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Hypothalamic hamartomas (HH) are rare, basilar developmental lesions with widespread comorbidities often associated with refractory epilepsy and encephalopathy. Imaging advances allow for early, even prenatal, detection. Genetic studies suggest mutations in GLI3 and other patterning genes are involved in HH pathogenesis. About 50%–80% of children with HH have severe rage and aggression and a majority of patients exhibit externalizing disorders. Behavioral disruption and intellectual disability may predate epilepsy. Neuropsychological, sleep, and endocrine disorders are typical. The purpose of this article is to provide a summary of the current understanding of HH and to highlight opportunities for future research.

The preoptic area (POA) is a key brain region for regulation of body temperature (Tb), dictating thermogenic, cardiovascular, and behavioral responses that control Tb. Previously characterized POA neuronal populations all reduced Tb when activated. Using mice, we now identify POA neurons expressing bombesin-like receptor 3 (POA(BRS3)) as a population whose activation increased Tb; inversely, acute inhibition of these neurons reduced Tb. POA(BRS3) neurons that project to either the paraventricular nucleus of the hypothalamus or the dorsomedial hypothalamus increased Tb, heart rate, and blood pressure via the sympathetic nervous system. Long-term inactivation of POA(BRS3) neurons caused increased Tb variability, overshooting both increases and decreases in Tb set point, with RNA expression profiles suggesting multiple types of POA(BRS3) neurons. Thus, POA(BRS3) neuronal populations regulate Tb and heart rate, contribute to cold-defense, and fine-tune feedback control of Tb. These findings advance understanding of homeothermy, a defining feature of mammalian biology.

There has been an explosion recently in our understanding of the neuronal populations in the preoptic area involved in thermoregulation of mice. Recent studies have identified several genetically specified populations of neurons predominantly in the median preoptic nucleus (MnPO) but spreading caudolaterally into the preoptic area that regulate body temperature. . These include warm-responsive neurons that express the peptides PACAP, BDNF, or QRFP; and receptors for temperature, leptin, estrogen, or prostaglandin E2 (PGE2). These neurons are predominantly glutamatergic and driving them opto- or chemogenetically can cause profound hypothermia, and in some cases, periods of torpor or a hibernation-like state. Conversely, fever response is likely to depend upon inhibiting the activity of these neurons through the PGE2 receptor EP3. Another cell group, the Brs3-expressing MnPO neurons, are apparently cold-responsive and cause increases in body temperature. MnPO-QRFP neurons cause hypothermia via activation of their terminals in the region of the dorsomedial nucleus of the hypothalamus (DMH). As the MnPO-QRFP neurons are essentially glutamatergic, and the DMH largely uses glutamatergic projections to the raphe pallidus to increase body temperature, this model suggests the existence of local inhibitory interneurons in the DMH region between the MnPO-QRFP glutamatergic neurons that cause hypothermia and the DMH glutamatergic neurons that cause hyperthermia. The new genetically targeted studies in mice provide a way to identify the precise neuronal circuitry that is responsible for our physiological observations in this species, and will suggest critical experiments that can be undertaken to compare these with the thermoregulatory circuitry in other species.

Homeostasis is a widely used term in physiology that is broadly defined as the maintenance of internal physiological conditions in the face of altered environmental conditions. Conditions which are normally homeostatically maintained include body weight, blood glucose, body temperature, sleep, and thyroid hormone economy, among others. The coining of the term homeostasis is largely credited to Walter Cannon and was outlined in his famous book The Wisdom of the Body. Cannon’s work extended the concepts set forth around the turn of the twentieth century. Prominent among these early pioneers was Claude Bernard and his seminal work outlining the concept of “milieu interieur” (interior milieu). These fundamental concepts are now widely accepted in the fields of neuroscience, endocrinology, and medicine. Indeed maintenance of homeostasis is critical and allows mammals to survive periods of environmental stressors such as starvation, ultimately permitting the species to reproduce. The nervous system, in particular the hypothalamus, is responsible for maintaining homeostasis. As we outline in this chapter, the hypothalamus does this through a number of mechanisms. In a broad sense, the hypothalamus can be

