microRNAs as novel antidepressant targets: converging effects of ketamine and electroconvulsive shock therapy in the rat hippocampus

Abstract Early-life stress is a main contributory factor to the onset of depression. Treatments remain inadequate and as such, a large unmet medical need for novel therapeutics remains. Impeding advancement is the poor understanding of the molecular pathology. microRNAs (miRNAs) are novel regulators of gene expression. A paucity of information regarding their role in depressive pathology and antidepressant action remains. This study investigated changes to hippocampal miRNA levels induced via early-life stress in Sprague–Dawley rats and whether antidepressant treatments could reverse these changes. Investigated were the selective serotonin reuptake inhibitor fluoxetine, the rapid acting N-methyl-d-aspartate receptor antagonist ketamine and electroconvulsive shock therapy (ECT). Microarray analysis revealed early-life stress affected the expression of multiple hippocampal miRNAs. Antidepressant treatments reversed some of these effects including a stress-induced change to miR-451. Ketamine and ECT possessed the highest number of common targets suggesting convergence on common pathways. Interestingly all three treatments possessed miR-598-5p as a common target. This demonstrates that changes to hippocampal miRNA expression may represent an important component of stress-induced pathology and antidepressant action may reverse these.

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P5.2 The effect of voluntary exercise and high fat diet on tyrosine hydroxylase phosphorylation in male Sprague–Dawley rats exposed to early life stress

Autonomic Neuroscience ◽

10.1016/j.autneu.2009.05.192 ◽

2009 ◽

Vol 149 (1-2) ◽

pp. 103

Author(s):

L.K. Ong ◽

J. Maniam ◽

P.R. Dunkley ◽

L. Bobrovskaya ◽

M.J. Morris

Keyword(s):

Tyrosine Hydroxylase ◽

High Fat Diet ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Voluntary Exercise ◽

Sprague Dawley ◽

High Fat ◽

Sprague Dawley Rats ◽

Tyrosine Hydroxylase Phosphorylation

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Impact of early-life stress, on group III mGlu receptor levels in the rat hippocampus: Effects of ketamine, electroconvulsive shock therapy and fluoxetine treatment

Neuropharmacology ◽

10.1016/j.neuropharm.2012.05.006 ◽

2013 ◽

Vol 66 ◽

pp. 236-241 ◽

Cited By ~ 27

Author(s):

Richard M. O' Connor ◽

Matteo M. Pusceddu ◽

Timothy G. Dinan ◽

John F. Cryan

Keyword(s):

Electroconvulsive Shock ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Shock Therapy ◽

Rat Hippocampus ◽

Group Iii ◽

Mglu Receptor ◽

Fluoxetine Treatment

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Abstract 17: Early Life Stress Sensitizes The Angiotensin II-elicited Hypertensive Response

Hypertension ◽

10.1161/hyp.76.suppl_1.17 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Baojian Xue ◽

Terry Beltz ◽

Fang Guo ◽

David M Pollock ◽

Jennifer S Pollock ◽

...

Keyword(s):

Mrna Expression ◽

Proinflammatory Cytokines ◽

Life Stress ◽

Early Life ◽

Early Life Stress ◽

Male Rats ◽

Sprague Dawley ◽

Cns Inflammation ◽

Wide Range ◽

The Brain

Separation of neonatal rodent pups from their mothers has been used as a model to study the effects of early life stress (ELS) on behavioral and physiological responses in adults. Using an Induction-Delay-Expression experimental paradigm, our previous studies demonstrate that a wide range of stressors administered during an induction period produces hypertensive response sensitization (HTRS) in response to a subsequent pro-hypertensive stimulus. HTRS is accompanied by activation of the brain renin-angiotensin system (RAS) and CNS inflammation. The present study investigated whether ELS induces HTRS and changes in brain-related underlying mechanisms. Rat neonates from Sprague-Dawley breeders were subjected to ELS by separating them each morning from their mothers for 3 h on postnatal days 2 to 14. Pups from non-handled litters formed control groups. At 10 weeks of age, male rats were used to evaluate blood pressure and autonomic function using telemetric probes and pharmacological methods. In addition, in separate control and ELS groups, the lamina terminalis (LT) structures and the hypothalamic paraventricular nucleus (PVN) were analyzed for mRNA expression of RAS components and proinflammatory cytokines. Adult ELS rats as compared to non-separated controls exhibited 1) HTRS during expression testing using 2 week ANG II infusions (120 ng/kg/min s.c.; ELS animals, Δ45.5±4.5 mmHg vs. controls, Δ22.4±3.1 mmHg); 2) a greater reduction in mean arterial pressure following ganglionic blockade (hexamethonium, 30 mg/kg, ip), 3) increased sympathetic drive to the heart (atenolol, 8 mg/kg, ip), 4) decreased vagal tone (atropine, 8 mg/kg, ip), and 5) increased mRNA expression of several components of the brain RAS and proinflammatory cytokines in the LT and PVN. These results suggest that maternal ELS may predispose individuals to hypertension that is mediated by upregulation of the brain RAS and proinflammatory cytokines and increased sympathetic drive to the cardiovascular system.

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