PHYSIOLOGICAL REVIEW ARTICLE: Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons

doi:10.1053/smrv.2000.0116

Sleep Medicine Reviews

Volume 4, Issue 5, October 2000, Pages 471-503

https://doi.org/10.1053/smrv.2000.0116 Get rights and content

Abstract

Wakefulness is a functional brain state that allows the performance of several “high brain functions”, such as diverse behavioural, cognitive and emotional activities. Present knowledge at the whole animal or cellular level suggests that the maintenance of the cerebral cortex in this highly complex state necessitates the convergent and divergent activity of an ascending network within a large reticular zone, extending from the medulla to the forebrain and involving four major subcortical structures (the thalamus, basal forebrain, posterior hypothalamus and brainstem monoaminergic nuclei), their integral interconnections and several neurotransmitters, such as glutamate, acetylcholine, histamine and noradrenaline. In this mini-review, the importance of the thalamus, basal forebrain and brainstem monoÍaminergic neurons in wake control is briefly summarized, before turning our attention to the posterior hypothalamus and histaminergic neurons, which have been far less studied. Classical and recent experimental data are summarized, supporting the hypothesis that (1) the posterior hypothalamus constitutes one of the brain ascending activating systems and plays an important role in waking; (2) this function is mediated, in part, by histaminergic neurons, which constitute one of the excitatory sources for cortical activation during waking; (3) the mechanisms of histaminergic arousal involve both the ascending and descending projections of histaminergic neurons and their interactions with diverse neuronal populations, such as neurons in the pre-optic area and cholinergic neurons; and (4) other widespread-projecting neurons in the posterior hypothalamus also contribute to the tonic cortical activation during wakefulness and/or paradoxical sleep.

References (106)

G Moruzzi et al.
Brainstem reticular formation and activation of the EEG
Electroenceph Clin Neurophysiol
(1949)
DA McCormick
Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity
Prog Neurobiol
(1992)
M Denoyer et al.
Neurotoxic lesion of the mesencephalic reticular formation and/or the posterior hypothalamus does not alter waking in the rat
Brain Res
(1991)
CH Vanderwolf et al.
Thalamic control of neocortical activation: a critical reevaluation
Brain Res Bull
(1988)
A Khateb et al.
Cholinergic nucleus basalis neurons are excited by histamine in vitro
Neuroscience
(1995)
R Szymusiak et al.
Sleep suppression following kainic acid-induced lesions of the basal forebrain
Exp Neurol
(1986)
DJ McGinty et al.
Dorsal raphe neurons: depression of firing during sleep in cats
Brain Res
(1976)
BE Jones et al.
The effects of lesions of catecholamine containing neurons upon monoamine content of the brain and EEG and behavioral waking in the cat
Brain Res
(1973)
BE Jones et al.
Effects of locus coeruleus lesions upon cerebral monoamine content, sleep–wakefulness states and the response to amphetamine in the cat
Brain Res
(1977)
HC Dringenberg et al.
Involvement of direct and indirect pathways in electroÍcorticographic activation
Neurosci Behav Rev
(1998)

CB Saper

Lateral hypothalamic innervation of the cerebral cortex: immunoreactive staining for a peptide resembling but immunochemically distinct from pituitary/arcuate α-melanocyte stimulating hormone

Brain Res Bull

(1986)

RM Chemelli et al.

Narcolepsy in orexin knockout mice: molecular genetics of sleep regulation

Cell

(1999)

T Watanabe et al.

Distribution of histaminergic system in the central nervous system of rats: a fluorescent immunohistochemical analysis with histidine decarboxylase as a marker

Brain Res

(1984)

Y Yoshimoto et al.

Forebrain afferents to the cat posterior hypothalamus: a double labeling study

Brain Res Bull

(1989)

K Sakai et al.

Lower brainstem afferents to the cat posterior hypothalamus: a double labeling study

Brain Res Bull

(1990)

CL Wilson et al.

