Electroconvulsive seizures modulate levels of thyrotropin releasing hormone and related peptides in rat hypothalamus, cingulate and lateral cerebellum

We have studied the neuroanatomic extent of electroconvulsive (ECS)-responsive prepro-TRH and TRH-related gene expression and its possible interaction with forced swimming. Young adult male Wistar rats were treated in a 2×2 Latin square protocol of swimming, no swimming, three daily ECS or sham ECS. Sixteen different brain regions were dissected and immunoreactivity measured for TRH (pGlu–His–Pro–NH₂); TRH–Gly, a TRH precursor; Ps4, a prepro-TRH-derived TRH-enhancing decapeptide, and EEP (pGlu–Glu–Pro–NH₂). ECS, in addition to elevating TRH–immunoreactivity (TRH–IR), TRH–Gly–IR, Ps4–IR and EEP–IR levels in the limbic regions, as we have previously reported, also significantly increased Ps4–IR levels in hypothalamus, posterior cingulate and lateral cerebellum, and increased TRH–Gly–IR levels in hypothalamus. Interestingly, the combination of ECS and swimming significantly reduced the levels of TRH–Gly–IR in the anterior cingulate compared to the sham ECS-no swim group. The combined use of high-pressure liquid chromatography and the EEP radioimmunoassay (RIA) revealed that pGlu–Tyr–Pro–NH₂ and/or pGlu–Phe–Pro–NH₂ occur in amygdala, anterior cingulate, frontal cortex, entorhinal cortex, lateral cerebellum and striatum and make a substantial contribution to the EEP–IR and TRH–IR. We conclude that ECS can alter the expression and secretion of TRH-related peptides in the hypothalamus, cingulate and lateral cerebellum. Such effects have not previously been reported in these limbic and extra-limbic regions which are increasingly implicated in the autonomic, behavioral and volitional changes which accompany severe depression and its treatment.     

c-Fos expression in rat brain after repetitive transcranial magnetic stimulation

We investigated neuronal response to repetitive transcranial magnetic stimulation (rTMS) and electroconvulsive shock (ECS) in terms of c-Fos expression. In rats at postnatal day 49, six rTMS sessions induced widespread nuclear c-Fos-like immunoreactivity in frontal cortex, lateral orbital cortex, striatum, lateral septal nucleus, piriform cortex, dentate gyrus, Ammon's horn, cingulate cortex, parietal cortex, thalamus, occipital cortex, and amygdala; this reactivity was greater than with two sessions of rTMS or sham rTMS. ECS produced even stronger c-Fos expression than six sessions of rTMS in all regions except thalamus (no difference) and striatum (stronger with rTMS). Thus, functional modification of neuroanatomic substrates as demonstrated by c-Fos expression may partially differ between rTMS and ECS.     

The role of TRH and related peptides in the mechanism of action of ECT

Thyrotropin-releasing hormone (TRH) has been known anecdotally to produce antidepressant (AD) effects since the 1970s. Recent clinical reports have shown that intrathecal administration of TRH can more reliably induce remissions of major depression that last for 2-3 days. Although clinically impractical, it is important to note that these remissions are rapid within hours, and they survive at least 1 night's sleep. This review summarizes and integrates clinical and preclinical research on TRH and related peptides, which have regulatory effects in the limbic forebrain. Electroconvulsive shock (ECS) in rats induces synthesis of TRH in multiple subcortical limbic and frontal cortical regions, which are known, in humans, to be involved in both depression and in sleep. The increases in TRH and related peptides are regionally specific. The quantitative TRH increases in individual limbic regions have been correlated with the amount of forced swimming done by the individual animal after ECS (forced-swim test of AD effects). Intraperitoneal TRH also gives a positive response in this test, as do all effective AD medications. By considering neurobiological phenomena in depression and sleep, it is possible to outline a role for TRH and related peptides that may assist in the understanding both of depression and of the depressogenic effect of sleep in depressively vulnerable people. It is concluded that TRH and related peptides are likely to play a significant role in the inhibition of glutamatergic subcortical limbic neurons, which may be hyperactive in depression. Electroconvulsive therapy is believed to act, in part, by augmenting this inhibition. AD medications are believed to act indirectly, by activation of a subset of GABAergic interneurons, which then inhibit the pathologically hyperactive glutamatergic limbic neurons. Continued exploration of TRH and related peptides will be essential for further progress toward the control of these debilitating and often lethal diseases.     

