Reticular Core Research Articles

Biological Functions of Rat Ultrasonic Vocalizations, Arousal Mechanisms, and Call Initiation.

This review summarizes all reported and suspected functions of ultrasonic vocalizations in infant and adult rats. The review leads to the conclusion that all types of ultrasonic vocalizations subserving all functions are vocal expressions of emotional arousal initiated by the activity of the reticular core of the brainstem. The emotional arousal is dichotomic in nature and is initiated by two opposite-in-function ascending reticular systems that are separate from the cognitive reticular activating system. The mesolimbic cholinergic system initiates the aversive state of anxiety with concomitant emission of 22 kHz calls, while the mesolimbic dopaminergic system initiates the appetitive state of hedonia with concomitant emission of 50 kHz vocalizations. These two mutually exclusive arousal systems prepare the animal for two different behavioral outcomes. The transition from broadband infant isolation calls to the well-structured adult types of vocalizations is explained, and the social importance of adult rat vocal communication is emphasized. The association of 22 kHz and 50 kHz vocalizations with aversive and appetitive states, respectively, was utilized in numerous quantitatively measured preclinical models of physiological, psychological, neurological, neuropsychiatric, and neurodevelopmental investigations. The present review should help in understanding and the interpretation of these models in biomedical research.

Arousal and sleep circuits.

The principal neurons of the arousal and sleep circuits are comprised by glutamate and GABA neurons, which are distributed within the reticular core of the brain and, through local and distant projections and interactions, regulate cortical activity and behavior across wake-sleep states. These are in turn modulated by the neuromodulatory systems that are comprised by acetylcholine, noradrenaline, dopamine, serotonin, histamine, orexin (hypocretin), and melanin-concentrating hormone (MCH) neurons. Glutamate and GABA neurons are heterogeneous in their profiles of discharge, forming distinct functional cell types by selective or maximal discharge during (1) waking and paradoxical (REM) sleep, (2) during slow wave sleep, (3) during waking, or (4) during paradoxical (REM) sleep. The neuromodulatory systems are each homogeneous in their profile of discharge, the majority discharging maximally during waking and paradoxical sleep or during waking. Only MCH neurons discharge maximally during sleep. They each exert their modulatory influence upon other neurons through excitatory and inhibitory receptors thus effecting a concerted differential change in the functionally different cell groups. Both arousal and sleep circuit neurons are homeostatically regulated as a function of their activity in part through changes in receptors. The major pharmacological agents used for the treatment of wake and sleep disorders act upon GABA and neuromodulatory transmission.

Ages at Onset of Anxiety and Depressive Disorders in Parkinson's Disease.

Parkinson's disease (PD) is a quintessential neuropsychiatric condition in which anxiety and depressive symptoms are common and may precede motor manifestations. The authors explored the ages at onset of anxiety and depressive disorders among patients with PD evaluated by psychiatrists at a deep brain stimulation center. Psychiatric diagnoses and ages at onset were collected via clinical interviews. The ages at PD diagnosis were ascertained by chart review. Onset ages for anxiety and depressive disorders (overall and for specific disorders) were compared with patients' ages at PD diagnosis by using t tests. Onset ages for major depressive disorder (MDD), generalized anxiety disorder (GAD), and panic disorder were compared with typical onset ages in the general population by using the sign test. A total of 108 patients (66.7% men; age 63.7 years [SD=8.9]) were included in the analysis. Anxiety and depressive disorders occurred significantly earlier than PD diagnoses. Among patients whose anxiety and depression predated motor symptoms, the mean age at onset of anxiety disorders was 25.6 years earlier, and the mean age at onset of depressive disorders was 17.6 years earlier compared with the mean age at PD diagnosis (both p values <0.0001). Median onset ages for MDD (p<0.0001), GAD (p=0.0002), and panic disorder (p=0.0005) were significantly higher than typical median onset ages in the general population. These results may indicate that neurodegenerative changes are present in parts of the brainstem reticular core and limbic system before motor circuits are affected to a degree that causes motor symptoms. Psychiatrists should be mindful that onset of MDD, GAD, and panic disorder after age 45 might signal a neurodegenerative movement disorder such as PD.

