal pathways might be an underlying molecular cause of synucleinopathies. Here, we evaluated if increased brain glycation modulated motor and/or non-motor phenotypes in a mouse model of synucleinopathies. In addition, we dissected the specific impact of methylglyoxal (MGO, a glycating agent) in mice overexpressing aSyn in the brain, and unveiled the major molecular pathways altered. Age-matched (16 weeks old) male aSyn transgenic (Thy1-aSyn) or WT mice received a single dose of MGO or vehicle via intracerebroventricular (ICV) injection. Behavioural phenotypes were analysed 4 weeks post-treatment, and, at the end of the tests, biochemical and histological studies were conducted on brain tissue. We found that glycation potentiates motor dysfunction, assessed by vertical pole, rotarod and hindlimb clasping tests in Thy1-aSyn mice. In addition, it induces cognitive impairment (Y maze test), olfactory disturbances (block test), and colonic dysfunction. These behavioural changes were accompanied by the accumulation of aSyn in the midbrain, striatum, and prefrontal cortex, and by an overall increase in glycation in the midbrain and cerebellum. Furthermore, MGO induced neuronal and dopaminergic cell loss in the midbrain of Thy1-aSyn mice. Quantitative proteomic analysis revealed that, in Thy1-aSyn mice, MGO mainly impacts on glutamatergic proteins in the midbrain, but not in the prefrontal cortex, where it mainly affects the electron transport chain. Among the altered proteins in the midbrain, we found an upregulation of N-Methyl-D-Aspartate (NMDA) and -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors levels, glutaminase, vesicle glutamate transporter (VGLUT), and the excitatory amino acid transporter (EAAT1), suggesting potentiation of glutamatergic signalling. Overall, we demonstrated that MGO-induced glycation accelerates Parkinsonian-like sensorimotor and cognitive alterations. The increase in glutamatergic-related proteins in the midbrain may represent a compensatory mechanism to the MGO-induced dopaminergic neurodegeneration. Our study sheds light into the enhanced vulnerability of the midbrain in Parkinsons disease-related synaptic dysfunction that, ultimately leads to cell loss, and provides molecular insight into the observation that glycation suppressors and anti-glutamatergic drugs hold promise as disease-modifying therapies for synucleinopathies.

neuroscience↗