Locus coeruleus

Major technical progress in the development of computer-based image analysis has made possible the entry of autoradiography and immunohistochemistry into a new era where quantification by densitometry has become easily accessible. Autoradiography could become quantitative and displayed adequate reproducibility with the help of emulsion-coated films and the use of scales of standards of known radioactivity exposed and analyzed in parallel to the tissue sections.Immunohistochemistry after revelation by a color-based enzymatic technique can also become quantitative, providing that standardization of the crucial steps of the procedure and calibration through a parallel treatment ofa scale of antigen standards can be ensured. Such an approach is described here in the rat with reference to tyrosine hydroxylase (TH), the main synthesizing enzyme for catecholamines, and with dopamine (DA) itself, a catecholaminergic neurotransmitter. The different parts of the procedure, which can influence the results, such as the fixation of the animals by perfusion and the evaluation of the fluctuations via the calibration curve, are discussed in detail.Biological validation of the proposed procedure is described by reference to experiments already well documented biochemically, such as the induction effect of reserpine on TH in the rat locus coeruleus and the depleting effect of α-methyltyrosine (AMPT), a well-known blocker of TH activity, on rat striatal DA content. Finally the importance of restricting the measurements to the (pseudo)linear portion of the calibration curve is illustrated by the autoradiographic identification of the differential intrastriatal repartition of the dopaminergic D1 and D2 receptorsites, particularly the dual patch-matrix compartments.

Our earlier studies demonstrated that representative microbial substances--lipopolysaccharide, peptidoglycan, and poly-inosine: poly-cytosine (poly(I):(C))--increased the spontaneous discharge rates and sensory-evoked responses of isolated locus coeruleus (LC) neurons in a dose- and time-related manner after i.p. injection into rats. We then turned our attention to the mechanism by which microbial substances administered into the peritoneal cavity affect the LC neurons. The involvement of the subdiaphragmatic vagus nerves was examined in this regard since several brain responses to peripherally administered lipopolysaccharide have been found to depend upon the integrity of these nerves. The experiments reported here show that lipopolysaccharide, peptidoglycan, and poly(I):(C) all failed to excite LC neurons after i.p. injection into rats that had previously been subjected to complete transection of the subdiaphragmatic vagus nerves. Furthermore, selective transection of the subdiaph...

Altered noradrenergic function is associated with alcoholism. Reduced brain norepinephrine (NE) concentrations and /3-adrenergic receptor supersensitivity following chronic alcohol consumption suggest a reduced level of noradrcnergic ncurotransmission. To further elucidate the reason for changes in noradrenergic function, we determined the number of melanin-containing noradrencrgic neurons in the locus cocruleus (LC) postmortem from 11 controls and 7 alcoholics. Controls did not have a known history of psychiatric or ncurologic disorders and wcrc drug-free by toxicological screen. The diagnosis of alcohol-dependence was based on DSM-III-R criteria. Alcoholics differed from controls in having 23% fewer LC neurons (control: 43,472 + 1,021; alcoholic: 33,398 + 2184; P < 0.0005) and 46% lower density of neurons (control: 1,227 + 89 cells per mm~; alcoholic: 663 + 94 cells per mm3; P = 0.001). The reduction in neurons was bilateral and throughout the middle third of the LC. The two groups did not differ with respect to LC length (control: 16.1 + 0.6 mm; alcoholic: 15.3 + 0.9 mm; P = 11.47) or total LC volume (control: 37.3 + 2.8 mm3; alcoholic: 46.5 + 4.2 mm3; P = 0.119). Changes in noradrcncrgic ncurotransmission in alcoholics may bc duc to fewer noradrenergic neurons in the locus coeruleus and may contribute to memory loss and depression, common consequences of alcoholism.

ZORNETZER, S. F., W. C. ABRAHAM AND R. APPLETON. The locus coeruleus and labile memory. PHARMAC. BIOCHEM. BEHAV. 9(2) 227-234, 1978.--Memory lability is defined as the period of time recently-formed memory remains susceptible to experimental modification. Electrolytic lesions delivered through chronic indwelling electrodes to the locus coeruleus (LC) complex of mice, made shortly after learning, resulted in an extension of memory lability. Mice with unilateral, but not bilateral LC damage became amnesic following electroconvulsive shock (ECS) administered 7 days (168 hr) after memory formation. ECS had no effect on memory in LC-lesioned mice when administered 14 days following training. In a second experiment, the temporal relationship between time of memory formation and time of LC damage was found to be critical to the occurrence of this extended period of lability. In a third experiment, we tested the possibility that prolonged trace lability was the result of weaker memory formation as reflected by decreased persistence (i.e. faster forgetting) of the memory. The results indicated equal rates of forgetting for normal and LC-lesioned mice. Present results support the hypothesis that the locus coeruleus complex normally plays an important role in delimiting the time-course of initially labile stages of memory. By inference, these data suggest further that such a delimiting function of the locus coeruleus is mediated through its noradrenergic modulation of other brain regions.