Afferent and efferent connections of C1 cells with spinal cord or hypothalamic projections in mice.

The axonal projections and synaptic input of the C1 adrenergic neurons of the rostral ventrolateral medulla (VLM) were examined using transgenic dopamine-beta hydroxylase Cre mice and modified rabies virus. Cre-dependent viral vectors expressing TVA (receptor for envelopeA) and rabies glycoprotein were injected into the left VLM. EnvelopeA-pseudotyped rabies-EGFP glycoprotein-deficient virus (rabies-EGFP) was injected 4-6weeks later in either thoracic spinal cord (SC) or hypothalamus. TVA immunoreactivity was detected almost exclusively (95%) in VLM C1 neurons. In mice with SC injections of rabies-EGFP, starter cells (expressing TVA+EGFP) were found at the rostral end of the VLM; in mice with hypothalamic injections starter C1 cells were located more caudally. C1 neurons innervating SC or hypothalamus had other terminal fields in common (e.g., dorsal vagal complex, locus coeruleus, raphe pallidus and periaqueductal gray matter). Putative inputs to C1 cells with SC or hypothalamic projections originated from the same brain regions, especially the lower brainstem reticular core from spinomedullary border to rostral pons. Putative input neurons to C1 cells were also observed in the nucleus of the solitary tract, caudal VLM, caudal spinal trigeminal nucleus, cerebellum, periaqueductal gray matter and inferior and superior colliculi. In sum, regardless of whether they innervate SC or hypothalamus, VLM C1 neurons receive input from the same general brain regions. One interpretation is that many types of somatic or internal stimuli recruit these neurons en bloc to produce a stereotyped acute stress response with sympathetic, parasympathetic, vigilance and neuroendocrine components.

Brain Structural Alterations Induced by Fetal Exposure to Cocaine Persist Into Adolescence and Affect Behavior

Thirty years ago, an epidemic of crack cocaine abuse swept the country and had particularly devastating effects on poor individuals andminorities.Thisheavily addictive formof smokedcocaineensnaredmanyyoungwomenwhobecamepregnant.At the time, several clinical reports from small cohorts of cocaine-exposed infants suggestedsevereadverseneurobehavioraloutcomes, leading to the designation“crackbabies.”Nevertheless, thoughtful clinicians raised concerns about facile inferences that cocaine alone caused this phenotype.1,2 They noted a number of other well-established risk factors for these adverse outcomes that could be difficult to disentangle from exposure to cocaine including concurrent use of tobaccoandalcohol, knownbehavioral teratogens,poorperinatal care, and other adverse consequences of poverty such as poor diet. Cocainecauses its rewardingeffectsby inhibitionofthedopaminetransporter, which activates reward circuits in the forebrain.3 However, it is alsoan inhibitorof thenorepinephrine transporter aswell as the serotonintransporter, therebypotentiatingtheeffectsof theseother 2neurotransmitters. These “biogenic amine”neurotransmitter systems, the cell bodies of which are located in the midbrainbrainstem and compose the reticular core, are among the earliest neural systemstodevelop in thebrain.4Preclinical researchhasdemonstrated that during fetal brain development they play important roles inmodulatingneurogenesis, neuronalmigration, neuronal differentiation,andsynaptogenesis.5Thus, it isnotsurprising thatstudies in fetal rodents have demonstrated that cocaine causes a persistentdisruption indopaminesignaling,corticalGABAergic function, and pyramidal neuron dendritic structure in the prefrontal cortex, a dopamine-rich region.6 Other studies have shown that inhibition of serotonin transport in the fetal braindisrupts the formationof the so-called barrel fields in the rodent primary sensory cortex, a cortiJAMAPEDIATRICS

