Ronald S Duman

Recent studies have implicated the endogenous opioid system in the antidepressant actions of ketamine, but the underlying mechanisms remain unclear. We used a combination of pharmacological, behavioral, and molecular approaches in rats to test the contribution of the prefrontal endogenous opioid system to the antidepressant-like effects of a single dose of ketamine. Both the behavioral actions of ketamine and their molecular correlates in the medial prefrontal cortex (mPFC) are blocked by acute systemic administration of naltrexone, a competitive opioid receptor antagonist. Naltrexone delivered directly into the mPFC similarly disrupts the behavioral effects of ketamine. Ketamine treatment rapidly increases levels of β-endorphin and the expression of the μ-opioid receptor gene (Oprm1) in the mPFC, and the expression of gene that encodes proopiomelanocortin, the precursor of β-endorphin, in the …

QFJCIRLUMZQUOT-HPLJOQBZSA-N sirolimus Chemical compound C1C [C@@ H](O)[C@ H](OC) C [C@@ H] 1C [C@@ H](C)[C@ H] 1OC (= O)[C@@ H] 2CCCCN2C (= O) C (= O)[C@](O)(O2)[C@ H](C) CC [C@ H] 2C [C@ H](OC)/C (C)= C/C= C/C= C/[C@@ H](C) C [C@@ H](C) C (= O)[C@ H](OC)[C@ H](O)/C (C)= C/[C@@ H](C) C (= O) C1 QFJCIRLUMZQUOT-HPLJOQBZSA-N 0.000 claims description 32

BackgroundAstroglia loss and decreased expression of specific markers expressed by GFAP (glial fibrillary acidic protein)-astroglia have been found in key brain regions such as the prefrontal cortex (PFC) in MDD patients and rodent chronic stress models. In this study, we examined the consequences of PFC GFAP-astroglia ablation on depressive-like behaviors and potential reversal of chronic stress-induced deficits by enhancing PFC GFAP-astroglia activity.MethodsGFAP-cre mice infused in the PFC with an AAV5-DOI-CMV-DTR (diphtheria toxin (DT) receptor) were behaviorally assessed following ip injection with DT in several tests measuring anhedonia-and anxiety-like behaviors. We also infused wild-type mice with an AAV5-GFAP-DREADD (designer receptor exclusively activated by designer drug) Gq in the PFC to activate GFAP-astrocytes upon clozapine-N-oxide administration.ResultsWe found that PFC …

Monocytes comprise two major subsets, Ly6C hi classical monocytes and Ly6C lo nonclassical monocytes. Notch2 signaling in Ly6C hi monocytes triggers transition to Ly6C lo monocytes, which require Nr4a1, Bcl6, Irf2, and Cebpb. By comparison, less is known...

Vascular endothelial growth factor (VEGF) signaling is known to be involved in the antidepressant‐like effects of conventional antidepressants, such as desipramine (DMI), a tricyclic antidepressant, and fluoxetine (FLX), a selective serotonin reuptake inhibitor; however, the precise role of neuronal VEGF signaling in mediating these effects remains unclear. Using mice with excitatory neuron‐specific deletion of VEGF and its receptor, fetal liver kinase 1 (Flk‐1) in the forebrain, we examined the effects of forebrain excitatory neuron‐specific deletion of VEGF or Flk‐1 on the antidepressant‐like effects of repeated DMI and chronic FLX administration in the forced swim test (FST). Repeated intraperitoneal (i.p.) injections of DMI (10, 10, and 20 mg/kg at 24, 4, and 1 h before the FST, respectively) significantly decreased immobility in control mice; however, this effect was completely blocked in mice with neuron‐specific …

Background Electroconvulsive seizure therapy is often used in both treatment-resistant and geriatric depression. However, preclinical studies identifying targets of chronic electroconvulsive seizure (ECS) are predominantly focused on animal models in young adulthood. Given that putative transcriptional, neurogenic, and neuroplastic mechanisms implicated in the behavioral effects of chronic ECS themselves exhibit age-dependent modulation, it remains unknown whether the molecular and cellular targets of chronic ECS vary with age. Methods We subjected young adult (2–3 months) and middle-aged (12–13 months), male Sprague Dawley rats to sham or chronic ECS and assessed for despair-like behavior, hippocampal gene expression, hippocampal neurogenesis, and neuroplastic changes in the extracellular matrix, reelin, and perineuronal net numbers …

Post-traumatic stress disorder (PTSD) is a common and disabling psychiatric disorder. Here we present findings from the first proteome-wide study of the postmortem PTSD brain. We performed tandem mass spectrometry on large cohort of donors (N = 66) in two prefrontal cortical areas and found differentially expressed proteins and co-expression modules disturbed in PTSD. Integrative analysis pointed to hsa-mir-589 as a regulatory miRNA responsible for disruptions in neuronal protein networks for PTSD, including the GABA vesicular transporter, SLC32A1. In addition, we identified significant enrichment of risk genes for Alzheimers Disease (N= 94,403), major depression (N = 807,553), and schizophrenia (N = 35,802) within PTSD co-expression protein modules, suggesting shared molecular pathology. Our findings highlight the altered proteomic landscape of postmortem PTSD brain and provide a novel framework for future studies integrating proteomic profiling with transcriptomics in postmortem human brain tissue.

Reductions of astroglia expressing glial fibrillary acidic protein (GFAP) are consistently found in the prefrontal cortex (PFC) of patients with depression and in rodent chronic stress models. Here, we examine the consequences of PFC GFAP+ cell depletion and cell activity enhancement on depressive-like behaviors in rodents. Using viral expression of diphtheria toxin receptor in PFC GFAP+ cells, which allows experimental depletion of these cells following diphtheria toxin administration, we demonstrated that PFC GFAP+ cell depletion induced anhedonia-like behavior within 2 days and lasting up to 8 days, but no anxiety-like deficits. Conversely, activating PFC GFAP+ cell activity for 3 weeks using designer receptor exclusively activated by designer drugs (DREADDs) reversed chronic restraint stress-induced anhedonia-like deficits, but not anxiety-like deficits. Our results highlight a critical role of cortical astroglia in the development of anhedonia and further support the idea of targeting astroglia for the treatment of depression.