Forebrain connectivity of the prefrontal cortex in the marmoset monkey (Callithrix jacchus): an anterograde and retrograde tract-tracing study

The cortical and subcortical forebrain connections of the marmoset prefrontal cortex (PFC) were examined by injecting the retrograde tracer, choleratoxin, and the anterograde tracer, biotin dextran amine, into four sites within the PFC. Two of the sites, the lateral and orbital regions, had previously been shown to provide functionally dissociable contributions to distinct forms of behavioral flexibility, attentional set-shifting and discrimination reversal learning, respectively. The dysgranular and agranular regions lying on the orbital and medial surfaces of the frontal lobes were most closely connected with limbic structures including cingulate cortex, amygdala, parahippocampal cortex, subiculum, hippocampus, hypothalamus, medial caudate nucleus, and nucleus accumbens as well as the magnocellular division of the mediodorsal nucleus of the thalamus and midline thalamic nuclei, consistent with findings in the rhesus monkey. In contrast, the granular region on the dorsal surface closely resembled area 8Ad in macaques and had connections restricted to posterior parietal cortex primarily associated with visuospatial functions. However, it also had connections with limbic cortex, including retrosplenial and caudal cingulate cortex as well as auditory processing regions in the superior temporal cortex. The granular region on the lateral convexity had the most extensive connections. Based on its architectonics and functionality, it resembled areas 12/45 in macaques. It had connections with high-order visual processing regions in the inferotemporal cortex and posterior parietal cortex, higher-order auditory and polymodal processing regions in the superior temporal cortex. In addition it had extensive connections with limbic regions including the amygdala, parahippocampal cortex, cingulate, and retrosplenial cortex.     

Afferents from limbic system-related regions to the frontal cortex in the bush baby (Galago senegalensis)

Afferents from limbic system-related structures (aside from the cingulate and retrosplenial cortex) to medial and lateral regions of the bush baby's frontal cortex were investigated by means of the somatopetal transport of horseradish peroxidase. The frontopolar region received afferents from the subicular cortex, the lateral nucleus of the amygdala, from hypothalamic nuclei, the ventral tegmental area and other brain stem nuclei. Injections of horseradish peroxidase into other frontal regions usually resulted in labeled cells in brain stem nuclei and in the hypothalamus, but not in telencephalic regions; only the large injection into the posterior part of the frontal cortex was followed by labeled amygdaloid neurons. From these results it is concluded that a small number of limbic system-related telecephalic areas projects to the frontal cortex and that a somewhat larger number of diencephalic and brain stem nuclei reaches this part of the cortex.     

Evidence for thyrotropin-releasing hormone and glucocorticoid receptor-immunoreactive neurons in various preoptic and hypothalamic nuclei of the male rat

Neurons containing thyrotropin-releasing hormone (TRH) and glucocorticoid receptor (GR) immunoreactivity (IR) were demonstrated by a two-colour immunoperoxidase method in coronal cryotome sections of the preoptic region and the hypothalamus of the male rat brain. All the TRH-IR neurons (TRH-IR) located in the dorsal hypothalamus - medial and dorsal parvocellular parts of the paraventricular hypothalamic nucleus and the dorsomedial hypothalamic nucleus - and in the anterior periventricular hypothalamic nucleus were strongly GR-IR. The TRH-IR neurons of the medial preoptic area, the perifornical nucleus and the medial tuberal area were mostly weakly GR-IR and some lacked GR-IR. These data indicate a differential regulation of diencephalic TRH-IR neurons by glucocorticoids. They also imply that the inhibitory effect of glucocorticoids on TSH secretion may involve a direct inhibition of TRH synthesis and/or release by a nuclear action in the TRH-IR nerve cells of the paraventricular hypothalamic nucleus projecting to the median eminence.     