A study was carried out on the effects of unilateral microinjection of melanin-concentrating hormone (MCH) into the right locus coeruleus (LC) on the sleep-wake cycle in rats prepared for chronic sleep recordings. MCH 200 ng significantly augmented rapid-eye-movement sleep (REMS) time during the first, second and third 2-h of recording. Furthermore, MCH 100 ng induced a significant increase of REMS during the first 2-h period after treatment. The increment of the behavioral state was related to a greater number of REMS episodes. It is suggested that MCH deactivation of noradrenergic neurons located in the LC facilitates the occurrence of REMS.

Ageing of the central nervous system (CNS) is the major risk factor for Alzheimer&#39;s disease (AD), a type of neurodegeneration that is associated with deficits in cognition and memory and clinically manifested as severe senile dementia. Numerous mental processes underline cognition, including attention, producing and understanding language, learning, reasoning, problem solving, decision making and memory formation. In the past, neurones or their parts have been considered to be the exclusive cellular sites of memory and cognitive processes. However, it has become evident that astrocytes, the major homeostatic glial cell of the CNS, provide an essential contribution to memory formation, and astroglial failure may promote cognitive decline in AD. In response to the network reset mechanisms mediated by the noradrenergic projections of neurones located in the locus coeruleus, astrocytes get excited and participate in the morphological remodelling associated with synaptic plasticity, ...

A chronic, and at times, progressive neurologic syndrome associated with boxing has been recognized for some time by boxing fans and people involved with the sport. Since Martland&amp;#39;s first description of the syndrome in 1929, there has been only one randomly selected study of ex-boxers, that of Roberts, which showed a 17 per cent prevalence of this syndrome among boxers who fought between 1929 and 1955. This syndrome can be progressive but often is not. Furthermore, the extent of occupational exposure is probably a significant risk factor. Because of this, it would be expected that the prevalance of the syndrome in the modern boxer, as well as the amateur, would be significantly less than during the first half of the century, and, indeed, several studies appear to support this. Recent studies provide evidence that brain damage does exist in modern boxers and suggests that &amp;quot;subclinical&amp;quot; brain damage is likely to be more prevalent than obvious clinical dysfunction. There is clearly a discrepancy between subclinical evidence of neurologic involvement (for example, an abnormal CT scan) and signs of clinical neurologic dysfunction (for example, clinical exam and neuropsychological testing). The latter tend to show less frequent and consistent evidence of brain damage in boxers than does the CT scan. Although it is tempting to assume that an abnormal CT scan presages the development of neurologic dysfunction, it is not clear that this is the case. The prevalence of the syndrome, risk for progression to functional deficit, warning signs, and the natural history cannot be defined at this time. The only way to better define these parameters would be a controlled prospective study, which has yet to be undertaken.

In addition to repeated reexperiencing of the event, the delayed effects of severe psychological trauma, i.e., post traumatic stress disorder (PTSD), present a paradoxical mix of symptoms. There is enhancement of the self-preservative catecholamine states; anger and fear with a contrasting sense of meaninglessness and a blunting of the emotional responses of the attachment behavior so critical for species preservation. Hormonally, there is a striking separation of the catecholamine response, which stays elevated and that of the hypothalamo-pituitary-adrenal (HPA) axis, which may remain at normal levels. Pathophysiologically, the reexperiencing of the trauma and the arousal may be associated with dysfunction of the locus coeruleus, amygdala and hippocampal systems. This article explores the consequences of an additional dysfunction: a dissociation of the hemispheres that appears to be responsible for the alexithymic avoidance and failure of the cortisol response that so often follow severe psychological trauma. There is neurophysiological evidence that the left and right hemispheres subserve different emotional sets that correspond to “control” and “appraisal,” i.e., very approximately to the self and species preservative behavioral complexes, respectively. Several studies point to physiological dissociation of hemispheric functions during alexithymia. This raises the question: What has been lost if in this condition the right side no longer fully contributes to integrated cerebral function? Right hemispheric damaged children lose critical social skills and in adults the related sense of familiarity critical for bonding is lost. Such losses of social sensibilities may account for the lack of empathy and difficulties with bonding found in sociopathy and borderline personality: conditions now believed to result from repeated psychological trauma during development. On the other hand, systems that promote right hemispheric contributions provide solacing access to a “Higher Power.” They also appear to protect against socially disordered behavior, substance abuse, the failure of the HPA axis and some aspects of the pathophysiology of chronic disease.

This study investigated event-related potential (ERP) indices of information processing in sufferers of posttraumatic stress disorder (PTSD ). ERPs were obtained from 18 PTSD patients and 20 controls while they performed a target discrimination task requiring the detection of infrequent target tones from a background sequence of frequent and infrequent distractor tones. A delayed N2 and an attenuated P3 that failed to differentiate target from distractor tones indicated that patients had abnormal difficulty distinguishing task stimuli of differing relevance. It is proposed that this difficulty is reflected behaviorally in the slowed reaction time by patients to target stimuli and may underlie the disturbed concentration and memory impairments found in PTSD. It may also be related to dysfunction in central noradrenaline function, which has been shown to be both crucial in selective attention and abnormal in PTSD.