Nearly 14% of Americans experience chronic circadian disruption due to shift work, increasing their risk of obesity, diabetes, and other cardiometabolic disorders. These disorders are also exacerbated by modern eating habits such as frequent snacking and consumption of high-fat foods.We investigated the effects of recurrent circadian disruption (RCD) on glucose metabolism in C57BL/6 mice and in human participants exposed to non-24-h light-dark (LD) schedules vs. those on standard 24-h LD schedules. These LD schedules were designed to induce circadian misalignment between behaviors including rest/activity and fasting/eating with the output of the near-24-h central circadian pacemaker, while minimizing sleep loss, and were maintained for 12 weeks in mice and 3 weeks in humans. We examined interactions of these circadian-disrupted schedules compared to control 24-h schedules with a lower-fat diet (LFD, 13% in mouse and 25-27% in humans) and high-fat diet (HFD, 45% in mouse and 45-50% in humans). We also used young vs. older mice to determine whether they would respond differently to RCD.When combined with a HFD, we found that RCD caused significant weight gain in mice and increased body fat in humans, and significantly impaired glucose tolerance and insulin sensitivity in both mice and humans, but this did not occur when RCD was combined with a LFD. This effect was similar in both young and older mice.These results in both humans and a model organism indicate that circadian disruption has an adverse effect on metabolism among individuals eating a high-fat Western-style diet, even in the absence of significant sleep loss, and suggest that reducing dietary fat may protect against the metabolic consequences of a lifestyle (such as shift work) that involves chronic circadian disruption.

The intermediate nucleus of Brockhaus (INH), also known as the interstitial nucleus of the anterior hypothalamus-1 of Allen and Gorski (INAH-1), the sexually dimorphic nucleus of Swaab and colleagues (SDN), and the ventrolateral preoptic nucleus of Saper and colleagues (VLPO), is a cluster of largely galanin-expressing neurons in the lateral preoptic area, at the level of the crossing of the anterior commissure and dorsal to the supraoptic nucleus. The number of Nissl-stained neurons in the INH has been reported to be larger in men than women and to decrease with aging, although these findings have been controversial, in part because of differences in patient populations and methods used to assess the nucleus. However, recent studies have confirmed that the number of galanin-immunoreactive INH neurons is larger in men than women and decreases with age and have reported further loss with Alzheimer disease. The galanin-immunoreactive VLPO neurons have been thought to drive sleep behavior in many species, and their numbers in older humans correlate with the amount of consolidated sleep they experience. Sleep differences between men and women, during aging, and with Alzheimer disease may also depend upon the integrity of this nucleus.

The histaminergic neurons of the tuberomammillary nucleus (TMNHDC) of the posterior hypothalamus have long been implicated in promoting arousal. More recently, a role for GABAergic signaling by the TMNHDCneurons in arousal control has been proposed. Here, we investigated the effects of selective chronic disruption of GABA synthesis (via genetic deletion of the GABA synthesis enzyme, glutamic acid decarboxylase 67) or GABAergic transmission (via genetic deletion of the vesicular GABA transporter (VGAT)) in the TMNHDCneurons on sleep–wake in male mice. We also examined the effects of acute chemogenetic activation and optogenetic inhibition of TMNHDCneurons upon arousal in male mice. Unexpectedly, we found that neither disruption of GABA synthesis nor GABAergic transmission altered hourly sleep–wake quantities, perhaps because very few TMNHDCneurons coexpressed VGAT. Acute chemogenetic activation of TMNHDCneurons did not increase arousal levels above baseline but did enhance vigilance when the mice were exposed to a behavioral cage change challenge. Similarly, acute optogenetic inhibition had little effect upon baseline levels of arousal. In conclusion, we could not identify a role for GABA release by TMNHDCneurons in arousal control. Further, if TMNHDCneurons do release GABA, the mechanism by which they do so remains unclear. Our findings support the view that TMNHDCneurons may be important for enhancing arousal under certain conditions, such as exposure to a novel environment, but play only a minor role in behavioral and EEG arousal under baseline conditions.SIGNIFICANCE STATEMENTThe histaminergic neurons of the tuberomammillary nucleus of the hypothalamus (TMNHDC) have long been thought to promote arousal. Additionally, TMNHDCneurons may counter-regulate the wake-promoting effects of histamine through co-release of the inhibitory neurotransmitter, GABA. Here, we show that impairing GABA signaling from TMNHDCneurons does not impact sleep–wake amounts and that few TMNHDCneurons contain the vesicular GABA transporter, which is presumably required to release GABA. We further show that acute activation or inhibition of TMNHDCneurons has limited effects upon baseline arousal levels and that activation enhances vigilance during a behavioral challenge. Counter to general belief, our findings support the view that TMNHDCneurons are neither necessary nor sufficient for the initiation and maintenance of arousal under baseline conditions.

