Download cerebellum

Ascending Reticular
Activating System &
Diffuse Modulatory
Systems
Objectives
1. Describe
the anatomy of the reticular
formation of the brainstem
2. Discuss the general and specific roles of the
reticular formation in control of wakefulness,
sleep, and motor
3. Describe the anatomy of the dopaminergic,
cholinergic and monoamine systems of the
CNS
4. Discuss the role of these systems in
modulating forebrain areas involved in mood
and executive functioning
Reticular Formation: What is it?
 Archaic brain structure (so-called “reptilian
brain”)
 Conveniently located at the interface
between spinal cord and higher brain
structures
 Consists of network of nuclei located
throughout the brainstem; extending from
the spinal cord to the hypothalamus
 Active in both directions: ascending and
descending pathways
 Present in all vertebrates, including reptiles
 Essential for survival
Where is it?
What does it do?
It is involved in a wide range of functions:
 Alertness
 Sleep/Wake cycle
 Pain modulation
 Motor regulation
 Autonomic functions
 Diffuse modulatory systems
The reticular formation is
anatomically organized
 Longitudinally
 Transversely
(Modified with permission from Barr ML, and Kiernan JA: The Human Nervous System,
1993) in: Essential Neuroscience, Allan Siegel, Ph.D; Hreday N. Sapru PhD
Nucleus reticularis pontis
caudalis (caudal pons)
Light
green
Nucleus reticularis lateralis
(lateral)
Blue
Nucleus reticularis
gigantocellularis
(magnocellular)
Light
blue
Nucleus funiculi reticularis
(lateral medulla)
Red
Nucleus reticularis pontis
oralis (rostral pons)
Pink
Nucleus reticularis ventralis
(ventral)
Brown
Nucleus reticularis tegmenti
(tegmentum)
Light
brown
Nucleus reticularis
paramedianis (paramedian)
Green
Formation reticularis
mesencephali (midbrain)
Locus coeruleus (“nucleus
pontis”)
Raphe nucleus
From: Kmayer, W. and Pilleri, G.The Brainstem Reticular Formation and its Significance for Autonomic
and Affective Behavior. Montreal: Hoffman-LaRoche Ltd., 1966.
yellow
RF: General functional considerations
 RF is involved in a large array
of functions including:
 Long distance modulation
 Intra-RF sensory and motor
integration
 Synchronization of
downstream and upstream
processes


Role in Alertness
ARAS - “Ascending Reticular Activating System”
Integrates afferents from all sensory systems:
 Direct afferents from somatosensory, taste, auditory and
vestibular
 Indirect afferents from olfactory (via limbic structures) and
visual (via colliculus superior).
 In process, signals
1. Loses their specificity
2. Are summed
3. Projected to the thalamus
4. Modulate global level of alertness
 Modulation influences:
 Cortical excitability
 Reaction to new stimuli
 State of consciousness
In alertness modulation, RF
 Scans & integrates multiple sensory
information
 filters out repetitive stimuli
 accentuates new stimuli with impact for
survival
 projects to non-specific (intralaminar)
nuclei of the thalamus
 which in turn projects to wide cortical
regions, especially to the frontal lobes
EEG features:


Absence of active sensory input: Quiet awake state and
drowsiness: Alpha rhythm (synchronized cortical electrical
pattern)
Active sensory input: Alertness: Beta rhythms (Low amplitude,
with multiple/varying frequencies)
in: Essential Neuroscience,
Allan Siegel, Ph.D; Hreday N. Sapru PhD
© Dr. Gershon Leisman, 2009
Pathology: Coma
 Lesions of the RF are associated with loss of
consciousness
Role in Sleep
 “ARAS” was earlier believed to be the sole
mechanism responsible of wake/sleep cycles:
 activation associated with wakefulness
 deactivation associated with sleep
 Concept not supported by newer information
 Sleep is now believed to be active process
 depending on activation of a network involving RF and
hypothalamus.
