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Original article Abstract The fiber degenerations resulting from variously located lesions of the lentiform nucleus were studied in the rhesus monkey by the aid of the Nauta-Gygax and Albrecht-Fernstrom techniques. The following observations were made. (1) Putaminofugal connections . Thin fibers originating in the putamen and composing Wilson's ‘pencil’ bundles traverse the globus pallidus, converging toward the medial point of the lentiform nucleus. The mjority of these fibers terminate in both segments of the globus pallidus, but a considerable number continue caudalward, perforating the cerebral peduncle as ventral components of Edinger's comb system, and terminate in lateral parts of the substantia nigra, pars reticulata. (2) Pallidofugal connections . The ansa lenticularis as defined by von Monakow originates exclusively from the globus pallidus. Its middle division, composed of fibers of medium calibre, arises in the external pallidal segment and traverses the cerebral peduncle as the dorsal component of the comb system to end in the subthalamic nucleus. The thick-fibered dorsal and ventral ansal divisions arise in the internal pallidal segment and combine to form the fasciculus lenticularis which represents the only apparent direct connection of the globus pallidus with the thalamus and the mesencephalic tegmentum. (a) Pallidothalamic fibers follow successively the lenticular and thalamic fasciculi and are distributed to the nuclei ventralis lateralis (subnuclei medialis and oralis of Olszewski and Baxter; none to Zone X and subnucleus caudalis) and ventralis anterior (except subnucleus VAmc). A considerable number of thinner fibers, possibly collaterals of those to VL and VA, terminate in the ‘centre median’; this connection appears to close a potential transthalamic circuit: putamen-globus pallidus-‘centre median’-putamen. (b) There is suggestive evidence of pallidofugal fibers following the stratum zonale thalami to the habenula. (c) Pallidohypothalamic connections could not be identified. Most, and possibly all, of the ansal fibers composing the so-called pallidohypothalamic tract loop back into Forel's fields after a shorter or longer descent into the hypothalamus. (d) Fibers of the fasciculus lenticularis by-passing the thalamus are distributed to the nucleus of Forel's field H (prerubral field). Longer fibers of the same category pass caudalward lateral and ventral to the red nucleus and terminate in the nucleus tegmenti pedunculopontinus, particularly in the latter's caudal subnucleus compactus (terminology of Olszewski and Baxter). A few such pallidomesencephalic fibers appear to end in a small circumscript caudal area of the substantia nigra, pars compacta. No evidence was obtained of pallidotegmental fibers extending caudally beyond the mesencephalon. (e) Pallidal efferents to the zona incerta could not be identified. Only sporadic pallidofugal fibers could be followed to the red nucleus, nucleus interstitialis, and nucleus of Darkschewitsch. Article abstract The article, ‘Projections of the lentiform nucleus in the monkey’, by Walle J.H. Nauta and William R. Mehler used a relatively new anatomical tracing method that allowed visualization of degenerating myelin following carefully placed lesions to identify the efferent projections from the lentiform nucleus. While several of the basal ganglia pathways had been described or suspected, this publication validated many of these, resolved controversies regarding some connections, and demonstrated a few that had not previously been shown. This seminal paper became a main reference for basal ganglia connections until newer, more specific tracer techniques were developed. Several students and colleagues who worked closely with Nauta continued to use anatomical tracing methods to make key important contributions to delineating basal ganglia circuits and function. Collectively these studies have impacted greatly on our understanding of the role of the basal ganglia in normal behavior and in neurological and psychiatric disorders. This article is part of a Special Issue entitled SI:50th Anniversary Issue .

A post-proline cleaving enzyme isolated from bovine brain and previously shown to act on the neuropeptides thyrotropin releasing hormone (TRH: pGlu-His-Pro-NH2) and luteinizing hormone releasing hormone (LRH: pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) has now been found to cleave the Pro4-Gln5 bond in substance P (SP: H-Arg-Pro-Lys-Pro-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2) to yield the N-terminal tetrapeptide H-Arg-Pro-Lys-Pro-OH and the C-terminal heptapeptide H-Gln-Gln-Phe-Phe-Gly-Leu-Met-NH2. The site of cleavage of the undecapeptide was confirmed by chemical synthesis of SP peptide fragments, by high performance liquid chromatographic analysis, and by high-voltage paper electrophoresis, thin layer chromatography and amino acid analysis. In addition, SP was shown by enzyme kinetic analysis to act as a potent competitive inhibitor of the enzymatic hydrolysis of the synthetic post-proline cleaving enzyme substrate carbobenzoxy-Gly-Pro-para-nitroanilide. It is known that the heptapeptide is as active as SP itself in a variety of bioassays, whereas the tetrapeptide has been reported to induced cyclic AMP formation and neurite extension in neuroblastoma cells and to enehance the phagocytosis activity of macrophages. These observations suggest that SP may play a dual role, with one activity residing in its C-terminal part, and the other in the N-terminal part of the molecule.

Nerve ending particles isolated from prenatal and postnatal rats by means of density-gradient centrifugation in a ficoll medium actively incorporated [32P]-orthophosphate into nucleotides, phosphoproteins and phospholipids. This process requires Mg2+; is dependent on malate plus pyruvate but not glucose, and is inhibited by dinitrophenol, gramicidin, oligomycin, azide, p-chloromercuribenzoate, CaCl2 but not iodoacetate. It was concluded that the metabolic energy at the synapse is derived largely from the mitochondria of the synaptic complex rather than from its cytoplasm. Thin-layer chromatography and paper electrophoresis revealed that the metabolically active phospholipids, namely phosphatidic acid, phosphatidyl inositol and the polyphosphoinositides which were found to be tightly bound to the phosphoprotein fraction, contained more than 90% of the total radioactivity but constituted less than 9% of the total phospholipids. The highest phosphoprotein and phospholipid content of the nerve endings (expressed in μmoles P/mg nerve ending protein) as well as maximal 32P-incorporation occurred just prior to and continued into the stage when functional changes are formed. It is suggested that an increase in the amount of enzymatic activity coupled with an increase in the permeability of the synaptosomal membrane to inorganic phosphate and other metabolites could trigger the rapid morpho-biochemical and functional changes observed in rat brain during this period of development. A simple density-gradient withdrawing device for the isolation of the submitochondrial particles after density-gradient centrifugation of the conventional mitochondrial fraction was described.

Neonatal and juvenile female rats were given a subcutaneous injection of tritium-labeled testosterone propionate (TP) or testosterone (T), with or without added carrier. Levels of radioactivity in plasma, hypothalamus, amygdala and cerebral cortex were measured at various time intervals after injection. Free radioactive steroids in the brain were separated from conjugated steroids by solvent partition, and the free steroids were further fractionated by paper chromatography. (1) No preferential accumulation of radioactivity from plasma by the hypothalamus, amygdala or cortex was observed after injection of [ 3 H]-TP or [ 3 H]-T, irrespective of the age of the females (1, 5, 6, 11 or 21 days) and time of determination (1–48 h after injection): the ratio of brain region disint./min: plasma disint./min did not exceed 0.5. (2) Cold TP or T, administered simultaneously with [ 3 H]-TP or [ 3 H]-T, respectively, did not reduce the uptake of radioactivity by the hypothalamus, amygdala or cortex of the 5-day-old females. (3) The concentration of free steroids in the brain (disint./min/mg wet wt), 1–4 h after injection of [ 3 H]-T, was several times higher than after [ 3 H]-TP injection. At 8 h or later, the concentration of free steroids, and particularly of unconjugated testosterone 5α-dihydrotestosterone and androstenedione, was higher in the brains of the [ 3 H]-TP-treated animals. (4) A decline in the uptake of [ 3 H]-T was observed between the 1st and 6th days of life, with no further changes until the 11th day. Thus the progressive fall in effectiveness of TP in producing androgenization known to occur between the 6th to 11th days of life was not paralleled by changes in the uptake of [ 3 H]-T by the hypothalamus, amygdala or cortex as assayed 2 h after injection. The results do not support the existence of a specific high-affinity low-capacity uptake mechanism for testosterone in the brain of the neonatal female rat comparable with the demonstrable in adrogen-responsive organs such as prostate gland.