Brain monoamines (serotonin, norepinephrine, dopamine, and histamine) play an important role in emotions, cognition and in pathophysiology and treatment of mental disorders. The interactions between serotonin, norepinephrine and dopamine were studied in numerous works, however, histamine system received less attention. The aim of this study was to investigate the interactions between histamine and other monoamines, using in vivo microdialys and electrophysiology. It was found that the inverse agonist of histamine-3 receptors, thioperamide, increased the firing activity of dopamine neurons in the ventral tegmental area. Selective agonist of histamine-3 receptors, immepip, reversed thiperamide-induced stimulation of firing activity of dopamine neurons. The firing rates of serotonin and norepinephrine neurons were not attenuated by immepip or thioperamide. Thioperamide robustly and significantly increased extracellular concentrations of serotonin, norepinephrine, and dopamine in the rat prefrontal cortex and slightly increased norepinephrine and dopamine levels in the tuberomammillary nucleus of the hypothalamus. It can be concluded that histamine stimulates serotonin, norepinephrine, and dopamine transmission in the brain. Modulation of firing of dopamine neurons is a key element in functional interactions between histamine and other monoamines. Antagonists of histamine-3 receptors, because of their potential ability to stimulate monoamine neurotransmission, might be beneficial in the treatment of mental disorders.

Parkinson's disease (PD) is a slowly progressive neurodegenerative disorder mainly characterized by degeneration of dopaminergic neurons in the substantia nigra and the ventral tegmental area, in combination with a varying loss of central noradrenergic (locus coeruleus), cholinergic (nucleus basalis of Meynert) and serotonergic (dorsal raphe nuclei) integrity, leading to a multitude of motor and non-motor behavioral disturbances.

This review focuses on the role of norepinephrine (NE) in traumatic stress. The review is divided into three sections. The first section, "Norepinephrine and Arousal," describes preclinical studies related to norepinephrine's role in arousal, orienting to novel stimuli, selective attention and vigilance. It also contains a brief discussion of NE and its relationship to fear-provoking stimuli followed by preclinical and clinical studies that demonstrate heightened noradrenergic neuronal reactivity, increased ␣ 2 receptor sensitivity and exaggerated arousal in organisms that have been exposed to chronic uncontrollable stress. The second section, "Norepinephrine and Memory," describes preclinical and clinical studies related to norepinephrine's role in enhanced encoding of memory for arousing and aversive events and in subsequent re-experiencing symptoms such as, intrusive memories and nightmares. The third section, "Norepinephrine and Pharmacologic Treatment," briefly discusses the use of adrenergic blockers, clonidine and propranol, as well as tricyclic and MAO inhibitors, for the treatment of PTSD. Finally, we attempt to synthesize trauma-related preclinical and clinical studies of norepinephrine. We do this, in part, by focusing on a series of yohimbine studies in subjects with PTSD because data from these studies allow for a discussion that brings together preclinical and clinical findings relevant to trauma-related alterations in arousal and memory.

Rationale In a previous study in healthy volunteers, the anti-Parkinsonian drug pramipexole caused sedation and pupil dilatation, consistent with the stimulation of inhibitory D2/D3 autoreceptors on the ventral tegmental area dopaminergic neurones. The sedation may be related to the removal of the dopaminergic excitation of the locus coeruleus (via the meso-coerulear pathway), whereas the pupil dilatation may be due to the removal of the dopaminergic excitation of the Edinger–Westphal nucleus (via a putative meso-pupillomotor pathway). Objectives We investigated the hypothesis that amisulpride, a D2/D3 receptor antagonist, would have effects opposite to those of pramipexole on alertness, pupillary and endocrine functions. Materials and methods Pramipexole (0.5 mg), amisulpride (50 mg), and their combination were administered to 16 healthy males in a balanced, cross-over, double-blind design. Tests included measures of alertness (Pupillographic Sleepiness Test, critical flicker fusion frequency, visual analogue scales), pupillary functions (resting pupil diameter, light and darkness reflex responses), non-pupillary autonomic functions (heart rate, blood pressure, salivation, core temperature), and endocrine functions [blood concentrations of prolactin, growth hormone (GH) and thyroid stimulating hormone (TSH)]. Data were analysed by ANOVA. Results Pramipexole reduced alertness and pupillary light reflex response amplitude, tended to reduce core temperature, reduced prolactin levels and increased GH levels. Amisulpride reduced pupil diameter, increased the amplitude of the light reflex response and prolactin and TSH levels. Conclusions The opposite effects of pramipexole and amisulpride on alertness, pupillary function and pituitary hormone levels are consistent with their interactions with inhibitory D2/D3 receptors on VTA neurones and in the tuberoinfundibular system.

Neuropathic pain has been described as the "most terrible of all tortures which a nerve wound may inflict" and arises as a consequence of nerve injury either of the peripheral or central nervous system. Following peripheral nerve injury, a cascade of events in the primary afferents leads to peripheral sensitization resulting in spontaneous nociceptor activity, decreased threshold and increased response to supra-threshold stimuli. A series of molecular changes in spinal cord and brain centers are associated with central sensitization which is responsible for the pain to non-injured extra-territory regions (extraterritorial pain) and contralateral parts (mirror-image pain). The peripheral nerve injury has been reported to induce neuroplastic changes in different brain regions including the anterior cingulate cortex, insular cortex, ventrolateral orbitofrontal area, amygdala, striatum, thalamus, hypothalamus, rostral ventromedial medulla, periaqueductal gray, pons (locus coeruleus), red nucleus, and medulla oblongata. The present review article discusses the involvement of these different brain areas in the development of peripheral nerve injury-induced neuropathic pain.

