the cerebral cortex and higher intellectual...
TRANSCRIPT
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The Cerebral Cortex
and
Higher Intellectual Functions
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Lobes in a lateral
view
of left hemisphere
Atlas Fig.2-11
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The Insula
The Hidden Lobe
Atlas Fig. 2-39
Atlas Fig. 2-11
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Lobes in a lateral
view
of left hemisphere
Atlas Fig.2-11
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Lobes in a anterior (ventral) view
Text, Fig. 16-6 Atlas, Fig. 2-14
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The Insula
The Hidden Lobe
Atlas Fig. 2-39
Atlas Fig. 2-11
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Primary, Secondary
and Association
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Communication Between
Neurons
• Synapse: A specialized site of contact, and
transmission of information between a neuron
and an effector cell
Figure 45-5
Anterior
Motor
Neuron
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Communication Between
Neurons
• Electrical synapse
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Communication Between
Neurons
• Electrical synapse Chemical synapse
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Communication Between
Neurons
• Chemical synapse
Neurotransmitter:
is a messenger of
neurologic
information from
one cell to another.
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Action of Neurotransmitter on
Postsynaptic Neuron
• postsynaptic membrane contains receptor
proteins for the transmitter released from the
presynaptic terminal.
• The effect of neurotransmitter on the post
synaptic neuron depend on the type of the
receptor
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Action of Neurotransmitter on
Postsynaptic Neuron
• Two types of receptors
– Ion channels receptors
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Action of Neurotransmitter on
Postsynaptic Neuron
• Two types of receptors
– Ion channels receptors Ionotropic
– Second messenger receptors Metatropic
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Ion Channels receptors
• transmitters that open sodium
channels excite the postsynaptic
neuron.
• transmitters that open chloride
channels inhibit the postsynaptic
neuron.
• transmitters that open potassium
channels inhibit the postsynaptic
neuron.
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Seconded messenger receptors
(as example G-protein)
Ion
Channel
1. Opening specific ion channels
2. Activation of cAMP or cGMP
3. Activation of one or more intracellular enzymes
4. Activation of gene transcription.
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G-Protein-Coupled Receptors and
Effectors • GPCR Effector Systems (Cont’d)
• Push-pull method (e.g., different G proteins for
stimulating or inhibiting adenylyl cyclase)
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G-Protein-Coupled Receptors and
Effectors • GPCR Effector Systems (Cont’d)
• Some cascades split
– G-protein activates PLC generates DAG and IP3 activate different effectors
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G-Protein-Coupled Receptors and
Effectors
• GPCR Effector Systems
(Cont’d) • Signal amplification
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Drugs and the Synapse
1) at the receptor
• The study of the influence of various kinds of drugs has
provided us with knowledge about many aspects of neural
communication at the synaptic level.
• Drugs either facilitate or inhibit activity at the synapse.
– Antagonistic drugs block the effects of
neurotransmitters (e.g., novacaine, caffeine).
– Agonist drugs mimic or increase the effects of
neurotransmitters (e.g., receptors in the brain respond
to heroin, LSD and cocaine)
– Allosteric modulation
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Drugs and the Synapse
• A drug has an affinity for a particular type of
receptor if it binds to that receptor.
– Can vary from strong to weak.
• The efficacy of the drug is its tendency to activate
the receptor .
• Drugs can have a high affinity but low efficacy.
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Agonists and Antagonists
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Agonists and Antagonists
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Agonists and Antagonists
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Agonists and Antagonists
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Allosteric modulation
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Synaptic Transmission
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Drugs and the Synapse
2) alter various stages of synaptic
processing.
• Drugs work by doing one or more of the following to neurotransmitters:
1. Increasing the synthesis.
2. Causing vesicles to leak.
3. Increasing release.
4. Decreasing reuptake.
5. Blocking the breakdown into inactive chemical.
6. Directly stimulating or blocking postsynaptic receptors.
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Neurotransmitters
• Synthesis : esp. rate-limiting enzyme and/or
substrate
• Clearance and inactivation
• Location and pathway
• Dysfunction and CNS pathology
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Neurotransmitters • More than 50 chemical substances does
function as synaptic transmitters.
– small molecules which act as rapidly acting
transmitters.