Changes in limbic dopamine metabolism following quinolinic acid lesions of the left entorhinal cortex in rats

To examine the effects of lesions of the entorhinal cortex on limbic dopamine (DA) metabolism, DA and its metabolites were assayed in five brain regions (the medial prefrontal cortex, anterior cingulate cortex, caudate-putamen, accumbens nucleus, and lateral amygdala), 14 and 28 days after quinolinic acid or sham lesions of the left entorhinal cortex in rats. Concentrations of 3,4-dihydroxyphenylacetic acid (DOPAC) on day 14 in the medial prefrontal cortex, accumbens nucleus, and lateral amygdala of the entorhinal cortex lesioned animals were significantly decreased compared with the controls, but they returned to control levels on day 28. The concentration of DA in the lateral amygdala and spontaneous locomotion to a novel environment were significantly increased on day 28 after the lesion. These results suggest that entorhinal cortex lesions alter mesolimbic dopamine metabolism, particularly in the amygdala.     

Distribution of cholecystokinin (CCK) in the hypothalamus and limbic system of the rat

Cholecystokinin (CCK) concentrations were determined in microdissected individual nuclei of the hypothalamus and limbic system using a specific and sensitive CCK radioimmunoassay (RIA). The CCK levels in the hypothalamus were highest (> 2 mg CCK8 sulfate equivalents/mg protein) in the ventromedial, dorsomedial, periventricular, arcuate nuclei, the median eminence, and mamillary body. Most regions of the limbic system had higher levels of CCK than the hypothalamus and in particular the CA3 region of the hippocampus, the lateral septal nucleus and the medial and lateral amygdaloid nuclei had levels of CCK which were similar to some cerebral cortical areas.This study confirms previous preliminary CCK distribution studies in the rat and indicates that CCK in addition to its wide distribution in the cerebral cortex, is present in abundance in many areas of the hypothalamus and limbic system.     

Reduced expression of amyloid precursor protein, presenilin-1 and rab3a in cortical brain regions in Alzheimer's disease

To study the role of amyloid precursor protein (APP) in the pathogenesis of Alzheimer's disease (AD), the level of APP was analysed by quantitative immunoblotting in 6 AD patients and 6 age-matched controls in 9 brain regions. These were associative cortices (orbital frontal cortex, inferior temporal cortex, inferior parietal cortex), primary cortex (occipital cortex), limbic structures (anterior cingulate gyrus, hippocampus), subcortical structures (putamen, thalamus) and cerebellum. To assess a potential relationship between APP and presenilin-1 (PS-1) and/or synaptic proteins, the levels of PS-1 and rab3a, a specific synaptic vesicle protein, were also determined in the same tissue samples. The level of APP was almost the same in the association cortical regions, primary cortex, and limbic structures and in the subcortical structures, while the lowest level was found in the cerebellum. There were more marked differences in the level of PS-1 and rab3a between different brain regions. The highest levels of PS-1 and rab3a were found in the association cortical areas, while intermediate levels were found in primary cortex, limbic structures and subcortical structures. As for APP, the lowest level was found in cerebellum. We found significantly reduced levels of all three proteins in the association cortices and in hippocampus in AD. Our data show that the protein levels are reduced in specific areas, restricted to neuronal populations that are known to degenerate in AD. Due to the similarity of the expression of APP, PS-1 and rab3a, it is tempting to speculate whether there is a functional relationship between these proteins.     