Radiological features of childhood giant cavernous malformations

Giant cavernous malformations (GCM) are very large, low-flow vascular malformations, which usually have atypical imaging features and are commonly misdiagnosed preoperatively as neoplasms or vascular malformations. These lesions have mostly been reported in children. As cavernomas show different features in children compared to adults, we evaluated the imaging features of pediatric GCMs in order to help in the preoperative diagnosis of these malformations. Brain MR studies of nine children (mean age of 4years; 8months-9years) with biopsy-proven GCM were retrospectively evaluated. We defined GCMs as cavernomas of ≥4cm. Lesions were evaluated regarding their size, location, signal characteristics, general appearance (uni/multilocular) as well as regarding the presence of mass effect, edema, and fluid-fluid levels and were classified according to the Mottolese classification of pediatric cavernomas. Lesion locations were parietal (n = 5), frontal (n = 2), temporal, and intraventricular. Seven lesions were in the periventricular region (with five in the periatrial region). Six patients had T1 hyperintense multilobulated lesions with "bubbles of blood" appearance and three patients had heterogeneous lesions with reticular core. All lesions had mass effect, edema (marked in four cases), and peripheral hemosiderin rim. Fluid-fluid levels were also common (n = 7). Most of our lesions (six of nine) were classified as type IIIA, two as type IIIC, and one as type IA. In children, a GCM should be considered in case of very large hemorrhagic intra-axial mass with "bubbles of blood" multicystic appearance, surrounding hemosiderin ring, fluid-fluid levels, and accompanying edema-mass effect, especially in the periatrial location.

Distribution of progesterone receptor immunoreactivity in the midbrain and hindbrain of postnatal rats

Nuclear steroid hormone receptors are powerful transcription factors and therefore have the potential to influence and regulate fundamental processes of neural development. The expression of progesterone receptors (PR) has been described in the developing forebrain of rats and mice, and the mammalian brain may be exposed to significant amounts of progesterone, either from maternal sources and/or de novo synthesis of progesterone from cholesterol within the brain. The present study examined the distribution of PR immunoreactive (PRir) cells within the midbrain and hindbrain of postnatal rats. The results demonstrate that PR is transiently expressed within the first 2 weeks of life in specific motor, sensory and reticular core nuclei as well as within midbrain dopaminergic cell groups such as the substantia nigra and the ventral tegmental area. Additionally, robust PRir was observed in cells of the lower rhombic lip, a transient structure giving rise to precerebellar nuclei. These results suggest that progestins and progesterone receptors may play a fundamental role in the postnatal development of numerous midbrain and hindbrain nuclei, including some areas implicated in human disorders. Additionally, these findings contribute to the increasing evidence that steroid hormones and their receptors influence neural development in a wide range of brain areas, including many not typically associated with reproduction or neuroendocrine function.

El sistema de neurotransmisión hipocretinérgico/orexinérgico en la regulación de los estados de vigilia y sueño

The hypocretins/orexins are neuropeptides synthesized by a small neuronal cell group located in the posterior and lateral hypothalamus. These peptides have been considered modulators of the sleep-wakefulness cycle since their discovery in 1998; the hypocretinergic/orexinergic system is very active during wakefulness. In addition, the absence of either these peptides or their receptors is associated to narcolepsy-cataplexy, a disease in which the sleep-wakefulness cycle is completely disorganized. Hypocretinergic/orexinergic neurons directly activate the cerebral cortex and neuronal cell groups of the reticular activating system containing noradrenaline, serotonin, dopamine, acetylcholine and histamine, through which they may also indirectly activate the cerebral cortex and enhance wakefulness; as well, these neurons inhibit REM sleep generation in the ventral pontine tegmentum. The decrease in the activity of hypocretinergic/orexinergic neurons during sleep inhibits the aminergic and cholinergic neurons of the reticular activating core, decreasing cortical activation and renewing REM sleep generation in the ventral pontine tegmentum. Hypocretins/orexins modulate wakefulness and EEG activation in part through their actions on reticular core neurons projecting to the cortex and suppress REM sleep generation through inhibition of ventral pontine tegmentum neurons within the ventral oral pontine tegmentum. The hypoactivity of this system supports the sleep cycle fragmentation and general disorganization appearing in narcolepsy, as well as momentary interruption of wakefulness by REM sleep episodes.