Orexins (OXs) regulate sleep with possible interactions with brain noradrenergic neurons. In addition, noradrenergic activity affects barbiturate anesthesia. As we have also recently reported that OXs selectively evoke norepinephrine release from rat cerebrocortical slices we hypothesized that barbiturate anesthesia may result from of an interaction with central orexinergic systems. To test this hypothesis, we performed a series of in vivo and in vitro studies in rats. In vivo, the effects of i.c.v. OX A, B and SB-334867-A (OX1 receptor antagonist) on pentobarbital, thiopental or phenobarbital-induced anesthesia times (loss of righting reflex) was assessed. In vitro effects of barbiturates and SB-334867-A on OX-evoked norepinephrine release from cerebrocortical slice was examined. In Chinese hamster ovary cells expressing human OX1/OX2 receptors OX A- and B-evoked increases in intracellular Ca2+ were measured with and without barbiturates. OX A and B significantly decreased pentobar...

Like a number of neuropeptides, galanin can alter neural activity in brain areas that are important for both stress-related behaviors and responses to drugs of abuse. Accordingly, drugs that target galanin receptors can alter behavioral responses to drugs of abuse and can modulate stress-related behaviors. Stress and drug-related behaviors are interrelated: stress can promote drug-seeking, and the behavioral signs of drug withdrawal result from increased activity in brain circuits involved in the stress response. We review here what is known about the ability of galanin and galanin receptors to alter neuronal activity, and we discuss potential mechanisms that may underlie the effects of galanin on behaviors involved in responses to stress and addictive drugs. Understanding the mechanisms underlying galanin's effects on neuronal function in brain regions related to stress and addiction may be useful in developing novel therapeutics for the treatment of stress-and addiction-related disorders.

The lateral paragigantocellular nucleus (LPGi) is located in the ventrolateral medulla and is known as a sympathoexcitatory area involved in the control of blood pressure. In recent experiments, we showed that the LPGi contains a large number of neurons activated during PS hypersomnia following a selective deprivation. Among these neurons, more than two-thirds are GABAergic and more than one fourth send efferent fibers to the wake-active locus coeruleus nucleus. To get more insight into the role of the LPGi in PS regulation, we combined an electrophysiological and anatomical approach in the rat, using extracellular recordings in the head-restrained model and injections of tracers followed by the immunohistochemical detection of Fos in control, PS-deprived and PS-recovery animals. With the head-restrained preparation, we showed that the LPGi contains neurons specifically active during PS (PS-On neurons), neurons inactive during PS (PS-Off neurons) and neurons indifferent to the sleep-waking cycle. After injection of CTb in the facial nucleus, the neurons of which are hyperpolarized during PS, the largest population of Fos/CTb neurons visualized in the medulla in the PS-recovery condition was observed in the LPGi. After injection of CTb in the LPGi itself and PS-recovery, the nucleus containing the highest number of Fos/CTb neurons, moreover bilaterally, was the sublaterodorsal nucleus (SLD). The SLD is known as the pontine executive PS area and triggers PS through glutamatergic neurons. We propose that, during PS, the LPGi is strongly excited by the SLD and hyperpolarizes the motoneurons of the facial nucleus in addition to local and locus coeruleus PS-Off neurons, and by this means contributes to PS genesis.

Based on the results of independent studies the involvement of norepinephrine in REM sleep regulation was known. Isolated studies showed that the effect could be mediated through either one or more subtypes of adrenoceptors. Earlier we have reported that REM-OFF neurons continue firing during REM sleep deprivation and mild but continuous stimulation of locus coeruleus (LC) or picrotoxin injection into the LC, that did not allow the REM-OFF neurons in the LC to stop firing, reduced REM sleep. However, the mechanism of action and type of adrenoreceptors involved in REM sleep regulation were unknown. The possible mechanism of action has been investigated in this study. It was proposed that if LC stimulation-induced decrease in REM sleep was due to norepinephrine, adrenergic antagonist must prevent the effect. Therefore, in this study, the effects of ␣ 1 , ␣ 2 and ␤-antagonists, viz. prazosin, yohimbine and propranolol, respectively, and ␣ 2 agonist, clonidine, on LC stimulation-induced reduction in REM sleep were investigated. The results showed that stimulation of LC inhibited REM sleep by reducing the frequency of generation of REM sleep, although the duration per episode remained unaffected. This decrease in the frequency of REM sleep was blocked by ␤-antagonist propranolol while the duration of REM sleep per episode was blocked by ␣ 1 -antagonist, prazosin. Also, a critical level of norepinephrine in the system was required for the generation of REM sleep, however, a higher level may be inhibitory. Based on the results of this study and our earlier studies, an interaction between neurons, containing different neurotransmitters and their subtypes of receptors for LC-mediated regulation of REM sleep has been proposed.