Previous studies have shown that bovine dorsal root contains a peptide which depolarizes the frog's spinal motoneurons. In the present study, pharmacological, chemical, enzymatic and immunological properties of this motoneuron-depolarizing peptide were investigated, and the results indicated that the peptide is identical with substance P recently isolated from hypothalamus. The amount of substance P in the dorsal root was 24–130 pmoles/g wet weight, while that in the ventral root was 9–27 times less. These results support the hypothesis that substance P might be an excitatory transmitter released from primary sensory neurons.

Intravenously injected [1,2-3H]deoxycorticosterone (DOC) readily enters all parts of the central nervous system. In intact and eviscerated rats the highest concentration of radioactive label was recovered from areas corresponding to the reticular formation from the brain stem. In addrenalectomized animals, in addition to high brain stem concentration, there was also a marked increase in the uptake of radioactivity in the septum, hippocampus and pituitary. Data from the eviscerated rat point to a uniform distribution of [1,2-3H]DOC in neural tissues and suggest that the higher levels of radioactivity found in the brain stem may be due to a DOC metabolite with the chromatographic characteristics of allo-tetrahydro-DOC, an anaesthetic-type steroid. A decrease in the amplitude of evoked sciatic potentials in brain stem sites but not in the thalamic relay nucleus was observed in 52% of the cases studied, following the i.v. injection of 100-150 mug DOC.

The distribution of HVA in various regions of the grey and white matter of the human brain has been examined. HVA was found to occur in appreciable amounts in the following regions: (a) Grey matter - putamen, caudate nucleus, globus pallidus, substantia nigra, red nucleus, subthalamic nucleus, thalamus, lamina quadrigemina; (b) White matter - all components of the internal capsule (anterior limb, genu, posterior limb, supralenticular part), pes pedunculi, white matter of the cortex. From the characteristics distribution pattern of HVA within the internal capsule (lowest concentrations in the caudal parts of the posterior limb, highest values in the anterior limb), and from the results obtained in parkinsonian brains, it is concluded that dopamine-containing fibres are present in the internal capsule running in rostral direction to reach the striatum. These dopamine fibres are assumed to originate in the substantia nigra. Contrary to this, the biochemical source and significance of the HVA found in other brain regions than the striatum, the substantia nigra and the internal capsule (i.e. globus pallidus, red and subthalamic nuclei, thalamus, lamina quadrigemina, and possibly also pes pedunculi and white matter of the cortex) remain unexplained as yet.

Summary [ 14 C]Bicarbonate and l -[U- 14 C]aspartate were injected intraventricularly into the brains of nembutalized mice, and the cerebral metabolism of each of these substrates compared with that occurring when the injection solution also contained the neuronal excitant, N -methyl- d -aspartate (NMDA). Over a 7-min period, during which the distribution of radioactivity was measured at 1-min intervals, NMDA caused an increased rate of loss of radioactivity newly incorporated into endogenous aspartate from [ 14 C]bicarbonate. A commensurate increase in the labelling of either glutamate or glutamine was not detected. These results are taken to indicate heterogeneity of the systems responsible for the metabolism of the injected bicarbonate. The major system would appear to involve the predominant part of the glutamate and glutamine labelled from this precursor and to be unaffected by the neuronal excitation effected by NMDA. This system may involve a substantial glial component. The minor system may be localized intraneuronally, and be associated with that particular aspartate pool, the turnover rate of which was shown previously, in [U- 14 C]glucose studies, to be greatly increased by the action of NMDA. Slight changes observed in the metabolism of l -[U- 14 C]aspartate in the presence and absence of NMDA, studied over a single 5-min period, could be interpreted in a similar way, but the differences were not statistically significant in this case.

Summary The effects of a 96 h paradoxical sleep deprivation (PS) on the metabolism of serotonin have been studied in the brain stem-mesencephalon, cortex-diencephalon and spinal cord of rats. A marked increased formation of [ 3 H]serotonin was observed in tissues of PS-deprived animals after intracisternal administration of [ 3 H]tryptophan or after incubation with [ 3 H]tryptophan when compared with control animals. No effect could be seen when [ 3 H]5-hydroxytryptophan was used instead of [ 3 H]tryptophan in experiments in vivo as well as in vitro . As indicated by the changes on [ 3 H]tryptophan accumulation in tissues and on serotonin-specific activity in the experiment in vitro , the increased [ 3 H]serotonin synthesis in PS-deprived animals seemed to result from both an increased transport of [ 3 H]tryptophan and an increased rate of conversion of [ 3 H]tryptophan to [ 3 H]5-hydroxytryptophan. The utilization of brain [ 3 H]serotonin endogenously synthesized from [ 3 H]tryptophan was accelerated during PS deprivation. The increased turnover of serotonin in PS-deprived animals appeared to be related to the impossibility of triggering PS.

The accumulation of 131 I in motor neurons, liver, muscle and spinal cord grey matter after intravenous injection with 131 I-labeled triiodothyronine was determined by liquid scintilattion counting procedures. It was observed that the thyroid hormone which accumulates in the brain (spinal cord) was largely present in the neurons, which had significantly higher accumulations than did masses of spinal grey matter which would contain comparable motor neurons. The nerve cell 131 I activity was also significantly higher than that seen in striated muscle. Liver, which takes up thyroid hormones very rapidly, had levels of radioactivity which were significantly higher than muscle, spinal grey matter, plasma or ventral horn motor neurons at most time intervals investigated. A chromatographic analysis of unfixed, ethanol (pH 8.5) extracted neurons revealed that most of the 131 I detected in the motor neuron samples was associated with triiodothyronine, which is comparable to what has been previously reported for whole brain after intravenous injection of [ 131I ]triiodothyronine.

Summary Glycine:2-oxoglutarate transaminase activity was higher in cat spinal grey matter than in white matter. In subcellular fractions of cat spinal cord homogenates, most of the transaminase activity was associated with the soluble cytoplasmic fraction, in contrast to the bimodal subcellular distribution found in rat brain homogenates.

Summary Mice aged from 2 to 32 days were injected i.p. with [14C6]glucose and sacrificed at 1, 2 and 4 h post-injection. Free and bound glucose and galactose were reisolated from brain, and their radioactivity was determined, as well as the integrity of the hexose carbon chain. A 10–15-fold increase in the free galactose to free glucose ratio was observed between 16 and 22 days post-partum. Lower values were observed for bound sugar ratios. These changes coincide with increased brain UDP-galactose-4-epimerase activity and with active myelination. The incorporation of radiocarbon in myelin was determined by subcellular fractionation of brain 24 h after i.p. injection of [14C6]glucose. Optimal incorporation of radiocarbon was observed at 16 days post-partum and is consistent with a primary role for UDP-galactose-4-epimerase in myelin biosynthesis. These results also support the hypothesis that the sharply increased brain requirements for galactose during myelination are met by in situ conversion of dietary milk glucose to galactose through the UDP-galactose-4-epimerase pathway.

Levels of radioactivity in various brain structures were measured after intraperitoneal injections of [3H]testosterone into adult male rats (castrated neonatally or in adulthood) and adult ovariectomized female rats (androgenized by neonatal testosterone injection or given control oil injection). (1) Brain structures concentrated radioactivity after [3H]testosterone injections to levels one to two times blood levels. In male rats castrated as adults, highest uptake was found in the pituitary, hypothalamus, preoptic area and septum. (2) The same pattern of uptake across brain structures was seen in the other treatment groups (neonatally castrated males and two group of females). However, neonatal castrates tended to accumulate less testosterone in all brain structures than the other treatment groups, and the pituitary of the adult-castrated male retained significantly more testosterone than in the other treatment groups. (3) Castrated prepuberal male rats showed a similar pattern of uptake across brain regions, compared to adult males, except for particularly high accumulation in the olfactory bulbs and lower accumulation in the brain stem. (4) Hypophysectomized castrated male rats accumulated less testosterone in all brain structures than castrated males with intact pituitaries. The hypophysectomy effect was largest in the preoptic area and septum and, in general, was larger in structures showing higher levels of uptake. (5) The percentage of radioactivity taken up as unchanged testorterone was greatest in the adult-castrated males and least in the neonatally-castrated males. This effect of sex difference and neonatal treatment was latent, and did not appear until after puberty. In all animals, brain regions showing competition effects were equivalent in percentage of unchanged testosterone to brain regions not showing competition effects. In adults, per cent unchanged testosterone was uniformly higher in the brain than in the blood.

