Yasushi Ishida

Prenatal psychological stress causes higher emotionality, depression-like behavior, and elevated activity in the hypothalamo-pituitary-adrenal axis.

In humans, stressful events during pregnancy may raise the risk of psychiatric disorders in offspring, and studies with rodents have found that physical prenatal stress can cause changes in the physiology, neurobiology, and behavior of offspring. In the present study, we examined whether psychological prenatal stress with little physical stress could cause changes in the neurobiology and behavior of offspring in Sprague-Dawley rats, as physical prenatal stress did. Dams received psychological stress by observing a rat being electrically shocked behind a transparent wall in the social communication box during the last trimester of gestation but were not exposed to any physical stress. Male offspring from the dams exposed to psychological stress showed enhanced emotionality in an open field test, depression-like behavior in a forced swim test, and enhanced activity in the hypothalamo-pituitary-adrenal axis, compared with rats from untreated dams. However, the prenatally stressed rats showed intact ability to acquire context conditioning. This is the first report that psychological prenatal stress in the communication box can cause changes in the neurobiology and behavior of offspring in rodents.

Perirhinal N-methyl-d-aspartate and muscarinic systems participate in object recognition in rats

To determine the possible involvement of N-methyl-d-aspartate (NMDA) and muscarinic activation of the perirhinal cortex in object recognition, an NMDA antagonist (d,l-2-amino-5-phosphonopentanoic acid (AP5)) and a muscarinic antagonist (scopolamine) were injected into the perirhinal cortex of rats. A high dose of AP5 (60 mM) and two doses of scopolamine (20 and 80 mM), but not a low dose of AP5 (30 mM) alone, significantly impaired discrimination between novel and familiar objects in a spontaneous object recognition task, which is one of the recognition memory tasks. These results suggest that activation of both NMDA and muscarinic receptors in the perirhinal cortex contributes to object recognition.

Effect of intrathecal administration of hemokinin-1 on the withdrawal response to noxious thermal stimulation of the rat hind paw

Hemokinin-1 (HK-1) is a new peptide described as a member of the tachykinin family. HK-1 has biological effects similar to substance P (SP), a representative of the tachykinin family, following central administration. However, the biological function of HK-1 at the spinal level has not been well characterized. Thus, we investigated the effect of intrathecal administration of HK-1 by comparing it with that of SP. Intrathecal administration of HK-1 as well as SP at 10(-3) M caused pain-related behavior such as scratching. The scratching by HK-1 administration was inhibited by pretreatment with an antagonist of substance P receptor. In addition, SP (10(-8)-10(-6) M) decreased the latency of the withdrawal response of the hind paw to noxious thermal stimulation 20-30 min after intrathecal administration, whereas administration of HK-1 had little effect on this response. These results suggest that there may exist a proper receptor related to HK-1.

Unilateral lesions of mesostriatal dopaminergic pathway alters the withdrawal response of the rat hindpaw to mechanical stimulation

To investigate the role mesostriatal dopamine system plays in pain processing, we examined the withdrawal response of rat hindpaws to mechanical stimulus at 1, 4, and 12 weeks after unilateral 6-hydroxydopamine (6-OHDA) lesions of the mesostriatal pathway. In all of the 6-OHDA rats examined, almost no tyrosine hydroxylase (TH) immunoreactivity was detected in the substantia nigra, ventral tegmental area, and striatum ipsilateral to 6-OHDA lesions. Alteration in the withdrawal response in this model animal was evaluated by comparing the latency of withdrawal reflex following the mechanical stimulus to the hindpaw. The latency of withdrawal response in the 6-OHDA rats was significantly reduced in the side ipsilateral to 6-OHDA lesions at all times observed, whereas that was not changed through the period observed in the contralateral side, indicating that dopamine depletion in the mesostriatal system has the influence on withdrawal response to the mechanical stimulus. These results show that the unilateral dopamine depletion causes hypersensitivity to the mechanical stimulus in the ipsilateral side, suggesting that, at least in part, dopamine in the mesostriatal system may be involved in sensory processing including pain sensation induced by mechanical stimulation.