 Five sleep stages corresponding to five
patterns of brain waves (as measured by
EEG):
 REM sleep (rapid eye movement, dream stage)
 Non-REM stage 1
 Non-REM stage 2
 Non-REM stage 3
 Non-REM stage 4 (deep sleep)
EEG characteristics of sleep stages
From Bear MF, et al.: Neuroscience: Exploring the Brain, 2001
Looking at Sleep - Awake
Looking at Sleep – REM
Looking at Sleep – Stage 1
Looking at Sleep – Stage 2
Looking at Sleep – Stage 3
Looking at Sleep – Stage 4
Physiological Changes During non-REM
and REM sleep
Characteristics of Three
Functional States of the Brain
Sleep and Learning
Learn A
Learn
A
Learn A
Learn A
8 Hrs.
Sleep
8 Hrs.
Waking Activity
8 Hrs.
Sleep
8 Hrs.
Waking
Activity
%
Savings
Relearn A
79
49
Relearn A
8 Hrs.
Waking
Activity
Relearn A
81
8 Hrs.
Sleep
Relearn A
51
LEARNING AND ECS
Homeostatic Decline in Recall
Grades as a Function of Hours of
Wakefulness
Neonatal and Infant Sleep Patterns
Sleep +/-17 hrs with 50% of this time in
REM.
Adult NREM/REM pattern does not
emerge for several months after birth.
At 32 weeks REM/NREM cycles
distinguished When infants “sleep through
he night.”
Brainstem reaches developmental high
btwn 28- 31 wks.
Neonatal and Infant Sleep Patterns
Similarities
Both newborn & near-term fetuses (as
young as 36-38 weeks) display high
arousal sleep states accompanied by
REM.
Neonates and the fetus display similar
wake-sleep cycles and,
REM & non-REM periods similar to
adults.
Neonatal and Adult Sleep Patterns
Differences
Neonates & Fetuses
Immediately enter REM &
demonstrate ↑ voltage fast activity
(deep"paradoxical" sleep)
Initially have 2 sleep cycles, REM &
non-REM (active/quiet sleep). Only +/3-4 months does adult sleep pattern
appear.
Neonatal and Adult Sleep Patterns
Adults
Adult sleep onset characterized by slow
wave, non-REM (light sleep) cycle.
Sleep cycle followed by intermediate sleep
stages culminating (+/- 90 min.) in deep
sleep demonstrated by REM and irregular
fast EEG activity (as if the brain were
highly aroused: hence, the term
"paradoxical sleep").
TMS, Sleep, and Functional
Connectivity
Sleeping subject undergoes TMS. Tononi found
why consciousness fades when we fall into
deep sleep.
TMS, Sleep, and Functional
Awake
Connectivity Asleep
TMS
of
awake
subject. Cells in a
specific region of
brain can relay
signals to critical
regions
mediating
perception, thought
and action.
TMS of subject asleep.
Stimulation
quickly
extinguishes & activity
does not propagate
far.
Fading
consciousness in sleep
result of functional
disconnections.
WE POSSESS, ESPECIALLY AS
ADULTS, LOCALIATION OF
FUNCTION, BUT THAT IS NOT
ENOUGH TO EXPALIN THE
CAPCITY FOR PLASTICITY,
REGENERATION, SPONTANEOUS
RECOVERY, AND OPTIMIZATION
Plastic Brain Development in Childhood
(L)CT of normal
brain; (R) Schiavo's
2002 CT showing
hydrocephalus & loss
of brain tissue.
CT of congenitally
hydrocephalic
female aged 18. FS
IQ= 118.
