Abstract Background Cognitive impairment is a core feature of major depressive disorder and is associated with greater severity and resistance to antidepressant treatment. Dysfunction of the medial prefrontal cortex (mPFC), a region essential for cognitive control, emotional regulation, and motivational decision-making, has been implicated in stress-related psychopathologies and treatment resistance. Chronic stress disrupts mPFC function, yet the behavioral and neural consequences of distinct stress paradigms across mPFC-dependent domains remain poorly characterized. Aims & Objectives This study investigated the effects of two chronic stress models, inescapable footshock stress (FS) and social defeat stress (SDS), with emphasis on mPFC activity underlying anxiety-like behavior and memory function. Method Male C57BL/6 mice were exposed to FS or SDS protocols (both daily for 10 days). Behavioral assessments included social interaction with CD1 mice (for SDS), the open-field test, the novelty-suppressed feeding test (NFST), and the novel object recognition (NOR) test. To monitor mPFC neural dynamics, mice were previously transfected with GCaMP(AAV2/9-CaMKII-GCaMP8m), a calcium sensor selectively expressed in excitatory neurons, followed by the implantation of optical fibers targeting the mPFC for fiber photometry recordings time-locked to specific behavioral events during task performance. The protocol was approved by the FMRP Ethical Committee for Animal Experimentation (No. 1335/2024). Results Neither stress paradigms affected locomotion. However, both stressors significantly reduced center exploration in the open field (F(2,38) = 16.23, p<0.01). Stressed mice also displayed increased latency to feed in the NFST (F(2,33)=7.81, p<0.01), with a high proportion of non-feeding animals following SDS (SDS 55.6% vs. 0% in CTRL or FS). In the NOR test, both stressors impaired recognition of the novel object, with significant effects of novelty (F(1,76) = 17.01, p<0.01) and stress condition (F(2,76)=4.73, p=0.01). During both the training session and the familiar and novel object exploration in the test session, control and FS mice exhibited robust bulk mPFC calcium activity. In contrast, SDS-exposed mice showed reduced mPFC activation (AUC 0-2s after event; t=1.625, df=9, p=0.1). Exploration of the novel object was associated with an initial calcium peak, followed by a suggested deactivation, which was more pronounced in SDS animals. Although FS mice also showed no preference for exploring the novel object, there was no difference in mPFC calcium dynamics in the NOR test. Additionally, during exposure to an unfamiliar aggressor mouse, SDS mice displayed reduced mPFC activation when interacting with the aggressor mouse (ZScore before x after event; stress F(1,9)=10.83, p<0.01). Discussion & Conclusions Chronic stress induces anxiety-like behaviors and memory impairment. However, only the latter was associated with mPFC dysfunction in animals exposed to SDS. Integrating behavioral analyses with event-locked fiber photometry may provide a translational framework for investigating the prefrontal circuit mechanisms underlying stress-related cognitive deficits. Funding NARSAD Young Investigator Award from BBRF, CNPq, CAPES-PROEX, FAPESP.
L. D. Godoy, F. Verza, G. Wegener et al.· International Journal of Neu...· 0 citations
Abstract Background Major Depressive Disorder (MDD) frequently co-occurs with obesity, insulin resistance, and other metabolic disorders, conditions that share a state of chronic low-grade inflammation. A substantial subgroup of depressed patients exhibits elevated inflammatory biomarkers such as CRP and IL-6, which predict poorer antidepressant response and increased treatment resistance. Existing anti-inflammatory approaches (e.g., cytokine antagonists, COX-2 inhibitors) provide only modest benefits because they block inflammatory signals without restoring endogenous mechanisms that actively resolve inflammation. Specialized pro-resolving mediators (SPMs), including resolvins, lipoxins, and Annexin-A1, represent an active resolution pathway implicated in both mood regulation and metabolic homeostasis. Preliminary evidence shows impaired resolution signaling in depression-prone FSL rats, suggesting a mechanistic link between unresolved inflammation, metabolic vulnerability, and depressive symptoms. Aims & Objectives This project aims to determine whether enhancing inflammatory-resolution pathways using a novel pro-resolving drug (Compound X) improves depressive-like behavior, metabolic dysfunction, and inflammatory biomarkers. A four-phase translational program evaluates: (1) baseline disturbances in resolution pathways in depression models, (2) the antidepressant-like efficacy of Compound X under normal and high-fat diet conditions, (3) Compound X as an augmentation strategy versus classical anti-inflammatory drugs, and (4) a clinical proof-of-concept trial in patients with inflammation-associated depression. Method We combine mechanistic, behavioral, metabolic, molecular, and clinical approaches. Preclinically, depression-prone FSL rats will be investigated under standard or high-fat diets. Compound X will be tested as monotherapy and in combination with low-dose antidepressants to model treatment resistance. Behavioral readouts include forced swim test, sucrose preference, social interaction, and anxiety-related assays. Metabolic outcomes include OGTT, insulin sensitivity, body weight, liver enzymes, and lipidomics. Inflammatory and resolution markers (CRP, cytokines, SPMs, ChemR23, Annexin-A1) will be assessed by ELISA, Olink panels, lipidomics, and molecular profiling. A double-blind randomized trial (60–90 patients with CRP ≥3 mg/L or metabolic syndrome) will evaluate Compound X added to standard antidepressants over 8 weeks. Results We expect (1) impaired resolution signaling in depressed and metabolically challenged animals, (2) antidepressant-like and metabolic-improving effects of Compound X, especially under high-inflammation conditions, (3) restoration of central and peripheral resolution biomarkers, (4) superior augmentation effects compared with classical anti-inflammatory strategies, and (5) clinical improvement in depressive symptoms and inflammatory/metabolic markers in the patient subgroup with elevated inflammation. Discussion & Conclusions This project addresses a major therapeutic gap by directly targeting the resolution of inflammation rather than suppression of inflammatory pathways. Demonstrating that Compound X improves depressive and metabolic outcomes would establish resolution pharmacology as a novel treatment avenue for inflammation-associated depression and facilitate biomarker-guided precision psychiatry.
A. Akhgari, Y. Chaves, S. Joca et al.· International Journal of Neu...· 0 citations
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