The role of co-neurotransmitters in sleep and wake regulation.

Sleep and wakefulness control in the mammalian brain requires the coordination of various discrete interconnected neurons. According to the most conventional sleep model, wake-promoting neurons (WPNs) and sleep-promoting neurons (SPNs) compete for network dominance, creating a systematic "switch" that results in either the sleep or awake state. WPNs and SPNs are ubiquitous in the brainstem and diencephalon, areas that together contain <1% of the neurons in the human brain. Interestingly, many of these WPNs and SPNs co-express and co-release various types of the neurotransmitters that often have opposing modulatory effects on the network. Co-transmission is often beneficial to structures with limited numbers of neurons because it provides increasing computational capability and flexibility. Moreover, co-transmission allows subcortical structures to bi-directionally control postsynaptic neurons, thus helping to orchestrate several complex physiological functions such as sleep. Here, we present an in-depth review of co-transmission in hypothalamic WPNs and SPNs and discuss its functional significance in the sleep-wake network.

Bottom-Up and Top-Down Mechanisms of General Anesthetics Modulate Different Dimensions of Consciousness.

There has been controversy regarding the precise mechanisms of anesthetic-induced unconsciousness, with two salient approaches that have emerged within systems neuroscience. One prominent approach is the "bottom up" paradigm, which argues that anesthetics suppress consciousness by modulating sleep-wake nuclei and neural circuits in the brainstem and diencephalon that have evolved to control arousal states. Another approach is the "top-down" paradigm, which argues that anesthetics suppress consciousness by modulating the cortical and thalamocortical circuits involved in the integration of neural information. In this article, we synthesize these approaches by mapping bottom-up and top-down mechanisms of general anesthetics to two distinct but inter-related dimensions of consciousness: level and content. We show how this explains certain empirical observations regarding the diversity of anesthetic drug effects. We conclude with a more nuanced discussion of how levels and contents of consciousness interact to generate subjective experience and what this implies for the mechanisms of anesthetic-induced unconsciousness.

A neuronal migratory pathway crossing from diencephalon to telencephalon populates amygdala nuclei.

Neurons usually migrate and differentiate in one particular encephalic vesicle. We identified a murine population of diencephalic neurons that colonized the telencephalic amygdaloid complex, migrating along a tangential route that crosses a boundary between developing brain vesicles. The diencephalic transcription factor OTP was necessary for this migratory behavior.

Sonic hedgehog from the basal plate and the zona limitans intrathalamica exhibits differential activity on diencephalic molecular regionalization and nuclear structure.

The diencephalon is the most complex area of the vertebrate brain, being particularly complex in amniotes. It has been suggested that diencephalic regionalization partially depends on local signaling mediated by sonic hedgehog (Shh). However, since the Shh gene is expressed in both the diencephalic basal plate and the zona limitans intrathalamica (ZLI), it is still unclear which of these tissues exerts morphogenetic influence on thalamic regionalization. In the present study using chick and quail embryos, we have found that although Shh from the ZLI and the basal plate induces ectopic expression of diencephalic genes in the posterior prosencephalic alar plate, only Shh originating from the ZLI can induce ectopic gene expression in the anterior alar plate, indicating that the ZLI exerts specific activity in the anterior epithelium. By introducing microbarriers between the diencephalic alar neuroepithelium and either the ZLI or the basal plate, we generated local loss of Shh expression in the ZLI, leading to alterations in molecular regionalization and subsequently, in the nuclear organization of the alar diencephalic derivatives on both sides of the ZLI. We thus demonstrate in vivo that basal signals are required to induce Shh expression in the ZLI and that Shh from the ZLI plays a pivotal role in regionalizing the alar diencephalon. The structural phenotype of Shh abolition in the ZLI consisted of a progressive pattern of alterations in diencephalic organization which were associated with the observed gradient effects in the molecular regionalization of the diencephalon. We conclude that the ZLI is a secondary organizer which exerts its morphogenetic activity through Shh.

Evidence for serotonin influencing the thalamic infiltration of mast cells in rat.

