Gomes-Ribeiro, J. | 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.

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bioRxiv2023

Mapping functional traces of opioid memories in the rat brain

Addiction to psychoactive substances is a maladaptive learned behavior. Contexts surrounding drug use integrate this aberrant mnemonic process and hold strong relapse triggering ability. Here we asked where context and salience might be concurrently represented in the brain, and found circuitry hubs specific to morphine-related contextual information storage. Starting with a classical rodent morphine-conditioned place preference (CPP) apparatus, we developed a CPP protocol that allows stimuli presentation inside a magnetic resonance imaging scanner, to allow the investigation of whole brain activity during retrieval of drug-context paired associations, as well as resting state functional connectivity under the effect of morphine conditioning. Using fMRI we found context-specific responses to stimulus onset in multiple brain regions, namely limbic, sensory, and striatal. Furthermore, we found increased functional connectivity of lateral septum with regions within and beyond a proposed limbic network, and of the lateral habenula with hippocampal CA1 region, in response to repeated pairings of drug and context. Subsequent exposure to either morphine or saline-conditioned contexts led to significant, context-specific, functional interconnectivity among amygdala, lateral habenula, and lateral septum. Resting-state connectivity of the lateral habenula and amygdala, and that during saline-paired context presentation significantly predicted inter-individual CPP score differences. In sum, our findings show that drug- and saline-paired contexts form distinct memory traces in overlapping functional brain microcircuits, and intrinsic connectivity of habenula, septum, and amygdala likely influences the maladaptive contextual learning in response to opioids. We identify functional mechanisms involved in the acquisition and retrieval of drug-related memories that might be behind the relapse-triggering ability of opioid-associated sensory/contextual cues. Graphical abstractTo investigate the brain-wide regional activity underlying drug addiction Gomes-Ribeiro et al. have developed a rodent morphine-induced CPP (conditioned place preference) protocol whose contextual cues can be consistently presented inside an MRI apparatus. The authors found a common circuitry supporting the neural mechanisms responsible for memorizing an association between distinct contexts, and morphine or the absence thereof, that includes regions involved in affect, reward, contextual perception and memory, with subtle, intriguing, functional specificities ultimately underlying the storage of distinct, individual, CPP memory engrams across the different animals. Animals that are more prone to strong emotional responses (as measured by the baseline resting state amygdala and habenula functional connectivity), exhibit a kind of neural circuit priming effect, and thus develop stronger connectivity patterns in anticipation of stronger morphine addiction behavior. These findings could help to clarify the inter-individual sensitivity to opioids in humans, since despite responding positively to the effects of opioids, many humans do not develop an addiction. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/552221v2_ufig1.gif" ALT="Figure 1"> View larger version (49K): org.highwire.dtl.DTLVardef@1cd4989org.highwire.dtl.DTLVardef@96c76corg.highwire.dtl.DTLVardef@feadd0org.highwire.dtl.DTLVardef@4547b6_HPS_FORMAT_FIGEXP M_FIG C_FIG

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