Release of endomorphin (ENDO)-2 like substances from the dorsal horn of the isolated rat spinal cord was measured by the immobilized-antibody microprobe technique. Spinal cords were removed from anesthetized 4-6 week old rats and superfused with oxygenated Krebs solution at room temperature. Glass microprobes coated with ENDO-2 antibodies were inserted into the dorsal horn of the lumbar spinal cord 1.5 mm lateral to the midline to a depth 2.5 mm below the dorsal surface of the cord. Each probe remained in situ for 10 min periods before, during and after electrical stimulation applied to the dorsal root entry zone of the same spinal segment. There was no detectable basal release of immunoreactive endomorphin-2 like substance (irENDO) from the dorsal horns during the pre-stimulation, nor following the stimulation period. A significant release of irENDO was measured during the electrical stimulation. These results provide the first evidence of a irEndo release that is correlated spatially with the dorsal horn laminae I and II where ENDO-2-immunoreactive fibers are concentrated in the dorsal horn in response to electrical activation of primary afferent fibers.

Retrograde tract tracing combined with immunohistochemical techniques were used to identify the origin of orexin A-immunoreactive (OrA-ir) fibers in the rat medulla. One to 5 days following injection of the fluorescent dye Fluorogold into the dorsal medulla, labeled neurons were found in the lateral half of the lateral hypothalamus, paraventricular, perifornical, dorsomedial, dorsal and posterior hypothalamic nuclei. Labeling the same sections with OrA antisera revealed a concentration of OrA-ir neurons in the perifornical and dorsomedial regions of the tuberal hypothalamus. A maximum of 10% of Fluorogold-labeled hypothalamic neurons were OrA-ir and 15% of OrA-ir hypothalamic neurons contained Fluorogold. Our results demonstrate that a fraction of OrA-ir neurons in the tuberal hypothalamus project to areas of the medulla that are involved in autonomic functions.

Several seemingly conflicting sets of data have been reported on the regenerative capacity of central noradrenergic neurons, following transection of the ascending noradrenergic fiber tract in neonatal rats (Iacovitti et al., Dev Brain Res 1: 21-33, 1981; Jonsson and Sachs, Brain Res Bull 9: 641-650, 1982). In order to more fully investigate changes in noradrenergic neurons in the brain after such a transection, rats were lesioned at various times after birth, sometimes in conjunction with administration of the neurotoxin, 6-hydroxydopa (6-OHDOPA). Animals were sacrifced at 7, 10, 14, 28, 42 or 56 days after birth, in order to assess the pattern of noradrenergic neuronal damage, as well as the recovery rate. Dorsal bundle lesions were associated with neocortical and hippocampal hypoinnervation by noradrenergic fibers, and sprouting of a collateral fiber group, with production of noradrenergic hyperinnervation of the cerebellum and pons-medulla. Recovery of the norepinephrine (NE) content to control levels occurred in the neocortex at 8 weeks, when the dorsal bundle was lesioned at birth. When the lesion was produced at a later time (3 days or 5 days after birth), less recovery in the neocortex and hippocampus was found. Histofluorescent fiber number, as observed with a glyoxylic acid method, correlated with NE changes. It appears that 6-OHDOPA (20 μg/g IP) does not modify long-term recovery from a dorsal bundle lesion, when rats are co-treated at 3 days after birth. However, the length of the proximal noradrenergic fiber stump may be an important factor affecting the capacity for recovery from injury. These results suggest that a shorter fiber stump, as produced with a dorsal bundle lesion at the level of the pons, may be associated with a greater degree of recovery from injury. Also, the younger the rat at the time of injury, the greater appears to be the capacity for regeneration. These results demonstrate that regeneration can occur in one part of the brain without modification of a collateral hyperinnervation of a different part of the brain. Therefore, our findings discount a programming of central noradrenergic fibers to express a specific number of nerve terminal arborizations, (i.e., the "pruning hypothesis").

Metastin, the product of metastasis suppressor gene KiSS-1, is proposed to be the natural ligand for the G-protein-coupled receptor GPR54, known also as AXOR12. This immunohistochemical study, using a rabbit polyclonal antiserum against the human metastin fragment (45-54)-NH2, showed that in rats metastin-like immunoreactivity (MTS-LI) was present in neurons of the nucleus of the solitary tract and caudoventrolateral reticular nucleus, and in cell processes of the spinal trigeminal tract and lateral reticular nucleus. MTS-LI was confined mainly to neurons and fibers at or caudal to the area postrema. In the spinal cord, MTS-LI cell processes formed a dense plexus in superficial layers I and II of the dorsal horn. The pattern of distribution of MTS-LI in the medulla and spinal cord suggests that this novel peptide may participate in autonomic and sensory neural signaling.

Insulin-like 6 immunoreactivity (irINSL6) was detected in Leydig cells of the mouse testis. In the brain, labeled somata were detected mainly in the caudal hypothalamus and midbrain. Double labeling the brainstem sections revealed that irINSL6 somata were 5-hydroxytryptamine (5-HT) positive. The presence of irINSL6 in discrete populations of hypothalamic and brainstem neurons and in Leydig cells of the testis suggests a diverse biological function of this novel peptide.