Brainstem-thalamic neurons implicated in hallucinations

I propose that hyperactivity (or increased numbers) of neurons in the brainstem reticular core promote hallucinations by excessive excitation, coupled with disinhibition, of target thalamocortical neurons. This idea stems from animal experiments using kainate-induced overexcitation of midbrain reticular neurons leading to hallucinatory-type behavior during wakefulness, as well as from data in schizophrenic patients showing an increased number of neurons in mesopontine cholinergic neurons.

Branching projection of the nucleus “k” neurons to the rabbit cerebellar paramedian lobule: a retrograde fluorescent tracing study

The nucleus "k", in the reticular core of the rabbit caudal pons, is divided into a large medial (composed of dorsal k1 and ventral k2) and a small lateral (k3) subdivision. In this study, the nucleus "k" subdivisions were examined in the rabbit with respect to projections to the cortex of rostral (rPML; face-forelimb region) and caudal (cPML; hindlimb region) paramedian lobule of the cerebellum. The retrograde fluorescent labeling method with Fast Blue (FB) and Diamidino Yellow (DY) was used. Numerous single FB or DY labeled neurons were found in defined regions of all nucleus "k" subdivisions bilaterally, with an ipsilateral preponderance. The distribution of these neurons indicated that afferents originating from different nucleus "k" subdivisions terminated in overlapping regions within the rPML and the cPML rather than in separate domains. Apart from this, double FB + DY labeled neurons (n = 104) were intermingled within a common region of single labeling, but exclusively on the ipsilateral side. Such neurons occupied predominantly the central and lateral regions of the caudal two thirds of the k1 subdivision, and were scattered in the caudal half of k2 as well as throughout the entire rostrocaudal extent of the k3 subdivision. The size of labeled perikarya varied from 20 to 40 microm in diameter. The number of neurons with branching axons was considerably lower than those with single projections to the rPML and the cPML. It amounted to about 3% in k1 and k3, and 2% in the k2 subdivision. However, this population may form an intralobular link between two somatotopically non-corresponding PML regions. The present study provides a morphological basis for further investigations for comparison with other species using both anatomical and electrophysiological methods, also with respect to other connections of the nucleus "k".

Chemical neuromodulation of frontal-executive functions in humans and other animals.

Neuromodulation of frontal-executive function is reviewed in the context of experiments on rats, monkeys and human subjects. The different functions of the chemically identified systems of the reticular core are analysed from the perspective of their possible different interactions with the prefrontal cortex. The role of dopamine in spatial working memory is reviewed, taking account of its deleterious as well as facilitatory effects. Baseline-dependent effects of dopaminergic manipulation are described in rats on an attentional task, including evidence of enhanced function following infusions of D1 receptor agonists into the prefrontal cortex. The precise nature of the cognitive task under study is shown to be a powerful determinant of the effects of mesofrontal dopamine depletion in monkeys. Parallels are identified in human subjects receiving drugs such as the indirect catecholamine agonists L-dopa, methylphenidate and the dopamine D2 receptor blocker sulpiride. The effects of these drugs on different types of cognitive function sensitive to frontal lobe dysfunction are contrasted with those of a manipulation of 5-HT function, dietary tryptophan depletion. Hypotheses are advanced that accord the ascending systems a greater deal of specificity in modulating prefrontal cortical function than has hitherto been entertained, and clinical and theoretical implications of this hypothesis are discussed.

Affect and the Limbic System: Some Hard Problems

Affect and the Limbic System: Some Hard Problems

MRNA for the m4 muscarinic receptor subtype is expressed in adult rat brain cholinergic neurons