Summary The accumulation of [3H]dopamine into brain mitochondria incubated in the presence of iproniazid was examined under a variety of conditions. The mitochondrial to medium ratios remained less than one, although the levels of [3H]dopamine were increased by raising the external concentrations of amine. The accumulation of [3H]-dopamine did not require oxygen, glucose, succinate or mono- or divalent cations and was not influenced by nitrogen, temperature change or by inhibitors of active transport mechanism. The levels of [3H]dopamine were markedly decreased in mitochondria incubated in a buffer medium below pH 7.1. ATP alone or with Mg2+ caused considerable inhibition. Of several compounds tested, 3,4-dimethoxyphenylethylamine, tryptamine,N-acetylserotonin, 5-methoxytryptamine, bufotenin and a number of phenotiazines markedly inhibited dopamine accumulation.

We have studied the kinetics of uptake of several l -amino acids into homogenates of rat cerebral cortex and spinal cord. These accumulated amino acids are localized to synaptosomal fractions obtained by sucrose density gradient centrifugation. The accumulations of glutamic and aspartic acids in the cerebral cortex and spinal cord and glycine in the spinal cord are best described by two kinetic systems with low and high affinities respectively. By contrast, for glycine in the cerebral cortex and for several other amino acids in both areas, only single low affinity transport systems are detected. The uptakes of glutamic and aspartic acids were mutually competitive in both cerebral cortical and spinal cord preparations, suggesting that they utilize the same uptake mechanism.

The products ofin vivo andin vitro incorporation of radioactive glucosamine into glycoproteins associated with the nerve ending (synaptosome) fraction were studied by polyacrylamide gel electrophoresis and also by gel filtration of glycopeptides derived from these glycoproteins by pronase digestion. Afterin vivo labeling for 1 h a heterogeneous group of [14C]glucosamine labeled glycoproteins was found associated with the nerve ending fraction. The predominant [14C]glucosamine containing glycopeptide derived by pronase digestion of the nerve ending fraction had an apparent molecular weight of 1250. It constituted a larger percentage of the labeled glycopeptides associated with the nerve ending fraction, as compared with other subcellular fractions. After 4 h ofin vivo labeling other glycopeptides constituted a greater percentage of the total labeled glycopeptides derived from the nerve ending fraction. This suggests that a different group of [14C]glucosamine containing glycoproteins were now relatively abundant in nerve endings. Presumably they had arrived by axoplasmic transport to the nerve endings. Afterin vitro labeling the nerve ending fraction incorporated [14C]glucosamine more actively than the microsomal or mitochondrial fractions. The radioactive products found upon polyacrylamide gel electrophoresis of the nerve ending fraction appeared to be less heterogeneous than afterin vivo labeling. Upon pronase digestion a single class of labeled glycopeptides was found with the same apparent molecular weight as the predominant labeled glycopeptide in the nerve ending fraction afterin vivo labeling. The results indicate that some [14C]glucosamine is incorporated into specific products by components of the nerve ending fraction and that this glycosylation cannot readily be attributed to contamination with other particles containing glycosyl transferases. Other glucosamine containing products are apparently transported to the nerve endings after glycosylation in the nerve cell body.

The brainstem nucleus locus coeruleus (LC) is a major source of norepinephrine (NE) projections throughout the CNS. This important property was masked in very early studies by the inability to visualize endogenous monoamines. The development of monoamine histofluorescence methods by Swedish scientists led to a plethora of studies, including a paper published in Brain Research by Loizou in 1969. That paper was highly cited (making it a focal point for the 50th anniversary issue of this journal), and helped to spark a large and continuing set of investigations to further refine our understating of the LC-NE system and its contribution to brain function and behavior. This paper very briefly reviews the ensuing advances in anatomical, physiological and behavioral aspects of the LC-NE system. Although its projections are ubiquitously present throughout the CNS, recent studies find surprising specificity within the organizational and operational domains of LC neurons. These and other findings lead us to expect that future work will unmask additional features of the LC-NE system and its roles in normative and pathological brain and behavioral processes. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

In this paper, Dr. Corrigall and collaborators described elegant experiments designed to elucidate the neurobiology of nicotine reinforcement. The nicotinic receptor antagonist dihydro-β-erythroidine (DHβE) was infused in the ventral tegmental area (VTA) or nucleus accumbens (NAC) of rats trained to self-administer nicotine intravenously. Additionally, DHβE was infused in the VTA of rats trained to self-administer food or cocaine, and nicotine self-administration was assessed in rats with lesions to the peduculopontine tegmental nucleus (PPT). A number of key themes emerged from this fundamental study that remain relevant today. The primary finding was that infusions of DHβE in the VTA, but not in the NAC, lowered nicotine self-administration, suggesting that nicotinic receptors in VTA are involved in the reinforcing action of nicotine. This conclusion has been confirmed by subsequent findings, and the nature of the nicotinic receptors has also been elucidated. The authors also reported that DHβE in the VTA had no effect on food or cocaine self-administration, and that lesions to the PPT did not alter nicotine self-administration. Since this initial investigation, the question of whether nicotinic receptors in the VTA are necessary for the reinforcing action of other stimuli, and by which mechanisms, has been extensively explored. Similarly, many groups have further investigated the role of mesopontine cholinergic nuclei in reinforcement. This paper not only contributed in important ways to our understanding of the neurochemical basis of nicotine reinforcement, but was also a key catalyst that gave rise to several research themes central to the neuropharmacology of substance abuse. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

The history, content and consequences of the highly-cited 1982 Brain Research paper by Halliwell and Adams are summarized. The paper pioneered the use of the single-electrode voltage clamp in mammalian brain slices, described 2 novel sub-threshold voltage-dependent ionic currents, IM and IQ/H, and suggested that cholinergic inputs “enabled” pyramidal cell firing in response to conventional synaptic input, the first example of central neuromodulation. The paper, published in Brain Research to give the first author appropriate importance, heralded an ongoing tidal wave of quantitative electrophysiology in mammalian central neurons. original article abstract Voltage-clamp analysis of muscarinic excitation in hippocampal neurons Pyramidal cells in the CA1 field of guinea pig hippocampal slices were voltage-clamped using a single microelectrode, at 23–30 °C. Small inwardly relaxing currents triggered by step hyperpolarizations from holding potentials of −80 to −40 mV were investigated. Inward relaxations occurring for negative steps between −40 mV and −70 mV resembled M-currents of sympathetic ganglion cells: they were abolished by addition of carbachol, muscarine or bethanechol, as well as by 1 mM barium; the relaxations appeared to invert at around −80 mV; they became faster at more negative potentials; and the inversion potential was shifted positively by raising external K+ concentration. Inward relaxations triggered by steps negative to −80 mV, in contrast, appeared to reflect passage of another current species, which has been labeled IQ.Thus IQ did not invert negative to −80 mV, it was insensitive to muscarinic agonizts or to barium, and it was blocked by 0.5–3 mM cesium (which does not block IM). Turn-on of IQ causes the well known droop in the hyperpolarizing electrotonic potential in these cells. The combined effects of IQ and IM make the steady-state current–voltage relation of CA1 cells slightly sigmoidal around rest potential. It is suggested that activation of cholinergic septal inputs to the hippocampus facilitates repetitive firing off pyramidal cells by turning off the M-conductance, without much change in the resting potential of the cell. © 1982. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