Previous studies suggest that the median preoptic nucleus (MnPO) of the hypothalamus plays an important role in regulating the wake-sleep cycle and in particular homeostatic sleep drive. However, the precise cellular phenotypes, targets and central mechanisms by which the MnPO neurons regulate the wake-sleep cycle remain unknown. Both excitatory and inhibitory MnPO neurons innervate brain regions implicated in sleep promotion and maintenance, suggesting that both cell types may participate in sleep control. Using genetically-targeted approaches, we investigated the role of the MnPO GABAergic (MnPO(Vgat)) and glutamatergic (MnPO(Vglut2)) neurons in modulating wake-sleep behavior of mice. We found that both neuron populations differentially participate in wake-sleep control, with MnPO(Vgat) neurons being involved in sleep homeostasis, and MnPO(Vglut2) neurons promoting sleep during allostatic (stressful) challenges.

The intermediate nucleus of Brockhaus (INH), also known as the interstitial nucleus of the anterior hypothalamus-1 of Allen and Gorski (INAH-1), the sexually dimorphic nucleus of Swaab and colleagues (SDN), and the ventrolateral preoptic nucleus of Saper and colleagues (VLPO), is a cluster of largely galanin-expressing neurons in the lateral preoptic area, at the level of the crossing of the anterior commissure and dorsal to the supraoptic nucleus. The number of Nissl-stained neurons in the INH has been reported to be larger in men than women and to decrease with aging, although these findings have been controversial, in part because of differences in patient populations and methods used to assess the nucleus. However, recent studies have confirmed that the number of galanin-immunoreactive INH neurons is larger in men than women and decreases with age and have reported further loss with Alzheimer disease. The galanin-immunoreactive VLPO neurons have been thought to drive sleep behavior in many species, and their numbers in older humans correlate with the amount of consolidated sleep they experience. Sleep differences between men and women, during aging, and with Alzheimer disease may also depend upon the integrity of this nucleus.

Introduction Previous studies suggest that the median preoptic nucleus (MnPO) plays an important role in regulating the wake-sleep cycle and in particular homeostatic sleep drive. However, the precise cellular phenotypes, targets and central mechanisms by which the MnPO neurons regulate the wake-sleep cycle remain unknown. Both glutamatergic (Vglut2+) and GABAergic (Vgat+) MnPO neurons innervate brain regions implicated in sleep promotion and maintenance, suggesting that both cell types may participate on sleep control. Methods In this study, we used two genetically-targeted approaches associated with electroencephalographic (EEG) and electromyographic (EMG) recordings in Vgat-IRES-cre and Vglut2-IRES-cre mice to investigate the role of the MnPOVgat and MnPOVglut2 neurons in modulating wake-sleep behavior. Results First, using a chemogenetic approach, we found that activation of MnPOVgat neurons reduced the latency for the first NREM sleep episode, produced an increase in NREM sleep and reduced wakefulness. Then, to test the role of MnPOVgat and MnPOVglut2 neurons in regulating sleep homeostasis, we recorded EEG and EMG responses in mice that had the Vgat+ or Vglut2+ neurons deleted from the MnPO. After deletion of MnPOVgat neurons, mice showed a reduction of NREM sleep and an increase in wakefulness during the light phase. Deletion of MnPOVgat neurons also reduced sleep recovery after 4 hours of sleep deprivation (SD). On the other hand, deletion of the MnPOVglut2 neurons did not change the wake-sleep cycle during the 24h baseline condition, but prevented the sleep recovery immediately after SD. To understand the underlying mechanism in preventing sleep recovery in both MnPOVglut2- and MnPOVgat-deleted mice groups, we exposed these animals to a psychological stress protocol. In response to a psychological stressor, mice with deletion of glutamatergic, but not GABAergic MnPO neurons, had an exacerbation of the stress-induced insomnia. Conclusion Our results suggest that both neuron populations differentially participate in wake-sleep control, with MnPOVgat neurons being critically involved in sleep homeostasis, and MnPOVglut2 neurons promoting sleep during allostatic (stressful) challenges. Support (if any) NIH Grants NS085477, NS072337, HL095491 and Sleep Research Society Foundation (Award 026-JP-20).