We found previously that damage to a cluster of sleep-active neurons (Fos-positive during sleep) in the ventrolateral preoptic nucleus (VLPO) decreases non-rapid eye movement (NREM) sleep in rats, whereas injury to the sleep-active cells extending dorsally and medially from the VLPO cluster (the extended VLPO) diminishes REM sleep. These results led us to examine whether neurons in the extended VLPO are activated during REM sleep and the connectivity of these neurons with pontine sites implicated in producing REM sleep: the laterodorsal tegmental nucleus (LDT), dorsal raphe nucleus (DRN), and locus ceruleus (LC). After periods of dark exposure that triggered enrichment of REM sleep, the number of Fos-positive cells in the extended VLPO was highly correlated with REM but not NREM sleep. In contrast, the number of Fos-positive cells in the VLPO cluster was correlated with NREM but not REM sleep.

The descending projections of the periaqueductal gray (PAG) have been studied in the rat using the anterograde tracer Phaseolus vulgaris-leucoagglutinin. The tracer was injected into the dorsolateral or ventrolateral subdivisions of the PAG at rostral or caudal sites. It was found that the patterns of the descending projections of the rostral and caudal parts of the dorsolateral PAG were the same and that the patterns of the descending projections of the rostral and caudal parts of the ventrolateral PAG were the same. However, the patterns of projections of the dorsolateral and ventrolateral PAG subregions were substantially different. These results suggest that the dorsolateral and ventrolateral parts of the PAG are organized into longitudinal columns that extend throughout the length of the PAG. The axons of PAG neurons descended through the pons and medulla via two routes. A small fiber bundle was present in the periaqueductal gray and in the periventricular area. This bundle distributed fibers and terminals locally within the periaqueductal gray and in the locus coeruleus and Barrington's nucleus. A larger bundle had a diffuse arrangement in the pontine reticular formation, however, and it had a more restricted distribution in the medulla, where it occupied a position dorsolateral to the pyramid. This bundle supplied structures in the pontine and medullary tegmentum. The dorsolateral column preferentially supplied the locus coeruleus, subcoeruleus, the gigantocellular nucleus pars alpha, the rostral part of the paragigantocellular nucleus, and the region of the A5 noradrenergic cell group. The ventrolateral column preferentially supplied the nucleus raphe magnus, the caudal part of the lateral paragigantocellular nucleus, and the rostroventrolateral reticular nucleus. © 1995 Willy-Liss, Inc.

. Ž . The nucleus paragigantocellularis lateralis PGL is located in the rostral ventrolateral medulla RVLM , a brainstem region that regulates homeostatic functions, such as blood pressure and cardiovascular reflexes, respiration, central chemosensitivity and pain. In the present study, we examined anatomic relationships of the human nucleus paragigantocellularis lateralis using a bidirectional lipophilic X X X Ž . fluorescent tracer, 1,1 -dioctadecyl-3,3,3 ,3 -tetramethylindocarbocyanine perchlorate DiI , in nine postmortem human fetal midgestational brainstems. The areas which were labeled by diffusion of DiI from the nucleus paragigantocellularis lateralis included the arcuate Ž . Ž . nucleus ARC of the medulla, caudal raphe nucleus raphe obscurus and pallidus , hilum and amiculum of the inferior olive, bilateral Ž Areticular formationB including the nucleus paragigantocellularis lateralis, nucleus gigantocellularis and the intermediate reticular zone Ž .. IRZ , vestibular and cochlear nuclei, cells and fibers at the floor of the fourth ventricle with morphologic features of tanycytes, Ž . parabrachial nuclei PBN , medial lemniscus, lateral lemniscus, inferior cerebellar peduncle and cerebellar white matter, central tegmental tract, and the capsule of the red nucleus. This pattern of DiI labeling bears many similarities with the pattern of connections of the nucleus paragigantocellularis lateralis previously demonstrated by tract-tracing methods in experimental animals, and is consistent with the role of the nucleus paragigantocellularis lateralis in central regulation of homeostatic functions. In contrast to the animal studies, however, we did Ž . Ž not demonstrate connections of the nucleus paragigantocellularis lateralis with the nucleus of the tractus solitarius nTS only . Ž. connections with the rostral subdivision were examined , locus coeruleus, or the periaqueductal gray PAG in the human midgestational brainstem. In our previous studies, six medullary areas showed reduced serotonin receptor binding in a subset of victims of sudden infant Ž . death syndrome SIDS . The present study demonstrated DiI labeling in all of these six areas, suggesting that they are interconnected. q 2001 Published by Elsevier Science B.V.

Oestrogen, progestagens and androgens are able to modulate several brain functions. Receptors for gonadal steroids have been identified in several brain areas: amygdala, hippocampus, cortex, basal forebrain, cerebellum, locus coeruleus, midbrain rafe nuclei, glial cells, pituitary gland, hypo- thalamus and central grey matter. The mechanism of action of sex steroids at this level is similar to that observed in the