Extensive research implicates disturbed immune function and development in the etiology and pathology of schizophrenia. In addition to reviewing evidence for immunological factors in schizophrenia, this paper discusses how an emerging model of atypical immune function and development helps explain a wide variety of well-established – but puzzling – findings about schizophrenia. A number of theorists have presented hypotheses that early immune system programming, disrupted by pre- and perinatal adversity, often combines with abnormal brain development to produce schizophrenia. The present paper focuses on the hypothesis that disruption of early immune system development produces a latent immune vulnerability that manifests more fully after puberty, when changes in immune function and the thymus leave individuals more susceptible to infections and immune dysfunctions that contribute to schizophrenia. Complementing neurodevelopmental models, this hypothesis integrates findings on many contributing factors to schizophrenia, including prenatal adversity, genes, climate, migration, infections, and stress, among others. It helps explain, for example, why (a) schizophrenia onset is typically delayed until years after prenatal adversity, (b) individual risk factors alone often do not lead to schizophrenia, and (c) schizophrenia prevalence rates actually tend to be higher in economically advantaged countries. Here we discuss how the hypothesis explains 10 key findings, and suggests new, potentially highly cost-effective, strategies for treatment and prevention of schizophrenia. Moreover, while most human research linking immune factors to schizophrenia has been correlational, these strategies provide ethical ways to experimentally test in humans theories about immune function and schizophrenia. This article is part of a Special Issue entitled SI: Neuroimmunology in Health And Disease.

The Falck-Hillarp, formaldehyde fluorescence method for the demonstration of monoamine neurons in a microscope was established in Lund, Sweden and published in 1962. In the same year Hillarp moved to Karolinska Institutet in Stockholm. Two years later Dahlstrom and Fuxe published the famous supplement in Acta Physiologica Scandinavica, describing the distribution of the dopamine, noradrenaline and serotonin cell groups in the rat brain. This landmark paper also represented an important contribution to an emerging discipline in neuroscience - chemical neuroanatomy. During the following years several modifications of the original method were developed, attempting to solve some shortcomings, one being the reproducible demonstration of noradrenaline nerve terminals in cortical regions. One result was the paper focused on in the present article, which also describes other efforts in the same direction going on in parallel, primarily, in Lund and Stockholm. As a result there was, in the mid 1970s, a fairly complete knowledge of the catecholamine systems in the rat brain. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

The 1967 paper from Hans Kuypers and Don Lawrence provided the first complete description of the projections from every major cortical area to the red nucleus and brainstem in the monkey. The study includes descriptions of some of the major cortical influences on sensory and motor circuits subserving vision, hearing and proprioception, as well as movements of the eyes, head and limbs. It also describes the detailed anatomy of the red nucleus in the monkey, and highlights species differences in this structure. It also postulates that cortical projections to the parvicellular component of the red nucleus provide a recurrent loop returning via the thalamus to the motor cortex. The findings reported in this paper helped to substantiate Kuypers' new theory on the organisation of the descending motor pathways by showing that the primary motor cortex, as well as providing a direct crossed corticospinal input to spinal circuits controlling movements of the distal extremities (hand and foot), also influenced these same circuits through ipsilateral projections to the cells of origin of the rubrospinal tract. In contrast, projections from more rostral motor, premotor and prefrontal regions terminated bilaterally in the parvicellular red nucleus, and influenced ventromedial descending pathways controlling movements of the head, neck, trunk and proximal limbs. The paper has proved of lasting value to our understanding of sensorimotor control and the contribution of different pathways to it. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

Udgivelsesdato: 2010-Jan-11 The discovery of neural stem cells (NSCs) provides new therapeutic strategies for brain injury by means of endogenous cell renewal. In the injured mouse brain, bio-liberated gold ions from gold implants mediate anti-inflammatory and antiapoptotic effects and activation of NSCs. This paper investigates the neuroprotective effects of gold following brain injury in mice. We show for the first time that endogenous NSCs express macrophage colony-stimulating factor (M-CSF) as part of their post-injury activation and that gold implants increase this response. Also, gold increases expression of neurotrophin (NT)-4, transforming growth factor-beta 3 (TGF-beta3), leukemia inhibitory factor (LIF) and metallothionein I+II (MT-I+II) post-injury. This paper shows that gold ions modulate neurotrophic factors after injury and that hematopoietic factor M-CSF is expressed in activated NSCs.

brain research 1621 (2015) 1–4 Available online at www.sciencedirect.com www.elsevier.com/locate/brainres Editorial Brain and memory: Old arguments and new perspectives The question of how the brain stores, organizes, and retrieves memories is one of the longest running and intensely argued issues in the biological sciences. It is easy to find reasons why this should be so. Casual introspection, more than a century of research and debates tells us that an understanding of memory is an essential, early step towards a theory of mental life and the phenomenon is profoundly mysterious, a feature bound to attract scholars. Memories form quickly (albeit with a still poorly understood stabilization period), can be remark- ably persistent, and the brain possesses an almost unbelie- vable storage capacity. Moreover, all lines of evidence point to the conclusion that memories are scattered throughout the brain and yet are (1) organized into computationally efficient structures, and along several dimensions, and (2) rapidly recalled even across different sensory modalities. Finding a unifying explanation for these qualities makes for a fascinat- ing and challenging problem; this challenge, combined with the central role played by memory in all human experience, likely explains the continuing intensity of research in the field. But the very nature of the properties of memories suggests that consensus definitions, conclusive experiments and con- vincing arguments will be hard to come by. The past 50 years of work has amply confirmed this prediction. Seen in this light, the many and sometimes acrimonious arguments associated with memory research were probably inevitable. However, scientific controversies often have useful outcomes and the question arises as to whether this has been the case for memory research. The contributions to this Special Issue were intended to address this question. They are organized into sections on a spectrum beginning with studies related to encoding mechanisms and ending with psychiatric disorders. The papers in each group deal with old arguments, including those related to the brain changes that encode new memory, how these are affected by events in the body, where storage occurs, and how all of these processes are integrated into higher cognitive functions. They describe the latest develop- ments along with intriguing new perspectives. the coining of the term ‘synapse’ by Sherrington in 1897. The French psychologist, Theodule Ribot wrote in 1882 that ‘the physiological conditions of memory’ must include ‘an asso- ciation, a specific connection established between a given number of elements’. Later, he speculates that the associa- tion will ‘… by repetition, become as stable as the primitive anatomical connections’. Ribot was worried that permanent changes in the state of a neuron (‘permanently polarized’ in his terminology) would limit storage capacity, an issue that continues to encourage the assumption that storage occurs at connections rather than through whole cell modifications. Today, of course, we have much stronger, experimentally grounded reasons for accepting the hypothesis that synaptic modifications are the substrate for encoding. The discovery of the long-term potentiation (LTP) phenomenon by Bliss and Lomo (1973) demonstrated that synapses possess character- istics required for a storage element; rapid changes in strength, triggered by physiologically reasonable stimulation patterns, and extreme persistence. Those first experiments also provided evidence that the changes were synapse specific, a point that was firmly established by studies using the then newly introduced hippocampal slice preparation. Later came results showing that drugs that block LTP cause amnesia (Morris et al., 1986) and clear demonstrations that the potentiation effect occurs at predicted synapses during learning (Roman et al., 1987). Ribot would have understood and been delighted by these discoveries. But intense controversies soon erupted. The first, and perhaps most severe of these, concerned the locus of the synaptic modification underlying LTP was due to an increase in transmitter release or an enhanced post-synaptic response. This debate has subsided in part because the post- but not the pre-synaptic camp succeeded in identifying detailed mechanisms supporting their argument. But the signaling cascades leading to post-synaptic LTP have them- selves become the subjects of considerable argument. Papers in Section A of this Special Issue review the canonical ideas and show that these are either questionable or far from complete. The next part of the section deals with a historical, Synapses and memory and very contemporary, dispute about the reasons why LTP and memory endures for such remarkable periods. Three The idea that connections between neurons are encoding and storage sites for memories is very old, and probably predates very different ideas have been advanced, including new synapse formation, self-regenerating chemical systems that