A number of pharmacological, anatomical, and immunological studies have previously addressed the subtype identity of the hippocampal muscarinic pre-synaptic autoreceptor. A preponderance of findings indicate that it is of the M2 pharmacological type. Both the m2 and m4 molecular subtypes exhibit M2 pharmacology and there are few drugs that differentiate between these receptors. Pharmacological attempts at defining the hippocampal autoreceptor have yielded conflicting results. The basal forebrain is relatively enriched in m2 muscarinic receptor mRNA and protein, and lesions that denervate the hippocampus of its basal forebrain cholinergic input have shown a decrement in m2, but not m4, receptor protein in the hippocampus. Thus, the anatomical data obtained to date tend to support the view that the m2 subtype is expressed as the hippocampal autoreceptor. We have combined in situ hybridization histochemistry (ISHH) with immunocytochemistry to choline acetyltransferase to examine whether mRNA for the m4 subtype of muscarinic receptor is expressed in central cholinergic neurons. The m4 muscarinic mRNA was found at moderate levels in all subdivisions of the cholinergic basal forebrain, including the medial septum/diagonal band complex (MS/DB). The m4 mRNA was also found in striatal cholinergic interneurons, in the cholinergic reticular core of the upper brainstem, and in brainstem cholinergic motor neurons. Muscarinic m4 receptor mRNA was also found in many non-cholinergic cells in the brain. For example, the hippocampal pyramidal neurons, dentate gyrus granule cells, and entorhinal cortical pyramidal neurons express relatively high levels of m4 mRNA, while in the brainstem the dorsal raphe and pontine reticular nuclei express relatively high levels of this mRNA. The finding of m4 mRNA in the (MS/DB) cholinergic neurons suggests that this receptor protein might be expressed as an autoreceptor in hippocampal cholinergic terminals.

Electrical stimulation of the cholinergic laterodorsal tegmental nucleus elicits scopolamine-sensitive excitatory postsynaptic potentials in medial pontine reticular formation neurons

A large and consistent body of data implicates mesopontine cholinergic neurons in the production of rapid eye movement sleep, and indicates that many rapid eye movement sleep events are mediated by activation of pontine reticular formation neurons. There is anatomical evidence for projections from the mesopontine cholinergic nuclei to the pontine reticular formation, but no study has shown that stimulation of this cholinergic zone produces excitatory postsynaptic potentials in pontine reticular formation neurons. In the present study, intracellular recordings were made from 168 pontine reticular formation neurons, identified by antidromic activation from the bulbar reticular formation and by neurobiotin intracellular labeling, in acutely anesthetized cats. The effects of single-pulse electrical stimulation of the laterordorsal tegmental nucleus portion of the ipsilateral mesopontine cholinergic zone were evaluated in these neurons. Under urethane anesthesia this stimulation produced, in 21 of 22 recorded neurons, long-latency excitatory postsynaptic potentials (mean = 3 ms), consistent with the conduction velocity of unmyelinated cholinergic fibers (measured conduction velocity was 2 m/s). This excitatory postsynaptic potential was virtually abolished by intravenous administration of the muscarinic cholinergic receptor blocker scopolamine ( n = 40 neurons), and by acute cuts separating the laterodorsal tegmental nucleus and the recorded neurons ( n = 40). In contrast, a short-latency excitatory postsynaptic potential (0.7–1.5 ms) was not reduced in amplitude by scopolamine and could still be elicited following acute transverse cuts. Unlike the longer-latency excitatory postsynaptic potential, its amplitude was not reduced by barbiturate anesthesia. These data, suggesting the presence of an excitatory, cholinergic laterodorsal tegmental nucleus projection to the pontine reticular formation, provide further support to other lines of evidence implicating mesopontine cholinergic neurons in the production of rapid eye movement sleep, and are compatible with a model of rapid eye movement sleep generation in which a key element is mesopontine cholinergic input depolarizing and increasing the excitability of reticular core neurons.

Developmental changes in [3H]kainate binding in human brainstem sites vulnerable to perinatal hypoxia-ischemia.

