"Sky-blue place" IV: Descending modulation

In reference to:
Locus Ceruleus: "Sky-blue place"
"Sky-blue place" II: Projections
"Sky-blue place" III: Input

This will be the last post in this series.
I think I've turned over most of the stones I could find learning about this cool little brain spot that seems to know just when to wake up the brain and when to be quiet.

I want to bring forward a few more juicy tidbits here, however, from Textbook of Pain 5th Ed.

1. The PAG (periaqueductal grey) and locus ceruleus seem to enhance one another's function: (p. 394:)

"Concurrent delivery".. (of "ethylketocyclazocine,""reported to have μ-agonist properties"), "at doses that together were less than injected in either site alone, produced a significant, naloxone-reversible increase in response latency. These observations were argued to reflect a synergic interaction between these two anatomically distinct systems (Bodnar et al 1991)."

If something is naloxone-reversible it means it has an opioid effect of some kind.

2. Anterior insular cortex projects to LC: (p. 127:)

"Dorsolateral pontine systems may also contribute to cortical control of spinal nociceptive transmission. Increasing GABA levels in the anterior insular cortex produces an analgesic effect that is blocked by intrathecal administration of α-adrenergic antagonists. Because this cortical region projects to the locus coeruleus as well as the RVM, it was suggested that inhibition of the insular outflow disinhibits noradrenergic neurons of the locus coeruleus (Jasmin et al 2003b). This could be through an action in the pons or via the RVM."

I missed this when I did the projections post.
(Note: RVM = rostral ventromedial medulla)

3. Linkage to affective states: (p. 234:)

"Chapman (2004) described how processing of nociceptive signals produces affect in multiple neurotransmitter pathways that project to the cortex. Noradrenergic, serotonergic, dopaminergic and acetylcholinergic fibres and pathways are involved. Drawing on an extensive literature on the biology of emotions (e.g. Gray 1987), noradrenergic pathways are recognized as linked most closely to negative emotional states. Of particular importance are nociceptive afferent systems operating and transmitting through the limbic brain-in particular the locus coeruleus, the dorsal noradrenergic bundle, the ventral noradrenergic bundle, and the hypothalamo-pituitary-adrenocortical axis-to all of the neocortex. These are not specific in their activation to nociception, but are also responsive to non-nociceptive, aversive emotional states. These systems are recognized as fostering survival by allowing biological vigilance to threatening and harmful stimuli, both external and internal. Chapman proposes that the affective dimensions of pain can best be conceptualized as involving a two-stage mechanism. The immediate experience would be akin to hypervigilance or fear, with this rapid response giving rise through efferent messages to visceral and other event-related, autonomic activity that creates a strong negative subjective experience and an affective response involving images and symbols."

4. Supraspinal analgesia: (p. 431:)

"Fibres descending from the RVM to the dorsal horn of the spinal cord are mostly serotonergic, enkephalinergic, glycinergic and GABAergic. The nucleus raphe magnus contained within the RVM and the noradrenergic nuclei (locus coeruleus, subcoeruleus, A5 and A7 cell groups) are major PAG relays for noradrenergic and serotonergic descending pathways, respectively, to the dorsal horn (Kwiat & Basbaum 1992). Rather than the RVM being a homogeneous population of serotonergic neurons, GABA- (and glycine-) releasing neurons are now thought to constitute a significant proportion of spinally projecting RVM fibres (Antal et al 1996). The pharmacology of noradrenergic and serotonergic modulation in the dorsal horn is complex but opioids can also interact with noradrenergic mechanisms and there are many studies showing that the effector mechanism and location for the major noradrenaline target receptor-the α2 adrenoceptor-is very similar to that of opioid receptors."

Here is a picture of where LC is to be found in the brain (see red arrow, image from Atlas of Functional Neuroanatomy and modified).

Look at how tiny it is. (I think if you click on the picture you can enlarge it some more.)

Here is a link to a set of notes I made on this little brain part.

"Sky-blue place" III: Input

In reference to "Sky-blue place" II: Projections:

In the post referenced above I provided a very very sketchy list of all the places LC fibers go to, what they affect, i.e., which parts hear the "alarm."

I now have pages and pages of info on that, but finding out which bits feed into LC is a bit harder. I guess the pathways are a bit less well worked out.

The Appenzeller source lists a couple of places, nucleus paragigantocellularis lateralis (of the rostral ventrolateral medulla), and nucleus prepositus hypoglossi of the rostral dorsomedial medulla.

