ABSTRACT
Posttraumatic stress disorder (PTSD), a trauma-related mental disorder, is associated with mitochondrial dysfunction in the brain. However, the biologic approach to identifying the mitochondria-focused genes underlying the pathogenesis of PTSD is still in its infancy. Previous research, using a human mitochondria-focused cDNA microarray (hMitChip3) found dysregulated mitochondria-focused genes present in postmortem brains of PTSD patients, indicating that those genes might be PTSD-related biomarkers. To further test this idea, this research examines profiles of mitochondria-focused gene expression in the stressed-rodent model (inescapable tail shock in rats), which shows characteristics of PTSD-like behaviors and also in the blood of subjects with PTSD. This study found that 34 mitochondria-focused genes being upregulated in stressed-rat amygdala. Ten common pathways, including fatty acid metabolism and peroxisome proliferator-activated receptors (PPAR) pathways were dysregulated in the amygdala of the stressed rats. Carnitine palmitoyltransferase 1B (CPT1B), an enzyme in the fatty acid metabolism and PPAR pathways, was significantly over-expressed in the amygdala (P < 0.007) and in the blood (P < 0.01) of stressed rats compared with non-stressed controls. In human subjects with (n = 28) or without PTSD (n = 31), significant over-expression of CPT1B in PTSD was also observed in the two common dysregulated pathways: fatty acid metabolism (P = 0.0027, false discovery rate (FDR) = 0.043) and PPAR (P = 0.006, FDR = 0.08). Quantitative real-time polymerase chain reaction validated the microarray findings and the CPT1B result. These findings indicate that blood can be used as a specimen in the search for PTSD biomarkers in fatty acid metabolism and PPAR pathways, and, in addition, that CPT1B may contribute to the pathology of PTSD.
Subject(s)
Amygdala/metabolism , Carnitine O-Palmitoyltransferase/genetics , Fatty Acids/metabolism , Mitochondria/genetics , Peroxisome Proliferator-Activated Receptors/metabolism , RNA, Messenger/metabolism , Stress Disorders, Post-Traumatic/genetics , Adolescent , Adult , Animals , Brain/metabolism , Carnitine O-Palmitoyltransferase/metabolism , Case-Control Studies , Disease Models, Animal , Female , Humans , Lipid Metabolism , Male , Military Personnel , Mitochondria/metabolism , Oligonucleotide Array Sequence Analysis , Rats , Real-Time Polymerase Chain Reaction , Stress Disorders, Post-Traumatic/metabolism , Transcriptome , Young AdultSubject(s)
Leukocytes/metabolism , Life Change Events , Stress Disorders, Post-Traumatic/genetics , Stress, Psychological/genetics , Telomere Shortening/genetics , Adolescent , Adult , Age Factors , Case-Control Studies , Humans , Middle Aged , Stress Disorders, Post-Traumatic/pathology , Stress, Psychological/pathology , Young AdultABSTRACT
Coordination between the urinary bladder and the urethra is mediated by multiple reflex pathways organized in the brain and spinal cord. Some reflexes promote urine storage; whereas other reflexes facilitate voiding. During bladder filling, activation of mechanoreceptor afferent nerves in the bladder wall triggers firing in the cholinergic efferent pathways to the external urethral sphincter (EUS) and in sympathetic adrenergic pathways to the urethral smooth muscle. These storage reflexes are dependent upon interneuronal circuitry in the spinal cord. During voiding the spinal storage reflexes are inhibited by supraspinal mechanisms which originate in the pontine micturition center. Glutamatergic, serotonergic and alpha, adrenergic excitatory transmission as well as GABAergic/glycinergic inhibitory transmission have been implicated in the central control of sphincter reflexes. During voiding, a parasympathetic nitrergic inhibitory input to the urethral smooth is activated. This reflex mechanism which is triggered by bladder afferents persists in paraplegic rats and therefore must be mediated at least in part by spinal interneuronal circuitry. In female rats, the parasympathetic nitrergic pathway is prominent; but in male rats it is obscured by a dominant parasympathetic cholinergic excitatory input to the urethral smooth muscle. The function of the cholinergic pathway in voiding is uncertain. Stimulation of urethral afferents can also influence bladder activity. Contraction of the external urethral sphincter activates afferents that inhibit reflex bladder contractions; whereas infusion of fluid through the urethra facilitates bladder contractions. These reflexes are also organized in the spinal cord and presumably play a role in urine storage and elimination. Alterations in primitive bladder-to-urethra and urethra-to-bladder reflex mechanisms may contribute to neurogenic bladder dysfunction.
Subject(s)
Urethra/innervation , Urethra/physiology , Afferent Pathways/physiology , Humans , Reflex , Spinal Nerves/physiology , Urethra/drug effects , Urinary Bladder/physiologyABSTRACT
Epinephrine given intravenously or intraventricularly has a half-life in the brain of the rat of 2 to 2.5 hours. After intravenous administration of the drug the principal route of metabolism is O-methylation, whereas after intraventricular administration the principal route is conjugation.