During obstructive sleep apnea, elevation of CO2 during apneas contributes to awakening and restoring airway patency. We previously found that glutamatergic neurons in the external lateral parabrachial nucleus (PBel) containing calcitonin gene related peptide (PBelCGRP neurons) are critical for causing arousal during hypercapnia. However, others found that genetic deletion of serotonin (5HT) neurons in the brainstem also prevented arousal from hypercapnia. To examine interactions between the two systems, we showed that dorsal raphe (DR) 5HT neurons selectively targeted the PBel. Either genetically directed deletion or acute optogenetic silencing of DRSert neurons dramatically increased the latency of mice to arouse during hypercapnia, as did silencing DRSert terminals in the PBel. This effect was mediated by 5HT2a receptors which are expressed by PBelCGRP neurons. Our results indicate that the serotonergic input from the DR to the PBel via 5HT2a receptors is critical for modulating the sensitivity of the PBelCGRP neurons that cause arousal to rising levels of blood CO2., Dorsal raphe 5HT(DRSert) neurons regulate arousal from hypercapnia by their projections to the neurons in the external lateral parabrachial nucleus (PBel) that are glutamatergic and also express calcitonin gene related peptide (PBelCGRP). The DRSert input to the PBel modulates the arousal system to rising levels of blood CO2, and may be mediated by 5HT2a receptors on the PBelCGRP neurons.

Fever is a common phenomenon during infection or inflammatory conditions. This stereotypic rise in body temperature (Tb) in response to inflammatory stimuli is a result of autonomic responses triggered by prostaglandin E2 action on EP3 receptors expressed by neurons in the median preoptic nucleus (MnPOEP3Rneurons). To investigate the identity of MnPOEP3Rneurons, we first usedin situhybridization to show coexpression of EP3R and the VGluT2 transporter in MnPO neurons. Retrograde tracing showed extensive direct projections from MnPOVGluT2but few from MnPOVgatneurons to a key site for fever production, the raphe pallidus. Ablation of MnPOVGluT2but not MnPOVgatneurons abolished fever responses but not changes in Tb induced by behavioral stress or thermal challenges. Finally, we crossed EP3R conditional knock-out mice with either VGluT2-IRES-cre or Vgat-IRES-cre mice and used both male and female mice to confirm that the neurons that express EP3R and mediate fever are glutamatergic, not GABAergic. This finding will require rethinking current concepts concerning the central thermoregulatory pathways based on the MnPOEP3Rneurons being GABAergic.SIGNIFICANCE STATEMENTBody temperature is regulated by the CNS. The rise of the body temperature, or fever, is an important brain-orchestrated mechanism for fighting against infectious or inflammatory disease, and is tightly regulated by the neurons located in the median preoptic nucleus (MnPO). Here we demonstrate that excitatory MnPO neurons mediate fever and examine a potential central circuit underlying the development of fever responses.

'Sundowning' in dementia and Alzheimer's disease is characterized by early-evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZGABA) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZGABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZGABA transmission phase-dependently increases aggression. Finally, SPZGABA-recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression.

Basic and clinical observations suggest that the caudal hypothalamus comprises a key node of the ascending arousal system, but the cell types underlying this are not fully understood. Here we report that glutamate-releasing neurons of the supramammillary region (SuMvglut2) produce sustained behavioral and EEG arousal when chemogenetically activated. This effect is nearly abolished following selective genetic disruption of glutamate release from SuMvglut2 neurons. Inhibition of SuMvglut2 neurons decreases and fragments wake, also suppressing theta and gamma frequency EEG activity. SuMvglut2 neurons include a subpopulation containing both glutamate and GABA (SuMvgat/vglut2) and another also expressing nitric oxide synthase (SuMNos1/Vglut2). Activation of SuMvgat/vglut2 neurons produces minimal wake and optogenetic stimulation of SuMvgat/vglut2 terminals elicits monosynaptic release of both glutamate and GABA onto dentate granule cells. Activation of SuMNos1/Vglut2 neurons potently drives wakefulness, whereas inhibition reduces REM sleep theta activity. These results identify SuMvglut2 neurons as a key node of the wake−sleep regulatory system., Supramammillary nucleus (SuM) neurons have been studied in the context of REM sleep but their possible role in mediating wakefulness is not known. Here the authors elucidate the distinct functional contributions of three subpopulations in the SuM on electrographical and behavioral arousal in mice using genetically targeted approaches.

