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Publications (67)
Introduction:
The hypocretinergic/orexinergic (Hcrt/Ox) system comprises two hypothalamic neuropeptides -Hcrt1/OxA and Hcrt2/OxB-, which differentially bind two receptors -Hcrt/OxR1 and Hcrt/OxR2-. Despite low cerebrospinal fluid (CSF)-Hcrt1/OxA concentration is a narcolepsy type1 biomarker, its releasing mechanism remains unknown. Hcrt/Ox-peptides...
The hypocretinergic/orexinergic (Hcrt/Ox) system is an hypothalamic neuromodulatory system comprising two excitatory neuropeptides -Hcrt1/OxA and Hcrt2/OxB-. Hcrt/Ox peptides are packaged in vesicles and transported close to plasma membrane along the axon to many target areas, including the oral pontine tegmentum (OPT), but their releasing mechanis...
The hypothalamic hypocretinergic/orexinergic (Hcrt/Ox) system is involved in many physiological and pathophysiological processes. Malfunction of Hcrt/Ox transmission results in narcolepsy, a sleep disease caused in humans by progressive neurodegeneration of hypothalamic neurons containing Hcrt/Ox.
To explore the Hcrt/Ox system plasticity we system...
Objectives/Introduction:
The hypothalamic hypocretinergic/orexinergic (Hcrt/Ox) system is involved in many physiological processes including sleep-wake cycle, and its malfunction is involved in narcolepsy. It acts through two G-protein-coupled receptors -Hcrt/OxR1 and Hcrt/OxR2- widely distributed throughout the central nervous system. In the pres...
Introduction: Autosomal Dominant Cerebellar Ataxia-Deafness and Narcolepsy (ADCA-DN, OMIM #604121) and Hereditary Sensory Neuropathy with Dementia and Hearing Loss (HSN-IE, OMIM #614116) are two neurodegenerative syndromes caused by dominant mutations in the replication foci targeting sequence on the DNA methyltransferase 1 gene. The wide spectrum...
Chronic adolescent administration of marijuana's major psychoactive compound, ∆9-tetrahydrocannabinol (Δ9-THC), produces adaptive changes in adult social and cognitive functions sustained by prelimbic prefrontal cortex (PL-PFC). Memory and learning processes in PL-PFC neurons can be regulated through cholinergic muscarinic-2 receptors (M2R) and mod...
Long-term cannabis use during adolescence has deleterious effects in brain that are largely ascribed to the activation of cannabinoid-1 receptors (CB1Rs) by delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive compound in marijuana. Systemic administration of ∆9-THC inhibits acetylcholine release in the prelimbic-prefrontal cortex (PL-PF...
The Locus Coeruleus (LC) is a pontine nucleus involved in many physiological processes, including the control of the sleep/wake cycle (SWC). At cellular level, the LC displays a high density of opioid receptors whose activation decreases the activity of LC noradrenergic neurons. Also, microinjections of morphine administered locally in the LC of th...
There is little information on either the transition state occurring between slow-wave sleep (SWS) and rapid eye movement (REM) sleep, as well as about its neurobiological bases. This transition state, which is known as the intermediate state (IS), is well-defined in rats but poorly characterized in cats. Previous studies in our laboratory demonstr...
Previous data indicate that the hypothalamic perifornical hypocretin neurons promote wakefulness by concurrent activation of dorsal pontine areas implicated in waking enhancement (locus coeruleus [LC]) and inhibition of ventral pontine areas implicated in REM sleep generation (oral pontine reticular nucleus [PnO]). Histamine neurons (HA), which are...
Muscarinic m2 receptors (M2Rs) are implicated in autoregulatory control of cholinergic output neurons located within the pedunculopontine (PPT) and laterodorsal tegmental (LTD) nuclei of the mesopontine tegmentum (MPT). However, these nuclei contain many non-cholinergic neurons in which activation of M2R heteroceptors may contribute significantly t...
Resumen
Objetivos: Determinar si en los individuos adultos sanos existe una apertura óptima del dinamómetro para conseguir la máxima fuerza de puño y si esta se relaciona con los valores de los parámetros antropométricos del antebrazo y la mano. Saber si a través de las medidas antropométricas del antebrazo y la mano es posible predecir la fuerza d...