Influences of hypothalamic stimulation upon septal and hippocampal electrical activity in the cat

Brain Res

(1976)

JS Lin et al.

A critical role of the posterior hypothalamus in the mechanisms of wakefulness determined by microinjection of muscimol in freely moving cats

Brain Res

(1989)

M Sallanon et al.

Long-lasting insomnia induced by preoptic neuron lesions and its transient reversal by muscimol injection into the posterior hypoÍthalamus in the cat

Neuroscience

(1989)

JS Lin et al.

Role of catecholamines in the modafinil and amphetamine induced wakefulness, a comparative pharmacological study in the cat

Brain Res

(1992)

A Shekhar et al.

Defense reaction elicited by injection of GABA antagonists and synthesis inhibitors into the posterior hypothalamus in rats

Neuropharmacology

(1987)

TG Waldrop et al.

Microinjection of GABA antagonists into the posterior hypothalamus elicits locomotor activity and a cardiorespiratory activation

Brain Res

(1988)

RM Bauer et al.

A GABAergic mechanism in the posterior hypothalamus modulates baroreflex bradycardia

Brain Res

(1988)

SE Spencer et al.

L-glutamate mapping of cardioreactive areas in the rat posterior hypothalamus

Brain Res

(1990)

L Lin et al.

The sleep disorder canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene

Cell

(1999)

LB Hough

Cellular localization and possible functions for brain histamine: recent progress

Progr Neurobiol

(1988)

ML Vizuete et al.

Detailed mapping of the histamine H2 receptor and its gene transcripts in guinea-pig brain

Neuroscience

(1997)

T Mochizuki et al.

Circadian rhythm of histamine release from the hypothalamus of freely moving rat

Physiol Behav

(1992)

PB Reiner et al.

Mechanisms of antihistamine-induced sedation in the human brain: H₁receptor activation reduces a background leakage potassium current

Neuroscience

(1994)

A Khateb et al.

Histamine excites pedunculopontine neurones in guinea pig brainstem slices

Neurosci Lett

(1990)

VS Vorobjev et al.

Histamine potentiates N-Methyl-D-Aspartate responses in acutely isolated hippocampal neurons

Neuron

(1993)

JS Lin et al.

Evidence for histaminergic arousal mechanisms in the hypothalamus of cats

Neuropharmacology

(1988)

JS Lin et al.

Involvement of histaminergic neurons in arousal mechanisms demonstrated with H₃-receptor ligands in the cat

Brain Res

(1990)

JM Monti et al.

Effects of selective activation or blockade of the histamine H₃-receptor on sleep and wakefulness

Eur J Pharmacol

(1991)

F Bremer

Cerveau “isolé” et physiologie du sommeil

C R Soc Biol (Paris)

(1935)

M Jouvet

The role of monoamines and acetylcholine containing neurons in the regulation of the sleep–waking cycle

Ergebn Physiol

(1972)

G Moruzzi

The sleep–waking cycle

Ergeb Physiol

(1972)

Steriade, M, Alertness, quiet sleep, dreaming. In: Peters A (ed.). Cerebral Cortex, Vol. 9. New York: Plenum Publishing...

Steriade, M, Buzsaki, G, Parallel activation of thalamic and cortical neurons by brainstem and basal forebrain...

Jones, BE, Basic mechanisms of sleep–wake states. In: Kryger MH, Roth T, Dement WC (eds). Principles and Practice of...

Jones, BE, Mühlethaler, M, Cholinergic and GABAergic neurons of the basal forebrain: role in cortical activation. In:...

M Steriade et al.

Thalamocortical oscillations in the sleeping and aroused brain

Science

(1993)

F Angeleri et al.

Effects of chronic thalamic lesion on the electrical activity of the neocortex and on sleep

Arch Ital Biol

(1969)

Villablanca, J, Role of the thalamus in sleep control: sleep–wakefulness in chronic diencephalic and athalamic cats....