Mood disturbances and regional cerebral metabolic abnormalities in recently abstinent methamphetamine abusers

BACKGROUND: Mood disturbances in methamphetamine (MA) abusers likely influence drug use, but the neurobiological bases for these problems are poorly understood. OBJECTIVE: To assess regional brain function and its possible relationships with negative affect in newly abstinent MA abusers. DESIGN: Two groups were compared by measures of mood and cerebral glucose metabolism ([18F]fluorodeoxyglucose positron emission tomography) during performance of a vigilance task. SETTING: Participants were recruited from the general community to a research center. PARTICIPANTS: Seventeen abstaining (4-7 days) MA abusers (6 women) were compared with 18 control subjects (8 women). MAIN OUTCOME MEASURES: Self-reports of depressive symptoms and anxiety were measured, as were global and relative glucose metabolism in the orbitofrontal, cingulate, lateral prefrontal, and insular cortices and the amygdala, striatum, and cerebellum. RESULTS: Abusers of MA provided higher self-ratings of depression and anxiety than control subjects and differed significantly in relative regional glucose metabolism: lower in the anterior cingulate and insula and higher in the lateral orbitofrontal area, middle and posterior cingulate, amygdala, ventral striatum, and cerebellum. In MA abusers, self-reports of depressive symptoms covaried positively with relative glucose metabolism in limbic regions (eg, perigenual anterior cingulate gyrus and amygdala) and ratings of state and trait anxiety covaried negatively with relative activity in the anterior cingulate cortex and left insula. Trait anxiety also covaried negatively with relative activity in the orbitofrontal cortex and positively with amygdala activity. CONCLUSIONS: Abusers of MA have abnormalities in brain regions implicated in mood disorders. Relationships between relative glucose metabolism in limbic and paralimbic regions and self-reports of depression and anxiety in MA abusers suggest that these regions are involved in affective dysregulation and may be an important target of intervention for MA dependence.     

Localization of neurotensin NTS2 receptors in rat brain, using

The brain localization of the neurotensin receptor NTS2 was studied with [3H]levocabastine, using an autoradiographic procedure. This study suggests that NTS2 receptors are mainly intracellular. High densities of binding sites were observed in the cingulate, insular, temporal, occipital, enthorhinal cortex, amygdaloid complex, septohippocampal nuclei, medial thalamus, mammillary bodies and superior colliculi; a moderate labelling was observed in the anterior and medial hippocampus, olfactory tubercle, hypothalamus, periaqueductal gray matter, caudate putamen, nucleus accumbens, septum, lateral thalamus, dorsal raphe nucleus and cerebellum; finally, a low labelling was apparent in the ventral tegmentum area and substantia nigra. Thus it appears that NTS2 receptors are particularly abundant in the cerebral cortex, the limbic areas and some areas involved in pain perception.     

Afferent fibers to rat cingulate cortex

Afferent fibers to the rat cingulate cortex were studied by the retrograde labeling technique using horseradish peroxidase-wheat germ agglutinin conjugate as the tracer. The results showed that the posterior cingulate cortex, but not the anterior, received input from the anterior dorsal and anterior ventral nuclei of the anterior thalamic group of nuclei (part of the so-called limbic thalamus), and from the subicular complex. The anterior cingulate cortex, but not the posterior, received input from the mediodorsal and ventral thalamic nuclei. Both posterior and anterior cingulate cortex received input from the hippocampus pars anterior; claustrum; globus pallidus; nucleus of the diagonal band of Broca (a particularly reliable source of afferent fibers); anterior medial, lateral, rhomboid, and reuniens nuclei of the thalamus; region of the medial forebrain bundle; periventricular nucleus of the hypothalamus; the dorsal and median raphe; and the locus ceruleus. Corticocortical projections were seen anterior, posterior, and lateral to the injection site, and in the homologous contralateral cingulate cortex. The results demonstrate a prominent source of cingulate afferent fibers from the subicular complex, provide evidence for a functional division of anterior and posterior cingulate cortices in the rat, and provide information about the relative anatomic importance of cingulate afferent fibers from those different regions.     