The human brainstem is especially susceptible to hypoxia-ischemia in early life. To test the hypothesis that the period of vulnerability of the developing human brainstem to hypoxia-ischemia correlates with a transient elevation in kainate receptor binding, we compared the quantitative distribution of [3H]kainate binding in brainstem nuclei between four fetuses (19-26 gestational weeks), four infants (one to nine months), and three "mature" individuals (one child and two adults) without neurological disease. Quantitative tissues autoradiography was used. [3H]Kainate binding decreased in all brainstem regions from early life to maturity with the most significant decreases occurring in nuclei thought to be especially vulnerable to perinatal hypoxia-ischemia (e.g. principal inferior olive, griseum pontis, inferior colliculus and reticular core). The highest binding in the fetal and infant period was found primarily in the major cerebellar-relay nuclei. In the inferior olive and arcuate nucleus, binding increased from the fetal to the infant period, and then fell 50-61% to low mature levels. In the griseum pontis, binding decreased 60% between the fetal and mature periods. In the reticular formation, binding fell 67-78% from the fetal to mature period. These data support a correlation between the period of brainstem vulnerability to hypoxia-ischemia in early life to transient elevation in kainate binding, and are particularly relevant to the topographic brainstem patterns in perinatal hypoxia-ischemia of infantile olivary gliosis, pontosubicular necrosis and reticular core damage. Striking localization of [3H]kainate binding to rhombic lip derivatives further suggests that kainate receptors may be involved in the development and function of human brainstem-cerebellar circuitry.

Brain activation, then (1949) and now: coherent fast rhythms in corticothalamic networks.

The hypothesis of forebrain activation elicited by brainstem reticular core stimulation, formulated almost a half century ago, is now fully substantiated at the intracellular level of thalamic and neocortical neurons. Data show that stimulation of mesopontine cholinergic nuclei induces a prolonged muscarinic depolarization of thalamocortical neurons, associated with an increase in their apparent input resistance (that explains the enhanced probability of thalamic responses to incoming volleys upon arousal) and accompanied by a long-lasting activation of cortical rhythms. Activation also includes the preservation or even enhancement of short-lasting sculpturing inhibitory processes in thalamic and neocortical cells, a basic requirement for discrimination purposes. The notion of activation, that was erroneously termed as a "desynchronized" activity in thalamocortical networks, is now demonstrated to include spontaneously occurring, synchronous fast (20-40 Hz) rhythms. While the spatial coherence of sleep rhythms extends over wide territories, fast oscillations during brain arousal are synchronous within a cortical column and among closely spaced cortical areas, thalamic nuclei, and corticothalamic systems. Fast oscillations do not exclusively characterize brain-active states of waking and REM sleep, as they are also present during the depolarizing phase of the slow sleep oscillation in both cortical and thalamic cells. The subthreshold fast depolarizing spontaneous oscillations may bias thalamic and cortical cells to respond synchronously, at fast frequencies, to external stimuli in the wake state and to internal drives (such as ponto-geniculo-occipital signals) during REM sleep.

Dendritic reorganisation in the basal forebrain under degenerative conditions and its defects in Alzheimer's disease. III. The basal forebrain compared with other subcortical areas

The distribution of the reticular neuronal type in the human brain and its involvement in both degeneration and dendritic reorganisation under the conditions of ageing, Korsakoff's disease (KD), Alzheimer's disease (AD), and Parkinson's disease (PD) was comparatively investigated after Golgi impregnation. Reticular neurones are distributed throughout different areas along the brain axis. The cholinergic basal forebrain nuclei, i.e., the basal nucleus of Meynert, the nucleus of the diagonal band, and the medial septal nucleus form the most rostral part of this network of "open nuclei," which is collectively referred to as the "reticular core." Reticular neurones of the following areas were quantitatively investigated by a computer-based three-dimensional analysis: caudate nucleus, globus pallidus, medial septal nucleus, nucleus of the vertical limb of the diagonal band, basal nucleus, medial amygdaloid nucleus, reticular thalamic nucleus, lateral hypothalamic area, subthalamic nucleus, substantia nigra, locus coeruleus, pedunculopontine tegmental nucleus, and raphe magnus nucleus. There are three major findings. First, neurones that were found to be susceptible to degeneration in AD were largely part of the same neuronal populations prone to degeneration during ageing, in KD and PD. Thus, areas could be classified according to their overall degree of vulnerability under the present degenerative conditions as being highly vulnerable (basal forebrain nuclei, caudate nucleus, locus coeruleus), moderately vulnerable (medial amygdaloid nucleus, raphe magnus nucleus, lateral hypothalamic area, substantia nigra, pedunculopontine tegmental nucleus), or marginally vulnerable (globus pallidus, subthalamic nucleus, reticular thalamic nucleus). Second, neuronal populations that are particularly vulnerable to degenerative changes show a high degree of structural plasticity. Third, the degree of this dendritic plasticity is inversely related to the complexity of dendritic arborisation of the neurone. It is concluded that the sparsely ramified reticular type of neurone forms a pool of pluripotent neurones that have retained their plastic capacity throughout life, which makes them vulnerable to a variety of perturbations.