The tuberomammillary nucleus (TMN) is the major source of histaminergic innervation of the mammalian brain and is thought to play a major role in regulating wake-sleep states. We recently found that sleep-active neurons in the ventrolateral preoptic nucleus (VLPO) provide a major input to the TMN, but the specificity of this projection and the neurotransmitters involved remain unknown. In this study, we examined the relationship of VLPO efferents to the TMN using both retrograde and anterograde tracing, combined with immunocytochemistry. We found that the descending projection from the VLPO selectively targets the cell bodies and proximal dendrites of the histaminergic TMN. In addition, VLPO axons could be traced into the brainstem, where they provided terminals in the the serotoninergic dorsal and median raphe nuclei, and the core of the noradrenergic locus coeruleus. Approximately 80% of the VLPO neurons that were retrogradely labeled by tracer injections including the TMN were immunoreactive either for galanin or for glutamic acid decarboxylase (GAD), the synthetic enzyme for GABA. Virtually all of the galaninergic neurons in the VLPO were also GAD positive. Our results indicate that the VLPO may provide inhibitory GABAergic and galaninergic inputs to the cell bodies and proximal dendrites of the TMN and other components of the ascending monoaminergic arousal system. Because these cell groups are simultaneously inhibited during sleep, the VLPO sleep-active neurons may play a key role in silencing the ascending monoaminergic arousal system during sleep.

Nonrapid eye movement (NREM) sleep is characterized by periodic changes in cortical excitability that are reflected in the electroencephalography (EEG) as high-amplitude slow oscillations, indicative of cortical Up/Down states. These slow oscillations are thought to be involved in NREM sleep-dependent memory consolidation. Although the locus coeruleus (LC) noradrenergic system is known to play a role in off-line memory consolidation (that may occur during NREM sleep), cortico--coerulear interactions during NREM sleep have not yet been studied in detail. Here, we investigated the timing of LC spikes as a function of sleep-associated slow oscillations. Cortical EEG was monitored, along with activity of LC neurons recorded extracellularly, in nonanesthetized naturally sleeping rats. LC spike-triggered averaging of EEG, together with phase-locking analysis, revealed preferential firing of LC neurons along the ascending edge of the EEG slow oscillation, correlating with Down-to-Up state transition. LC neurons were locked best when spikes were shifted forward~50 ms in time with respect to the EEG slow oscillation. These results suggest that during NREM sleep, firing of LC neurons may contribute to the rising phase of the EEG slow wave by providing a neuromodulatory input that increases cortical excitability, thereby promoting plasticity within these circuits.

Using the recent burgeoning of information on how the stress response systems interact, and combining this with advances in our understanding of neuroimmune communication, a proposed neuroendocrine-neuroimmune stress response system incorporating autoimmunoregulation is reviewed. The study of immunocyte behavior in certain clinical conditions associated with a variant stress response may help illuminate the functioning of the neuroendocrine-neuroimmune stress response system.

Adult male albino rats were exposed to varying numbers of tailshocks (0, 10, 50 or 100). The following day, their escape latencies in a shuttlebox were measured in order to estimate the degree of learned helplessness (LH) produced by the varying number of shocks. Only the groups exposed to 50 or 100 shocks displayed evidence of LH. In a parallel experiment, c-fos activation was used to determine the degree of activation of raphe serotonergic neurons (FosIR + 5-HT) and locus coeruleus (LC) noradrenergic neurons (FosIR + TH) produced by the same shock conditions. Compared to unhandled cage controls, all shock groups (0 shocks was a restrained group) significantly activated both raphe and LC neurons. The 50 and 100 shock groups had significantly higher degrees of activation of serotonergic neurons in the rostral raphe groups and the LC than the 0 and 10 shock groups. These data are consistent with the hypothesis that activation of rostral raphe serotonergic neurons and LC noradrenergic neurons beyond a certain threshold may be critical for the development of LH. The relevance of these results for elucidating the neural bases of psychopathology is discussed.

Brain stem afferent connections of the amygdala in the rat with special references to a projection from the parabigeminal nucleus: a fluorescent retrograde tracing study Abstract A recently revealed important function of the amygdala (Am) is that it acts as the brain's ''lighthouse'', which constantly monitors the environment for stimuli which signal a threat to the organism. The data from patients with extensive lesions of the striate cortex indicate that ''unseen'' fearful and fear-conditioned faces elicit increased Am responses. Thus, also extrageniculostriate pathways are involved. A multisynaptic pathway from the retina to the Am via the superior colliculus (SC) and the pulvinar was recently suggested. We here present data based on retrograde neuronal labeling following injection of the fluorescent tracer Fluoro-Gold in the rat Am that the parabigeminal nucleus (Pbg) emits a substantial, bilateral projection to the Am. This small cholinergic nucleus (Ch8 group) in the midbrain tegmentum is a subcortical relay visual center that is reciprocally connected with the SC. We suggest the existence of a second extrageniculo-striate multisynaptic connection to Am: retina-SC-Pbg-Am, that might be very effective since all tracts listed above are bilateral. In addition, we present hodological details on other brainstem afferent connections of the Am, some of which are only recently described, and some others that still remain equivocal. Following selective injections of Fluoro-Gold in the Am, retrogradely labeled neurons were observed in parasubthalamic nucleus, peripeduncular nucleus, periaqueductal gray, dopaminergic nuclear complex (substantia nigra pars lateralis and pars compacta, paranigral, parabrachial pigmented and interfascicular nuclei, rostral and caudal linear nuclei, retrorubral area), deep mesencephalic nucleus, serotoninergic structures (dorsal, median and pontine raphe nuclei), laterodorsal and pedunculopontine tegmental nuclei (Ch6 and Ch5 groups), parabrachial nuclear complex, locus coeruleus, nucleus incertus, ventrolateral pontine tegmentum (A5 group), dorsomedial medulla (nucleus of the solitary tract, A2 group), ventrolateral medulla (A1/C1 group), and pars caudalis of the spinal trigeminal nucleus. A bilateral labeling of the upper cervical spinal cord was also observed.

