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Reticular Formation

Let’s talk about one of the oldest parts of our brain that controls our movements, the way we perceive pain, our sleep and even our consciousness – the reticular formation.

It is a group of nuclei, neurons and nerve fibres forming a meshwork in the brain stem. Its neurons have unusually long dendrites and integrate signals from most of the nerve fibres passing through the brain stem. The reticular formation has both ascending and descending pathways. Some of the functions of the reticular formation include:

  • Body posture
  • Eye movements
  • Reducing pain signals
  • Sleep-arousal cycle
  • Maintaining consciousness
  • Cardiovascular control
  • Breathing patterns
  • Filtering out noise

Studying the reticular formation is challenging because its nuclei do not in general represent specific functions or mechanisms. Instead many of its nuclei and neurons act in concert to maintain specific roles. I assume you’re somewhat familiar with the anatomy of the brain in order to understand the concepts below. With that said, let’s start with the history.

History

Coining the name

About 56 years after it was discovered by Johann Christian Reil. Another German neuroanatomist Otto Deiters (pictured above) coined the term the reticular formation. He used carmine stain to add colour to the nervous tissue, then separated individual neurons with a needle under a microscope making detailed depictions of neurons.

Discovering descending pathways

A few years later, Camillo Golgi came up with a significantly better method of staining neurons so that they can be examined under a microscope without separating them. Ramon y Cajal used that staining technique to further investigate the reticular formation and described it in detail in 1897. He noted that the neurons of the reticular formation branch out horizontally as well ascend and descend through the brainstem. Later, James Papez published his work on the reticulospinal (descending) tract in cats.

Golgi stained pyramidal neuron. Image by MethoxyRoxy, CC

Discovering ascending pathways

In 1935 Frederic Bremer published his studies where he described how the state of deep sleep in cats was induced by lesioning the brainstem. If he cut the brainstem between the midbrain and the pons, the cat would slip into a coma and never wake up. If he cut the brainstem at the medullary-spinal level, the cat would sleep and wake up as normal. These experiments were taken further by Giuseppe Moruzzi and Horace Magoun who managed to trigger coma in cats by destroying their reticular formation and separately managed to wake up cats by electrically stimulating their reticular formation. They proposed the concept of the ascending reticular activating system (ARAS).

Confirming the innate releasing mechanism

In 1961 Eric von Holst and Ursula von Saint-Paul electrically stimulated the reticular formation in chicken. A stuffed polecat, which is a natural predator of chicken, was placed near the birds. When the birds were not stimulated, they simply ignored the polecat. However a stimulated rooster would attack the polecat or even the face of the human handler. This supported the theory of the the motivation releasing mechanism that states that animals have built-in neural structures that trigger an automatic behavioural response based on specific stimuli.

Discovering new connections

In the 1960’s the nerve degeneration method was used to discover that the reticular formation receives signals about the body state from spinal cord, balance from the vestibular nuclei and gastrointestinal information from the solitary complex. This provided an insight into the role of the reticular formation in locomotion, in maintaining balance and posture and other functions. Methods based on axoplasmic transport in 1970’s showed further connections between hypothalamus an the reticular formation forming a circuit mediating behaviour.

Structure

Reticular formation nuclei (based on Bear, 2016, p. 144)

As you recall the nuclei and neurons in the reticular formation do not represent specific functions, instead many act together in complex activity involving many parts of the brain. Still, according to [1], certain groups of nuclei are recognised based on their cell structure, connections and functions:

  • precerebellar
  • raphe
  • central
  • cholinergic
  • catecholamine
  • parvocellular reticular area
  • parabrachial
  • superficial medullary

If you’d like to memorise the reticular formation nuclei please feel free to download and print this picture and practice identifying the nuclei a few times until you remember them.

Precerebellar Reticular Nuclei

These are the pontine reticulotegmental nucleus, the paramedian reticular nucleus and the lateral reticular nucleus. They all project into the cerebellum.

