scholarly journals Insufficiency of ventral hippocampus to medial prefrontal cortex transmission explains antidepressant non-response

2021 ◽  
pp. 026988112110482 ◽  
Author(s):  
Mariusz Papp ◽  
Piotr Gruca ◽  
Magdalena Lason ◽  
Ewa Litwa ◽  
Wojciech Solecki ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Antidepressant Drug ◽  
Antidepressant Drugs ◽  
Ventral Hippocampus ◽  
Normal Brain ◽  
Mild Stress ◽  
Sucrose Intake ◽  
Normal Behaviour ◽  
Wky Rats

Background: There is extensive evidence that antidepressant drugs restore normal brain function by repairing damage to ventral hippocampus (vHPC) and medial prefrontal cortex (mPFC). While the damage is more extensive in hippocampus, the evidence of treatments, such as deep brain stimulation, suggests that functional changes in prefrontal cortex may be more critical. We hypothesized that antidepressant non-response may result from an insufficiency of transmission from vHPC to mPFC. Method: Antidepressant non-responsive Wistar Kyoto (WKY) rats were subjected to chronic mild stress (CMS), then treated with chronic daily administration of the antidepressant drug venlafaxine (VEN) and/or repeated weekly optogenetic stimulation (OGS) of afferents to mPFC originating from vHPC or dorsal HPC (dHPC). Results: As in many previous studies, CMS decreased sucrose intake, open-arm entries on the elevated plus maze (EPM), and novel object recognition (NOR). Neither VEN nor vHPC–mPFC OGS alone was effective in reversing the effects of CMS, but the combination of chronic VEN and repeated OGS restored normal behaviour on all three measures. dHPC–mPFC OGS restored normal behaviour in the EPM and NOR test irrespective of concomitant VEN treatment, and had no effect on sucrose intake. Conclusions: The synergism between VEN and vHPC–mPFC OGS supports the hypothesis that the antidepressant non-responsiveness of WKY rats results from a failure of antidepressant treatment fully to restore transmission in the vHPC–mPFC pathway.

scholarly journals AMPA receptors mediate the pro-cognitive effects of electrical and optogenetic stimulation of the medial prefrontal cortex in antidepressant non-responsive Wistar–Kyoto rats

2020 ◽  
Vol 34 (12) ◽  
pp. 1418-1430
Author(s):  
Mariusz Papp ◽  
Piotr Gruca ◽  
Magdalena Lason ◽  
Ewa Litwa ◽  
Wojciech Solecki ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Medial Prefrontal Cortex ◽  
Ampa Receptor ◽  
Ampa Receptors ◽  
Antidepressant Drugs ◽  
Mild Stress ◽  
Sucrose Intake ◽  
Wky Rats ◽  
Optogenetic Stimulation ◽  
Wistar Kyoto

Background: The chronic mild stress (CMS) procedure is a widely used animal model of depression, and its application in Wistar–Kyoto (WKY) rats has been validated as a model of antidepressant-refractory depression. While not responding to chronic treatment with antidepressant drugs, WKY rats do respond to acute deep brain stimulation (DBS) of the medial prefrontal cortex (mPFC). In antidepressant-responsive strains there is evidence suggesting a role for AMPA subtype of glutamate receptor in the action mechanism of both antidepressants and DBS. Methods: Animals were subjected to CMS for 6 to 8 weeks; sucrose intake was monitored weekly and novel object recognition (NOR) test was conducted following recovery from CMS. Wistars were treated chronically with venlafaxine (VEN), while WKY were treated acutely with either DBS, optogenetic stimulation (OGS) of virally-transduced (AAV5-hSyn-ChR2-EYFP) mPFC or ventral hippocampus, or acute intra-mPFC injection of the AMPA receptor positive allosteric modulator CX-516. The AMPA receptor antagonist NBQX was administered, at identical sites in mPFC, immediately following the exposure trial in the NOR. Results: Sucrose intake and NOR were suppressed by CMS, and restored by VEN in Wistars and by DBS, OGS, or CX-516 in WKY. However, OGS of the ventral hippocampal afferents to mPFC was ineffective. A low dose of NBQX selectively blocked the procognitive effect of VEN, DBS and OGS. Conclusions: These results suggest that activation of AMPA receptors in the mPFC represents a common pathway for the antidepressant effects of both conventional (VEN) and novel (DBS, OGS) antidepressant modalities, in both antidepressant responsive (Wistar) and antidepressant-resistant (WKY) rats.