The present study examined the effects of acute and chronic neurogenic stressors on the expression of two distinct angiotensin receptors in two stress-related brain nuclei: angiotensin type 1A receptor in the paraventricular nucleus of the hypothalamus and angiotensin type 2 receptor in the nucleus locus coeruleus. Male Wistar rats were divided into four experimental groups. The first two groups were subjected once to an acute 90-min immobilization or air-jet stress session, respectively. The other two groups were subjected to 10 days of daily 90-min immobilization sessions and, on the 11th day, one group was exposed to an additional 90-min immobilization and the other to a single air-jet stress (heterotypic but still neurogenic) session. In each group, rats were perfused before stress (0 min), immediately following stress (90 min) or 150, 180, 270 or 360 min (and 24 h in chronic immobilization) after the beginning of the last stress session. Basal expression of both angiotensin receptor subtype 1A and angiotensin receptor subtype 2 messenger RNA was minimal in non-stressed animals. Acute immobilization as well as air-jet stress induced similar patterns (time-course and maximal values) of angiotensin receptor subtype 1A messenger RNA expression in the paraventricular nucleus. Angiotensin receptor subtype 1A messenger RNA expression increased 90-150 min after the beginning of the stress and returned to basal levels by 360 min. Chronic stress immobilization slightly modified the pattern, but not maximal values of angiotensin receptor subtype 1A messenger RNA expression to further immobilization (homotypic) or air-jet stress (heterotypic). Acute immobilization and air-jet stress sessions induced similar locus coeruleus-specific angiotensin receptor subtype 2 messenger RNA expression. This expression increased 90 min following the onset of the stress session and remained elevated for at least 360 min. Chronic immobilization stress increased angiotensin receptor subtype 2 messenger RNA expression to levels comparable to those observed in acute stress conditions. Novel acute exposure to neurogenic stressors did not further increase these levels in either homotypic (immobilization) or in heterotypic (air-jet stress) conditions. These results suggest that central angiotensin receptors are targets of regulation in stress; therefore, stress may modulate angiotensin function in the paraventricular nucleus and locus coeruleus during chronic exposure to neurogenic stressors. ᭧ 1999 IBRO. Published by Elsevier Science Ltd.

By application of a modified glyoxylic acid-paraformaldehyde histofluorescence technique, catecholamine perikarya, varicosities, and pathways were delineated within the brainstem of kittens that were either untreated, pretreated pharmacologically, or injected intracerebrally with 6-OHDA. Three principal catecholamine cell groups were identified within the medulla and pons: the dorsomedial medullary cell group, the dorsolateral pontine cell group, and a ventrolateral cell group extending from the medulla into the pons. Induced axonal accumulation of catecholamines with intracerebral6-OHDA injections revealed a major longitudinal catecholamine bundle which courses in a dorsolateral position through the entire brainstem tegmentum. The dorsomedial medullary and dorsolateral pontine cell groups contribute ascending and descending fibers to this bundle. Axons of the ventrolateral pontomedullary cells also feed into the bundle at successive levels through radially coursing transverse fibers. Via this major dorsolateral conduit and its ventrally and medially coursing tributaries, catecholamine fibers and terminals are distributed to multiple nuclei through the brainstem. The regions of the catecholamine cell groups and the serotonin raphe nuclei all receive a dense catecholamine innervation. Varicosities are also dense in the visceral cranial nerve nuclei, moderately dense in most somatic spinal and cranial nerve motor nuclei, and moderate to light in sensory cranial nerve and relay nuclei. The lateral and ventromedial reticular formation are moderately innervated by varicose catecholamine fibers that traverse these regions. The longitudinal catecholamine bundle continues caudally into the lateral funiculus to descend into and innervate the spinal cord. Rostrally it continues into the tegmental fascicles of the midbrain to ascend into and innervate the diencephalon and there join the medial forebrain bundle to ascend into the telencephalon. Thus, the catecholamine neurons utilize this dorsolateral longitudinal bundle to distribute collaterals to multiple bulbar nuclei and to travel beyond the brainstem to innervate the spinal cord and forebrain.