• acetylcholine, norepinephrine, dopamine,
serotonin, GABA, glycine, glutamate, NO.
– neuropeptides.
• endorphins, enkephalins, VIP, ect.
• hypothalamic releasing hormones.
– TRH, LHRH, ect.
• pituitary peptides.
– ACTH, prolactin, vasopressin, ect.
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Fast Neurotransmitteres
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Glutamate (L-glutamic acid)
• Main excitatory neurotransmitter in the
mammalian CNS
• 95% of excitatory synapses in the brain are
glutamatergic
• Precursor for the GABA (major inhibitory
neurotransmitter)
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Enzymatic Pathways Involved in the Metabolism of Glutamate
Glutamate
Gluck et al, Am J Psychiatry 2002; 159;1165-1173
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Slow synaptic transmission Fast synaptic transmission
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NMDA
AMPA
Kainate Kainate
Na+
Ca++
presynaptic
postsynaptic
95% of excitatory synapses in the brain are glutamatergic
Kainate
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The Glutamate Synapse
Note – significant
Glu uptake (mainly
astrocytes)
Interconversion of
glutamate to
glutamine
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Glutamate and CNS disorders
1) Stroke
Ischemia
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Glutamate and CNS disorders
1) Stroke
Ischemia no ATP
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Glutamate and CNS disorders
1) Stroke
Ischemia no ATP increase Glutamate
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Glutamate and CNS disorders
1) Stroke
Ischemia no ATP increase Glutamate
Over activation NMDA R & AMPA R
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Glutamate and CNS disorders
1) Stroke
Ischemia no ATP increase Glutamate
Over activation NMDA R & AMPA R
increase Ca+ cell death
2) dysfunction of glutamatergic transmission may
also involve in schizophrenia-like symptoms,
cognitive dysfunction, Depression and memory
impairment
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GABA
• Main inhibitory neurotransmitter in the
mammalian CNS
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GABA
• Main inhibitory neurotransmitter in the
mammalian CNS
Ionotropic GABAA
Heterooligomeric protein
complex that consists of
several binding sites
coupled to an integral Cl-
channel
Metabotropic GABAB
G - protein coupled
receptor, seven
transmembrane domain
protein
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GABA-A- ionotropic receptor
• An integral chloride channel activated by competitive agonists: GABA and muscimol
• Blocked by convulsant bicuculine (competitive antagonist) and picrotoxin (noncompetitive antagonist)
• Allosterically modulated by benzodiazepines and barbiturates, which potentiate the effect of GABA
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GABAA receptor
Actions at GABAA Receptors
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Benzodiazepines potentiate GABA-induced
responses
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Benzodiazepines potentiate GABA-induced
responses
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GABA A and ethanol
Ethanol facilitates GABA ability to activate the
receptor and prolongs the time that the Cl-
channel remains open
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GABA
Glutamate GABA GAD
GABA is formed by the α-decarboxylation of glutamate
in the reaction catalyzed by GAD (glutamic acid
decarboxylase)
Synthesis
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GABA
GABA GABA-T
succinic
semialdehyde
GABA is catabolized into the succinic semialdehade
in the reaction catalyzed by GABA-T (GABA-Transaminase)
Degradation
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EEG and Seizures
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Electroencephalography (EEG)
• Electro: relating to electricity.
• Encephalo: relating to the brain.
• Graphy: writing or representation produced in a
specified manner.
• Therefore, EEG produces a graphed representation
of the electrical activity occurring in a person’s
brain.
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Origin of EEG waves
EEG is the record of
electrical activity of
brain( superficial layer
i.e. the dendrites of
pyramidal cells) by
placing the electrodes
on the scalp.
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EEG Electrode Placement
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Seizure
• Abnormal electrical
discharge.
• Initially synchronous
• May have no motor
component
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Convulsion
• Indicative of seizure
activity
• Motoric output of
synchronous neuronal
firing.
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Primary (Idiopathic) Seizure
Disorders
• No identifiable
cause
• Not the result of
overt disease or
injury
• In short, a guess.
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Secondary (Symptomatic) Seizure
Disorders
• Associated with or
secondary to
disease or injury
• e.g. trauma,
neoplasm, or
infection.