Background
Hypocretins/orexins (Hcrt/Ox) are hypothalamic neuropeptides involved in sleep-wakefulness regulation. Deficiency in Hcrt/Ox neurotransmission results in the sleep disorder narcolepsy, which is characterized by an inability to maintain wakefulness. The Hcrt/Ox neurons are maximally active during wakefulness and project widely to the vent...
There is growing evidence that leptin is able to ameliorate Alzheimer's disease (AD)-like pathologies, including brain amyloid-β (Aβ) burden. In order to improve the therapeutic potential for AD, we generated a lentivirus vector expressing leptin protein in a self-inactivating HIV-1 vector (HIV-leptin), and delivered this by intra-cerebroventricula...
Introduction
GABA and its receptors are widely distributed in sleep-wakefulness cycle (SWC) network structures, but action of extrasynaptic GABAA receptors in SWC mechanisms is not yet fully understood. The cat has been extensively used in SWC research, but to our knowledge there are no previous studies about the response of this species to the adm...
The perifornical area in the posterior lateral hypothalamus (PeFLH) has been implicated in several physiological functions including the sleep-wakefulness regulation. The PeFLH area contains several cell types including those expressing orexins (Orx; also known as hypocretins), mainly located in the PeF nucleus. The aim of the present study was to...
Muscarinic modulation of mesolimbic dopaminergic neurons in the ventral tegmental area (VTA) plays an important role in reward, potentially mediated through the M5 muscarinic acetylcholine receptor (M5R). However, the key sites for M5R mediated control of dopamine neurons within this region are still unknown. To address this question we examined th...
Alpha7 nicotinic acetylcholine receptors (α7nAChRs) mediate nicotine-induced burst-firing of dopamine neurons in the ventral tegmental area (VTA), a limbic brain region critically involved in reward and in dopamine D2 receptor (D2R)-related cortical dysfunctions associated with psychosis. The known presence of α7nAChRs and Gi-coupled D2Rs in dopami...
The state of non-REM sleep (NREM), or slow wave sleep, is associated with a synchronized EEG pattern in which sleep spindles and/or K complexes and high-voltage slow wave activity (SWA) can be recorded over the entire cortical surface. In humans, NREM is subdivided into stages 2 and 3–4 (presently named N3) depending on the proportions of each of t...
The wakefulness (W) phase of the SWC in humans usually happens during the day. Only during W are we aware of ourselves and
our environment; that is, only during W do we feel, think, and work in full knowledge of what we do and fully use our senses
and faculties. During W is when we properly process all the information that reaches the thalamus and...
Wakefulness (W) is necessary for a thoughtful and precise knowledge of things, allowing us to recognize our essential attributes and the changes that we experience in ourselves. We spend about two-thirds of our life in W. This state is circadian and homeostatically regulated and precisely meshed with sleep into the sleep–wakefulness cycle (SWC). Sl...
The Hypocretin1/OrexinA (Hcrt1/OxA) neuropeptides are found in a group of posterolateral hypothalamus neurons and are involved in sleep-wakefulness cycle regulation. Hcrt1/OxA neurons project widely to brainstem aminergic structures, such as the locus coeruleus (LC), which are involved in maintenance of wakefulness and EEG activation through intens...
Cortical activation and goal-directed behaviors characterize wakefulness. One cortical region especially involved in these phenomena is the medial prefrontal cortex (mPFC), which receives many inputs from cholinergic-containing neurons in brain stem structures implicated in arousal and wakefulness, such as the laterodorsal tegmental nucleus (LDT)....
From the first bioelectric description by Berger (1929), which characterized W as an EEG of fast, low voltage waves (later
called activated or desynchronized EEG) and sleep as an EEG of slow, high voltage waves (later called synchronized EEG), experimental
researchers have looked for the brain structures responsible for the synchronization or activ...
The glutamate-glutamine cycle faces a drain of glutamate by oxidation, which is balanced by the anaplerotic synthesis of glutamate and glutamine in astrocytes. De novo synthesis of glutamate by astrocytes requires an amino group whose origin is unknown. The deficiency in Aralar/AGC1, the main mitochondrial carrier for aspartate-glutamate expressed...