Distinct Distributions of Mu, Delta and Kappa Opioid Receptor mRNA in Rat Brain

We present a comprehensive comparison of the anatomical distributions of the cloned mu, delta and kappa opioid receptor mRNA in rat brain. Northern blot analysis revealed that mRNA species encoding the three receptors differed in size and were differentially localized in brain regions. In peripheral tissues analyzed, the 3 mRNA species were detected only in the spinal cord. The distributions of mu, delta and kappa receptor mRNA in rat brain were examined by in situ hybridization histochemistry using gene-specific probes. Mu receptor mRNA was predominately localized to thalamic, brainstem and reticular core nuclei and was highest in the habenular and thalamic nuclei. In contrast, kappa receptor mRNA was expressed in hippocampus including dentate gyrus, hypothalamic and some thalamic nuclei and also present in cortex, caudate putamen, olfactory tubercle and nucleus accumbens. Delta receptor mRNA was prominent in cerebral cortex, olfactory tubercle, hippocampus, caudate putamen and nucleus accumbens. These results show that the mRNA distribution for each opioid receptor subtype in brain is unique and correlate well with the known distribution of the corresponding opioid receptor binding sites.

Chapter 5: The organization of central cholinergic systems and their functional importance in sleep-waking states

Since the demonstration some 50 years ago of the presence and synthesis of acetylcholine (ACh) in specific neuronal systems within the brain, a wealth of information concerning the organization and functional importance of central cholinergic neurons has emerged through immunohistochemical, neuroanatomical, pharmacological, biochemical and neurophysiological studies. Many of the original theses have proven valid concerning the key structural and functional position of cholinergic neurons within the central reticular core of the brain, where the basic sleep-waking cycle is determined. The two major cholinergic cell groups of this core, one within the pontomesencephalic tegmentum that projects rostrally into the non-specific thalamo-cortical relay system and the other within the basal forebrain that receives input from the brainstem reticular formation and projects in turn as the ventral, extrathalamic relay upon the cerebral cortex, are critically involved in processes of cerebral activation that accompany the states of wakefulness and paradoxical sleep. By interaction with other cell groups, including monoaminergic and GABAergic neurons, and by differential modes of firing, the cholinergic neurons may furthermore shape the responsiveness and activity of the reticular core and thalamo-cortical systems across the sleep-waking cycle.

Viruses and Behavioural Changes: A Review of Clinical and Experimental Findings

This review focuses on behavioural neurovirology. Profound changes in behaviour are observed following infection of the central nervous system by some viruses. Irritability, insomnia, hyperactivity and learning disability are some of the behavioural disturbances that have been described in both humans and animals with central nervous system infection. The reticular core neurons which innervate the entire brain play an important role in regulating behaviour. Some of these neurons--locus coeruleus, raphe and diagonal bands--send projections to the olfactory bulbs and can be targets for exogenous agents attacking the olfactory epithelium. In infant rats, vesicular stomatitis virus is transported along the olfactory pathway by retrograde transport and reaches the reticular core neurons causing destruction of raphe, diagonal bands and, to a lesser extent, the locus coeruleus. As the neurons degenerate, the viral antigens disappear and the animals sustain severe deficits in neurotransmitter levels and behaviour. Such a "hit and run" effect of the virus suggests the possibility that a similar mechanism may be operating in some human disorders. Apart from their intrinsic interest as possible aetiological factors, viruses may provide valuable tools in experimental work seeking to correlate behaviour, morphology and neurotransmitter function.