Pictorial History of Adult with Congenital
Hydrocephalus: A Case for Plasticity
CT of congenitally
hydrocephalic
female aged 18
Image of rCBF of
congenitally
hydrocephalic
female aged 18
↑CMRGlc during 3-10 yrs. corresponds to era of exuberant connectivity needed for energy
needs of neuronal processes. > by a factor of 2 compared to adults. PET shows relative
glucose metabolic rate. We see the complexity of dendritic structures of cortical neurons
consistent with expansion of synaptic connectivities and increases in capillary density in
COMPUTATIONAL
NEUROSCIENCE
SUPPORTS THE
UNDERSTANDING OF
PLASTICITY
haracterization, Organization & Development o
Large-Scale Brain Networks in Children Usin
Graph-Theoretical Metrics
haracterization, Organization & Development o
Large-Scale Brain Networks in Children Usin
Graph-Theoretical Metrics
Functional connectivity along the posterior-anterior & ventraldorsal axes showing ↑ subcortical connectivity (●), ↓paralimbic
connectivity (●) in children, compared to young-adults. Brain
regions plotted using y and z coordinates of centroids (in mm), 430
pairs of regions show ↑ r’s in children & 321 pairs showed
RF nuclei implicated in sleep
 Initiation of the REM state:
 pedunculopontine nucleus and lateral dorsal nucleus
 cholinergic pontine nucleus of the RF
 project to other parts of the RF, hypothalamus, basal forebrain and
thalamus
 Modulation of sleep:
 Locus coeruleus (noradrenaline)
 Raphe (serotonin)
Pathology: Sleep
Lesion or neurochemical imbalance in the
sleep associated RF nuclei produce sleep
pathology:
 Narcolepsy
 Sleep apnea
 Sleep impairments in depression and posttraumatic disorder
Role in Pain modulation
 RF receives and filters pain and temperature afferents
from the spinoreticulothalamic pathway
 Transmits pain information to the thalamus
 Top-down feedback from the midbrain periaqueductal
gray (PAG) to the raphe nucleus of the midbrain
 PAG produce enkephalin that stimulates serotonin
neurons from the raphe, which in turn modulate
(inhibition) the nociceptive pathway at the level of
the spinal cord
Role in Motor activity
Reticular formation (precerebellar & lateral groups):
 Receives extensive afferents from sensorimotor cortex
 Generates feedback loop with cerebellum
 Input from the cortex is integrated in that loop
 Projects to the spinal cord (via reticulospinal fibers)
 Modulates motorneuron activity of the extensor muscles
(e.g. modulation of postural reflex in reaction to a fall)
 Influences both voluntary and reflex motor functions, as
well as posture
 RF nuclei use two (2) descending pathways (medial
and lateral reticulospinal tracts) to influence alpha
and gamma motoneurons of extensors in the spinal
cord
 Excitatory (facilitatory) output arising from RF nucleus
located in the pons
 Inhibitory output arising from RF nuclei located in the
medulla
 Combined together, they modulate muscle tone and
regulate posture
Reticular formation also modulates eye movements
 Influences oculomotor saccade and gaze:
 integrates inputs from the cortex (frontal eye
field) and the vestibular nuclei
 controls horizontal gaze
 refines posture with position of head in space
 Must be inhibited to allow saccades
Pathology: Motor
Disruption of RF-cerebello-cortical
network results in significant motor
deficits such as:
 spasticity
 rigidity
 hypertonicity
Role in Autonomic functions
Reticular formation
 Receives inputs from cranial nerves
(glossopharyngeal IX and Vagus X)
 Modulates blood pressure, heart rate and
respiration
 Via two descending pathways: inhibitory and
excitatory
 Additional inputs from hypothalamus, midbrain
PAG, amygdala and prefrontal cortex, participate in
regulation of blood pressure
Summary of
organization and
roles of the
Reticular
Formation
SENSORY
INPUTS
Spinal cord
[Pain/temperature signal]
Cranial nerves
[Direct sensory signal]
Limbic structures
[secondary sensory signal]
Colliculus superior
[secondary sensory signal]
Spinal cord
[Ascending pain
modulation fibers]
R.F.
OUTPUTS
Diffuse modulatory systems
Parvocellular nuclei
of pons and medulla
Cerebral cortex
Magnocellular nuclei
of pons and medulla
Thalamus
Peri Aqueductal Gray
(enkephalinergic inhibition)
Spinal cord
[Descending pain
modulation fibers]
MOTOR
INPUTS
R.F.
OUTPUTS
Motor cerebral
cortex
Cerebellum
Magnocellular nuclei
(a) of the pons
[excitatory]
Spinal cord
[descending fibers]
(b) of the medulla
[inhibitory]
Alpha & Gamma
Motor neurons
[extensor muscles]
AUTONOMIC: Respiration
INPUTS
Cranial nerves IX & X
R.F.