Tesis doctoral inédita realizada en la Universidad Autónoma de Madrid. Facultad de Medicina, Departamento de Anatomía Humana y Neurociencia. Fecha de lectura: 22 de Noviembre de 2010.
Sleep is a necessary, diverse, periodic, and an active condition circadian and homeostatically regulated and precisely meshed with waking time into the sleep-wakefulness cycle (SWC). Photic retinal stimulation modulates the suprachiasmatic nucleus, which acts as the pacemaker for SWC rhythmicity. Both the light period and social cues adjust the int...
Increasing evidence has implicated megalin, a low-density lipoprotein receptor-related protein, in the pathogenesis of Alzheimer's disease (AD). In the brain, megalin is expressed in brain capillaries, ependymal cells and choroid plexus, where it participates in the clearance of brain amyloid β-peptide (Aβ) complex. Recently, megalin has also been...
The medial prefrontal cortex (mPFC) is strongly involved in cognition and behavior. It receives input from brainstem nuclei implicated in behavioral wakefulness and electrographic cortical activation, such as the dorsal raphe nucleus (DRN). Moreover, the hypocretinergic/orexinergic (Hcrt/Ox) hypothalamic neurons innervate DRN, thus modulating its a...
The ventral part of the oral pontine reticular nucleus (vRPO) is a nodal link in the neuronal network responsible for the generation and maintenance of rapid eye movement (REM) sleep and is reciprocally connected with structures involved in the control of wakefulness and non-REM (NREM) sleep. Shifting from one sleep state to another depends on the...
The present study describes at the ultrastructural level the hypocretinergic innervation of brainstem reticular formation neurons that project to the medial frontal cortex in the rat. In addition, we assess, by using dual immunofluorescence techniques, the proportion of those reticular neurons containing specific neurotransmitters. Our results indi...
Hypocretins or orexins (Hcrt/Orx) are hypothalamic neuropeptides that are synthesized by neurons located mainly in the perifornical area of the posterolateral hypothalamus. These hypothalamic neurons are the origin of an extensive and divergent projection system innervating numerous structures of the central nervous system. In recent years it has b...
Hypocretinergic/orexinergic neurons, which are known to be implicated in narcolepsy, project to the pontine tegmentum areas involved in the control of rapid eye movement (REM) sleep. Here, we report the effects on sleep-wakefulness produced by low-volume microinjections of hypocretin (Hcrt)1 (20-30 nL, 100, 500 and 1000 microm) and carbachol (20-30...
We recently identified the thalamic dopaminergic system in the human and macaque monkey brains, and, based on earlier reports on the paucity of dopamine in the rat thalamus, hypothesized that this dopaminergic system was particularly developed in primates. Here we test this hypothesis using immunohistochemistry against the dopamine transporter (DAT...
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 eit...
The ventral division of the reticular oral pontine nucleus (vRPO) is a pontine tegmentum region critically involved in REM sleep generation. Previous reports of morphine microinjections in the cat pontine tegmentum have shown that opioid receptor activation in this region modulates REM sleep. Even though opiate administration has marked effects on...
The perifornical (PeF) area in the posterior lateral hypothalamus has been implicated in several physiological functions including the regulation of sleep-wakefulness. Some PeF neurons, which contain hypocretin, have been suggested to play an important role in sleep-wake regulation. The aim of the present study was to examine the effect of the PeF...
Acetylcholine can affect cognitive functions and reward, in part, through activation of muscarinic receptors in the ventral tegmental area (VTA) to evoke changes in mesocorticolimbic dopaminergic transmission. Among the known muscarinic receptor subtypes present in the VTA, the M2 receptor (M2R) is most implicated in autoregulation and also may pla...
Enkephalin (ENK) immunoreactivity is widely distributed in the ventral tegmental area (VTA), where endogenous ENK and dynorphin opioid peptides are known to have opposing actions in reward, stress, cognition, and fear-related behaviors. Many neurons in the VTA give rise to mesocortical projections terminating in the medial prefrontal cortex (mPFC),...
