Reticular Formation George R. Leichnetz, Ph.D.

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1 Reticular Formation George R. Leichnetz, Ph.D. OBJECTIVES 1. To understand the anatomical and functional organization of the brainstem reticular formation into three general regions: median (raphe), medial (magnocellular), and lateral (parvicellular) regions. 2. To understand the location of neurotransmitter-specific cell groups in the reticular formation, and their role in the regulation of states of consciousness (wakefulness and sleep) 3. To understand the anatomical basis of the concept of the physiological "reticular activating system" (RAS) and its effects on the cortical EEG (sleep/walking), and to appreciate the complex roles of the reticular formation in somatomotor, oculomotor, and visceromotor (autonomic) functions. I. INTRODUCTION A. DEFINITIONS The term "reticular formation" was first used by Forel (1877) for the core of the brainstem from the rostral midbrain to the caudal medulla, consisting of a loosely arranged network of diffuse neurons surrounding the more clearly delineated principal motor and sensory nuclei and tracts. The reticular formation is phylogenetically old and coordinates involuntary vital functions (automatic visceromotor activities, such as heart rate, respiration) and levels of consciousness (awake vs. sleep). Whereas in past years it was thought to lack any obvious nuclear organization, studies of its connections and neurotransmitter chemistry in recent years have led to a better appreciation of its organization.

2 B. SUBDIVISIONS OF THE RETICULAR FORMATION/ NUCLEI Because of its diffuse nature, it is difficult to distinguish distinct cell groups. Consequently, the naming of nuclei is done on the basis of: Region (e.g., oral pons vs. caudal pons), Cell size (e.g., magnocellular (large-cell) vs. parvicellular (small-cell)) Neurotransmitter chemistry (e.g., noradrenergic cell groups A1-A10; B1-B9, and cholinergic Ch5, Ch6) C. GENERAL REGIONAL ORGANIZATION There are three longitudinal regions in the reticular formation in the core of the brainstem. Median Region - serotonergic cell groups (B1-B9) in the midline brainstem raphe; give rise to ascending and descending serotonergic (5-HT) projections. Medial Region - contains the largest cells of the reticular form (magnocellular); projects rostrally into the thalamus and caudally to spinal cord (reticulospinal tracts). Lateral Region - located most laterally; it contains smaller cells (parvicellular), NE cell groups A1-A7 and Ch5, Ch6, vital centers (respiratory, cardiac), receives collaterals from asc. sensory systems (somatic and visceral); projects rostrally to hypothalamus, and caudally to spinal cord. The reticular formation. Semidiagrammatic representation in a dorsal view of the brain stem. left: cytoarchitecture; Right: subdivisions/ nuclei. The cranial nerve motor nuclei are darkly shaded. From Nieuwenhuys et al, The Human Central Nervous System

pallidus (B1). The medial region (magnocellular) contains the nucleus reticularis gigantocellularis.

3 Brainstem section of the Rostral Medulla showing Median, Medial, and Lateral regions of the Reticular Formation at this level. At this level (above), the median region (raphe) contains the nucleus raphe magnus (B3), nucleus raphe obscurus (B2) and nucleus raphe pallidus (B1). The medial region (magnocellular) contains the nucleus reticularis gigantocellularis. The lateral region (parvicellular) contains neurotransmitter-specific cell groups, such as noradrenergic (NE) cell groups A1-A3 and vital centers concerned with the control of respiration.

II. MEDIAN REGION (Raphe) On the midline of the brainstem from caudal midbrain to medulla, the raphe consists of: dorsal raphe nucleus, superior central nucleus, nucleus raphe pontis, nucleus raphe

4 II. MEDIAN REGION (Raphe) On the midline of the brainstem from caudal midbrain to medulla, the raphe consists of: dorsal raphe nucleus, superior central nucleus, nucleus raphe pontis, nucleus raphe magnus, nucleus raphe obscurus, nucleus raphe pallidus. These cell groups are serotonergic and have "B" classifications according to Dahlstrom and Fuxe terminology (see also Leichnetz neurotransmitter lecture). The midbrain raphe gives rise to ascending serotonergic projections to higher levels of the CNS (e.g., cortex, thalamus) involved in states of consciousness (awake vs. sleep). Lesion of the midbrain raphe (dorsal raphe nucleus, superior central nucleus) produces prolonged awake state (ie. EEG is desynchronized) and prevents going into the initial stages of sleep (EEG synchronization; called slow wave sleep). The medullary raphe gives rise to descending (raphespinal) projections to the spinal cord involved in analgesia (nucleus raphe magnus to dorsal horn), gain-setting of somatomotor neurons (pallidus and obscurus to intermediate and ventral horn), and autonomic (visceromotor) responses (to lateral horn, intermediolateral sympathetic cell column).