G Buzsaki et al.

Nucleus basalis and thalamic control of neocortical activity in the freely moving rat

J Neurosci

(1988)

CCD Shute et al.

The ascending cholinergic reticular system: neocortical, olfactory and subcortical projections

Brain

(1967)

Jones, BE, The organization of central cholinergic systems and their functional importance in sleep–waking states. In:...

F Belardetti et al.

Prosencephalic mechanisms of ECoG desynchronization in cerveau isolé cats

Electroenceph Clin Neurophysiol

(1977)

F Casamenti et al.

Changes in cortical acetylcholine output induced by modulation of the nucleus basalis

Brain Res Bull

(1986)

TF Freund et al.

γ-Aminobutyric acid-containing basal forebrain neurons innervate inhibitory interneurons in the neocortex

Proc Natl Acad Sci USA

(1992)

Lin, JS, Système histaminergique central et les états de vigilance chez le chat. Thèse de Doctorat d»Etat es Sciences....

Cited by (227)

Etiologies of insomnia in Parkinson's disease – Lessons from human studies and animal models
2022, Experimental Neurology
Citation Excerpt :
Exerting an excitatory input that is highly specific to wakefulness, they are strategically positioned to drive cortical activation (Lin et al., 2011). Indeed, a large body of work demonstrates their role in maintaining normal wakefulness (Lin, 2000; Parmentier et al., 2002). Although Lewy bodies and Lewy neurites are found in the TMN in PD, neuronal histamine production is not affected by PD (Shan et al., 2012), histaminergic neurons themselves do not appear to degenerate (Nakamura et al., 1996) and the level of histamine synthesis, as judged by the mRNA levels of the rate-limiting enzyme, L-histidine decarboxylase, is not different between PD and controls (Garbarg et al., 1983).
Sleep disorders are integral to Parkinson's disease (PD). Insomnia, an inability to maintain stable sleep, affects most patients and is widely rated as one of the most debilitating facets of this disease. PD insomnia is often perceived as a multifactorial entity – a consequence of several of the disease symptoms, comorbidities and therapeutic strategies. Yet, this view evolved against a backdrop of a relative scarcity of works trying to directly dissect the underlying neural correlates and mechanisms in animal models. The last years have seen the emergence of a wealth of new evidence regarding the neural underpinnings of insomnia in PD. Here, we review early and recent reports from patients and animal models evaluating the etiology of PD insomnia. We start by outlining the phenomenology of PD insomnia and continue to analyze the evidence supporting insomnia as emanating from four distinct subdivisions of etiologies – the symptoms and comorbidities of the disease, the medical therapy, the degeneration of non-dopaminergic cell groups and subsequent alterations in circadian rhythms, and the degeneration of dopaminergic neurons in the brainstem and its resulting effect on the basal ganglia. Finally, we review emerging neuromodulation-based therapeutic avenues for PD insomnia.
Attachment Style Moderates Polygenic Risk for Incident Posttraumatic Stress in U.S. Military Veterans: A 7-Year, Nationally Representative, Prospective Cohort Study
2022, Biological Psychiatry
Posttraumatic stress disorder (PTSD) develops consequent to complex gene-by-environment interactions beyond the precipitating trauma. To date, however, no known study has used a prospective design to examine how polygenic risk scores (PRSs) interact with social-environmental factors such as attachment style to predict PTSD development.
PRSs were derived from a genome-wide association study of PTSD symptoms (N = 186,689; Million Veteran Program cohort). We evaluated combined effects of PRS and attachment style in predicting incident PTSD in a 7-year, nationally representative cohort of trauma-exposed, European-American U.S. military veterans without PTSD (N = 1083). We also conducted multivariate gene-by-environment interaction and drug repositioning analyses to identify loci that interact with multiple environmental factors and potential pharmacotherapies that may be repurposed for this disorder.
Veterans with higher PTSD PRS were more likely to have an incident-positive screen for PTSD over 7 years. A gene-by-environment interaction was also observed, such that higher PRS only predicted incident PTSD in veterans with an insecure attachment style and not those with a secure attachment style. At an individual locus level, the strongest gene-by-environment interaction was observed for the rs4702 variant of the FURIN gene with cumulative lifetime trauma burden. Drug repositioning revealed that genes implicated in PRS are perturbated by the drug doxylamine.
Attachment style moderates polygenic risk for the development of PTSD in European-American veterans. These findings may inform PTSD prevention and treatment for veterans with high polygenic risk for PTSD and suggest a potential pharmacotherapeutic target for risk genes moderated by social-environmental factors.
Systemic mastocytosis: The roles of histamine and its receptors in the central nervous system disorders
2021, Journal of the Neurological Sciences
Mastocytosis is a rare disease of clonal hematological disorders characterized by a pathological accumulation of Mast Cells (MCs) in different tissues, with variable symptomatology and prognosis.
Signs and symptoms of Systemic Mastocytosis (SM) are due to pathological infiltration of MCs and to the release of chemical mediators, mainly histamine.