Metastin, the gene product of metastasis suppressor gene KiSS-1, is the endogenous ligand for the G-protein-coupled receptor GPR54 (or AXOR12, or OT7T175). The expression of KiSS-1 gene and peptide and the distribution of metastin were studied in the rat central nervous system by reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical methods. KiSS-1 gene and peptide expression was higher in the hypothalamus than in the brainstem and spinal cord. In the brain, metastin-like immunoreactivity (irMT) was found mainly in three groups of cells: dorsomedial hypothalamic nucleus, nucleus of the solitary tract, and caudal ventrolateral medulla. Immunoreactive fibers of varying density were noted in bed nucleus of stria terminalis, septal nuclei, nucleus accumbens, caudate putamen, diagonal band, amygdala, hypothalamus, zona incerta, thalamus, periaqueductal gray, raphe nuclei, lateral parabrachial nucleus, locus coeruleus, spinal trigeminal tract, rostral ventrolateral medulla, and medullary reticular nucleus. Preabsorption of the antiserum with metastin peptide fragment (45-54)-NH2 (1 μg/ml) resulted in no staining in any of the sections. The biological activity of metastin was assessed by monitoring intracellular calcium [Ca2+]i in cultured hippocampal neurons, which are known to express GPR54. Metastin increased [Ca 2+]i in a population of cultured hippocampal neurons. The results show that metastin is biologically active in rat central neurons, and its anatomical distribution suggests a possible role in nociception and autonomic and neuroendocrine functions.

Aberrant afferent signaling drives adverse remodeling of the cardiac nervous system in ischemic heart disease. The study objective was to determine whether thoracic spinal dorsal column stimulation (SCS) modulates cardiac afferent sensory transduction of the ischemic ventricle. In anesthetized canines (n = 16), extracellular activity generated by 62 dorsal root ganglia (DRG) soma (T1-T3), with verified myocardial ischemic (MI) sensitivity, were evaluated with and without 20-min preemptive SCS (T1-T3 spinal level; 50 Hz, 90% motor threshold). Transient MI was induced by 1-min coronary artery occlusion (CAO) of the left anterior descending (LAD) or circumflex (LCX) artery, randomized as to sequence. LAD and LCX CAO activated cardiac-related DRG neurons (LAD: 0.15 ± 0.04-1.05 ± 0.20 Hz, P < 0.00002; LCX: 0.08 ± 0.02-1.90 ± 0.45 Hz, P < 0.0003). SCS decreased basal neuronal activity of neurons that responded to LAD (0.15 ± 0.04 to 0.02 ± 0.01 Hz, P < 0.006) and LCX (0.08 ± 0.02 to 0.02 ± 0.01 Hz, P < 0.003). SCS suppressed responsiveness to transient MI (LAD: 1.05 ± 0.20-0.03 ± 0.01 Hz; P < 0.0001; LCX: 1.90 ± 0.45-0.03 ± 0.01 Hz; P < 0.001). Suprathreshold SCS (1 Hz) did not activate DRG neurons antidromically (n = 10 animals). Ventricular fibrillation (VF) was associated with a rapid increase in DRG activity to a maximum of 4.39 ± 1.07 Hz at 20 s after VF induction and a return to 90% of baseline within 10 s thereafter. SCS obtunds the capacity of DRG ventricular neurites to transduce the ischemic myocardium to second-order spinal neurons, a mechanism that would blunt reflex sympathoexcitation to myocardial ischemic stress, thereby contributing to its capacity to cardioprotect.NEW & NOTEWORTHY Aberrant afferent signaling drives adverse remodeling of the cardiac nervous system in ischemic heart disease. This study determined that thoracic spinal column stimulation (SCS) obtunds the capacity of dorsal root ganglia ventricular afferent neurons to transduce the ischemic myocardium to second-order spinal neurons, a mechanism that would blunt reflex sympathoexcitation to myocardial ischemic stress. This modulation does not reflect antidromic actions of SCS but likely reflects efferent-mediated changes at the myocyte-sensory neurite interface.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20076号 / 医博第4169号 / 新制||医||1018(附属図書館) / 33192 / 京都大学大学院医学研究科医学専攻 / (主査)教授 影山 龍一郎, 教授 斎藤 通紀, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20967号 / 医博第4313号 / 新制||医||1026(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 村井 俊哉, 教授 松田 秀一, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Cognitive dissonance is the uncomfortable psychological feeling that arises when something is perceived as contradictory. In 1957, Leon Festinger first developed the theory of cognitive dissonance, which has since continued to be of interest for, among other things, decision-making, moral reasoning, motivation, politics, and science. This systematic review summarises six peer-reviewed studies that use functional magnetic resonance imaging (fMRI) to measure if there is increased activity in the anterior cingulate cortex (ACC) and dorsal anterior cingulate cortex (dACC) during cognitive dissonance in adults. Four studies tested cognitive dissonance during forced choices and two during counter-attitudinal behaviours. The overall fMRI results indicate increased activity in ACC and dACC to dissonance versus control conditions, but with some inconsistency on the exact locations in the brain.