Reticular formation

The reticular formation is a part of the brain which is involved in stereotypical actions, such as walking, sleeping, and lying down. It is absolutely essential for life.

The reticular formation, phylogenetically one of the oldest portions of the brain, is a poorly-differentiated area of the brain stem, centered roughly in the pons, but with the ascending reticular activating system connecting to areas in the thalamus, hypothalamus, and cortex, and the descending reticular activating system connecting to the cerebellum and sensory nerves.

There is some reason to regard the reticular formation as "motivation central" for the brain, as it appears not only to control physical behaviors such as sleep, but also has been shown to play a major role in alertness, fatigue, and motivation to perform various activities. Some researchers have speculated that the reticular formation controls approximately 25 specific and mutually-exclusive behaviors, including sleep, walking, eating, urination, defecation, and sexual activity.

The reticular formation has also been traced as one of the sources for the introversion and extroversion character traits. Introverted people have been found to have a more easily stimulated reticular formation, resulting in a diminished desire to seek out stimulus. Extroverted people, however, have a less easily stimulated reticular formation, resulting in the need for more stimulation to maintain brain activity.

Lesions in the reticular formation have been found in the brains of people who have post-polio syndrome, and some imaging studies have shown abnormal activity in the area in people with chronic fatigue syndrome, indicating a high likelihood that damage to the reticular formation is responsible for the fatigue experienced with these syndromes.

There are also imaging studies that suggest that abnormalities in the reticular formation may be responsible for at least some cases of attention deficit hyperactivity disorder.

Introduction
The term "reticular formation" was coined in the late 19th century, coinciding with Ramon y Cajal’s "neuron doctrine". Allan Hobson states in his book The Reticular Formation revisited that he thought the name was an etymological vestige from the fallen era of the aggregate field theory in the neural sciences. The term “reticulum” means a “netlike structure”, which is what the Reticular Formation appears to be at first glance. It has been described as being either too complex to study or an undifferentiated part of the brain with no organization at all. Eric Kandel even describes the reticular formation as being organized in a similar manner to the intermediate gray matter of the spinal cord. This chaotic, loose and intricate form of organization is what has turned off many researchers from looking farther into this mysterious area of the brain which seems to be at the crux of our basic neurological and behavioral functions. The cells lack clear ganglionic boundaries, but do have clear functional organizations and distinct cell types. The reticular formation has been functionally cleaved both sagittally and coronally. The original functional differentiation was a division of caudal and rostral, this was based upon the observation that the lesioning of the rostral reticular formation induced a hypersomnia in the cat brain. Conversely, lesioning of the more caudal portion of the reticular formation produced insomnia in cats. This study has lead to the idea that the caudal portion inhibits the rostral portion of the reticular formation. The sagittal divisions are more morphological distinctions. The raphe nuclei form a ridge in the middle of the reticular formation and directly to its periphery there is a division called the medial reticular formation. The medial RF is large and has long ascending and descending fibers, and is surrounded by the lateral reticular formation. The lateral RF is close to the motor nuclei of the cranial nerves, and mostly mediates their function.

Medial and lateral reticular formation
The medial and lateral reticular formation are two columns of neuronal nuclei with ill-defined boundaries which go up through from the medulla and into the mesencephalon. The nuclei can only be teased out by function, cell type and projections of efferent or afferent nature.



The Medial Reticular formation
Surrounding the previously discussed ridge of serotonergic cells, the medial reticular formation has many roles and functions. The medial reticular formation is filled with a mixture of large and small neurons. The most famous and prominent cells in this region are the giant neurons, located mostly within the medial RF. These neurons have long axons in both the ascending and descending directions. Through their projections, this portion of the RF has been known to mediate posture, movement, pain, autonomic function and arousal. The nuclei of the medial reticular formation are: the nucleus reticularis gigantocellularis, the n.r. pontis caudalis, the n.r. pontis oralis, the n.r. parvocellularis, and the n.r. ventralis. These two columns have been the subject of much speculation and mystery because their intricate parts are so interwoven and specific. In fact it has taken decades to unravel them to this point, and there are still far more mysteries to unravel for future neural scientists. (Above in figure one can be seen a color diagram of the lateral and medial reticular formation, separated into nuclei, which blend into one another). Three out of the four nuclei mainly involved in mediating expiration and inspiration are located in the medial RF and should be discussed. Respiration has an autorhythmia, thought to be mediated by the dorsal reticular formation. Even when all afferent stimuli are eliminated, the respiration rhythm continues on. Expiration is mediated by the nucleus reticularis parvocellularis and the dorsorostral portion of the gigantocellularis. The nuclei which mediate inspiration are the rostral portion of the ventral reticular nucleus and part of the lateral RN. The efferent fibers for the inspiration nuclei follow the motor path of the glossopharyngeal nerve and the vagus nerve. This exhalation process takes place when the aforementioned nuclei inhibit the nuclei responsible for inspiration. In order for this to take place there must be inhibitory connections from the expiring neurons to the inspiring neurons.