We employed polygraphic recordings and behavioral measures to study the effects of chronic morphine use upon the isolated forebrain and the decerebrate animal in cats with a midbrain transection. Cats received morphine for 12 days, and 24 h recording sessions were conducted on days 1 and 11. For the decerebrate cat, the percent time of rapid eye mo...
To determine whether the brain stem can independently support the processes of rapid eye movement sleep rebound and pressure that follow deprivation.
Cats with a brain-stem separation from the forebrain were compared to intact subjects on their response to rapid eye movement sleep deprivation.
Eight adult mongrel cats of both sexes.
All cats had el...
Enkephalins are endogenous ligands for opioid receptors whose activation potently modulates the output of mesocorticolimbic dopaminergic neurons within the ventral tegmental area. Many of the reinforcing effects of enkephalins in the mesocorticolimbic system are mediated by mu-opioid receptors. To determine the sites for Leu(5)-enkephalin activatio...
Neuronal arborizations that were so elegantly demonstrated in the early drawings of Santiago Ramón y Cajal can now be viewed by high resolution electron microscopic immunocytochemical localization of vesicular and plasmalemmal neurotransmitter transporters and receptors. The subcellular distribution of these proteins confers both chemical selectivi...
Opiate-evoked reward and motivated behaviors reflect, in part, the enhanced release of dopamine produced by activation of the μ-opioid receptor (μOR) in the ventral tegmental area (VTA). We examined the functional sites for μOR activation and potential interactions with dopaminergic neurons within the rat VTA by using electron microscopy for the im...
Mesocorticolimbic projections originating from dopaminergic and GABAergic neurons in the ventral tegmental area (VTA) play a critical role in opiate addiction. Activation of μ-opioid receptors (MOR), which are located mainly within inhibitory neurons in the VTA, results in enhanced dopaminergic transmission in target regions, including the medial p...
This article reviews the central nervous mechanisms involved in the broad network that generates and maintains REM sleep. Experimental investigations have identified the pontine tegmentum as the critical substrate for REM sleep mechanisms. Several pontine structures are involved in the generation of each particular polygraphic event that characteri...
Autoregulation of cholinergic neurons in the laterodorsal tegmental (LDT) and pedunculopontine (PPT) nuclei has been implicated in many functions, most importantly in drug reinforcement and in the pathophysiology of schizophrenia. This autoregulation is attributed to the release of acetylcholine, but neither the storage or release sites are known....
Cholinergic activation of dopaminergic neurons in the ventral tegmental area (VTA) is thought to play a major role in cognitive functions and reward. These dopaminergic neurons differentially project to cortical and limbic forebrain regions, where their terminals differ in levels of expression of the plasmalemmal dopamine transporter (DAT). This tr...
Most neuroscientists today agree that the richest and best structured dreams occur during REM sleep. In fact, the structures responsible for REM sleep, the anatomy of which is controversial, are necessary for normal dreams. The pontine tegmentum structures with a definite role in the control of different events characterizing REM sleep (EEG activat...
This study examines dose-related effects on sleep produced by low-volume and low-dose carbachol microinjections in the ventral part of the cat nucleus reticularis pontis oralis. Carbachol microinjections (0.04, 0.08, 0.8 or 4 microg; volume 20 nl) in this location triggered paradoxical sleep with a very short dose-unrelated latency. The four carbac...
Neocortical and hippocampal EEG power spectra obtained during REM-like sleep induced by unilateral carbachol microinjections (0.01 M, 0.02 M and 0.2 M; volume 20 nl) into the ventral part of the nucleus reticularis pontis oralis have been compared with EEG power spectra obtained during spontaneous REM sleep. Our findings indicate that neocortical a...
The effects on sleep/wakefulness states of morphine, morphiceptin (specific mu agonist), DPDPE (delta agonist) and U-50,488H (kappa agonist) microinjections in the Locus coeruleus area (LC) were studied in cats. Morphine (0.8-1.75 nmols in 50 nl of saline) and morphiceptin (1.75 nmols) in LC significantly increased the total time spent in slow wave...