5 Serotonergic Projections From Niewenhuys, The Human Central Nervous System From Carpenter and Sutin, Human Neuroanatomy

6 III. MEDIAL REGION The median region is the large-celled (magnocellular) portion of the reticular formation. The large cells are found primarily in the pontine reticular formation (nuc. reticularis pontis oralis and caudalis) and rostral medullary reticular formation (nuc. reticularis gigantocellularis). These give rise to long ascending (reticulothalamic) projections to the thalamus and long descending projections to the spinal cord (reticulospinals). A. CYTOLOGY The largest cells of the medial region of the reticular formation are located primarily in the pons and medulla. From rostral to caudal these contiguous cell groups consist of the nuc. reticularis pontis oralis, nuc. reticularis pontis caudalis, and nuc. ret. gigantocellularis. Most of its large neurons have bifurcating axons with long ascending and descending processes. The ascending processes extend rostrally to terminate in the intralaminar nuclei (reticulothalamics) of the thalamus, and constitute the anatomical substrate of the classic "reticular activating system" of Moruzzi and Magoun. The descending processes of the large cells extend caudally in the pontine and medullary reticulospinal tracts to terminate in the medial portion of the ventral horn of the spinal gray (laminae VII, VIII; motoneurons involved with prox. limb and axial musculature for postural mechanisms). Numerous axon collaterals are given off this system. The cytology of this region of the brainstem is indicative of its extensive rostro-caudal influence on the central nervous system. Ascending collaterals are reticulothalamics involved in reticular activating system ( RAS). Descending collaterals project to spinal cord "reticulospinals". From Brodal, Neurological Anatomy

7 B. RETICULOSPINAL TRACTS 1. Pontine Reticulospinal Tract - originates from the large cells of the nucleus reticularis pontis oralis (NRPO) and caudalis (NRPC); projects primarily ipsilaterally (uncrossed) to the medial part of the ventral horn of the spinal gray, affecting motor neurons concerned with axial and proximal limb musculature. Stimulation produces excitation of extensor spinal motoneurons. From Carpenter and Sutin, Human Neuroanatomy 2. Medullary Reticulospinal Tract - originates in the nucleus reticularis gigantocellularis (NRGC); predominantly ipsilateral (uncrossed) to the medial portion of the ventral horn of the spinal gray. The function of this tract is more complex than the pontine reticulospinal tract. Stimulation of the rostral NRGC produces excitation; stimulation of the caudal/ventral NRGC produces inhibition. Classically, the medullary reticulospinal tract has been thought to be inhibitory on deep tendon reflexes. C. EYE MOVEMENT-RELATED NUCLEI (see also Dr. Leichnetz's lecture on the oculomotor system) 1. Rostral Midbrain Reticular Formation rostral imlf and interstitial nucleus of Cajal - center for vertical gaze. 2. Paramedian Pontine Reticular Formation (PPRF) - the caudal medial pontine reticular formation (NRPC) contains the center for horizontal gaze. Its large cells have collaterals that terminate in the ipsilateral abducens nucleus and cervical spinal

