Historically, the locus coeruleus-norepinephrine (LC-NE) system has been implicated in arousal, but recent findings suggest that this system plays a more complex and specific role in the control of behavior than investigators previously thought. We review neurophysiological and modeling studies in monkey that support a new theory of LC-NE function. LC neurons exhibit two modes of activity, phasic and tonic. Phasic LC activation is driven by the outcome of task-related decision processes and is proposed to facilitate ensuing behaviors and to help optimize task performance (exploitation). When utility in the task wanes, LC neurons exhibit a tonic activity mode, associated with disengagement from the current task and a search for alternative behaviors (exploration). Monkey LC receives prominent, direct inputs from the anterior cingulate (ACC) and orbitofrontal cortices (OFC), both of which are thought to monitor task-related utility. We propose that these frontal areas produce the above patterns of LC activity to optimize utility on both short and long timescales.

/pdf/an-integrative-theory-of-locus-coeruleus-norepinephrine-2ljsj0k79l.pdf

An Integrative Theory of Locus Coeruleus-Norepinephrine Function: Adaptive Gain and Optimal Performance.

The novel neuropeptides called hypocretins (orexins) have recently been identified as being localized exclusively in cell bodies in a subregion of the tuberal part of the hypothalamus. The structure of the hypocretins, their accumulation in vesicles of axon terminals, and their excitatory effect on cultured hypothalamic neurons suggest that the hypocretins function in intercellular communication. To characterize these peptides further and to help understand what physiological functions they may serve, we undertook an immunohistochemical study to examine the distribution of preprohypocretin-immunoreactive neurons and fibers in the rat brain. Preprohypocretin-positive neurons were found in the perifornical nucleus and in the dorsal and lateral hypothalamic areas. These cells were distinct from those that express melanin-concentrating hormone. Although they represent a restricted group of cells, their projections were widely distributed in the brain. We observed labeled fibers throughout the hypothalamus. The densest extrahypothalamic projection was found in the locus coeruleus. Fibers were also seen in the septal nuclei, the bed nucleus of the stria terminalis, the paraventricular and reuniens nuclei of the thalamus, the zona incerta, the subthalamic nucleus, the central gray, the substantia nigra, the raphe nuclei, the parabrachial area, the medullary reticular formation, and the nucleus of the solitary tract. Less prominent projections were found in cortical regions, central and anterior amygdaloid nuclei, and the olfactory bulb. These results suggest that hypocretins are likely to have a role in physiological functions in addition to food intake such as regulation of blood pressure, the neuroendocrine system, body temperature, and the sleep–waking cycle.

https://www.jneurosci.org/content/jneuro/18/23/9996.full.pdf

Neurons Containing Hypocretin (Orexin) Project to Multiple Neuronal Systems

Theta Oscillations in the Hippocampus

http://dept.wofford.edu/neuroscience/NeuroSeminar/pdfSpring2010/MolecularGenetics.pdf

Narcolepsy in orexin knockout mice: Molecular genetics of sleep regulation

Unilateral neglect reflects a disturbance in the spatial distribution of directed attention. A review of unilateral neglect syndromes in monkeys and humans suggests that four cerebral regions provide an integrated network for the modulation of directed attention within extrapersonal space. Each component region has a unique functional role that reflects its profile of anatomical connectivity, and each gives rise to a different clinical type of unilateral neglect when damaged. A posterior parietal component provides an internal sensory map and perhaps also a mechanism for modifying the extent of synaptic space devoted to specific portions of the external world; a limbic component in the cingulate gyrus regulates the spatial distribution of motivational valence; a frontal component coordinates the motor programs for exploration, scanning, reaching, and fixating; and a reticular component provides the underlying level of arousal and vigilance. This hypothetical network requires at least three complementary and interacting representations of extrapersonal space: a sensory representation in posterior parietal cortex, a schema for distributing exploratory movements in frontal cortex, and a motivational map in the cingulate cortex. Lesions in only one component of this network yield partial unilateral neglect syndromes, while those that encompass all the components result in profound deficits that transcend the mass effect of the larger lesion. This network approach to the localization of complex functions offers an alternative to more extreme approaches, some of which stress an exclusive concentration of function within individual centers in the brain and others which advocate a more uniform (equipotential or holistic) distribution. In human beings, unilateral neglect syndromes are more frequent and severe after lesions in the right hemisphere. Also, right hemisphere mechanisms appear more effective in the execution of attentional tasks. Furthermore, the attentional functions of the right hemisphere span both hemispaces, while the left hemisphere seems to contain the neural apparatus mostly for contralateral attention. This evidence indicates that the right hemisphere of dextrals has a functional specialization for the distribution of directed attention within extrapersonal space.

A cortical network for directed attention and unilateral neglect.

Effects of modafinil-induced wakefulness on glutamine synthetase regulation in the rat brain

Local cerebral glucose utilization in the free moving mouse: a comparison during two stages of the activity-rest cycle.

Immunohistochemical evidence for the adrenergic medullary longitudinal bundle as a major ascending pathway to the locus coeruleus

Effets de l'injection intraventriculaire de 6-hydroxydopamine. II. Sur le cycle veille-sommeils du chat

Dams from two strains of mice, BALB/c and C57BR were treated during gestation with caffeine, at doses of about 60, 80 and 100 mg/kg/day, in their drinking water. The resulting offspring were behaviourally tested over a 6-month period commencing at age 9 months. When compared with controls, mice from dams that had received caffeine demonstrated longer latencies in a passive avoidance test, and differences were also noted for female C57BR offspring in activity and habituation measures. Having controlled as far as possible for post-natal maternal and environmental effects, the most likely conclusion is that caffeine has a direct pharmacological action on the foetus, and should therefore be classed as a behavioural teratogen in mice.

Michel Jouvet

Papers

Effects of modafinil-induced wakefulness on glutamine synthetase regulation in the rat brain

Local cerebral glucose utilization in the free moving mouse: a comparison during two stages of the activity-rest cycle.

Immunohistochemical evidence for the adrenergic medullary longitudinal bundle as a major ascending pathway to the locus coeruleus

Effets de l'injection intraventriculaire de 6-hydroxydopamine. II. Sur le cycle veille-sommeils du chat

Gestational caffeine modifies offspring behaviour in mice