Previous studies in our laboratory have demonstrated that microinjection of N -methyl- d -aspartate (NMDA) agonist into the nucleus magnocellularis (NMC) of the medial medulla increases muscle tone and/or produces locomotion, while injection of corticotropin-releasing factor (CRF) and non-NMDA agonists into the same or nearby sites suppresses muscle tone. In the first paper of this series, we report that myoclonic twitches or coordinated rhythmic leg movement (locomotion) can be induced by either NMDA or hemorrhagic bilateral lesion of the ventral mesopontine junction (vMPJ). In this paper, we report that microinjection of CRF (10 nM) or non-NMDA agonists, kainic acid (0.1–0.2 mM) and quisqualic acid (1–10 mM), into the NMC block locomotion and myoclonic twitches. The latency and duration of CRF and non-NMDA agonist-induced blockade of motor activity were short, at 34 s and 3.6 min, respectively. However, microinjection of the NMDA antagonists dl -2-amino-5-phosphonovaleric acid (APV; 50 mM) or dl -2-amino-5-phosphonopentanoic acid (AP5, 20 mM) block myoclonus at a latency of 0.6–3 min with the block lasting for a mean of 7 h. Thus, activation of non-NMDA receptors or inactivation of NMDA receptors in NMC can block myoclonus. An imbalance between the inputs to these receptor systems may contribute to the generation of abnormal motor activation in waking and sleep.

The blood–brain barrier (BBB) is formed by the endothelial cells of cerebral microvessels and forms the critical interface regulating molecular flux between blood and brain. It contributes to homoeostasis of the microenvironment of the central nervous system and protection from pathogens and toxins. Key features of the BBB phenotype are presence of complex intercellular tight junctions giving a high transendothelial electrical resistance (TEER), and strongly polarised (apical:basal) localisation of transporters and receptors. In vitro BBB models have been developed from primary culture of brain endothelial cells of several mammalian species, but most require exposure to astrocytic factors to maintain the BBB phenotype. Other limitations include complicated procedures for isolation, poor yield and batch-to-batch variability. Some immortalised brain endothelial cell models have proved useful for transport studies but most lack certain BBB features and have low TEER. We have developed an in vitro BBB model using primary cultured porcine brain endothelial cells (PBECs) which is relatively simple to prepare, robust, and reliably gives high TEER (mean∼800 Ω cm2); it also shows good functional expression of key tight junction proteins, transporters, receptors and enzymes. The model can be used either in monoculture, for studies of molecular flux including permeability screening, or in co-culture with astrocytes when certain specialised features (e.g. receptor-mediated transcytosis) need to be maximally expressed. It is also suitable for a range of studies of cell:cell interaction in normal physiology and in pathology. The method for isolating and growing the PBECs is given in detail to facilitate adoption of the model. This article is part of a Special Issue entitled Companion Paper., Highlights • We have given a detailed method for preparation of an in vitro porcine BBB model. • The model is functionally characterised for major BBB features. • The monocultured model gives high transendothelial electrical resistance. • The monocultured model is suitable for BBB drug permeability screening. • Co-culture with astrocytes can be used if needed to enhance specific BBB features. This article is part of a Special Issue entitled Companion Paper. This article is part of a Special Issue entitled Companion Paper. This article is part of a Special Issue entitled Companion Paper.

The subpallial region of the avian telencephalon contains neural systems whose functions are critical to the survival of individual vertebrates and their species. The subpallial neural structures can be grouped into five major functional systems, namely the dorsal somatomotor basal ganglia; ventral viscerolimbic basal ganglia; subpallial extended amygdala including the central and medial extended amygdala and bed nuclei of the stria terminalis; basal telencephalic cholinergic and non-cholinergic corticopetal systems; and septum. The paper provides an overview of the major developmental, neuroanatomical and functional characteristics of the first four of these neural systems, all of which belong to the lateral telencephalic wall. The review particularly focuses on new findings that have emerged since the identity, extent and terminology for the regions were considered by the Avian Brain Nomenclature Forum. New terminology is introduced as appropriate based on the new findings. The paper also addresses regional similarities and differences between birds and mammals, and notes areas where gaps in knowledge occur for birds.

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80–100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5–40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The preceding companion paper and the present work were aimed at identifying the neuroanatomical loci at which opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 8 experiments included in the present paper examined the effect of microinjecting either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist) either into the third ventricle or over the frontal cortex. Taken together, these experiments demonstrate that the late (80–100 shock) opiate analgesia is mediated by delta opiate receptors located within subcortical structures rostral to the 4th ventricle. No evidence for supraspinal opiate involvement in the early (2 shock) opiate analgesia was found.

Multiple sclerosis (MS) patients may suffer from optic disturbances. Toxin-induced demyelinations have frequently been developed to investigate the cellular and structural aspects of demyelination and remyelination processes, separately. The present study describes functional consequence of lysolecithin (LPC)-induced lesion in the adult rat optic nerves and chiasm by recording the visual evoked potentials (VEPs) from the visual cortex and its correlation with myelin basic protein (MBP) expression in lesion site. Records of VEP were obtained at 2, 7, 14 and 28 days post-injection. We observed that the VEPs generated by light stimuli progressively changed in both amplitude and latency after the lesion as well as in comparison with those generated in control animals. These observations were confirmed through measurement of mRNA expression level for MBP which is one of the important genes expressed in mature oligodendrocytes and Schwann cells. The level of MBP mRNAs in demyelinated chiasm and optic nerves decreased following lysolecithin injection with its least value on day 7, and then it increased to the control level 14 days post-lesion. However, it continued to increase even after that and reached a maximum level 28 days post lesion. Results of the present paper show that, LPC injection in the chiasm share functional and molecular alterations which are found in demyelinating disorders in both the optic nerves and chiasm and also these alterations were coming back to level of control animal on 28 days post lesion, which is typically seen in myelin repair process. The present paper provides new insights into the experimental toxin-induced models that may be useful for evaluating the functional recovery of demyelinated optic nerves and chiasm following various repairing strategies. It also seems to be useful for studying the protective or remyelinating effects of different therapies in e.g. optic apparatus which is more affected by MS.

Sanfilippo B syndrome (Mucopolysaccharidosis IIIB, MPS IIIB) is a lysosomal storage disease due to mutations in the gene encoding alpha-N-acetylglucosaminidase and is characterized by a severe neurological disorder. Although several studies have been reported for the murine model of the disease, the molecular basis and the sequence of events leading to neurodegeneration remain to be clarified. We previously suggested the possible involvement of the reactive oxygen species in the disease pathogenesis. In the present paper we extended the analysis of oxidative stress by evaluating the production of superoxide ions throughout the CNS and by evaluating the effect of the stress on the cellular macromolecules. These approaches applied to one-month-old, three-month-old and six-month-old mice revealed that oxidative stress is present in the affected cerebrum and cerebellum tissues from one month from birth, and that it results primarily in protein oxidation, both in the cerebrum and cerebellum, with lipid peroxidation, and especially DNA oxidation, appearing milder and restricted essentially to the cerebellum. We also identified additional genes possibly associated with the neuropathology of MPS IIIB disease. Real time RT-PCR analysis revealed an altered expression of the Sod1, Ret, Bmp4, Tgfb, Gzmb and Prf1 genes. Since Gzmb and Prf1 are proteins secreted by NK/cytotoxic T-cells, these data suggest the involvement of cytotoxic cells in the neuronal pathogenesis. Extending our previous study, findings reported in the present paper show that oxidative stress and all the analyzed stress-related pathological changes occur very early in the disease course, most likely before one month of age.