8 cord involved in the control of horizontal gaze (eye and head movement). The descending processes travel in the pontine reticulospinal tract. The PPRF contains premotor excitatory and inhibitory neurons which collectively orchestrate horizontal saccadic eye movements. Unilateral lesion of the PPRF produces an ipsilateral conjugate gaze paralysis - eyes deviated contralaterally, cannot look into ipsilateral visual hemifield. Note: the center for vertical gaze is located in the rostral midbrain reticular formation in the rostral interstitial nucleus of the MLF (downward gaze) and interstitial nucleus of Cajal (upward gaze) so that the clinician can diagnose the level of brainstem lesions on the basis of deficits in vertical eye movement (midbrain lesion) vs. horizontal eye movement (pons lesion). The pontine reticular formation also orchestrates rapid eye movements (REM) and neck muscle atonia of paradoxical sleep. D. RETICULAR ACTIVATING SYSTEM AND STATES OF CONSCIOUSNESS Moruzzi and Magoun (1949) - demonstrated that large amplitude stimulation of the reticular core of the brainstem produced arousal, whereas large lesions produced sleep, leading to the view that the brainstem reticular formation is responsible for states of consciousness. They originated the concept of reticular activating system. The anatomical basis for this function was thought to be related to the fact that the reticular formation receives collaterals from ascending sensory systems and projects to non- specific thalamic nuclei (e.g., intralaminar nuclei) which have diffuse projections to the cortex which could potentially activate broad regions of cortex.

Reticular Activating System More recent research on mechanisms of consciousness have shown that it is more complex, involving structures in the brainstem reticular formation beyond the medial region,

9 Reticular Activating System More recent research on mechanisms of consciousness have shown that it is more complex, involving structures in the brainstem reticular formation beyond the medial region, in median and lateral regions. For example, the deepest sleep/paradoxical (dream) sleep results in muscular atonia (i.e., somatomotor modulation, spinal cord) with rapid eye movements (oculomotor modulation), while maintaining involuntary automated visceromotor activities (steady rate of breathing, heart rate). Moruzzi and Magoun's large current stimulation probably spread outside the medial region into reticular formation nuclei in adjacent regions: locus ceruleus (A6, noradrenergic), pedunculopontine nucleus (Ch5, cholinergic), and raphe nuclei (B7, B8, serotonergic) in lateral and median regions. Main Point: Behavioral changes that occur in various states of consciousness require the coordination of all regions of the brainstem reticular formation - medial, median, and lateral. Reduction in cerebral serotonin (i.e., lesions of the midbrain raphe, dorsal raphe nucleus and superior central nucleus) produce a prolonged awake state (arousal) with desynchronization of the EEG; stimulation of the midbrain raphe produces synchronization of the EEG. Cholinergic neurons in the dorsolateral pontine tegmentum (pedunculopontine nucleus) are inhibited during the waking state by aminergic neuromodulators. At onset of non-rem sleep cholinergic neurons are inactive, but as n-rem sleep proceeds ACh neurons develop a spontaneous burst pattern, providing the thalamus with strong pulses that cause the onset of REM sleep. Injection of cholinergic agonists into the DL pontine tegmentum can directly precipitate REM sleep (with activated EEG, EMG atonia, REM and PGO waves) from waking with no intervening non-rem sleep.

10 IV. LATERAL REGION The lateral region is the small-celled (parvicellular) portion of the reticular formation; contains NE and Ch cell groups. Through ascending NE projections to the hypothalamus and descending projections to autonomic regions of the medulla and spinal cord, it coordinates a variety of visceromotor activities. It contains vital centers for respiratory and cardiac function. It receives sensory inputs through collaterals off ascending sensory systems (somatosensory, auditory, vestibular), and visceral sensory from the solitary nucleus (which receives central connections of all GVA and SVA fibers in C.N.'s VII, IX, and X). Important NE and Ch Cell Groups in the Lateral Region: (See also Dr. Leichnetz's lecture on CNS Neurotransmitter Pathways) A. Control of Blood Pressure NE cell group A5, located in the caudal lateral brainstem reticular formation, is involved in blood pressure regulation A5- in caudal ventrolateral pontine tegmentum; ascending projections to hypothalamus; receives visceral afferent (GVA) input from solitary nucleus related to blood pressure from carotid sinus via cranial nerve IX; descending projections to dorsal vagal nucleus (parasympathetic preganglionics via C.N. X to heart), medullary respiratory centers, intermediolateral cell column (e.g., sympathetic preganglionics to heart); concerned with blood pressure regulation. It has both ascending and descending connections. Its ascending projections go to the hypothalamus for coordination with other higher-level autonomic function. Its descending projections go to vasomotor centers of the caudal brainstem (e.g., solitary nucleus, dorsal vagal nucleus) and autonomic centers in the spinal cord (e.g., sympathetic preganglionic neurons in the intermediolateral cell column).