Serotonin (5-HT) is involved in neuroimmunomodulation. We analyzed the effects of sumatriptan, a 5-HT(1B/1D) receptor agonist, and ondansetron, a 5-HT(3) receptor antagonist, on thalamic mast cell (TMC) population, the only immunocytes known to infiltrate the brain in physiological conditions. Only sumatriptan was effective, significantly increasing TMC numbers versus controls, and especially those containing 5-HT. 5-HT(1B) receptors are concentrated in the median eminence on non-serotonergic axonal endings, probably hypothalamic terminal fibers, involved in hypothalamic-pituitary neuroendocrine modulating processes. TMC variations could reflect serotonergic actions on these fibers. TMCs would thus be cellular interfaces mediating immune action in the nervous system in relation with the hormonal status of the organism.

Topographic representation of vestibular and somatosensory signals in the anuran thalamus.

In the isolated brain of the fire-bellied toad, Bombina orientalis, the spatial distribution of vestibular and somatosensory responses in thalamic nuclei was studied following electrical activation of the Vth nerve, the ramus anterior of the VIIIth nerve and of the dorsal roots of spinal nerves 3 and 8. Responses were systematically mapped in frontal planes through the diencephalon at four rostro-caudal levels. The calculated activity maps were superimposed on the outlines of diencephalic nuclei, and those nuclei that received particularly large inputs from the stimulated sensory nerve roots were indicated. Maximal response amplitudes coincided with ventral, central, and posterior thalamic areas and exhibited a topography that differed for each sensory nerve root. Maximal responses evoked from the Vth nerve were largely separated from those from spinal dorsal roots 3 and 8, whereas maximal vestibular responses partly overlapped with those from the other somatosensory nerve roots. Our findings indicate that within the amphibian thalamus sensory signals originating from different nerve roots are largely represented in separate areas as is the case in the thalamus of amniotes. However, the anterior dorsal thalamus which is the only origin of ascending pathways to the medial and dorsal pallium (assumed homologues of the mammalian hippocampus and neocortex, respectively) receives only minor vestibular and somatosensory input. This corroborates the view that amphibians lack a direct sensory thalamo-cortical, or "lemnothalamic," pathway typical of mammals and birds.

[Thermal regulation during sleep]. / La régulation thermique au cours du sommeil.

Many studies point out that ambient temperatures outside the thermoneutral zone disturb sleep. Thermal responses depend on the phase of sleep and it appears that rapid eye movement (REM) sleep and thermoregulation are mutually exclusive in animals. In humans, there is evidence that this thermoregulatory disruption is less important since the thermal responses to heat or cold exposures are not abolished. Thermal responses persist during slow wave sleep (SWS). These differences suggest that there is a hierarchical control of body temperature regulation. The control includes different integrators at many levels of the nervous system with each level facilitated or inhibited by levels above and below. During SWS, body temperature is controlled by diencephalic structures whereas during REM sleep there is a suspension of hypothalamic thermoregulatory influences. The thermoregulatory differences may be accounted for by the neural organization and the autonomy of brain stem and spinal operative levels which differ between sleep phases and species. However, in the neonate, thermoregulation is not impaired during active sleep (AS) and Quiet Sleep (QS) considered, from behavioral and polygraphic measures, as immature forms of REM and SWS, respectively. From a thermoregulatory point of view, AS seems to be a well-protected sleep phase. As regards the thermal responses, these observations suggest that neonatal active sleep may be a precursor both of REM sleep and SWS in adults.

Sleep, consciousness and the spontaneous and evoked electrical activity of the brain. Is there a cortical integrating mechanism?