Name Function
Pontine reticulotegmental nucleus Mediates saccadic eye movements (unconscious control).
Paramedian reticular nucleus Coordinates eye movements (saccades and horizontal gaze).
Lateral reticular nucleus Assists with the cerebellum control of complex forelimb movements. Lesions here stop an increase in blood pressure as a response to exercise [2].

Saccades are fast eye movements. In order to perceive an image gaze needs to move around, locate important parts and build a mental “map” of an image. This is done via saccadic eye movements, very quick and unconscious shifts in eye gaze.

Raphe Nuclei

These are the nuclei adjacent to the midline (raphe = seam). In medulla these are the nucleus raphe obscurus, nucleus raphe magnus, and nucleus pallidus. In the pontine area they are the nucleus raphe pontis and inferior central nucleus. And in the midbrain there are the superior central nucleus and nucleus raphe dorsalis. Raphe nuclei have extensive connections with most of the CNS.

Many of these nuclei release serotonin which is a neurotransmitter thought to contribute to the feeling of well-being and happiness. It also has an effect on mood, appetite, sleep and cognitive functions. Raphe nuclei modulate (reduce) pain sensations via their spinal cord projections, contribute to the circadian rhythms and affect levels of alertness.

Name Function
Nucleus raphe obscurus Assists in the out-breathing reflex, stimulates gastointestinal motility via serotonin, modulates the hypoglossal nerve (controlling the tongue).
Nucleus raphe magnus Releases serotonin, inhibits pain in the spinal cord (analgesic effect), seems to play a role in homeostasis and temperature regulation [3].
Nucleus pallidus Activates fever as an immunoreaction, mediates tachycardia (an extremely high heart rate due to stress).
Nucleus raphe pontis Implicated in the muscular rigidity associated with anaesthesia [4].
Inferior and superior central nuclei The superior central nucleus seems to play a role in long-term memory formation.
Nucleus raphe dorsalis It is the largest serotonergic nucleus. It is an important nucleus in pain inhibition [5], it also seems to play a role in morphine withdrawal and narcolepsy.

Central Reticular Nuclei

This group includes the paramedian reticular nucleus (PPRF), the gigantocellular reticular nucleus, the cuneiform and subcuneiform nuclei in the midbrain, and the oral and caudal pontine reticular nuclei. The latter two nuclei are lateral but have similar connections and functions to the central group. The central group nuclei typically form long ascending (the central tegmental tract) and descending axons (part of the reticulospinal tract) as well as horizontal branches in the brain stem.

Name Function
Paramedian reticular nucleus Coordinates eye movements (saccades and horizontal gaze).
Gigantocellular reticular nucleus It is composed of “giant” neuronal cells and seems to play a role in the hypoglossal nerve (controlling the tongue) and in the out-breathing reflex.
Cuneiform nucleus Implicated in the stress related cardiovascular response [6].
Subcuneiform nucleus Its neurons are activated during gait processes [7].
Oral pontine reticular nucleus Involved in the mediation of REM sleep.
Caudal pontine reticular nucleus Mediates head movements, suppresses muscle tone during REM sleep, activates eye movements, seems to be involved in mastication and play a role in the grinding of teeth during sleep.

Cholinergic Nuclei

These nuclei use acetylcholine (ACh) as their neurotransmitter. This group includes the pedunculopontine nucleus and the smaller lateral dorsal tegmental nucleus. These nuclei may be involved in motor functions, locomotion, arousal and consciousness.

Name Function
Pedunculopontine nucleus Is involved in arousal, attention, learning, reward, locomotion and somatic motor functions. It is involved in planning of movement. It is also implicated in the generation and maintenance of REM sleep.
Laterodorsal tegmental nucleus May be involved in modulating sustained attention, alerting responses. It may also work with the pedunculopontine nucleus in the generation of REM sleep.