11 Connections of the A5 NE cell group are representative of other nuclei in the lateral medullary and pontine reticular formation, i.e., ascending conn. s to hypothalamus, desc. conn. s to spinal cord From: Carpenter, Core Text of Neuroanatomy From Niewenhuys, The Human Nervous System B. Control of Respiration Dorsal Respiratory Area - in dorsal lateral medullary reticular formation surrounding the solitary tract and nucleus. It receives visceral afferent input from solitary nucleus (related to blood pco2 from carotid body via C.N. IX); concerned with the chemical aspects of respiration).

12 Ventral Respiratory Area - in the ventral lateral medullary reticular formation surrounding the nucleus ambiguus (NE cell groups A1-A3). It has descending projections to cervical spinal cord (phrenic motor nucleus to diaphragm), thoracic spinal cord lateral horn (intermediolateral cell column, i.e., sympathetic preganglionics to lung), and ventral horn (intercostal motoneurons); concerned with the mechanical aspects of respiration, i.e., breathing patterns. These centers coordinate responsiveness to changes in pco2 (blood chemistry, carotid body) through reflex connections with the dorsal vagal nucleus and changes in patterns of ventilation (rate of respiration) through spinal projections to somatomotor and autonomic nuclei (IML cell column). Dorsal and Ventral Respiratory Areas C. Effects on States of Consciousness A6- Locus ceruleus- Principal source of norepinephrine (NE) in the brain; located in the rostral peri-ivth-ventricular gray; ascending projections to all higher levels of the CNS; descending projections to spinal cord (affects the entire CNS neuroaxis); involved in arousal (awake state); central release of NE produces anxiety under stress Ch5- Pedunculopontine nucleus (PPN) in dorsolateral pontine tegmentum surrounding the superior cerebellar peduncle; cholinergic innervation of all subcortical structures; ACh trigger for onset of REM (paradoxical, dream) sleep (source of ponto-geniculo-occipital spikes in REM EEG)

13 SUMMARY: PRINCIPLES OF ORGANIZATION Three anatomical/functional regions of the brainstem reticular formation. All three regions have both ascending and descending projections. Median (Raphe) - predominantly serotonergic (5-HT)-containing neurons. Ascending 5-HT projections to higher centers originate from the midbrain raphe, and are concerned with sleep/waking. Descending 5-HT projections to spinal cord originate in the medullary raphe. Those from N.r. magnus to dorsal horn affect pain modulation; those from N.r. obscurus and pallidus to intermediolateral cell column (lat. horn) affect autonomics (visceromotor) and to ventral horn affect movement (gain-setting; state of readiness; somatomotor). Medial - contains the largest cells (magnocellular), primarily in pons and medulla. Many cells have bifurcating axons where ascending collaterals are reticulothalamics to intralaminar complex of the thalamus (part of "reticular activating system"), and descending collaterals make up the classical pontine and medullary reticulospinal tracts, which terminate in the medial ventral horn affecting axial and proximal limb musculature. Contains eye movement-related PPRF. Lateral - contains smaller cells (parvicellular). It receives collaterals off ascending lemniscal systems (somatosensory, auditory) and visceral afferents from solitary nucleus. It contains respiratory centers. It has ascending projections to the hypothalamus, and descending projections to the phrenic motor nucleus and intermediolateral cell column of the spinal cord, affecting respiration, heart rate, and blood pressure regulation. A Self-Assessment is available for this lecture.

Page 1 L 58. The University of Connecticut Schools of Medicine and Dental Medicine Humans Systems: Organ Systems /2013 RETICULAR FORMATION

Page 1 L 58. The University of Connecticut Schools of Medicine and Dental Medicine Humans Systems: Organ Systems /2013 RETICULAR FORMATION Page 1 L 58 Douglas L. Oliver, Ph.D. The University of Connecticut Schools of Medicine and Dental Medicine Humans Systems: Organ Systems 1 2012/2013 RETICULAR FORMATION Lecture Lecture: Douglas Oliver