The physiological mechanisms that underlie consciousness and unconsciousness are the sleep/wake mechanisms. Deep sleep is a state of physiological reversible unconsciousness. The change from that state to wakefulness is mediated by the reticular activating mechanism. The reverse change from wakefulness to sleep is also an active process effected by an arousal inhibitory mechanism based on a partial blockade of the thalamus and upper brain stem, associated with thalamic sleep spindles and also with cortical sub-delta activity (<1 Hz). The deactivation of the thalamus has been demonstrated both electrically and by positron emission tomography during deep sleep. Normally, wakefulness is associated with instant awareness (defined as the ability to integrate all sensory information from the external environment and the internal environment of the body). Awareness may be a function of the thalamo-cortical network in the cerebral hemispheres, which forms the final path of the sleep/wake mechanism. Anatomical and physiological studies suggest that there may be a double thalamo-cortical network; one relating to cortical and thalamic areas with specific functions and the other global, involving all cortical areas and so-called 'non-specific' thalamic nuclei. The global system might function as a cortical integrating mechanism permitting the spread of information between the specific cortical areas and thus underlying awareness. The global system may also be responsible for much of the spontaneous and evoked electrical activity of the brain. The cognitive change between sleep and wakefulness is accompanied by changes in the autonomic system, the cerebral blood flow and cerebral metabolism. Awareness is an essential component of total consciousness (defined as continuous awareness of the external and internal environment, both past and present, together with the emotions arising from it). In addition to awareness, full consciousness requires short-term and explicit memory and intact emotional responses.

Mesencephalic and diencephalic afferent connections to the thalamic nucleus rotundus in the lizard, Psammodromus algirus.

The present work is an analysis of the afferent projections to the thalamic nucleus rotundus in a lizard, both at the light- and electron-microscopic level, using biotinylated dextran amine (BDA) as a neuroanatomical tracer. This study has confirmed previously reported afferent projections to nucleus rotundus in reptiles and has also identified a number of new cellular aggregates projecting to this dorsal thalamic nucleus. After BDA injections into nucleus rotundus, retrogradely labelled neurons were observed consistently within the following neuronal groups in the midbrain and the diencephalon: (i) the stratum griseum centrale of the optic tectum; (ii) the nucleus subpretectalis in the pretectum; (iii) the nucleus ansa lenticularis posterior, the posterior nucleus of the ventral supraoptic commissure, and the posteroventral nucleus, in the dorsal thalamus and (iv) the lateral suprachiasmatic nucleus and part of the reticular complex in the ventral thalamus. Tectal axons entering nucleus rotundus were fine and varicose and formed exclusively asymmetric synaptic contacts, mainly on small dendritic profiles. Rotundal neurons had symmetric synapses made by large boutons probably of nontectal origin. After comparing our results with those in other reptiles, birds and mammals, we propose that the sauropsidian nucleus rotundus forms part of a visual tectofugal pathway that conveys mesencephalic visual information to the striatum and dorsal ventricular ridge, and is similar to the mammalian colliculo-posterior/intralaminar-striatoamygdaloid pathway, the function of which may be to participate in visually guided behaviour.

Vocal-acoustic circuitry and descending vocal pathways in teleost fish: convergence with terrestrial vertebrates reveals conserved traits.

Vocal behavior is multifaceted and requires that vocal-motor patterning be integrated at multiple brain levels with auditory, neuroendocrine, and other social behavior processes (e.g., courtship and aggression). We now provide anatomical evidence for an extensive vocal network in teleost fishes (Batrachoididae: Porichthys notatus; Opsanus beta) that is strongly integrated with neuroendocrine and auditory pathways and that exhibits striking similarities to the vocal-acoustic circuitry known for mammals. Biotin compound injections into neurophysiologically identified vocal regions of the forebrain (preoptic area and anterior hypothalamus) and of the midbrain (periaqueductal gray and paralemniscal tegmentum) reveal extensive connectivity within and between these regions, as well as reciprocal relationships with the auditory thalamus and/or auditory midbrain (torus semicircularis). Thus, specific components of the basal forebrain and midbrain are here designated as the forebrain vocal-acoustic complex (fVAC) and midbrain vocal-acoustic complex (mVAC), respectively. Biotin injections into the mVAC and a previously identified hindbrain vocal pattern generator likewise provide anatomical evidence for a distributed network of descending projections to the vocal pacemaker-motoneuron circuitry. Together, the present experiments establish a vocal-auditory-neuroendocrine network in teleost fish that links the forebrain and midbrain to the hindbrain vocal pattern generator (i.e., fVAC --> mVAC --> pattern generator) and provides an anatomical framework for the previously identified neuropeptide modulation of vocal activity elicited from the forebrain and midbrain, which contributes to the expression of sex- and male morph-specific behavior. We conclude with a broad comparison of these findings with those for other vertebrate taxa and suggest that the present findings provide novel insights into the structure of conserved behavioral regulatory circuits that have led to evolutionary convergence in vocal-acoustic systems.