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Epilepsy
• Seizures and/or convulsions can be acute and
isolated…
• …they can be associated with a treatable organic
disorder…
• When seizures/convulsions are chronic and of
undefined origin…
• …the condition is described as epilepsy.
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Scheme of Seizure Spread
Simple (Focal) Partial
Seizures
Contralateral spread
From M.I. Davila-
Garcia, Howard
Univ., 2003
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Seizure Pathophysiology
• Altered ionic conductance (increased excitability)
of neuron.
• Reduced inhibitory neuronal (primarily
GABAergic) control.
• Increased excitatory neuronal (primarily
glutamatergic) control.
• Probable mechanisms tend to overlap.
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Cellular and Synaptic Mechanisms of
Epileptic Seizures
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GABA-A- ionotropic receptor
• An integral chloride channel activated by competitive agonists: GABA and muscimol
• Blocked by convulsant bicuculine (competitive antagonist) and picrotoxin (noncompetitive antagonist)
• Allosterically modulated by benzodiazepines and barbiturates, which potentiate the effect of GABA
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Acetylcholine
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Acetylcholine
Choline + Acetyl CoA Acetyl choline + CoA
ChAT
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Acetylcholine synapse
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Acetylcholine receptors
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Acetylcholine receptors
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Drugs acting at cholinergic terminal
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Acetylcholine Pathway
Nucleus
basalis
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Acetylcholine Pathway
Nucleus
basalis
• arousal and reward
• enhancement of sensory
perceptions
• sustaining attention
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Acetylcholine Pathway
Nucleus
basalis
• arousal and reward
• enhancement of sensory
perceptions
• sustaining attention
Alzheimer’s disease – loss of
cholinergic cells in nucleus basalis
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Neuromodulators
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Biogenic Amines
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08/20/2008 Lerant: Catecholamines 2008 81
The biosynthetic pathway for the catecholamine
neurotransmitters
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Biogenic Amines Synapses
MAO : Monoamine Oxidase
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Dopamine
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Dopamine receptors
• G protein-coupled receptors
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Dopamine receptors
• G protein-coupled receptors
• D1 excite
• D2 inhibit
• D3 inhibit
• D4 inhibit
• D5 excite
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Dopamine receptors
• G protein-coupled receptors
• D1 excite
• D2 inhibit Mainly presynabtic (Autoreceptor)
• D3 inhibit
• D4 inhibit
• D5 excite
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08/20/2008 Lerant: Catecholamines 2008 87
3. Dopaminergic
(DA)
synapse
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Dopamine Pathways
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Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
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Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
PATHWAY INVOLVED IN MOTIVATION TO
EXPLORE THE ENVIRONMENT: CURIOSITY,
INTEREST, COGNITIVE FLEXIBILITY, DRIVE
FOR SOCIAL ENGAGEMENT.
Relative hypofunction in schizophrenia:
Primary mesocortical dopamine deficiency will
increase the NEGATIVE SYMPTOMS like
Cognitive blunting, social isolation, apathy,
anhedonia
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Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
• Degeneration of nigro-striatal DA system
and Decreased DAergic trans-mission in
the basal ganglia will lead to
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Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
• Degeneration of nigro-striatal DA system
and Decreased DAergic trans-mission in
the basal ganglia will lead to
Parkinson Disease
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Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
PLEASURE, REWARD AND BEHAVIOR
REINFORCING PATHWAY
PLEASURE,
REWARD AND
BEHAVIOR
REINFORCING
PATHWAY
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Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
PLEASURE,
REWARD AND
BEHAVIOR
REINFORCING
PATHWAY
natural
drug-induced
cocaine
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Lerant: Catecholamines 2008
DOPAMINERGIC PATHWAYS
Substrantia nigra
of midbrain
Ventral
tegmental area
of midbrain
Striatum
Nigrostriatal
pathway
Nucl.
accumbens
Mesolimbic
pathway
Prefrontal
CTX
Mesocortical
pathway
PLEASURE,
REWARD AND
BEHAVIOR
REINFORCING
PATHWAY
natural
drug-induced
cocaine
Hyperactivity of mesolimbic pathway:
- positive symptoms of schizophrenia
(hallucinations, etc)