Reticularis Gigantocellularis (The Giant Reticular Nucleus)
The nucleus reticularis gigantocellularis, as the name indicates, is mainly composed of the so called giant neuronal cells. This nucleus has been known to innervate the caudal hypoglossal nucleus, and responds to glutamateric stimuli. The gigantocellular nucleus excites the hypoglossal nucleus, and can play a role in the actions of the said nerve (16). This nucleus receives connections from the periaqueductal gray, the paraventricular hypothalamic nucleus, central nucleus of the amygdala, lateral hypothalamic area, and parvocellular reticular nucleus. Retrograde studies have shown that the deep mesencephalic reticular formation and oral pontine reticular nucleus project to the nucleus gigantocellularis. The dorsal rostral section of the nucleus reticularis gigantocellularis is also involved mediating in expiration (or out-breathing) along with the parvocellular nucleus.

Reticularis Pontis Caudalis
The Nucleus reticularis pontis caudalis is also composed of gigantocellular neurons. In rabbits and cats it is exclusively giant cells, however in humans there are normally sized cells as well. The pontis caudalis is rostral to the gigantocellular nucleus and is located in the caudal pons, as the name would indicate. The pontis caudalis has been known to mediate head movement, in concert with the nucleus gigantocellularis and the superior colliculus (21). The neurons in the dorsal half of this nuclei fire rhythmically during mastication, and in an anesthetized animal it is possible to induce mastication via electrical stimulation of the PC or adjacent areas of the gigantocellular nucleus (20). The pontis caudalis is also thought to play a hand in the grinding of teeth during sleep.

Reticularis Pontis Oralis
The nucleus reticularis pontis oralis is delineated from its caudal brother, with which it shares its first three names. This nucleus tapers into the lower mesencephalic reticular formation and contains sporadic giant cells. Different populations of the pontis oralis have displayed discharge patterns which coordinate with phasic movements to and from paradoxical sleep. From this information it has been implied that the n.r. pontis oralis is involved in the mediation of changing to from REM sleep (22).

Reticularis Parvocellularis
The nucleus reticularis parvocellaris is located dorsolatteral to the nucleus reticularis pontis caudalis. The dorsal portion of the reticular nucleus has been shown to innervate the mesencephalic trigeminal nucleus and its surrounding area. Also, it projects to the facial, hypoglossal and parabrachial nuclei along with parts of the caudal parvocellular reticular formation (23). This nucleus is also involved in expiration with a part of the gigantocellular nucleus.

Reticularis Ventralis
The nucleus reticularis ventralis is a continuation of the parvocellular nucleus in the brainstem. The ventral reticular nucleus has been shown to receive afferent projections from the dentate gyrus in rabbits (24). The rostral portion of the ventral reticular nucleus has been shown to mediate inspiration along with a portion of the lateral reticular nucleus.

The Lateral Reticular Formation
Moving caudally from the rostral midbrain, at the site of the rostral pons and the midbrain, the medial RF becomes less prominent, and the lateral RF becomes more prominent. Existing on the sides of the medial reticular formation is its lateral cousin, which is particularly pronounced in the rostral medulla and caudal pons. Out from this area spring the cranial nerves, including the very important vagus nerve. The Lateral RF is known for its ganglions and areas of interneurons around the cranial nerves, which serve to mediate their characteristic reflexes and functions. The dorsolateral reticular formation shoots long ascending axons to the thalamus, which relays their signals to the cortex, forming the Ascending Reticular Activation System or ARAS (seen below).