Responses of spinohypothalamic tract neurons in the thoracic spinal cord of rats to somatic stimuli and to graded distention of the bile duct.

Anatomical studies indicate that a relatively large percentage of spinohypothalamic tract (SHT) neurons are located within thoracic spinal segments. The aim of this study was to characterize the responses of SHT neurons in these segments of rats to innocuous and noxious stimulation of the skin and of a visceral structure, the bile duct. In addition, we attempted to determine the trajectories of the axons of the examined neurons within the diencephalon and brainstem. Fifty-three SHT neurons were recorded within segments T8-T13 in urethane anesthetized rats. Each cell was antidromically activated using current pulses < or = 30 microA delivered from the tip of an electrode located within the contralateral hypothalamus. The recording points were located in the superficial dorsal horn (9) and deep dorsal horn (44). All examined SHT neurons had receptive fields on the posterior thorax and anterior and ventral abdomen of the ipsilateral side. Ninety percent of the 41 SHT neurons responded exclusively (13) or preferentially (24) to noxious cutaneous stimuli. Thirteen of 27 (48%) examined units were activated by forceful distention of the bile duct. Response thresholds ranged from 30 to 40 mmHg. Responses incremented as pressures were increased to 50-80 mmHg. The axons of 22 of 28 (79%) examined SHT neurons appeared to cross the midline within the hypothalamus and terminate in the ipsilateral hypothalamus, thalamus or midbrain. The results indicate that SHT neurons in thoracic spinal cord of rats are capable of conveying somatic and visceral nociceptive information from the bile duct directly to targets at various levels of the brain bilaterally.

[Mesodiencephalic modulation (transcranial electrostimulation of the brain) in neurology and psychiatry]. / Mezodiéntsefal'naia moduliatsiia (transkranial'naia élektrostimuliatsiia golovnogo mozga) v nevrologii i psikhiatrii.

The paper outlines the results of mesodiencephalic modulation (MDM) as therapy in adults and children with neurological and mental diseases in the out- and inpatient setting. MDM is a method of transcranial electric therapy that normalizes the performance of the hypothalamohypophyseal and opioid systems of the brain, which ultimately improves the body's adaptive response in disease.

Systemic oxytocin treatment modulates alpha 2-adrenoceptors in telencephalic and diencephalic regions of the rat.

Systemic subchronic oxytocin treatment significantly and substantially increased the B(max) values of the alpha 2 agonist [(3)H]UK14.304 binding sites in the hypothalamus, the amygdala and the paraventricular thalamic nucleus of the rat as shown by quantitative receptor autoradiography. These results suggest that long-term modulation of autonomic and neuroendocrine functions and emotional behaviours elicited by brain oxytocin may involve enhancement of central alpha 2-adrenoceptor function.

Proliferation zones in the adult brain of a sequential hermaphrodite teleost species (Sparus aurata).

Teleost sex change is an important model to understand general principles of sexual differentiation and plasticity in the adult brain. The present study is the first to examine the proliferation zones in the adult brain of males, females and sex-changing individuals of a protandrous teleost species (Sparus aurata), by means of 5-bromo-2-deoxyuridine immunocytochemistry. Postnatal neurogenesis in the marine teleost brain was found in ventricular and subventricular areas of the brain that in most cases coincided with the embryonic proliferation zones. The molecular layer of corpus and valvula cerebelli exhibited the highest mitotic activity in the adult brain. High mitotic activity was observed in the hypothalamic, thalamic and telencephalic ventricular areas, as well as the dorsal and ventral rim of the optic tectum. Most of the labeled cells were elongated, indicating the initiation of migratory activity. There were no qualitative differences in the distribution of proliferation zones between the sex phases studied with the exception of the ventricular region of the dorsal hypothalamic area. Volume fraction analysis of the area occupied by the labeled cells suggested that this region included higher densities of newborn cells in the female animals. The proliferation pattern in the adult gilthead sea bream brain is in agreement with the hypothesis of the continuous generation of new cells in the teleost brain. Moreover, our data propose that cell proliferation differences possibly existing in the ventricular region of the dorsal hypothalamus between sexual phases, might be involved in central mechanisms of sexual plasticity in protandrous hermaphrodite teleosts.