Key points Glutamatergic neurons in the median preoptic area were stimulated using genetically targeted Channelrhodopsin 2 in transgenic mice. Stimulation of glutamatergic median preoptic area neurons produced a profound hypothermia due to cutaneous vasodilatation. Stimulation also produced drinking behaviour that was inhibited as water was ingested, suggesting pre-systemic feedback gating of drinking. Anatomical mapping of the stimulation sites showed that sites associated with hypothermia were more anteroventral than those associated with drinking, although there was substantial overlap. Abstract The median preoptic nucleus (MnPO) serves an important role in the integration of water/electrolyte homeostasis and thermoregulation, but we have a limited understanding these functions at a cellular level. Using Cre–Lox genetic targeting of Channelrhodospin 2 in VGluT2 transgenic mice, we examined the effect of glutamatergic MnPO neuron stimulation in freely behaving mice while monitoring drinking behaviour and core temperature. Stimulation produced a strong hypothermic response in 62% (13/21) of mice (core temperature: −4.6 ± 0.5°C, P = 0.001 vs. controls) caused by cutaneous vasodilatation. Stimulating glutamatergic MnPO neurons also produced robust drinking behaviour in 82% (18/22) of mice. Mice that drank during stimulation consumed 912 ± 163 μl (n = 8) during a 20 min trial in the dark phase, but markedly less during the light phase (421 ± 83 μl, P = 0.0025). Also, drinking during stimulation was inhibited as water was ingested, suggesting pre-systemic feedback gating of drinking. Both hypothermia and drinking during stimulation occurred in 50% of mice tested. Anatomical mapping of the stimulation sites showed that sites associated with hypothermia were more anteroventral than those associated with drinking, although there was substantial overlap. Thus, activation of separate but overlapping populations of glutamatergic MnPO neurons produces effects on drinking and autonomic thermoregulatory mechanisms, providing a structural basis for their frequently being coordinated (e.g. during hyperthermia).

A method for capturing gait signatures in neurological conditions that allows comparison of human gait with animal models would be of great value in translational research. However, the velocity dependence of gait parameters and differences between quadruped and biped gait have made this comparison challenging. Here we present an approach that accounts for changes in velocity during walking and allows for translation across species. In mice, we represented spatial and temporal gait parameters as a function of velocity and established regression models that reproducibly capture the signatures of these relationships during walking. In experimental parkinsonism models, regression curves representing these relationships shifted from baseline, implicating changes in gait signatures, but with marked differences between models. Gait parameters in healthy human subjects followed similar strict velocity dependent relationships which were altered in Parkinson’s patients in ways that resemble some but not all mouse models. This novel approach is suitable to quantify qualitative walking abnormalities related to CNS circuit dysfunction across species, identify appropriate animal models, and it provides important translational opportunities.

Although earlier models of brain circuitry controlling wake-sleep focused on monaminergic and cholinergic arousal systems, recent evidence indicates that these play mainly a modulatory role, and that the backbone of the wake-sleep regulatory system depends upon fast neurotransmitters, such as glutmate and GABA. We review here recent advances in understanding the role these systems play in controlling sleep and wakefulness.

Introduction Serotoninergic dorsal raphe neurons (DRSert) are CO2 responsive, and mice lacking serotonin have impaired arousal to CO2. We showed that the neurons in external lateral parabrachial nucleus containing calcitonin gene related peptide (PBelCGRP), are required for CO2-arousal. PBelCGRP neurons also receive serotoninergic innervation from the DRSert. 5HT2A agonist restores CO2 responsiveness in mice lacking serotonin, suggesting that DRSert may modulate CO2 arousal by acting on 5HT2A receptors possibly on the PBel neurons. Methods We used serotonin transporter (Sert)-Cre mice to optogenetically inhibit DRSert neurons and their terminals in the PBel. We injected AAV-FLEX-ArchT into the DR and implanted an optical fiber just above it in one set of Sert-Cre mice and bilaterally in the PBel in another set. All mice were instrumented for sleep and optogenetics and were tested for EEG arousals to 10% CO2. Latencies of arousal were compared with optogenetic inhibition of either the DR neurons or their terminals in the PBel with a 593nm laser light. We further tested whether a 5HT2A agonist (TCB-2) can reverse blockade of CO2 arousal in mice where DRSert terminals in PBel were inhibited. Finally, TCB-2 was injected in mice with PBelCGRP deletions and arousal latency to CO2 was compared. Results Compared to the control (Laser-OFF) condition, arousal latency to CO2 was significantly increased by photoinhibition of either the DRSert neurons (n=6; latency- 40.9 ± 6.4 vs. 13.81± 0.69 sec; F3, 17= 11.5; P< 0.001) or their terminals in PBel (n=8; latency-34.9 ± 2.3 sec vs. 16.62 ± 0.97sec, F1, 14= 56.9; P< 0.001). This was reversed by the 5HT2A agonist TCB-2 (5mg/kg), as it reduced the latency to CO2 arousal in mice with photoinhibition of terminals in PBel from 35.48 ± 7.31 sec to 16.24 ± 1.06 sec (F3, 9= 8.05; P= 0.006), but had no effect in mice with PBelCGRP neurons deletions. Conclusion The serotonin system modulate CO2-arousals by the DRSert input to the PBel. TCB-2 reversed the effect of inhibition of DRSert terminals in the PBel, but not in mice with PBelCGRP deletions, suggests that DRSert modulate PBelCGRP neurons through 5HT2a receptors. Support NIH- 2P01 HL095491 and NS112175