Cerebral blood flow abnormalities induced by transient hypothyroidism after thyroidectomy —Analysis by Tc-99m-HMPAO and SPM96—

The current study is an investigation of alterations in regional cerebral blood flow (rCBF) distribution in patients with transient hypothyroidism after thyroidectomy. In addition, the effects of thyroxine treatment on rCBF changes were studied.MethodsNoninvasive rCBF measurements using99mTc-HMPAO SPECT were performed on 24 post-thyroidectomy patients who were in a hypothyroidic state. The measurements were conducted before131I therapy and after thyroid hormone (thyroxine) replacement. We used adjusted rCBF images (normalization of global CBF for each subject to 50 m//100 g/min with proportional scaling) to compare these data with age-matched normal control groups (n=15) using SPM96. We also compared the absolute rCBF value of hypothyroidic patients with those of normal control groups. In addition, the association between rCBF alteration and the severity of depression was also analyzed. Finally, the effect of thyroid hormone replacement on rCBF was investigated individually using the Jack-knife test, in which patient data were compared with those from healthy volunteers. According to the result of this test, all cases were categorized into three subgroups, namely, improved, unchanged group and normal. To prove the reversibility of rCBF alteration after thyroid hormone replacement, a group comparison test between the normal controls and the improved group was done before and after thyroid hormone replacement. Similarly a group comparison test between the unchanged group and normal controls was also performed.ResultsIn the hypothyroidic condition, there was a significant decrease in the posterior part of the bilateral parietal lobes and in part of the bilateral occipital lobes, including the cuneus. These decreased rCBF areas extended to the bilateral prefrontal cortices as deterioration became more profound. On individual analysis, 16 of 24 patients (66.7%) demonstrated rCBF reduction, while 8 patient did not show significant rCBF change (33.3%, the normal group). After thyroxine replacement, improvement of rCBF was noted in nine of 16 patients (56.3%, the improved group). In seven of 16 patients (43.7% the unchanged group), the significant low rCBF area remained unchanged. Compared with the normal controls, the improved group showed significantly decreased rCBF of the bilateral parietal lobe and the occipital lobe in the hypothyroic condition. After thyroid hormone replacement, these abnormal rCBF areas disappeared. In contrast, in the unchanged group, the significant hypoperfusion area became localized but remained.Conclusion99mTc-HMPAO SPECT and SPM96 analysis demonstrated a significant rCBF decrease in the parietal lobe and part of the occipital lobe in patients with induced transient hypothyroidism after thyroidectomy. This phenomenon might contribute to understanding of the depressive state. Recovery of rCBF after thyroid hormone replacement was confirmed in some patients. However, rCBF improvement did not always occur in every patient during the follow up period. The reversibility of rCBF in transient hypothyroidism may be dependent on individual characteristics during a short-term period.

Psychological prenatal stress reduced the number of BrdU immunopositive cells in the dorsal hippocampus without affecting the open field behavior of male and female rats at one month of age.

We examined whether prenatal psychological stress with little physical stress causes changes in the behavior and neurogenesis of the offspring of Sprague-Dawley rats at one month. Dams in the last trimester of gestation were psychologically stressed by placing them in a social communication box and shocking a rat on the other side of a transparent wall. They suffered little physical stress. Male and female offspring from the dams showed little change in an open field test at postnatal day (PND) 30. To evaluate neurogenesis in the brain, BrdU was intraperitoneally injected at PND 35 into offspring not used in the open field test. Immunohistochemical examinations of BrdU in their dorsal hippocampus at PNDs 42 and 112 revealed that the number of BrdU immunopositive cells in the offspring of prenatally stressed rats was significantly smaller than in the offspring of unstressed ones. These results together with our previous finding that prenatal psychological stress can alter specific behaviors suggest that prenatal psychological stress can suppress neurogenesis in the dorsal hippocampus of rats of both sexes at PND 35 even though impairment in the behavioral task has not yet appeared.

Alteration of striatal [11C]raclopride and 6-[18F]fluoro-l-3,4-dihydroxyphenylalanine uptake precedes development of methamphetamine-induced rotation following unilateral 6-hydroxydopamine lesions of medial forebrain bundle in rats

We studied the positron emission tomography (PET) tracer distributions of ligands for dopamine D1 receptors ([11C]SCH23390) and D2 receptors ([11C]raclopride) and of the dopamine precursor analog 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA) in the brain after 6-hydroxydopamine (6-OHDA) lesions of the medial forebrain bundle in rats. The number of methamphetamine-induced rotation was higher at 14 days than at 3 days after the 6-OHDA lesions. The brains of 6-OHDA-treated rats were analyzed by tissue dissection following i.v. bolus of each tracer at 3 days (acute stage) or 3 weeks (chronic stage) postlesion. [11C]Raclopride, but not [11C]SCH23390, showed higher accumulation in the striatum on the lesion side than on the non-lesion (intact) side both at 3 days and 3 weeks postlesion. On the other hand, lower accumulation of [18F]FDOPA was observed in the striatum on the lesion side at 3 days postlesion and in both the striatum and cerebral cortex on the lesion side at 3 weeks postlesion. Our studies demonstrate that an increase in [11C]raclopride and a decrease in [18F]FDOPA uptake in the denervated striatum is evident even at 3 days after the 6-OHDA lesions when the methamphetamine-induced rotational behavior is not established.