Connections between cells of the internal capsule, thalamus, and cerebral cortex in embryonic rat.

The aim of our study is to understand the development of the earliest connections in the mammalian pallium by documenting the distribution of cells and fibres labelled from the dorsal and ventral thalamus, internal capsule, perirhinal, and dorsal cortex during the period between embryonic day (E) 14 and 17 by using carbocyanine dye tracing in fixed embryonic rat brains. Dye placed in the thalamus of E14 brains backlabels cells in the thalamic reticular nucleus and within the primitive internal capsule. Both anterograde and retrograde tracing confirmed that the first corticofugal projections reach the internal capsule by E14. At E15-E16, after the first cortical plate cells have migrated into the lateral cortex, some cells of the cortical plate and subplate and marginal zone, are backlabelled from the internal capsule, but still not from the dorsal thalamus, even with very long incubation periods. Crystal placement into the perirhinal cortex at E14-E15 labels numerous cells within the internal capsule, whereas no such cells are revealed from dorsal cerebral cortex until E17, suggesting that internal capsule cells establish early connections with the perirhinal and ventral but not dorsal cortex. We propose that the growth of axons from cortex to dorsal thalamus is delayed in two regions: first from E14-E15 at the lateral entrance of the internal capsule and then, from E16, closer to the thalamus, probably within the thalamic reticular nucleus. Subplate projections reach the proximity of the diencephalon at an early stage, but they might never enter the dorsal thalamus.

Mechanisms underlying the early establishment of thalamocortical connections in the rat.

We labeled axonal projections using carbocyanine dyes in the developing rat brain to study cellular interactions that might underlie the establishment of thalamocortical connectivity. By embryonic day 14 (E14), groups of neurons in the ventral diencephalon and the primitive internal capsule have established projections to the dorsal thalamus, and thalamic fibers pass in topographic order among them. Simultaneously, axons from the early-born cells in both subplate and marginal zone (i.e., the original cortical preplate) establish an ordered array that fills the intermediate zone. Thalamic axons and preplate fibers meet in the lateral part of the internal capsule (at E15 for occipital cortex and dorsolateral thalamus). Subsequently, selective labeling of corresponding thalamic and early corticofugal projections reveals thalamic fibers growing in association with early corticofugal axons, right up to the cortical subplate. A small carbocyanine crystal implanted at any point in the cortex shortly after the arrival of thalamic axons (E16 for the occipital cortex) labels a single, tight bundle containing both descending and ascending fibers, rather than two separate tracts, providing further evidence for intimate topographic association of the two axon systems. Crystals placed in a row, parasagittally or coronally along the hemisphere, reveal separate, topographically distributed, discrete fiber bundles throughout the pathway, leading to spatially ordered groups of back-labeled thalamic cells. These results indicate that the topography of thalamic axons is maintained throughout the pathway and that they reach the cortex by associating with the projections of a number of preexisting cells, including the preplate scaffold.

Retinal axon guidance by region-specific cues in diencephalon.