Catecholamine Nuclei

Catecholamines are hormones and neurotransmitters released in response to stress and include dopamine, adrenaline (epinephrine) and noradrenaline (norepinephrine).

This group consists of the locus coeruleus also known as the nucleus pigmentosus due to its bluish color and a few other noradrenergic and adrenergic groups.

The locus coeruleus is a part of the reticular activating system and is almost completely inactive during REM sleep. Emotional pain and stress trigger noadrenergic response; noradrenaline has an excitatory effect on most of the brain and mediates arousal. It also plays a role in sleep-wake cycle, attention, memory and cognition, emotions, posture and balance.

Parvocellular Reticular Nucleus

This area is located in the medulla and the pons. It receives inputs from the brain stem sensory nuclei and the cortex and projects to the trigeminal, facial, hypoglossal nuclei and the parabrachial area. It is involved in feeding reflexes and takes part in the exhalation process together with a part of the gigantocellular nucleus.

The Parabrachial Nuclei

Also known as the parabrachial complex, these are a group of nuclei surrounding superior cerebellar peduncles. They are involved in arousal, taste and some autonomic functions.

Name Function
Medial parabrachial nucleus Sends information from the taste area of the solitary nucleus to the thalamus.
Lateral parabrachial nucleus Mediates cardiovascular functions including blood pressure [8], is involved in behavioural thermoregulation [9].
Subparabrachial nucleus Regulates the breathing rate.

The Superficial Medullary Reticular Neurons

These are the neurons found in the posterior part of the medulla oblongata. They regulate cardiovascular functions and respiration.

Reticular Formation Functions

Filtering

Consider this situation. A tired parent sleeps through the loud noise of a nearby train line yet she wakes up at the slightest cough of her baby.

By filtering out the “background” information our brain makes our life much more bearable than it otherwise would be. The brain of people with schizophrenia may not be very effective at filtering out internal auditory information and as a result about 70% of people with schizophrenia end up hearing sounds or voices.

Popular science will have you believe that it is the reticular formation via its reticular activating system (RAS) that does all the filtering. The RAS certainly helps by filtering out some information that the reticular formation sends to the thalamus. However there’s a lot of other areas involved, for example the pulvinar nucleus of the thalamus, the frontal eye fields (FEF) area of the frontal lobe, or the lateral intraparietal cortex (LIP).

Sleep and Consciousness

Pain

The spinothalamic tract is the main pathway that transmits nociceptive (pain-related) signals. However when the spinothalamic tracts are severed, poorly localised pain can still be sensed via an ascending tract through the spinal afferents and their projections to the thalamus via the central group of reticular nuclei.

Upon arrival of the pain signals into the nuclei of the reticular formation, the latter reacts in a number of ways including increased alertness, attention, cardiovascular response and pain modulation.

There are prominent fibres from the nucleus raphe magnus and perhaps the gigantocellular reticular nucleus [10] projecting to the spinal trigeminal nucleus and the dorsal horns of most laminae. This pathway assists pronociceptive and antinociceptive systems of the reticular formation nuclei to modulate (increase or decrease) the perception of pain.

The area between the spinal trigeminal nucleus and the lateral reticular nucleus (including the LRt itself) reacts to pain by promoting the “fight or flight” and cardiovascular (i.e. increasing blood pressure) response.

In addition, the area around the cerebral aqueduct, called the periaqueductal gray, seems to play a role in pain control. Electrically stimulating the periaqueductal gray area results in analgesia.

It is thought that one of the reasons of chronic pain can be imbalance of the pain modulation system towards pain facilitation [10].

Motor Functions

The reticulospinal tract is one of the major motor tracts. It originates in the pontine reticular nuclei and the gigantocellular nucleus of the medulla and ends up synapsing on the interneurons in the ventral horn of the spinal cord. Specifically, the medial reticulospinal tract originates in the pontine nuclei and descends ipsilaterally. It is responsible for extensor muscles (e.g. extending legs for postural suport). The lateral reticulospinal tracts originates in the medulla and travels bilaterally, and enables flexor muscles while inhibiting extensors. Together with the corticospinal tract, the reticulospinal tract is involved in locomotion (walking, running) and in maintaining posture and balance.