Nucleus paragigantocellularis lateralis (what a name!) corresponds neuroanatomically to the neurochemical localization of C1 and A1 epinephrine and norepinephrine-containing cell bodies near the ventral surface of the brainstem. Nucleus prepositus hypoglossi corresponds to the localization of C3 adrenergic neurones near the dorsal surface of the medulla bordering on the 4th ventricle. (Riveting, I know..)

Other than that, apparently LC receives neurons from itself, with collaterals. Appenzeller says, p. 162:

"Both external and internal perturbations can activate the locus ceruleus, the latter after sensory processing in the medullary nuclei. Thus, if a stimulus were perceived as novel, severe or threatening, locus ceruleus activation could foster transmission of the signal to higher brain centers, facilitating active attention and memory consolidation and further orienting the organism to the stimulus."

The brain can perturb its own LC. Maybe it's the LC that becomes activated during times of cognitive dissonance.


New Territory

I looked into those two medullary or brainstem nuclei, which took me into the reticular formation, from which I'm yet to emerge. It is not an easy place to grasp. Gray's Anatomy (39th) says, (p. 347):

"The brain stem contains extensive fields of intermingled neurones and nerve fibres, which are collectively termed the reticular formation. The reticular regions are often regarded as phylogenetically ancient, representing a primitive nerve network upon which more anatomically organized, functionally selective, connections have developed during evolution. However, the most primitive nervous systems show both diffuse and highly organized regions, which cooperate in response to different demands.

"The general characteristics of reticular regions may be summarized as follows. They tend to be ill-defined collections of neurones and fibres with diffuse connections. Their conduction paths are difficult to define, complex and often polysynaptic, and they have ascending and descending components that are partly crossed and uncrossed. Their components subserve somatic and visceral functions. They include distinct chemoarchitectonic nuclear groups, including clusters of serotoninergic neurones (group B cells), which synthesize the indolamine 5-hydroxytryptamine (serotonin); cholinergic neurones (group Ch cells), which contain acetyltransferase, the enzyme which catalyses the synthesis of acetylcholine; and three catecholaminergic groups composed of noradrenergic (group A), adrenergic (group C), and dopaminergic (group A) neurones, which synthesize noradrenaline (norepinephrine), adrenaline (epinephrine) and dopamine respectively as neurotransmitters."

This seems daunting, but in persevering, I am learning quite a bit about the reticular formation system(s). They are generally grouped into three systems, raphe or median, medial (just to be confusing) located between the raphe and lateral, the third.


Are the neurons coming or going to LC?

The raphe system seems to connect to LC, but are the neurons afferent or efferent? From Gray's:

"the dorsal raphe nucleus, in addition to sending a large number of fibres to the locus coeruleus, projects to the dorsal tegmental nucleus and most of the rhombencephalic reticular formation, together with the central superior, pontine raphe and raphe magnus nuclei."

However, another source, an online book, Basic Neurochemistry, in its page on serotonin, says:

"The raphe nuclei also receive input from other cell body groups in the brainstem, such as the substantia nigra and ventral tegmental area (dopamine), superior vestibular nucleus (acetylcholine), locus ceruleus (norepinephrine) and nucleus prepositus hypoglossi and nucleus of the solitary tract (epinephrine)."

Regarding pain modulation

In Gray's this tantalizing bit appears: "Raphe spinal serotoninergic axons originate mainly from neurones in the raphe magnus, pallidus and obscurus nuclei. They project as ventral, dorsal and intermediate spinal tracts in the ventral and lateral funiculi, and terminate respectively in the ventral horns and laminae I, II and V of the dorsal horns of all segments, and in the thoracolumbar intermediolateral sympathetic and sacral parasympathetic preganglionic cell columns. The dorsal raphe spinal projections function as a pain-control pathway that descends from the mesencephalic pain-control centre, which is located in the periaqueductal grey matter, dorsal raphe and cuneiform nuclei. The intermediate raphe spinal projection is inhibitory, and, in part, modulates central sympathetic control of cardiovascular function. The ventral raphe spinal system excites ventral horn cells and could function to enhance motor responses to nociceptive stimuli and to promote the flight and fight response."

To be continued.

References:
1. Atlas of Functional Neurology (2006) Hendelman W (p. 114-19)
2. Gray's Anatomy (39th ed.) p. 347-350
3. Handbook of Clinical Neurology: The Autonomic Nervous System Part I, Elsevier 2000, Appenzeller O., Vinken PJ, Bruyn GW, p. 155
4. Basic Neurochemistry (1999) Siegal G

Additional reading:
1. Brainstem (scholarpedia)