Circadian rhythms of TRH-like peptide levels in rat brain

This is the first report of diurnal variations in the levels of thyrotropin-releasing hormone-like peptides (pGlu-X-Pro-NH(2), where "X" can be any amino acid residue) in brain regions involved in mood regulation. These peptides have neuroprotective and antidepressant-like properties that may help stabilize chronobiologic systems that are often abnormal in neuropsychiatric disease. We hypothesized that diurnal fluctuations in the levels of these neuropeptides are components of the chronobiologic regulation of autonomic, behavioral and emotional states. Optimal use of these potentially therapeutic agents will benefit from an understanding of their response to, and effect on, normal vegetative, activity and sleep patterns, and the corresponding disordered patterns of mental illness. For these reasons, 16 male, 200 g, Sprague-Dawley rats were maintained for 4 weeks in a stable 12 h lights on, 12 h lights off photoperiod. Levels of TRH and TRH-like peptides were measured at 3.0 h, 10.5 h, 13.5 h and 21.0 h, where the subjective midnight was 0.0 h, by a combination of HPLC and RIA. Highly significant changes in TRH-like peptide levels were observed in the striatum, posterior cingulate, cerebellum, pyriform cortex, nucleus accumbens and medulla oblongata. TRH-like peptide levels, in general, were highly correlated with changes in TRH concentration, within and between brain regions, and may be colocalized in large glutamatergic neurons innervating the rat limbic system. We conclude that TRH-like peptides may be important components of chronobiologic systems involved in maintaining autonomic, behavioral and mood equilibria.     

Changes in TRH and its degrading enzyme pyroglutamyl peptidase II, during the development of amygdaloid kindling

Pyroglutamyl peptidase II (PPII) is a neuronal ectoenzyme responsible for thyrotropin releasing hormone (TRH) degradation at the synaptic cleft. PPII, heterogeneously distributed in different brain regions and adenohypophysis, is regulated under various endocrine conditions where TRH is involved in thyrotropin or prolactin regulation but only at the adenohypophyseal level. TRH can downregulate PPII activity in cultured adenohypophyseal cells. TRH present in extrahypothalamic brain areas has been postulated to serve as a neuromodulator and levels of this peptide increase in amygdala, hippocampus and cortex after electrical stimulation (kindling or electroshock). To study whether brain PPII could be regulated in conditions that stimulate TRHergic neurons, TRH and PPII activity were determined during the development of amygdaloid kindling in the rat. TRH levels increased from stage II to V in amygdala and hippocampus in the ipsi- and contralateral side to stimulation. In n. accumbens a decrease, compared to sham was observed at stage II, but levels raised through stage V. In contrast, PPII activity was increased at stage II, in amygdala of both sides and in hippocampus, frontal cortex, n. accumbens and hypothalamus of the contralateral side; levels decreased at stage V to sham values in most structures (except amygdala and hippocampus where the activity was 30% below controls). These results suggest that PPII activity in the central nervous system can be regulated in conditions known to affect TRHergic neurons.     

Regional brain activity in women grieving a romantic relationship breakup

OBJECTIVE: Separation from loved ones commonly leads to grief reactions. In some individuals, grief can evolve into a major depressive episode. The brain regions involved in grief have not been specifically studied. The authors studied brain activity in women actively grieving a recent romantic relationship breakup. It was hypothesized that while remembering their ex-partner, subjects would have altered brain activity in regions identified in sadness imaging studies: the cerebellum, anterior temporal cortex, insula, anterior cingulate, and prefrontal cortex. METHOD: Nine right-handed women whose romantic relationship ended within the preceding 4 months were studied. Subjects were scanned using blood-oxygen-level-dependent functional magnetic resonance imaging while they alternated between recalling a sad, ruminative thought about their loved one (grief state) and a neutral thought about a different person they knew an equally long time. RESULTS: Acute grief (grief minus neutral state) was associated with increased group activity in posterior brain regions, including the cerebellum, posterior brainstem, and posterior temporoparietal and occipital brain regions. Decreased activity was more prominent anteriorly and on the left and included the anterior brainstem, thalamus, striatum, temporal cortex, insula, and dorsal and ventral anterior cingulate/prefrontal cortex. When a more lenient statistical threshold for regions of interest was used, additional increases were found in the lateral temporal cortex, supragenual anterior cingulate/medial prefrontal cortex, and right inferomedial dorsolateral prefrontal cortex, all of which were adjacent to spatially more prominent decreases. In nearly all brain regions showing brain activity decreases with acute grief, activity decreases were greater in women reporting higher grief levels over the past 2 weeks. CONCLUSIONS: During acute grief, subjects showed brain activity changes in the cerebellum, anterior temporal cortex, insula, anterior cingulate, and prefrontal cortex, consistent with the hypothesis. Subjects with greater baseline grief showed greater decreases in all these regions except for the cerebellum. Further imaging studies are needed to understand the relationship between normal sadness, grief, and depression.     