Patients with SM may also present with neurological symptoms or complications.
The pathophysiology of these neurological disorders remains uncertain to this day, but it can be associated with the infiltration of tissue mastocytes, release of mastocytes' mediators or both.
Moreover, there is a lot to understand about the role of neurological symptoms in SM and knowing, for example, what is the real frequency of neurological disorders in SM and if is present a relation between other SM subtypes, because it has been noted that the alteration of the histamine expression may be an initiating factor for susceptibility, gravity and progression of the epigenetic disease.
In this review we explain the possible pathophysiological mechanism about neurological symptomatology found in some patients affected by SM, describing the role of histamine and its receptors in the nervous system and, in light of the results, what the future prospects may be for a more specific course of treatment.
The tuberomamillary nucleus in neuropsychiatric disorders
2021, Handbook of Clinical Neurology
The tuberomamillary nucleus (TMN) is located within the posterior part of the hypothalamus. The histamine neurons in it synthesize histamine by means of the key enzyme histidine decarboxylase (HDC) and from the TMN, innervate a large number of brain areas, such as the cerebral cortex, hippocampus, amygdala as well as the thalamus, hypothalamus, and basal ganglia. Brain histamine is reduced to an inactivated form, tele-methylhistamine (t-MeHA), by histamine N-methyltransferase (HMT). In total, there are four types of histamine receptors (H_1–4Rs) in the brain, all of which are G-protein coupled.
The histaminergic system controls several basal physiological functions, including the sleep–wake cycle, energy and endocrine homeostasis, sensory and motor functions, and cognitive functions such as attention, learning, and memory. Histaminergic dysfunction may contribute to clinical disorders such as Parkinson's disease, Alzheimer's disease, Huntington's disease, narcolepsy type 1, schizophrenia, Tourette syndrome, and autism spectrum disorder.
In the current chapter, we focus on the role of the histaminergic system in these neurological/neuropsychiatric disorders. For each disorder, we first discuss human data, including genetic, postmortem brain, and cerebrospinal fluid studies. Then, we try to interpret the human changes by reviewing related animal studies and end by discussing, if present, recent progress in clinical studies on novel histamine-related therapeutic strategies.
The role of the orexin system in stress response
2019, Neuropharmacology
Orexins are neuropeptides that are exclusively produced by hypothalamic neurons, which project throughout the entire brain. Orexin, also known as hypocretins, were initially identified to play a fundamental role in food intake, arousal and the regulation of sleep and wakefulness. Recent studies identified orexins to be critical for diverse physiological processes including motivation, reward, attention, emotional regulation, stress and anxiety. Here, I review recent findings that indicate orexin has an important role in acute and chronic stress. I also summarize the recent optogenetic and chemogenetic studies that have advanced our understanding of the orexin system. I will conclude by discussing clinical studies that implicate orexins in mental health disorders.
This article is part of the Special Issue entitled ‘Hypothalamic Control of Homeostasis’.
The unfinished journey with modafinil and discovery of a novel population of modafinil-immunoreactive neurons
2018, Sleep Medicine
Modafinil, a wake-promoting compound now used worldwide in sleep medicine, was initially regarded as a sedative compound because mice were so quiet with respect to locomotion after receiving it that this behavioral state was qualified as sedation. In the early 1980's when modafinil was first assessed by polysomnography in a cat in our laboratory, surprisingly, the cat spent the whole night awake without even one minute of sleep! This initial observation resulted subsequently in a series of basic and clinical studies in order to define the pharmacological profile of modafinil and its mode of action and, notably, to identify the brain targets by which modafinil acts to promote wakefulness. These studies were undertaken using pharmacologic approach coupled with the Cerveau isolé (brain transection) preparation, c-fos labelling and knockout mouse models. It was also in this context that we have developed a purified polyclonal antibody against modafinil. We expected that using immunohistochemistry with this antibody would allow us to localize the brain distribution of modafinil dosing. Surprisingly, we found discrete modafinil immunoreactive neuronal populations in several brain areas of modafinil-naive cats, rodents and humans. The most numerous and intensely labeled modafinil-immunoreactive neurons characterized by granular staining were found in the basal forebrain. They shared the regional location with cholinergic and aspartate-containing neurons but did not colocalize with them. In summary, we here present a newly identified neuronal population located in the basal forebrain that has never previously been published and suggests that these modafinil-immunoreactive neurons might be involved in forebrain functions such as sleep-wake control and cognition. This paper briefly reviews our journey with modafinil research and presents new unpublished experimental data.