Currently available evidence indicates that neurons containing melanin-concentrating hormone (MCH) in the lateral hypothalamus are critical modulators of sleep-wakefulness, but their precise role in this function is not clear. Studies employing optogenetic stimulation of MCH neurons have yielded inconsistent results, presumably due to differences in the optogenetic stimulation protocols, which do not approximate normal patterns of cell firing. In order to resolve this discrepancy, we (1) selectively activated the MCH neurons using a chemogenetic approach (Cre-dependent hM3Dq expression) and (2) selectively destroyed MCH neurons using a genetically targeted diphtheria toxin deletion method, and studied the changes in sleep–wake in mice. Our results indicate that selective activation of MCH neurons causes specific increases in rapid eye movement (REM) sleep without altering wake or non-REM (NREM) sleep. On the other hand, selective deletions of MCH neurons altered the diurnal rhythm of wake and REM sleep without altering their total amounts. These results indicate that activation of MCH neurons primarily drives REM sleep and their presence may be necessary for normal expression of diurnal variation of REM sleep and wake.

Accumulating evidence supports the role of sleep in synaptic plasticity and memory consolidation. One line of investigation, the synaptic homeostasis hypothesis, has emphasized the increase in synaptic strength during waking, and compensatory downsizing of (presumably less frequently used) synapses during sleep. Conversely, other studies have reported downsizing and loss of dendritic spines following sleep deprivation. We wanted to determine the effect of sleep deprivation on dendritic spines of hippocampal CA1 neurons using genetic methods for fluorescent labeling of dendritic spines. Male Vglut2-Cre mice were injected with an AAV-DIO-ChR2-mCherry reporter in CA1 hippocampus. Gentle handling was used to sleep deprive mice for 5 hr, from lights on (7 am) to 12 noon. Control and sleep-deprived mice were euthanized at 12 noon and processed for quantification of dendritic spines. We used confocal microscope imaging and three-dimensional (3D) analysis to quantify thin, mushroom, and stubby spines from CA1 dendrites, distinguishing between branch segments. We observed significantly greater density of spines in CA1 of sleep-deprived mice, driven primarily by greater numbers of thin spines, and significantly larger spine volume and head diameter. Branch and region-specific analysis revealed that spine volume was greater in primary dendrites of apical and basal segments, along with proximal segments on both apical and basal dendrites, and spine density was increased in secondary branches and distal segments on apical dendrites following sleep deprivation. Our 3D quantification suggests sleep contributes to region- and branch-specific synaptic downscaling in the hippocampus, supporting the theory of broad but selective synaptic downscaling during sleep.

Chapter 6 explores psychiatric causes of unresponsiveness, which must be differentiated from organic causes of stupor and coma. The chapter notes that several psychiatric disorders can result in psychogenic unresponsiveness. These include conversion reaction, catatonic stupor, a dissociative or “fugue” state, and factitious disorder or malingering. The chapter looks at these in turn. Various diagnostic tests are described in detail, including the electroencephalogram, magnetic resonance imaging, computed tomographic imaging, caloric testing, and the “Amytal interview.” Sections describes the diagnosis and treatment of catatonia, psychogenic seizures (which must be differentiated from epileptic seizures), and cerebellar mutism. The authors emphasize the importance of treating patients with psychiatric causes of unresponsiveness with compassion and understanding.