Effects of pilocarpine- and kainate-induced seizures on thyrotropin-releasing hormone biosynthesis and receptors in the rat brain

Summary. The expression of mRNA coding for prepro-thyrotropin releasing hormone (preproTRH) was estimated in the rat brain in two animal models of limbic seizures, evoked by systemic administration of pilocarpine (400 mg/kg ip) or kainate (12 mg/kg ip). As shown by an in situ hybridization study, after 24 h both pilocarpine- and kainate-induced seizures profoundly increased the preproTRH mRNA level in the dentate gyrus. After 72 h, the preproTRH mRNA level was back to control values. Kainate-treated rats showed an elevated level of TRH in the hippocampus, septum, frontal and occipital cortex after 24 and 72 h, whereas in the striatum and amygdala the TRH level was raised after 72 h only. In the hypothalamus, TRH levels was lowered after 3 and 24 h, and returned to the control after 72 h. Pilocarpine-induced seizures also elevated the TRH level after 72 h in the majority of the above structures, except for the hypothalamus and amygdala where no changes were found at any time point. A radioreceptor assay showed that kainate decreased the B_max value of TRH receptors in the striatum and hippocampus after 3 and 24 h, respectively, and had no effect on the K_d values. In contrast, pilocarpine-induced seizures lowered the B_max of TRH receptors in the striatum, hippocampus and piriform cortex after 72 h only, and decreased K_d values in the striatum, amygdala and frontal cortex. These data showed that pilocarpine- and kainate-induced seizures enhanced likewise preproTRH mRNA in the dentate gyrus; on the other hand, they differed with respect to time- and structure-related changes in TRH tissue levels and TRH receptors. These differences may have functional significance in TRH-dependent control mechanism of the seizure activity in these two models of limbic epilepsy. Received February 2, 1998; accepted November 25, 1998     

Discrete regional distributions of thyrotropin releasing hormone (TRH) receptor binding in monkey central nervous system

Thyrotropin releasing hormone (TRH) directly influences central nervous system (CNS) function, independent of its pituitary action. Although these CNS effects have been behaviorally characterized, information is not yet available on the precise regional distribution of its receptor. TRH receptor binding was examined in the monkey CNS by the radioreceptor assay for clarifying the site of TRH action. TRH was bound to brain tissue membranes via high-affinity (K_d = 5.9 × 10⁻⁹M) and low-affinity (K_d = 11.2 × 10⁻⁸M) components. TRH receptor binding varied dramatically throughout the monkey brain, with more than a 40-fold variation. The limbic system contained the greatest amount of binding. The next highest areas were the cerebral cortex, hypothalamus, interpeduncular nucleus and periaqueductal gray matter of the midbrain. Receptor binding was very low or not detectable in the medial thalamus, cerebellum, brain stem, spinal cord and white matter. These data suggest that TRH has an effect on the CNS via limbic system, cerebral cortex and midbrain.     

Metabolic Changes of Cerebrum by Repetitive Transcranial Magnetic Stimulation over Lateral Cerebellum: A Study with FDG PET