This is part of the ascending reticular activation system which was mentioned earlier and pictured above. These axonal projections are both cholinergic and noradrenergic, the former of which projects to the sensory nucleus of the thalamus and the reticular nucleus of the thalamus. The reticular nucleus of the thalamus (not pictured) has nothing to do with the reticular formation; its naming was a coincidence. This nucleus wraps around the thalamus, forming a thin net, for which it is named (reticular means netlike or an intricate network). The reticular nucleus of the thalamus, when active, inhibits the sensory nucleus with GABA. The sensory nucleus is positively stimulated by acetylcholine, while the reticular nucleus is inhibited by acetylcholine. This means that when the Ascending Reticular Activation System is active, as during waking hours, the inhibitory actions of the reticular nucleus are inhibited. The thalamus is never fully stimulated to an action potential via these projections from the ARAS, but it is sensitized by them (17). During sleep, when the ARAS shuts down, the reticular nucleus is free to inhibit the sensory nucleus of the thalamus. This is how the reticular formation mediates attention and wakefulness. This makes sense because during wakefulness, it is easy to take in sensory stimuli. Once the ARAS system begins to shut down, the world seems duller, and it is much harder to take in information from the outside world. The chemical equivalent of this would be if the thalamus was being partially inhibited by GABA, making it more difficult to relay information to the cortex.

Lateral Reticular Nucleus
The lateral reticular nucleus, of the funiculus, can be divided into three subnuclei, the parvocellular, magnocellular and the subtrigeminal. As is typical of the reticular formation, none of these are very distinct subnuclei, but rather blurred distinctions between cell types and location. The lateral reticular nucleus sends all of its projections to the cerebellum. The parvocellular portion of the LRN and the immediately adjacent magnocellular portion send most their projections to the vermis of the cerebellum. The rest of the magnocellular subnucleus sends its projections to the hemisphere regions of the cerebellum. The subtrigeminal nucleus sends its projections to the flocculonodular lobe. All of these efferent pathways are projected in an ipsilateral manner to the cerebellum, the most abundant of which are those to the vermis. This nucleus is also involved in the mediation of inspiration (in-breathing) with a part of the ventral r. nucleus. The afferent pathways to the LRN come from the spinal cord and higher brain structures. Most of the afferents come from the ipsilateral dorsal horn of the spinal cord and project exclusively to the parts of the LRN that do not receive input from the cortex. The spinal cord projections terminate mostly in the parvocellular region along with the adjacent magnocellular cells. This implies that most input from the spinal cord is relayed into the vermis (1).

Paramedian Reticular Nucleus
The paramedian nucleus reticularis sends its connections to the spinal cord in a mostly ipsilateral manner, although there is some decussation. It projects to the vermis in the anterior lobe, the pyramis and the uvula. The paramedian nucleus also projects to the contralateral PRN, the gigantocellular nucleus, and the nucleus ambiguous (1).

The paramedian reticular formation is adjacent to the abducens nucleus in the pons and adjacent to the occularmotor nucleus in the midbrain. The paramedian nucleus receives afferents mostly from the fastigial nucleus in the cerebellum and the cerebral cortex; however, the projections from the spinal cord are very sparse. The descending afferent connections come mostly from the frontal and parietal lobes; however the pontine reticular formation also sends projections to the paramedian reticular nucleus. There are also very sparse innervations from the superior colliculus. Lesions in the paramedian reticular nucleus have been shown to cause a stereotyped increase in the random patterns of motion in rats (19). The paramedian nuclei on either side of the brain stem have been shown to mediate the horizontal eye movements on their ipsilateral sides. It seems possible to suppose that that the random motion patterns of the above rats were caused by an inability to mediate their horizontal eye movements.

The Pontine Reticular Nucleus of the Tegmentum
The nucleus reticularis tegmenti pontis is also known to affect the cerebellum with its axonal projections. These efferent connections have been proven to project not only ipsilaterally, but also to decussate and project to the contralateral side of the vermis. It has also been shown that the projections from the tegmenti pontis to the cerebellar lobes are only crossed fibers. The n.r. tegmenti pontis also receives afferent axons from the cerebellum. This nucleus is known for its large amount of multipolar cells and its particularly reticular structure. The n.r. tegmenti pontis is topographically related to pontine nuclei (non-reticular), being just dorsal to them. The nucleus reticularis has been known to mediate eye movements, otherwise known as so-called saccadic movement. This makes sense concerning their connections as it would require a nucleus which receives and projects to the cerebellum to mediate that kind of complex circuitry. Also, behaviorally this makes sense as no one thinks about saccadic movements when scanning a room and the saccadic movements are not directly controlled by the cortex.

The nuclei of the cerebellum are the most traditionally studied mostly because it is easy to see which nuclei degrade when the cerebellum is amputated. The neurons of the lateral reticular formation are very important for reflexes and the mediation of posture. It has been shown in cats that electrical stimulation of the reticular formation can make a standing cat lie down. Conversely if the cat is stimulated in an alternate spot it can make a lying cat stand.