Neuronal excitotoxic injury is initiated by activation of specific excitatory amino acid receptors and is mediated by ion flow through associated ion channels. In a companion paper we defined the age dependence of glutamate toxicity in striatal cultures. In this study we examined the correlation between age-dependent changes in the electrophysiologic responses to glutamate and N-methyl-D-aspartate (NMDA) and the development of excitotoxicity. Currents were recorded in voltage-clamped neurons in response to the pressure application of glutamate or NMDA. We found that 1-week-old cultures were resistant to excitotoxic effects of 1 or 3 mM glutamate (Freese et al., companion paper). Neurons from cultures of this age often did not exhibit current responses when exposed to NMDA (10 microM or 100 microM). However, most neurons were responsive to 10 microM glutamate. After 12 days in culture the current responses induced by NMDA were more prevalent and shifted toward higher amplitudes. These changes in NMDA current responses coincided temporally with major increases in excitotoxic sensitivity. However, we then found that excitotoxic susceptibility doubled between 12 and 18 days in culture without any parallel increase in glutamate- or NMDA-induced currents. Additionally, neurons which survived 1 mM glutamate exposure for 3 h were found to exhibit glutamate and NMDA responses. These data show that the expression of excitatory amino acid-induced currents is a prerequisite for excitotoxicity, but that additional factors must also contribute to the full maturation of in vitro neuronal vulnerability.

The purpose of this paper is to study the basic pharmacological action of sarsasapogenin, a sapogenin from the Chinese medicinal herb Rhizoma Anemarrhenae, (abbreviated as ZMS in this paper), on learning ability and memory of three animal models: aged rats and two neurodegeneration models produced either by single unilateral injection of beta-amyloid 1-40 (Abeta1-40) plus ibotenic acid (Ibot A) or by bilateral injection of Ibot A alone into nucleus basalis magnocellularis. Y-maze test and step-through test revealed that learning ability and memory were impaired in the three models and were improved by oral administration of ZMS. ZMS did not inhibit acetylcholinesterase nor did it occupy the binding sites of muscarinic acetylcholine receptor (M receptor), hence it is neither an cholinesterase inhibitor nor an agonist or antagonist of M receptors. On the other hand, the densities of total M receptor and its M1 subtype in the brain of the three models were significantly lower than control rats, and ZMS significantly raised the densities of total M receptors and its M1 subtype. Linear regression revealed significant correlation between the learning ability/memory and the density of either total M receptor or its M1 subtype. Autoradiographic study with 3H-pirenzipine showed that the M1 subtype density was significantly lowered in cortex, hippocampus and striatum of aged rats, and ZMS could reverse these changes towards normal control level. Interestingly, the M1 receptor density after ZMS administration only approached but did not exceed that of normal young control rats. Therefore, ZMS seems to represent a new approach to the pharmacological regulation of learning and memory and appears to be not simply palliative but may modify the progression of the disease.

The pathogenic mechanisms of gene-environment interactions determining variability of human neurodevelopmental disorders remain unclear. In the two consecutive papers, we used the neonatal Borna disease virus (BDV) infection rat model of neurodevelopmental damage to evaluate brain pathology, monoamine alterations, behavioral deficits, and responses to pharmacological treatments in two inbred rat strains, Lewis and Fisher344. The first paper reports that despite comparable virus replication and distribution in the brain of both rat strains, neonatal BDV infection produced significantly greater thinning of the neocortex in BDV-infected Fisher344 rats compared to BDV-infected Lewis rats, while no strain-related differences were found in BDV-induced granule cell loss in the dentate gyrus of the hippocampus and cerebellar hypoplasia. Unlike BDV-infected Lewis rats, more severe BDV-induced brain pathology in Fisher344 rats was associated with (1) greater locomotor activity to novelty and (2) impairment of habituation and prepulse inhibition of the acoustic startle response. The present data demonstrate that the same environmental insult can produce differential neuroanatomical and behavioral abnormalities in genetically different inbred rat strains.

The goal here and in the accompanying paper was to evaluate the two pathways used by the kidney to provide information to the central nervous system (CNS); e.g., the indirect, hormonal route via activation of the renin-angiotensin system and the direct pathway via activation of sympathetic afferents in the caudal thoracic spinal cord. Here, three experiments were designed to evaluate the actions of angiotensin elicited by subcutaneous injection of furosemide on neural activation of the CNS. The number of neurons immunocytochemically staining for the protein product (Fos) of the c-fos gene was used as an index of neuronal activation. In the first experiment, furosemide injection was preceded by treatment with a dose of Captopril, CAP, (an angiotensin-converting enzyme (ACE) inhibitor) that blocks the peripheral but not the central formation of angiotensin II. In the second experiment, furosemide injection was preceded by treatment with a higher dose of CAP; this dosage blocks the peripheral and central formation of angiotensin II. In the third experiment, furosemide injection was preceded by treatment with Losartan, a competitive receptor antagonist of type I angiotensin II receptors at a dose that would block central and peripheral angiotensin receptors. Control animals in each experiment received injections of vehicle (sterile isotonic saline) instead of furosemide. In each experiment, rats were sacrificed 1.75 h following furosemide or saline injection by transcardial perfusion and tissues were immunocytochemically processed for demonstration of Fos antigen. Rats receiving furosemide plus the low CAP dose showed more Fos-positive cells than control rats in the subfornical organ (SFO), organum vasculosum lamina terminalis (OVLT), supraoptic nucleus (SON), magnocellular region of the paraventricular nucleus, nucleus of the solitary tract (NTS), and caudal thoracic/rostral lumbar spinal cord dorsal horn. Rats receiving furosemide plus Losartan or furosemide plus the higher CAP dose did not show increased Fos immunoreactivity in any of the abovementioned structures relative to their respective control animals. We conclude that the receptor-mediated action of angiotensin II is in some way involved in the activation of the pathway that occurs in the SFO, OVLT, SON, and magnocellular region of the paraventricular nucleus (PVN) in response to furosemide treatment. It is possible that the furosemide-induced activation in the SON and PVN is not due to direct actions of angiotensin II on angiotensin receptors in those structures, but instead occurs synaptically as a result of inputs from the SFO and OVLT, which have themselves been activated directly by angiotensin II. In the accompanying paper, furosemide-induced activation in the NTS and caudal thoracic spinal cord is abolished by prior bilateral renal denervation, meaning that these neurons are likely part of a renal afferent pathway. Here, these structures did not elaborate Fos in animals injected with furosemide plus the high CAP dose or furosemide plus Losartan. Thus, the present results also suggest that the central blockade of the formation of angiotensin II or blockade of the actions of angiotensin II prevents in some way the activation of the renal afferent pathway mediated by the renal nerves (the direct pathway) in response to the actions of furosemide. Therefore, these results suggest that central angiotensin II is somehow involved in "priming" or increasing the sensitivity of the direct renal afferent pathway. Taken together with the accompanying paper, our results indicate that interruption of the direct pathway via renal denervation did not interfere with the elaboration of Fos in the lamina terminalis; in contrast, modification of the humoral renal afferent pathway can affect the sensitivity of the direct pathway. These results may have important implications for pathophysiological changes associated with fluid balance disorders including renal hypertension.

Methamphetamine (Meth) produces a variety of epigenetic effects in the brain, which are seminal to establish long-lasting alterations in neuronal activity. However, most epigenetic changes were described by measuring the rough amount of either histone acetylation and methylation or direct DNA methylation, without focusing on a specific DNA sequence. This point is key to comprehend Meth-induced phenotypic changes, brain plasticity, addiction and neurodegeneration. In this research paper we analyze the persistence of Meth-induced striatal synucleinopathy at a prolonged time interval of Meth withdrawal. At the same time, Meth-induced alterations, specifically within alpha-synuclein gene (SNCA) or its promoter, were evaluated. We found that exposure to high and/or prolonged doses of Meth, apart from producing nigro-striatal toxicity, determines a long-lasting increase in striatal alpha-synuclein levels. This is consistent along immune-blotting, immune-histochemistry, and electron microscopy. This was neither associated with an increase of SNCA copy number nor with alterations within SNCA sequence. However, we documented persistently demethylation within SNCA promoter, which matches the increase in alpha-synuclein protein. The amount of the native protein, which was measured stoichiometrically within striatal neurons, surpasses the increase reported following SNCA multiplications. Demethylation was remarkable (ten-fold of controls) and steady, even at prolonged time intervals being tested so far (up to 21 days of Meth withdrawal). Similarly alpha-synuclein protein assayed stoichiometrically steadily increased roughly ten-fold of controls. Meth-induced increase of alpha-synuclein was also described within limbic areas. These findings are discussed in the light of Meth-induced epigenetic changes, Meth-induced phenotype alterations, and Meth-induced neurodegeneration.