Changes in dopamine D2 receptors and 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine uptake in the brain of 6-hydroxydopamine-lesioned rats.

We studied tracer distributions in positron emission tomography of ligands for dopamine D1 receptors ([11C]SCH23390) and D2 receptors ([11C]raclopride) and the dopamine precursor analog 6-[18F]fluoro-L-3,4-dihydroxyphenylalanine ([18F]FDOPA), as a measurement of presynaptic dopaminergic function, in the brain after 6-hydroxydopamine lesioning of the medial forebrain bundle in rats. The unilateral lesions were confirmed behaviorally by methamphetamine-induced rotation 2 weeks after lesioning, and the brains were analyzed by tissue dissection following an intravenous bolus of each tracer 3 weeks after lesioning. [11C]Raclopride, but not [11C]SCH23390, showed a higher accumulation in the striatum on the lesion side compared with that on the non-lesioned (intact) side. On the other hand, a lower accumulation of [18F]FDOPA was found in the striatum and cerebral cortex on the lesion side. Our studies demonstrate upregulation of dopamine D2 receptors in the striatum and a decrease in FDOPA uptake in both the striatum and cerebral cortex ipsilateral to the 6-hydroxydopamine lesions. Therefore, the combination of a D2 antagonist and FDOPA may provide a potentially useful method for assessing the effects of dopamine depletion in Parkinson’s disease.

Regional differences in the expression of Fos-like immunoreactivity after central salt loading in conscious rats: modulation by endogenous vasopressin and role of the area postrema

In this study, we examined the quantitative relationship between centrally administered hypertonic saline (HS) concentrations and the expression of Fos-like immunoreactivity (FLI) in brain regions involved in the homeostasis of body fluids. The regions examined were the organum vasculosum laminae terminalis (OVLT), the median preoptic nucleus (MnPO), the subfornical organ (SFO), the paraventricular nucleus (PVN), the supraoptic nucleus of the hypothalamus, the nucleus of the solitary tract (NTS), and the area postrema (AP). The experiments were performed in conscious rats with attention to the actual changes in central [Na(+)]. Hypertonic saline (0.3, 0.67, or 1.0 M) was delivered at 1 microl/min for 20 min. The changes in cerebrospinal fluid [Na(+)] during i.c.v. administration of 0.3 M hypertonic saline were compatible with those expected for thermal dehydration. FLI increased in a dose-dependent manner in the dorsomedial cap of the PVN and NTS. Although the pressor responses during central salt loading were not significantly affected by pretreatment with the peripheral vasopressin V(1) receptor antagonist OPC-21268, FLI expression in the PVN was significantly augmented. In addition, in AP-lesioned rats, FLI expression in the lateral magnocellular part of the PVN and NTS was significantly enhanced after central salt loading. These results suggest that the peripheral vasopressin system participates in negative feedback to modulate neuronal activities in the PVN, probably through the AP or direct action at the PVN in response to central osmotic and/or Na(+) stimulation.

Differential expression of Fos and Zif268 in the nigrostriatal system after methamphetamine administration in a rat model of Parkinson's disease

The goal of this study was to examine the topological specificity of methamphetamine‐induced activation of the immediate‐early gene proteins, Fos and Zif268, in the nigrostriatal system in a unilateral 6‐hydroxydopamine (6‐OHDA) rat model of Parkinsons disease with or without intrastriatal grafts of fetal ventral mesencephalon. Methamphetamine (3 mg/kg, i.p.) induced Fos‐like immunoreactivity (FLI) dominantly in the striatum and the globus pallidus (GP) on the intact side as well as in the substantia nigra pars reticulata (SNr) on the lesioned side in the 6‐OHDA rats. Lower levels of methamphetamine‐induced FLI in the striatum and GP on the lesioned side were restored by intrastriatal grafts which could completely suppress the methamphetamine‐induced rotation. In the striatum, a similar tendency could be observed between Fos and Zif268 immunoreactivity following methamphetamine. However, sparse immunoreactivity of Zif268 could be detected in the GP and SNr on both sides in the 6‐OHDA rats. Intrastriatal grafts had little influence on Zif268 expression in these two regions. The differential expression of Fos and Zif268 was observed among the three regions of the nigrostriatal system following methamphetamine in the 6‐OHDA rats. This may suggest that Fos and Zif268 therefore possess gene‐specific and region‐specific functions in the basal ganglia nuclei. Synapse 62:920–926, 2008.