This article reviews and develops some theories about the neurobiological basis of creative innovation (CI). CI is defined as the ability to understand and express novel orderly relationships. A high level of general intelligence, domainspecific knowledge and special skills are necessary components of creativity. Specialized knowledge is stored in specific portions of the temporal and parietal lobes. Some anatomic studies suggest that talented people might have alterations of specific regions of the posterior neocortical architecture, but further systematic studies are needed. Intelligence, knowledge and special skills, however, are not sufficient for CI. Developing alternative solutions or divergent thinking has been posited to be a critical element of CI, and clinical as well as functional imaging studies suggest that the frontal lobes are important for these activities. The frontal lobes have strong connections with the polymodal and supramodal regions of the temporal and parietal lobes where concepts and knowledge are stored. These connections might selectively inhibit and activate portions of posterior neocortex and thus be important for developing alternative solutions. Although extensive knowledge and divergent thinking together are critical for creativity they alone are insufficient for allowing a person to find the thread that unites. Finding this thread might require the binding of different forms of knowledge, stored in separate cortical modules that have not been previously associated. Thus, CI might require the co-activation and communication between regions of the brain that ordinarily are not strongly connected. The observations that CI often occurs during levels of low arousal and that many people with depression are creative suggests that alterations of neurotransmitters such as norepinephrine might be important in CI. High levels of norepinephrine, produced by high rates of locus coeruleus firing, restrict the breadth of concept representations and increase the signal to noise ratio, but low levels of norepinephrine shift the brain toward intrinsic neuronal activation with an increase in the size of distributed concept representations and co-activation across modular networks. In addition to being important in divergent thinking, the frontal lobes are also the primary cortical region that controls the locus coeruleus-norepinephrine system. Thus creative people may be endowed with brains that are capable of storing extensive specialized knowledge in their temporoparietal cortex, be capable of frontal mediated divergent thinking and have a special ability to modulate the frontal lobe-locus coeruleus (norepinephrine) system, such that during creative innovation cerebral levels of norepinephrine diminish, leading to the discovery of novel orderly relationships.

We examined the effects of chronic activity wheel running on brain monoamines and latency to escape foot shock after prior exposure to uncontrollable, inescapable foot shock. Individually housed young (Ç50 day) female Sprague-Dawley rats were randomly assigned to standard cages (sedentary) or cages with activity wheels. After 9-12 weeks, animals were matched in pairs on body mass. Activity wheel animals were also matched on running distance. An animal from each matched pair was randomly assigned to controllable or uncontrollable inescapable foot shock followed the next day by a foot shock escape test in a shuttle box. Brain concentrations of norepinephrine (NE), dopamine (DA), dihydroxyphenylacetic acid (DOPAC), 5hydroxytryptamine (5-HT), and 5-hydroxyindole acetic acid (5-HIAA) were assayed in the locus coeruleus (LC), dorsal raphe (DR), central amygdala (AC), hippocampus (CA1), arcuate nucleus, paraventricular nucleus (PVN), and midbrain central gray. After prior exposure to uncontrollable foot shock, escape latency was reduced by 34% for wheel runners compared with sedentary controls. The shortened escape latency for wheel runners was associated with 61% higher NE concentrations in LC and 44% higher NE concentrations in DR compared with sedentary controls. Sedentary controls, compared with wheel runners, had 31% higher 5-HIAA concentrations in CA1 and 30% higher 5-HIAA concentrations in AC after uncontrollable foot shock and had 28% higher 5-HT and 33% higher 5-HIAA concentrations in AC averaged across both foot shock conditions. There were no group differences in monoamines in the central gray or in plasma prolactin or ACTH concentrations, despite 52% higher DA concentrations in the arcuate nucleus after uncontrollable foot shock and 50% higher DOPAC/DA and 17% higher 5-HIAA/5-HT concentrations in the PVN averaged across both foot shock conditions for sedentary compared with activity wheel animals. The present results extend understanding of the escape-deficit by indicating an attenuating role for circadian physical activity. The altered monoamine levels suggest brain regions for more direct probes of neural activity after wheel running and foot shock.

Background: The biological basis of unipolar-bipolar dichotomy of mood disorders was investigated in this postmortem study by morphological comparison of the locus coeruleus (LC) as the main source of noradrenergic transmission in the brain. Methods: Numbers and the rostro-caudal as well as ventro-dorsal distribution of neuromelanin-containing neurones in the LC were determined in brainstem of 12 patients with bipolar disorder (n 5 6) or major depression (n 5 6), and 12 normal comparison subjects. Results: Bipolar patients had significantly more neurones on both sides of the LC as a whole than patients with major depression. Topographical analysis revealed that this difference was restricted to the rostral two thirds and the dorsal part of the LC, in which bipolar patients showed at least a trend to higher neurone numbers as compared to unipolar patients or to controls. Limitations: Small case numbers. Conclusions: Results suggest differences of innervation arising from the LC of bipolar patients as compared to patients with major depression. These first data of brainstem transmitter system morphology in unipolar and bipolar disorder are in line with neuroanatomical studies of other brain regions indicating a biological basis of the unipolar-bipolar dichotomy of mood disorders.

The mechanisms underlying pathogenesis of epileptic rections have been studied insufficiently as yet. Therefore, it is considered that determining the structures, transmitters, and receptors of the brain, which putatively produce development and intensity modulation of the convulsions, is highly important. The locus coeruleus is a norepinephrinic structure and an endogenous modulator of epilepsy, determining a role of which in a course of seizure reactions is an important problem of epileptology. The goal of the study was assessment of importance of the norepinephrine synapses in development of the local hippocampal seizure activity. The studies were carried out in adult rats, in conditions of chronic experiments. Influences of microinjections of agonist (clonidine) and antagonist (yohimbine) of the alpha-2 norepinephrine receptors on a course of local hippocampal seizure reactions (without behavioral manifestation), have been evaluated. It was found that microinjection of alpha-2 n...