The four kinds of adenosine receptor subtypes (ARs), named as ARA1, ARA2A, ARA2B and ARA3, have multiple biological functions. ARs are differently distributed across the body and have distinguished ability of binding adenosine. We try to figure out how these ARs were expressed in astrocytes and which one has the first priority of utilizing adenosine. Firstly, mRNA expressions and membrane localization of all ARs were evaluated by qPCR and western blot. After the membrane localization of all ARs in astrocytes was being confirmed their individual adenosine binding ability was determined by radio-active ligand binding assay respectively. It was revealed that ARA1 had much superior adenosine binding ability than other AR subtypes. Functional study demonstrated that ARA1 potentially mediated an immune suppressive effect in astrocytes. The activation of ARA1 signaling lead to decreased IL-12 and IL-23 production, and decreased chemokine production, including CCL2, CXCL8 and IP-10. When interacted with CD4 cells ARA1 agonist pre-treated astrocytes showed hindered ability of stimulating CD4 cells to secret IL-17 and IFN-γ and inducing CD4 cells' chemo taxi. Finally, in vivo experiment confirmed that local administration of ARA1agonist ameliorated EAE in wild type B6 recipients, but not Ara1-/- recipients. As a conclusion, this paper suggested that adenosine receptor A1 subtype predominantly binds adenosine in astrocytes and mediates an immunosuppressive effect.

Previous work has demonstrated that 3 pharmacologically and neuroanatomically distinct analgesia systems can be sequentially activated by increasing numbers of transcutaneous tail-shock. To date, the categorization of the early (after 2 tail-shocks) and late (after 80-100 tail-shocks) analgesias as opiate-mediated has been based on the ability of systemic naltrexone and morphine tolerance to block these effects. In contrast, the analgesia observed after 5-40 tail-shocks is unaffected by these manipulations, leading to its categorization as non-opiate. The present work and the following companion paper were aimed at identifying the neuroanatomical loci at which endogenous opiates exert their analgesic effects in this tail-shock paradigm and, further, to identify which opiate receptor subtypes are involved. The 3 experiments included in the present paper focus on the role of spinal opiates in tail-shock induced analgesia. The first experiment demonstrates that the tail-shock parameters used do not directly activate pain suppressive circuitry within the spinal cord, but rather activate centrifugal pain modulation circuitry originating within the brain. The last two experiments examine the effect of intrathecal microinjection of either naltrexone (a relatively non-selective opiate receptor antagonist), binaltorphimine (kappa receptor antagonist), Cys2-Tyr3-Orn5-Pen7-amide (CTOP) (mu receptor antagonist), or naltrindole (delta receptor antagonist). Taken together, these latter 2 experiments demonstrate that both the early (after 2 shocks) and late (after 80-100 shocks) opiate analgesias are mediated by kappa opiate receptors within the spinal cord.

Introduction Research has suggested a link between the gut microbiota and Parkinson’s Disease (PD), and an early involvement of gastrointestinal dysfunction has been reported in patients. A mechanism review was performed to investigate whether the neurodegenerative cascade begins in the gut; mediated by gut dysbiosis and retrograde transport of α-synuclein. This review provides a summary of microbiome composition associated with PD, and evaluates pathophysiological mechanisms from animal and in vitro models of PD. Method A systematic literature search was performed in PubMed; 82 of 299 papers met the inclusion criteria. Results All twenty-two human case-control studies demonstrated an altered gut microbiota in PD compared to healthy controls, with results suggesting a proinflammatory phenotype present in PD. A germ-free animal study has demonstrated that gut microbiota are required for microglia activation, α-synuclein pathology and motor deficits. Accumulation of phosphorylated α-synuclein has been observed in the enteric nervous system prior to the onset of motor symptoms in animal models of PD, and there is data to support retrograde transport of α-synuclein from the gut to the brain. Different animal models of PD have demonstrated neuroinflammation, microglial activation and loss of dopaminergic neurons in the brain. Conclusion Evidence from this review supports the hypothesis that pathology spreads from the gut to the brain. Future animal studies using oral LPS or microbiota transplants from human PD cases could provide further insight into the entire mechanism. Prospective longitudinal microbiome studies and novel modelling approaches could help to identify functional dysbiosis and early biomarkers for PD.

Gadolinium-based contrast agents (GBCAs) exert effects in different regions of the brain; however, studies on this topic are mostly focused on radiological outcomes of GBCA exposure. This paper is a preliminary attempt to identify whether there are changes in behavioral, cognitive, histopathological, radiological and biochemical characteristics with repeated exposure to gadobutrol and gadoteric acid. The effects of GBCAs were tested with the assessment of 4 groups –each comprised of 6 rats [controls, gadobutrol, gadoteric acid (Doteram), and gadoteric acid (Clariscan)]. Respective treatments of 0.1 ml/kg were administered for 3 weeks, followed by a recovery period of 1 week without any treatment. At the end of this regimen, behavioral tests (open field and passive learning test) were performed. Additionally, histopathological analysis of the hippocampal CA1 and CA3 regions (GFAP measurement and total neuron count), biochemical measurements [TNF-a, Malondialdehyde (MDA), Superoxide dismutase (SOD), homovalinic acid (HVA) and choline acetyl transferase (ChAT) levels], and radiological findings (MRI-region of interest) were carried out in each group. There was a significant impairment in all groups that had received gadolinium in open field and passive avoidance learning tests. Oxidative stress and inflammation markers were significantly elevated in all gadolinium groups. Additionally, increased hippocampal gliosis and decreased MRI-ROIs were observed in rats exposed to gadolinium. Chronic gadoteric acid and gadobutrol exposure causes hippocampal gliosis and elevates oxidative stress and inflammation in rats. Radiological outcomes are also consistent with these findings. Long-term studies might be required to conclude whether gadolinium deposition in the brain causes subtle neurological deficits.

Novel technologies using the intermediate-frequency magnetic field (IF-MF) in living environments are becoming popular with the advance in electricity utilization. However, the biological effects induced by the high-intensity and burst-type IF-MF exposure used in the wireless power transfer technologies for electric vehicles or medical devices, such as the magnetic stimulation techniques, are not well understood. Here, we developed an experimental platform using rats, that combined an 18 kHz, high-intensity (Max. 88 mT), Gaussian-shaped burst IF-MF exposure system with an in vivo extracellular recording system. In this paper, we aimed to report the qualitative differences in stimulus responses in the regions of the somatosensory cortex and peripheral nerve fibers that were induced by the IF-MF exposure to the rat spinal cord. We also report the modulation of the stimulus responses in the somatosensory cortex under anesthesia or waking states. Using this experimental platform, we succeeded in the detection of the motor evoked potentials or the neuronal activity in the somatosensory cortex that was induced by the IF-MF exposure to the spinal cord in rats. Compared to the state of anesthesia, the neuronal activities in the somatosensory cortex was enhanced during the waking state. On the other hand, these neuronal responses could not be confirmed by the IF-MF exposure-related coil sound only. Our experimental results indicated the basic knowledge of the biological responses and excitation mechanisms of the spinal cord stimulation by the IF-MF exposure.

Ethanolamine plasmalogens (PlsEtn) are a class of glycerophospholipids characterized by a vinyl-ether bond at the sn-1 position that play an important role in the structure and function of membranes. Previous reports have suggested a link between reduced blood and brain PlsEtn levels and Parkinson's disease (PD). We recently reported that the DHA containing plasmalogen precursor PPI-1011 protected striatal dopamine (DA) against MPTP toxicity in mice. In this paper, we further investigate the specificity requirements of the lipid side chains by testing the oleic acid-containing plasmalogen precursor PPI-1025. Male mice were treated for 10days with daily oral administration of PPI-1025 (10, 50 or 200mg/kg). On day 5 mice received MPTP and were sacrificed on Day 11. Treatment with PPI-1025 prevented MPTP-induced decrease of DA and serotonin, as well as their metabolites. In addition, PPI-1025 treatment prevented the MPTP-induced decrease of the striatal dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) specific binding. Significant positive correlations were measured between striatal DA concentrations and DAT or VMAT2 specific binding, as well as with serum plasmalogen concentrations. The neuroprotective effect of PPI-1025 displayed a bell-curve dose-dependency losing effect at the highest dose tested. The similar protective response of oleic and docosahexaenoic acid (DHA)-containing plasmalogen precursors suggests that the neuroprotection observed is not only due to DHA but to the oleic substituent and the plasmalogen backbone.