To better understand the functional role of cerebellum within the large-scale cerebellocerebral neural network, we investigated the changes of neuronal activity elicited by cerebellar repetitive transcranial magnetic stimulation (rTMS) using (18)F-fluorodeoxyglucose (FDG) and positron emission tomography (PET). Twelve right-handed healthy volunteers were studied with brain FDG PET under two conditions: active rTMS of 1?Hz frequency over the left lateral cerebellum and sham stimulation. Compared to the sham condition, active rTMS induced decreased glucose metabolism in the stimulated left lateral cerebellum, the areas known to be involved in voluntary motor movement (supplementary motor area and posterior parietal cortex) in the right cerebral hemisphere, and the areas known to be involved in cognition and emotion (orbitofrontal, medial frontal, and anterior cingulate gyri) in the left cerebral hemisphere. Increased metabolism was found in cognition- and language-related brain regions such as the left inferior frontal gyrus including Broca's area, bilateral superior temporal gyri including Wernicke's area, and bilateral middle temporal gyri. Left cerebellar rTMS also led to increased metabolism in the left cerebellar dentate nucleus and pons. These results demonstrate that rTMS over the left lateral cerebellum modulates not only the target region excitability but also excitability of remote, but interconnected, motor-, language-, cognition-, and emotion-related cerebral regions. They provide further evidence that the cerebellum is involved not only in motor-related functions but also in higher cognitive abilities and emotion through the large-scale cerebellocereberal neural network.     

Glial fibrillary acidic protein expression after electroconvulsive shocks in rat brain

OBJECTIVE: The aim of the present study was to assess the effect of electroconvulsive shock (ECS) in glial fibrillary acidic protein (GFAP) expression in rat brain. METHODS: Rats were given either a single (acute) or a series of eight (chronic) ECS. Brain regions were isolated and levels of glial fibrillary acidic protein (GFAP) in the brain tissue (cortex, hippocampus, and cerebellum) were assessed using an enzyme-linked immunosorbent assay (ELISA). RESULTS: We showed that GFAP expression is reduced in the hippocampus within 48 h and 7 days after acute ECS. GFAP levels are increased in the cerebellum immediately after acute and chronic ECS. No changes were observed in the cortex. CONCLUSIONS: Our findings showed a differential effect of acute and chronic ECS in the astroglial response in the brain of rats.     

Lipopolysaccharide modulation of thyrotropin-releasing hormone (TRH) and TRH-like peptide levels in rat brain and endocrine organs

Lipopolysaccharide (LPS) is a proinflammatory and depressogenic agent whereas thyrotropin-releasing hormone (TRH; pGlu-His-Pro-NH₂) is an endogenous antidepressant and neuroprotective peptide. LPS and TRH also have opposing effects on K⁺ channel conductivity. We hypothesized that LPS can modulate the expression and release of not only TRH but also TRH-like peptides with the general structure pGlu-X-Pro-NH₂, where “X” can be any amino acid residue. The response might be “homeostatic,” that is, LPS might increase TRH and TRH-like peptide release, thereby moderating the cell damaging effects of this bacterial cell wall constituent. On the other hand, LPS might impair the synthesis and release of these neuropeptides, thus facilitating the induction of early response genes, cytokines, and other downstream biochemical changes that contribute to the “sickness syndrome.” Sprague-Dawley rats (300 g) received a single intraperitoneal injection of 100 μg/kg LPS. Animals were then decapitated 0, 2, 4, 8, and 24 h later. Serum cytokines and corticosterone peaked 2 h after intraperitoneal LPS along with a transient decrease in serum T3. TRH and TRH-like peptides were measured by a combination of high-performance liquid chromatography and radioimmunoassay. TRH declined in the nucleus accumbens and amygdala in a manner consistent with LPS-accelerated release and degradation. Various TRH-like peptide levels increased at 2 h in the anterior cingulate, hippocampus, striatum, entorhinal cortex, posterior cingulate, and cerebellum, indicating decreased release and clearance of these peptides. These brain regions are part of aneuroimmunomodulatory system that coordinates the behavioral, endocrine, and immune responses to the stresses of sickness, injury, and danger. A sustained rise in TRH levels in pancreatic β-cells accompanied LPS-impaired insulin secretion. TRH and Leu-TRH in prostate and TRH in epididymis remained elevated 2-24h after intraperitoneal LPS. We conclude that these endogenous neuroprotective and antidep resant-like peptides both mediate and moderate some of the behavioral and toxic effects of LPS.