Solitary nucleus
(a) ventral part
[expiration]
(b) dorsal part
[inspiration]
Hypothalamus
Limbic system
Medial parabrachial nucleus
[modulatory]
OUTPUTS
Spinal cord
[descending fibers]
AUTONOMIC pathway:
blood pressure and heart rate
INPUTS
Cranial nerves IX & X
R.F.
OUTPUTS
Solitary nucleus
Spinal cord
[descending fibers]
Ventrolateral Medulla
Hypothalamus
Periaqueductal Gray
Amygdala
AUTONOMIC pathway:
top-down modulation
INPUTS
R.F.
OUTPUTS
Prefrontal cortex
Hypothalamus
Amygdala
Periaqueductal Gray
Tegmental nucleus
Solitary nucleus
Spinal cord
[descending fibers]
Learning objectives
 Describe the anatomy of the reticular formation of the
brainstem
 Discuss the general and specific roles of the reticular formation
in control of wakefulness, sleep, pain, motor and autonomic
activities
 Describe in detail the anatomy of the dopaminergic,
cholinergic and monoamine systems of the CNS
 Discuss the role of these systems in modulating forebrain areas
involved in mood and executive functioning
 Describe the role of these transmitter systems in reward
pathways and in models of addiction
Diffuse modulatory systems of the reticular
formation – what is it?
 Consists of small groups of neurons that diffuse
neurotransmitters throughout large brain areas (by “volume
transmission”)
 These groups of special RF nuclei regulate diverse populations of
neurons
 Process of diffuse modulation differs from direct synaptic
transmission:
 Neurotransmitter is not quickly reabsorbed by the neuron
 Neurotransmitters is released in the space between neurons
(not necessarily at the synapse level)
Noradrenergic DMS: Synopsis
System
Origin
Targets
Effects
Noradrenaline
system
Locus
coeruleus
adrenergic receptors in:
* spinal cord
* thalamus
* hypothalamus
* striatum
* neocortex
* cingulate gyrus
* hippocampus
* amygdala
* arousal
* reward system
* sleep
* mood
Lateral
tegmental field
* hypothalamus
Norepinephrine
system
Cells of origin located in
pons/upper medulla,
mainly in:
 N. Locus Ceruleus (NLC)
 Lateral tegmental field
J. Nolte: The Human Brain, p. 281
Receives afferents from:
 Brain stem
 Hypothalamus
Sends extensive efferents to:
 Spinal Cord and Cerebellum
 Midbrain (VTA)
 Diencephalon
 Limbic system
 Basal Forebrain nuclei
 Somatosensory cortex
Barr’s, 2005: The Human Nervous System. P. 165
Locus ceruleus
Locus ceruleus
Key functional associations:
 Arousal: Most active in awake, attentive animals
 Sleep:
 Less active in non-REM sleep
 Non-active in REM sleep
 Mood:
 High activity associated with Mania
 Low activity associated with depression
 PCP (Phencyclidine) and Amphetamine potentiate activity
of NLC (probably mediated via Dopamine)
Lesions damaging N. Locus Ceruleus (NLC) and related nuclei produce arousal
difficulties, somnolence and has been associated with depressive disorders)
Test your knowledge
 Where is the largest collection of
Norepinephrine (NE) projecting cells
located in the human brain?
Serotonergic DMS: Synopsis
System
Origin
Targets
Effects
Serotonin
system
Caudal
dorsal raphe
nucleus
Serotonin receptors in:
* deep cerebellar nuclei
* cerebellar cortex
* spinal cord
Rostral
dorsal raphe
nucleus
Serotonin receptors in:
* thalamus
* striatum
* hypothalamus
* nucleus accumbens
* neocortex
* cingulate gyrus
* hippocampus
* amygdala
Increase mood,
satiety, body
temperature and
sleep, while
decreasing
nociception.