Hybrid compounds are suggested to be a more effective remedy for treatment of various diseases than combination therapy, since the attenuation or total disappearance of side effects, typically induced by a single moiety, can be observed. This is of great importance, especially when we consider problems resulting from the use of opioid analgesics. However, although it seems that such compounds can be valuable therapeutic tools, the lack of conviction among the public as to the appropriateness of their use still remains; therefore patients are commonly treated with polypharmacy. Thus, in the presented paper we show a comparison of the antinociceptive effect between a novel opioid-neurotensin chimera called [Ile 9 ]PK20 and a mixture of its structural elements, delivered intrathecally and systemically. Additionally, motor coordination was assessed in the rotarod test. The results clearly indicate that spinal administration of the examined compounds, resulted in a long-lasting, dose- and time-dependent antinociceptive effect. Although the mixture of both pharmacophores was found to be more active than [Ile 9 ]PK20, motor impairments surfaced as a side effect. This in turn illustrates the advantageous use of hybrid structures over drug cocktails.

The theta rhythm discovered in the posterior hypothalamus area (PHa) differs from theta observed in the hippocampal formation. In comparison to hippocampal spontaneous theta, the theta recorded in the PHa is rarely registered, has lower amplitude, often disappears, and sometimes returns after a few minutes. These features indicate that spontaneous theta recorded in the PHa is not an appropriate experimental model to search for the correlation between PHa cell discharges and local field potential. In this paper we present standard experimental conditions necessary to record theta-related cells in the PHa in anesthetized rats. Three pharmacological agents were used in the experiments to induce PHa theta rhythm in urethanized rats: carbachol (CCH), carbenoxolone and kainic acid, which are potent enough to induce well-synchronized PHa theta. However, CCH was found to be the best pharmacological tool to induce PHa theta oscillations, due to its longest duration of action and lack of preliminary epileptogenic effects. It seems that CCH-induced theta can be the most suitable pharmacological model for experiments with the use of protocol of long-lasting recordings of PHa theta-related cell discharges.

Historical perspective abstract:From the 90's to now: a historical perspective on more than two decades of estrogen neuroprotection: In the early 90's, estrogens were known to exert organizational and activational effects on reproductive tissues and sexual behavior. As well, the role of sex and gonadal hormones in altering the risk for developing Alzheimer's Disease (AD) was only beginning to be elucidated. Preliminary investigations suggested that estrogen-containing therapies typically given for the management of disruptive menopausal symptoms could reduce AD risk, attenuate disease-associated cognitive deficits, and modulate brain substrates known to be dysregulated by the condition, such as the cholingeric system. The findings from our seminal paper demonstrating cognitive benefits and cholinergic impacts with exogenous estrogen treatment in a rodent model of surgical hormone depletion provided initial support for use of estrogen-containing therapies as a treatment for age-related brain disorders. We then went on to demonstrate neuroprotective actions of estrogen in several other in vivo and in vitro models of neurological challenge, including stroke and AD. Further, our findings of the chemical structure requirements for estrogen's neuroprotective effects identified a novel approach for optimizing future estrogen-containing hormone therapy options. These early efforts laid the groundwork for later, large-scale clinical investigations into the potential of estrogen-based menopausal hormone therapies for the prevention of a variety of age-related disorders. Although findings of these studies were equivocal, the neuroprotective actions of estrogen, and specifically 17β-estradiol, identified by early investigations, remain well-documented. Future development of interventions that optimize cognitive aging are crucial and, with proper understanding of the factors that influence the realization of beneficial impacts, estrogen-containing treatments may still be among these.Ovarian steroid deprivation results in a reversible learning impairment and compromised cholinergic function in female Sprague-Dawley rats: We hypothesized that estradiol (E2) serves as a neurotrophomodulatory substance for basal forebrain cholinergic neurons thought to be involved in learning and memory. Learning/memory was assessed using the two-way active avoidance paradigm and the Morris water task. Female Sprague-Dawley rats were either ovariectomized (OVX) or OVX for 3 weeks, followed by s.c. implantation of a Silastic pellet containing 17-βE2 (E2 pellet), resulting in a replacement of E2 to physiological levels. Ovary-intact (INTACT) animals served as our positive control. Active avoidance behavior and choline acetyltransferase (ChAT) activity in the frontal cortex and hippocampus were assessed at 5 and 28 weeks postovariectomy while performance on the Morris water task and high-affinity choline uptake (HACU) were measured only at the 5-week time point. At the 5-week time point, E2 replacement caused a significant elevation in the level of active avoidance performance relative to OVX animals. At the 28-week time point, OVX animals demonstrated a significantly lower number of avoidances relative to controls (61%) whereas E2-pellet animals not only demonstrated superior performance relative to OVX animals but also showed an accelerated rate of learning. Morris water task performance, on the other hand, was not significantly affected by estrogenic milieu despite a trend towards better performance in the E2-pellet group. Neurochemical analyses revealed that 5 weeks of ovariectomy was sufficient to reduce HACU in both the frontal cortex and hippocampus by 24 and 34%, respectively, while E2 replacement was successful in elevating HACU relative to OVX animals in both regions. ChAT activity was decreased in the hippocampus but not the frontal cortex of 5-week OVX animals. E2 replacement resulted in a reversal of this effect. At the 28-week time period, an unexpected decrease in ChAT activity was observed across all treatment groups. Interestingly, E2-pellet animals demonstrated the least severe decline in ChAT. This phenomenon was most evident in the frontal cortex where ChAT decreased by 61 and 56% in INTACT and OVX animals, respectively, whereas the decline in E2-pellet animals was only 16% over the same time period, suggesting a previously unreported cytoprotective effect of E2. Taken together, these findings demonstrate important effects of estrogens on cholinergic neurons and support the potential use of estrogen therapy in treatment of dementias in postmenopausal women. © 1994. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

The discovery of steroid hormone receptors in brain regions that mediate virtually every aspect of brain function has broadened the definition of 'neuroendocrinology' to include the reciprocal communication between the brain and the body via hormonal and neural pathways. The brain is the central organ of stress and adaptation to stress because it perceives and determines what is threatening, as well as determining the behavioral and physiological responses to the stressor. The adult and developing brain possess remarkable structural and functional plasticity in response to stress, including neurogenesis leading to neuronal replacement, dendritic remodeling, and synapse turnover. Stress causes an imbalance of neural circuitry subserving cognition, decision-making, anxiety and mood that can alter expression of those behaviors and behavioral states. The two Brain Research papers noted in this review played an important role in triggering these advances. This article is part of a Special Issue entitled SI:50th Anniversary Issue.

Neurological diseases such as ischemic stroke can be debilitating and have limited treatments available. The progestin Nestorone® (segesterone acetate) has been evaluated for use in birth control and hormone replacement therapy due to its potency and high affinity for the progesterone receptor. Interestingly, Nestorone also exerts neuroprotection in animals afflicted with various central nervous system diseases, including stroke, which implicates its potential for treating these maladies in clinical settings. In fact, a recent Brain Research paper by Tanaka and colleagues demonstrates Nestorone's ability to reduce infarct sizes and preclude functional impairments in rats subjected to ischemic stroke. This commentary highlights Nestorone's properties as a progestin, its neuroprotective capabilities in animal studies, and how the Tanaka team's findings and previous clinical trials contribute to Nestorone's translation into a therapeutic agent for stroke and other neurological diseases.