Rapid antidepressant effects of deep brain stimulation of the pre-frontal cortex in an animal model of treatment-resistant depression

2018 ◽  
Vol 32 (10) ◽  
pp. 1133-1140 ◽  
Author(s):  
Mariusz Papp ◽  
Piotr Gruca ◽  
Magdalena Lason ◽  
Katarzyna Tota-Glowczyk ◽  
Monika Niemczyk ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Deep Brain Stimulation ◽  
Brain Stimulation ◽  
Antidepressant Drugs ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Sucrose Intake ◽  
Treatment Resistant ◽  
Deep Brain ◽  
Stimulation Of

Background: A significant proportion of depressed patients fail to respond to treatment with antidepressant drugs. Such patients might nonetheless respond to deep brain stimulation of the prefrontal cortex. Deep brain stimulation has also been shown to normalize behaviour in the chronic mild stress (CMS) model of depression. However, these studies have involved animals that are in general treatment responsive. Thus, this is not the ideal situation in which to investigate how deep brain stimulation is effective where antidepressant drugs are not. Aims: Here, we studied the behavioural effects of deep brain stimulation in treatment-resistant animals. Methods: Wistar rats were exposed to chronic mild stress and concurrent treatment with saline or one of three antidepressant drugs, imipramine, citalopram and venlafaxine. Individuals were selected from the CMS-exposed drug-treated groups that had failed to increase their sucrose intake by week 5 of drug treatment. All animals were then implanted with deep brain stimulation electrodes in the ventro-medial prefrontal cortex, and tested for sucrose intake and in the elevated plus maze and novel object recognition test, following 2 × 2 h of deep brain stimulation. Results: The selected drug-treated animals were found to be antidepressant-resistant in all three tests. With a single exception (sucrose intake in imipramine-treated animals), deep brain stimulation reversed the anhedonic, anxiogenic and dyscognitive effects of CMS in all four conditions, with no significant differences between saline- and drug-treated animals. Conclusions: These data provide a proof of principle that deep brain stimulation of the prefrontal cortex can be effective in a rat model of resistance to chronic antidepressant treatment, replicating the clinical effect of deep brain stimulation in treatment-resistant depression.

β-Carboline harmine reverses the effects induced by stress on behaviour and citrate synthase activity in the rat prefrontal cortex

2013 ◽  
Vol 25 (6) ◽  
pp. 328-333 ◽  
Author(s):  
Helena Mendes Abelaira ◽  
Gislaine Zilli Réus ◽  
Giselli Scaini ◽  
Emilio Luiz Streck ◽  
José Alexandre Crippa ◽  
...  
Keyword(s):  
Prefrontal Cortex ◽  
Energy Metabolism ◽  
Citrate Synthase ◽  
Memory Performance ◽  
Chronic Mild Stress ◽  
Mild Stress ◽  
Sucrose Intake ◽  
The Brain

ObjectivesThe present study was aimed at evaluating the effects of the administration of β-carboline harmine on behaviour and citrate synthase activity in the brain of rats exposed to chronic mild stress (CMS) procedure.MethodsTo this aim, after 40 days of exposure to CMS procedure, rats were treated with harmine (15 mg/kg/day) for 7 days, then memory, anhedonia and citrate synthase activity were assessed.ResultOur findings demonstrated that stressed rats treated with saline increased the sucrose intake, and the stressed rats treated with harmine reversed this effect. Neither stress nor harmine treatment altered memory performance in rats. In addition, chronic stressful situations induced increase in citrate synthase activity in the prefrontal cortex, but not in the hippocampus and striatum. Treatment with harmine reversed the increase in citrate synthase activity in the prefrontal cortex.ConclusionThese findings support the hypothesis that harmine could be involved in controlling the energy metabolism.

scholarly journals Molecular mechanism of reward treatment ameliorating chronic stress-induced depressive-like behavior assessed by sequencing miRNA and mRNA in medial prefrontal cortex

2020 ◽  
Author(s):  
Tingting An ◽  
Zhenhua Song ◽  
Jin-Hui Wang
Keyword(s):  
Major Depressive Disorder ◽  
Prefrontal Cortex ◽  
Depressive Disorder ◽  
Molecular Mechanism ◽  
Chronic Stress ◽  
Medial Prefrontal Cortex ◽  
Differentially Expressed ◽  
Mild Stress ◽  
Major Depressive ◽  
Differentially Expressed Mirnas

Abstract Background Major depressive disorder (MDD) is a disease that seriously endangers human health and mental state. Chronic stress and lack of reward may reduce the function of the brain's reward circuits, leading to major depressive disorder. The effect of reward treatment on chronic stress-induced depression-like behaviors and its molecular mechanism in the brain remain unclear.Methods Mice were divided into the groups of control, chronic unpredictable mild stress (CUMS), and CUMS-companion. Mice of CUMS group was performed by CUMS for 4 weeks, and CUMS-companion group was treated by CUMS accompanied with companion. The tests of sucrose preference, Y-maze, and forced swimming were conducted to assess depression-like behaviors or resilience. High-throughput sequencing was used to analyze mRNA and miRNA profiles in the medial prefrontal cortex harvested from control, CUMS-MDD (mice with depression-like behaviors in CUMS group), Reward-MDD (mice with depression-like behaviors in CUMS-companion group), CUMS-resilience (resilient mice in CUMS group), Reward-resilience (resilient mice in CUMS-companion group) mice.Results The results provided evidence that accompanying with companion ameliorated CUMS-induced depression-like behaviors in mice. 45 differentially expressed genes (DEGs) are associated with depression-like behaviors, 8 DEGs are associated with resilience and 59 DEGs are associated with nature reward (companion) were identified. Furthermore, 196 differentially expressed miRNAs were found to be associated with companion. Based on the differentially expressed miRNAs and DEGs data, miRNA-mRNA network was established to be associated with companion.Conclusion Taken together, our data here provided a method to ameliorate depression-like behaviors, and numerous potential drug targets for the prevention or treatment of depression.

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