View all citing articles on Scopus

^f1: Correspondence should be addressed to: J. S. Lin. Fax: +33 478 77 71 72; Email: lin@univ- lyon1.fr

View full text

Physiological Review ArticlePHYSIOLOGICAL REVIEW ARTICLE: Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons

Abstract

Electroenceph Clin Neurophysiol

Prog Neurobiol

Brain Res

Brain Res Bull

Neuroscience

Exp Neurol

Brain Res

Brain Res

Brain Res

Neurosci Behav Rev

Brain Res Bull

Cell

Brain Res

Brain Res Bull

Brain Res Bull

Brain Res

Brain Res

Neuroscience

Brain Res

Neuropharmacology

Brain Res

Brain Res

Brain Res

Cell

Progr Neurobiol

Neuroscience

Physiol Behav

Neuroscience

Neurosci Lett

Neuron

Neuropharmacology

Brain Res

Eur J Pharmacol

Cerveau “isolé” et physiologie du sommeil

C R Soc Biol (Paris)

The role of monoamines and acetylcholine containing neurons in the regulation of the sleep–waking cycle

Ergebn Physiol

The sleep–waking cycle

Ergeb Physiol

Thalamocortical oscillations in the sleeping and aroused brain

Science

Effects of chronic thalamic lesion on the electrical activity of the neocortex and on sleep

Arch Ital Biol

Nucleus basalis and thalamic control of neocortical activity in the freely moving rat

J Neurosci

The ascending cholinergic reticular system: neocortical, olfactory and subcortical projections

Brain

Prosencephalic mechanisms of ECoG desynchronization in cerveau isolé cats

Electroenceph Clin Neurophysiol

Changes in cortical acetylcholine output induced by modulation of the nucleus basalis

Brain Res Bull

γ-Aminobutyric acid-containing basal forebrain neurons innervate inhibitory interneurons in the neocortex

Proc Natl Acad Sci USA

Physiological Review Article
PHYSIOLOGICAL REVIEW ARTICLE: Brain structures and mechanisms involved in the control of cortical activation and wakefulness, with emphasis on the posterior hypothalamus and histaminergic neurons