In addition to the reticulospinal tract, the reticular formation controls locomotion indirectly by influencing the activities of the cerebellum, red nucleus, substantia nigra, the cerebral cortex and other areas.

Notice that maintaining posture does not mean flexing or extending just one group of muscles. For example, when lifting a weight, a whole number of muscles (legs, back, neck, etc) are instantly and unconsciously activated by the vestibular and reticular formation nuclei in an anticipatory balance maintenance.

Breathing

Breathing can be involuntary controlled by the brain stem or voluntary based on the input from the cerebral cortex affecting the respiratory nuclei in the brain stem or directly the motor neurons of intercostal muscles. There are three major groups of neurons involved in breathing.

Medullary neurons involved in breathing are divided into the dorsal respiratory group (DRG) with the centre in the solitary nucleus and the ventral respiratory group (VRG) centred around the nucleus ambiguus. Reticular formation neurons project to motor neurons that control intercostal muscles and the diaphragm. During breathing DRG promotes inhalation while VRG activation causes exhalation. These two groups inhibit each other to set the basic rhythm of respiration.

The pontine respiratory group (PRG) interacts with the medullary breathing centres to ensure smooth respiratory rhythm. The PRG is divided into the apneustic and pneumotaxic centres. The former stimulates the inspiratory neurons in the medulla while the latter inhibits them. As an example, the apneustic centre may become active during exercise when the oxygen requirement is higher.

Respiratory centres of the CNS. Image by OpenStax College, CC

Other than input from the cerebral cortex and the hypothalamus, the respiratory neurons receive information about the levels of oxygen, carbon dioxide and pH via afferents from the central chemoreceptors in the medulla and peripheral chemoreceptors in the aortic and carotid bodies.

Bifurcation of the carotid artery (location of the chemoreceptors). Image by Gray’s Anatomy, public domain

Cardiovascular Control

When the medial part of the reticular formation of the medulla is stimulated, this slows down the heart rate and lowers blood pressure (depressor effect). Stimulating the lateral part has the opposite effect [1].

Nucleus pallidus, cuneiform nucleus [6] and the lateral parabrachial nucleus [8] seem to mediates cardiovascular functions including blood pressure.

Sources

  1. John A. Kiernan, Nagalingam Rajakumar. 2014. Barr’s The Human Nervous System: An Anatomical Viewpoint.
  2. Gary A. Iwamoto et al. 1982. Effects of lateral reticular nucleus lesions on the exercise pressor reflex in cats.
  3. David C. M/ Taylor. 1981. The effects of nucleus raphe magnus lesions on an ascending thermal pathway in the rat.
  4. Blasco T. A. et al. 1986. The role of the nucleus raphe pontis and the caudate nucleus in alfentanil rigidity in the rat.
  5. Wang Q. P., Nakai Y. 1994. The dorsal raphe: an important nucleus in pain modulation.
  6. Korte S. M., Jaarsma D, Luiten P. G., Bohus B. 1992. Mesencephalic cuneiform nucleus and its ascending and descending projections serve stress-related cardiovascular responses in the rat.
  7. B. Piallat et al. 2009. Gait is associated with an increase in tonic firing of the sub-cuneiform nucleus neurons.
  8. Pamela J. Davern. 2014. A role for the lateral parabrachial nucleus in cardiovascular function and fluid homeostasis
  9. Takaki Yahiro et al. 2017. The lateral parabrachial nucleus, but not the thalamus, mediates thermosensory pathways for behavioural thermoregulation
  10. Isabel Martins, Isaura Tavares. 2017. Reticular Formation and Pain: The Past and the Future.

Credits

  1. Title image courtesy of Wikipedia (public domain).

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