This text is an update of a classic work on diagnosing the cause of coma, with the addition of new sections on the treatment of comatose patients. The first chapter provides an up-to-date review on the brain mechanisms that maintain a conscious state in humans and how lesions that damage these mechanisms cause loss of consciousness or coma. The second chapter reviews the neurological examination of the comatose patient, which provides the basis for determining whether the patient is suffering from a structural brain injury causing the coma or from a metabolic disorder of consciousness. The third and fourth chapters review the pathophysiology of structural lesions causing coma and the specific disease states that result in coma. Chapter 5 is a comprehensive treatment of the many causes of metabolic coma. Chapter 6 review psychiatric causes of unresponsiveness and how to identify and treat them. Chapters 7 and 8 review the overall emergency treatment of comatose patients, followed by the treatment of specific causes of coma. Chapter 9 examines the long-term outcomes of coma, including the minimally conscious state and the persistent vegetative state, how they can be distinguished, and their implications for eventual useful recovery. Chapter 10 reviews the topic of brain death, the standards for examination of a patient that are required to make the determination of brain death, and the ethics of diagnosis and treatment of patients who, by definition, have no way to approve of or communicate about their wishes.

Chapters 3 is the first of two chapters to discuss pathophysiology and specific causes of structural injury to the brain that result in defects of consciousness. It divides structural lesions causing coma into compressive and destructive lesions. It further indicates that lesions could be supratentorial, compressing, or destroying the diencephalon and upper midbrain, or infratentorial, directly affecting the pons and cerebellum. A physician attempting to determine the cause of coma resulting from a structural lesion must establish, first, the site of the lesion, determining whether the lesion is supratentorial or infratentorial, and, second, whether the lesion is causing its symptoms by compression or destruction or both.

This chapter provides a general approach to the emergency care of comatose patients. It presents a clinical regimen for the diagnosis and management of patients suffering from stupor or coma. Of all the acute problems in clinical medicine, as the chapter explains, none is more challenging than the prompt diagnosis and effective management of the patient in coma. This is largely because the causes of coma are so many and the physician possesses only a limited time in which to make the appropriate diagnostic and therapeutic judgments. The authors detail basic emergency procedures to evaluate and support the essential airway, breathing, and circulation, and then move through a methodical, step-by-step examination and evaluation of all body systems, focusing on eye and pupillary reactions, motor responses, reflexes, and muscle tone.

Chapter 5 examines the broad range of metabolic causes of unconsciousness and the specific treatments they require. The main feature distinguishing diffuse or metabolic impairment of consciousness is that it is normally not associated with focal neurological findings that would suggest a structural lesion of the brain. However, there are some features of the neurological examination of patients with metabolic encephalopathies that can help to pinpoint the cause of the disturbance. In addition, there are some findings on examination that may appear to be due to focal lesions, but which can be due to diffuse or metabolic disease. The chapter first examines the diagnostic features of metabolic encephalopathies. It then looks at the internal metabolic milieu in which the brain functions normally. It also considers specific types of metabolic and diffuse disturbances of that internal milieu that can cause encephalopathy. Finally, it considers various endogenous and exogenous toxins that produce toxic encephalopathies.

This chapter is the second of two chapters to discuss the pathophysiology and specific causes of structural injury to the brain that result in defects of consciousness. This chapter examines, in turn, the specific causes of supratentorial and infratentorial compressive and destructive lesions that cause coma. It also gives brief descriptions of the approach to treatment. Among the insults and injuries described are various hematomas, abscesses, empyema, tumors, infections, and, as well as infarctions, distal basilar occlusion, venous sinus thrombosis, vasculitis. Concussion and other traumatic brain injuries are described and discussed, as are vascular destructive and inflammatory disorders like basilar migraine, leukoencephalopathy syndrome, and myelinolysis.

This chapter presents a diagnostic and management outline to approach commonly encountered conditions associated unconsciousness. Once the specific cause is identified, attention should turn to dealing with the set of problems inherent to the underlying disorder. As it is not possible to cover all aspects of treatment of all possible causes of stupor and coma comprehensively, this chapter focuses instead on the management of frequently encountered pathologies within each of the main categorical clinical diagnoses: supratentorial or infratentorial compressive lesions; supratentorial or infratentorial destructive lesions; metabolic, diffuse, or multifocal coma. Management of psychogenic coma is discussed in Chapter 6.