Retinal axons show region-specific patterning along the dorsal-ventral axis of diencephalon: retinal axons grow in a compact bundle over hypothalamus, dramatically splay out over thalamus, and circumvent epithalamus as they continue toward the dorsal midbrain. In vitro, retinal axons are repulsed by substrate-bound and soluble activities in hypothalamus and epithalamus, but invade thalamus. The repulsion is mimicked by a soluble floor plate activity. Tenascin and neurocan, extracellular matrix molecules that inhibit retinal axon growth in vitro, are enriched in hypothalamus and epithalamus. Within thalamus, a stimulatory activity is specifically upregulated in target nuclei at the time that retinal axons invade them. These findings suggest that region-specific, axon repulsive and stimulatory activities control retinal axon patterning in the embryonic diencephalon.

Telencephalic connections in the Pacific hagfish (Eptatretus stouti), with special reference to the thalamopallial system.

The pallium of hagfishes (myxinoids) is unique: It consists of a superficial "cortical" mantle of gray matter which is subdivided into several layers and fields, but it is not clear whether or how these subdivisions can be compared to those of other craniates, i.e., lampreys and gnathostomes. The pallium of hagfishes receives extensive secondary olfactory projections (Wicht and Northcutt [1993] J. Comp. Neurol. 337:529-542), but there are no experimental data on its nonolfactory connections. We therefore investigated the pallial and dorsal thalamic connections of the Pacific hagfish. Injections of tracers into the pallium labeled many cells bilaterally in the olfactory bulbs. Other pallial afferents arise from the contralateral pallium, the dorsal thalamic nuclei, the preoptic region, and the posterior tubercular nuclei. Descending pallial efferents reach the preoptic region, the dorsal thalamus, and the mesencephalic tectum but not the motor or premotor centers of the brainstem. Injections of tracers into the dorsal thalamus confirmed the presence of reciprocal thalamopallial connections. In addition, these injections revealed that there is no "preferred" pallial target for the ascending thalamic fibers; instead, ascending thalamic and secondary olfactory projections overlap throughout the pallium. The mesencephalic tectum and tegmentum, which receive afferents from a variety of sensory sources, are interconnected with the dorsal thalamus; thus, ascending nonolfactory sensory information may reach myxinoid pallia via a tectal-thalamic-telencephalic route. A comparative analysis of pallial organization reveals that the subdivisions of the pallium in gnathostomes (i.e., medial, dorsal, and lateral pallia) cannot be recognized with certainty in hagfishes.

Some forebrain connections of the gustatory system in the goldfish Carassius auratus visualized by separate DiI application to the hypothalamic inferior lobe and the torus lateralis.

The neuroanatomical connections of the diencephalic torus lateralis and inferior lobe of the goldfish (Carassius auratus) were studied by retrograde and anterograde labeling with the carbocyanine dye DiI. Both structures have afferents originating in the central zone of the dorsal telencephalic area as well as in the supracommissural nucleus of the ventral telencephalic area, and in the secondary gustatory, tertiary gustatory, and posterior thalamic nuclei. Both structures investigated have efferents to the tertiary gustatory and posterior thalamic nuclei, as well as to the dorsal hypothalamus (dorsal hypothalamic neuropil) and superior reticular formation. The torus lateralis receives additional afferents from the secondary general visceral nucleus and, sparsely, from the dorsal tegmental nucleus. The inferior lobe receives additional afferents from the medial zone of the dorsal telencephalic area, as well as from the suprachiasmatic, posterior pretectal, central posterior thalamic, caudal preglomerular, two tegmental nuclei (T1 and T2), corpus mamillare, and, sparsely, from the cerebellar valvula. The inferior lobe has additional efferents to the dorsal and ventral thalamus and subglomerular nucleus. The lateral torus and inferior lobe are also mutually interconnected. The lateral torus and inferior lobe map topographically onto the vagal-related (intraoral) or onto the facial-related (extraoral) portions, respectively, of both the secondary and tertiary gustatory nuclei. Because the posterior thalamic nucleus is reciprocally connected with the lateral torus and inferior lobe and is further known to project in turn to the area doralis telencephali, it likely represents a quaternary gustatory projection nucleus to the telencephalon in cyprinids. Whereas the lateral torus seems to be exclusively involved with gustatory and general visceral systems, the inferior lobe has inputs from additional sensory (e.g., octavolateralis, visual) systems, and, thus, likely represents a multisensory integration center.