Neural Substrate of Cold-Seeking Behavior in Endotoxin Shock

Systemic inflammation is a leading cause of hospital death. Mild systemic inflammation is accompanied by warmth-seeking behavior (and fever), whereas severe inflammation is associated with cold-seeking behavior (and hypothermia). Both behaviors are adaptive. Which brain structures mediate which behavior is unknown. The involvement of hypothalamic structures, namely, the preoptic area (POA), paraventricular nucleus (PVH), or dorsomedial nucleus (DMH), in thermoregulatory behaviors associated with endotoxin (lipopolysaccharide [LPS])-induced systemic inflammation was studied in rats. The rats were allowed to select their thermal environment by freely moving in a thermogradient apparatus. A low intravenous dose of Escherichia coli LPS (10 µg/kg) caused warmth-seeking behavior, whereas a high, shock-inducing dose (5,000 µg/kg) caused cold-seeking behavior. Bilateral electrocoagulation of the PVH or DMH, but not of the POA, prevented this cold-seeking response. Lesioning the DMH with ibotenic acid, an excitotoxin that destroys neuronal bodies but spares fibers of passage, also prevented LPS-induced cold-seeking behavior; lesioning the PVH with ibotenate did not affect it. Lesion of no structure affected cold-seeking behavior induced by heat exposure or by pharmacological stimulation of the transient receptor potential (TRP) vanilloid-1 channel (“warmth receptor”). Nor did any lesion affect warmth-seeking behavior induced by a low dose of LPS, cold exposure, or pharmacological stimulation of the TRP melastatin-8 (“cold receptor”). We conclude that LPS-induced cold-seeking response is mediated by neuronal bodies located in the DMH and neural fibers passing through the PVH. These are the first two landmarks on the map of the circuitry of cold-seeking behavior associated with endotoxin shock

Circuit-based interrogation of sleep control.

Sleep is a fundamental biological process observed widely in the animal kingdom, but the neural circuits generating sleep remain poorly understood. Understanding the brain mechanisms controlling sleep requires the identification of key neurons in the control circuits and mapping of their synaptic connections. Technical innovations over the past decade have greatly facilitated dissection of the sleep circuits. This has set the stage for understanding how a variety of environmental and physiological factors influence sleep. The ability to initiate and terminate sleep on command will also help us to elucidate its functions within and beyond the brain

The reticular formation and the neuromodulatory systems

Almost a century ago, Constantin von Economo observed that in patients with encephalitis lethargica lesions in the upper brain stem and posterior hypothalamus impaired consciousness. From lesion studies in cats and anatomical data, the idea arose that the brain stem reticular formation is the origin of the ascending reticular activating system (ARAS) that would operate through the intralaminar nuclei and activate widespread regions of the cerebral cortex. This view of the reticular formation has been extensively modified, and nowadays the reticular formation is viewed as a series of highly specific cell groups, which closely surround the individual motor and sensory nuclei of the brain stem (Sects. 5.2 and 5.4). The diffuse system, driving arousal and consciousness, is now attributed to the neuromodulatory system, including the serotonergic raphe nuclei, the locus coeruleus and other noradrenergic or adrenergic cell groups and cholinergic cell groups, all close to the reticular formation (Sects. 5.3 and 5.5). The English terms of the Terminologia Neuroanatomica are used throughout. Although the basic notion of the ARAS concept that structures in the brain stem regulate states of consciousness still holds true, a much more complex picture has emerged. Experimental work in laboratory animals suggests that the following structures play key roles in the maintenance and modulation of wakefulness: cholinergic nuclei in the upper brain stem and basal forebrain; noradrenergic nuclei, in particular the locus coeruleus; a histaminergic projection from the tuberomamillary nucleus in the posterior hypothalamus; and dopaminergic and serotonergic pathways from the ventral tegmental area and raphe nuclei, respectively. These nuclei all participate in an ascending activating system to the cerebral cortex (Sect. 5.5). The hypothalamus also contains orexinergic neurons that are crucial for maintaining normal wakefulness and a sleep-promoting region in the ventrolateral preoptic area. These groups have mutually inhibiting connections, known as the sleep switch (Sect. 5.6). Some sleep disorders in which these structures are involved are discussed in Clinical Cases (Sect. 5.7). Damage to the upper brain stem reticular formation is known to cause the most radical disturbance of consciousness, i.e. coma, as illustrated in several Clinical Cases (Sect. 5.8)

Orexin/Hypocretin and Organizing Principles for a Diversity of Wake-Promoting Neurons in the Brain.

An enigmatic feature of behavioural state control is the rich diversity of wake-promoting neural systems. This diversity has been rationalized as 'robustness via redundancy', wherein wakefulness control is not critically dependent on one type of neuron or molecule. Studies of the brain orexin/hypocretin system challenge this view by demonstrating that wakefulness control fails upon loss of this neurotransmitter system. Since orexin neurons signal arousal need, and excite other wake-promoting neurons, their actions illuminate nonredundant principles of arousal control. Here, we suggest such principles by reviewing the orexin system from a collective viewpoint of biology, physics and engineering. Orexin peptides excite other arousal-promoting neurons (noradrenaline, histamine, serotonin, acetylcholine neurons), either by activating mixed-cation conductances or by inhibiting potassium conductances. Ohm's law predicts that these opposite conductance changes will produce opposite effects on sensitivity of neuronal excitability to current inputs, thus enabling orexin to differentially control input-output gain of its target networks. Orexin neurons also produce other transmitters, including glutamate. When orexin cells fire, glutamate-mediated downstream excitation displays temporal decay, but orexin-mediated excitation escalates, as if orexin transmission enabled arousal controllers to compute a time integral of arousal need. Since the anatomical and functional architecture of the orexin system contains negative feedback loops (e.g. orexin ➔ histamine ➔ noradrenaline/serotonin-orexin), such computations may stabilize wakefulness via integral feedback, a basic engineering strategy for set point control in uncertain environments. Such dynamic behavioural control requires several distinct wake-promoting modules, which perform nonredundant transformations of arousal signals and are connected in feedback loops