Serotonergic
system
Origin in:
 Raphe nuclei complex
of medulla, Pons and
midbrain
From: J. Nolte, 2002. The Human Brain, p. 284
Receives afferents from:
 Spinal cord
 Midbrain (PAG)
 Limbic system
 Hypothalamus
 Prefrontal cortex
Sends efferents to:
 Cerebral cortex
 Limbic system
 Diencephalon
 Cerebellum
 Locus ceruleus
 Spinal cord
From: J. Nolte, 2002. The Human Brain, p. 284
Serotonergic system
Serotonergic system
Key functional associations:
 Inhibitory to thalamic and cortical neurons (regulate affect
and sensory perception)
 Active in deep sleep, Less active in REM sleep
 Regulate sleep-wake cycle
 Regulate motor tone and pain perception
 Thermoregulation, food intake, sexual behaviors
 High activity associated with mania, narcolepsy
 Low activity associated with depression, anxiety and
insomnia
Test your knowledge
 Where is the largest collection of
Serotonergic (5HT) projecting cells
located in the human brain?
Originate in cells of:
 Upper pontine tegmentum
 Basal forebrain (nucleus
basalis of Meynert)
Afferents are from:
 Brain stem
 Diencephalon
 Striatum
Efferents go to:
 Brain stem
 Diencephalon
 Striatum
 Limbic system
 Cerebral cortex
From: J. Nolte, 2002. The Human Brain, p. 285
Cholinergic system
Cholinergic system
Key functional associations:
 Implicated in sleep/wakefulness cycle
 Active in awake states
 Active in REM sleep
 Non-active in non-REM sleep
 Enhance cortical responses to incoming sensory stimuli
 High activity associated with psychosis, insomnia,
hypertonia, hyper-reflexia, muscle rigidity, and severe
movement disorders
 Low activity associated with flat affect, dystonia, lack
of interest, somnolence
Test your knowledge
 Where is the largest collection of
Acetylcholine (Ach) projecting cells
located in the human brain?
Dopaminergic DMS: Synopsis
System
Origin
Targets
Effects
Dopamine
system
* Substantia nigra
(midbrain-cortical
pathway)
* Ventral Tegmental Area
(midbrain-limbic
pathway)
*frontal lobes
*basal ganglia
*nucleus
accumbens
motor system, reward
system, cognition,
endocrine system,
nausea
Origin in:
 Substantia nigra (pars compacta)
 Ventral Tegmental Area of midbrain, (VTA)
 Retrorubral field
 Dorsal hypothalamus
 Tubero-infundibular nuclei of hypothalamus
From: J. Nolte, 2002. The Human Brain, p. 283
Dopaminergic system
Dopaminergic system
Receives afferents from:
 Brain stem
 Diencephalon
 Striatum
 Limbic system
 Cerebral cortex
Sends efferents to:
 Somatosensory cortex
 Striatum
 Limbic system
 Hypothalamus
 Spinal cord
Dopaminergic system
Key functional associations:
 Emotion and behavioral response (Motivation, Drive states, Satiety, Sleepwakefulness cycle)
 Thought and thought disorders (e.g. as in Schizophrenia), Memory
 Movement and disorders of affect (e.g., in Parkinson’s disease)
 Autonomic and endocrine regulation (Pleasure and Reward seeking)
 High activity associated with obsessive-compulsive activity, agitation, catatonia,
psychosis, hypersexuality, loss of inhibition
 Low activity associated with apathy, withdrawal
 Cocaine related addictive behaviors and psychosis
Test your knowledge
 Where is the largest collection of
Dopamine (DA) projecting cells located
in the human brain?
Drugs and the DMS
Drugs targeting the neurotransmitter of DMS affect
the whole system
Mode of action of some drugs
 Prozac:
 selective serotonin reuptake inhibitor (SSRI)
 potentiates naturally released serotonin
 Cocaine:
 blocks the reuptake of dopamine
 leaves neurotransmitter in the synaptic gap longer
 Deprenyl:
 inhibits monoamine oxidase (MAO)-B
 increases dopamine levels.
Pathology DMS: Depression & Mania
 Serotonin modulatory system arising from
Raphe
 Noradrenaline modulatory system arising
from locus coeruleus
Associated with high levels
of neurotransmitters:
NE, DA and 5HT
Associated with low levels
of neurotransmitters:
NE, DA and 5HT