fundamental cns arousal; moods, molecules, maths. donald pfaff the rockefeller university laboratory...
TRANSCRIPT
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Fundamental CNS Arousal; Moods, Molecules, Maths.
Donald Pfaff
The Rockefeller University
Laboratory of Neurobiology and Behavior
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I. Looking backward: It is possible to explain mechanisms for a mammalian behavior.
II. Looking forward:
Sex Behavior Sexual Arousal Arousal.
III. Primitive, elementary arousal mechanisms: BBURP Theory
IV. Can we do the maths of arousal mechanisms? (Information Theory)
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MECHANISMS ESTABLISHED FOR A SIMPLE HORMONE – DEPENDENT SOCIAL
BEHAVIOR
• Pinpoint cellular targets for estrogens (cells express ER, ER). • Determine neural circuit for lordosis behavior. • Establish which neurons accomplish E/ERs Lordosis facilitation. • Show requirements for new mRNA, protein synthesis. • Discover certain E gene transcription inductions. • Test certain gene/lordosis behavior relations.
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MODULAR SYSTEMS DOWNSTREAM FROM HORMONE-FACILITATED TRANSCRIPTION RESPONSIBLE FOR A MAMMALIAN SOCIAL
BEHAVIOR: “GAPPS” .
• Growth (rRNA, cell body, synapses).• Amplify (pgst/PR downstream genes).• Prepare (indirect behavioral means;
analgesia (ENK gene) and anxiolysis (OT gene).
• Permit (NE alpha-1b; muscarinic receptors).• Synchronize (GnRH gene, GnRH Rcptr gene
synchronizes with ovulation).
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Construction of Cassette for an AAV Vector
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Western blot: ER is Knocked Down in Hypothalamus
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In Hypothalamus, VMN Neurons Do Not Have ER, and PR is Not Induced Following AAV Injection
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Musatov, S., et al.
2005
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A 4-gene micronet controls social recognition and thus affiliation & aggression.
Ovaries:Estrogen (E)productionSocial Recognition
OTER
OT
Individual-specificolfactory cues
Non volatile
volatile
Amygdala ER
MainOlfactory
Bulb/System
HypothalamusPVN and SON
VomeronasalOrgan
OTR
E
E
OTE
Blood Stream
AccessoryOlfactory
Bulb/System
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Question answered:
“Is it possible to explain mechanisms for any mammalian behavior?”
YES.
(II.) New Question:
“Can we approach mechanisms for the fundamental force in the CNS, which underlies all mammalian behaviors?”
YES
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Literature Review:
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(minutes)
(hours)
(lifetime)
FEELINGS
EMOTIONAL FUNCTION
MOODS
TEMPERAMENT
AROUSAL
COGNITIVE FUNCTION
SUSTAINED ATTENTION
ATTENTION
ALERTNESS
AROUSAL
DECISION MAKING
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Fundamental Arousal of Brain and Behavior: Applications
• Stupor, vegetative, coma
• Aging• Alzheimer’s• ADHD• Autism• Anesthesia• Sleep Disorders
• Mood Disorders (Depression, Bipolar Disorders)
• Vigilance/Military• Vigilance/Shift Work• Vigilance/Dangerous
Occupations• Toxicology (e.g., Lead in
water)• Fatigue states (CFIDS,
FMS, Gulf War)
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Operational Definition of Arousal
A more aroused animal or human is:
i. More alert to sensory stimuli in all modalities.
ii. Emitting more voluntary motor activity.
iii. More reactive emotionally.
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A = Arousal, as a function of generalized arousal (Ag) and specific forms of arousal (As). A is thought to be an increasing function of the variables Ag and As (1 to n) , sometimes additive, sometimes multiplicative or exponential and therefore potentially complex. While the constants (Kg and Ks 1 - n) reflect traits of the individual, arousal components (Ag, As) are determined by the immediate environment.
Re Inputs:
Re Operations:
Re Outputs:
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(III.) How does generalized
arousal of the CNS work?
(Neuroanat., Neurophys., Functional Genomics)
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Descending Arousal-controlling Systems
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Bilateral
Bidirectional
Universal
Response
Potentiation
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High throughput assay of all three components of CNS arousal
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Starting a Proof of Principle: CNS Arousal is Experimentally Tractable
• 3 Genes
– ER, Nuclear receptor
– PGDS, Enzyme
– Histamine Receptor, Type 1
• 3 Methods in Mouse CNS Functional Genomics– Null Mutation
– Anti-sense Oligos
– Mol. Pharmacology
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a) Running Wheel, ERKO(Older Mice)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 140
25000
50000
75000
100000WTERKO
Day #
# o
f R
evo
luti
on
sWT ERKO
100%
% o
f W
T
b) Running Wheel, ERKO(Younger Mice)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 140
25000
50000
75000
100000WTERKO
Day #
# o
f R
evo
luti
on
s
WT ERKO
100%
% o
f W
T
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1
10
100
1000
10000
100000
1000000
1 10 100 1000 10000 100000 1000000
24 hr Estradiol
24 h
r V
ehic
le
Gene Expression (N=11,669) of MBH following 24 hours Estradiol vs Vehicle Treatment in OVX Female Mice
PresentAbsent
Chip: Affymetrix Mu11 A,B
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Microarray Confirmation
Northern Blot
V E2 V E2 V E2 V E2
OBMBHCTX POA
Blotted total RNA was probed with a P32-labeled DNA probefor PGDS.
The same blot was re-probed with a DNA probe for 18s ribosomal RNA as a measure of RNA quantity per lane
PGD2S
18s
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Poly-[D,L-lactide-co-glycolide] Microspheres (PLGA)
RESOMER® RG 502 H
With Steven Little and Robert Langer at MIT
Average size Ø = 5 m
inside view
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Encapsulation Release
0
10
20
30
40
50
60
70
80
90
100
110
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Time (Days)
% R
elea
sePoly-[D,L-lactide-co-glycolide] Microspheres (PLGA)
Antisense
Scrambled
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Duration of Activity Vestibular Stimulus
0
10
20
30
40
50
60
SAL SALSCRM SCRM AS AS
OIL E2
** *
*
n=6 n=5 n=6 n=5 n=5 n=7
MIN
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MALES
FEMALES
time (minutes)
HA
CT
EFFECT OF AN H1 RECEPTOR ANTAGONIST ON SENSORY RESPONSIVENESS
TACTILE
0
50
100
150
200
b1 b2 1 2 3 4 5 6 7 8
OLFACTORY
0
40
80
120
160
b1 b2 1 2 3 4 5 6 7 8
OLFACTORY
0
40
80
120
160
b1 b2 1 2 3 4 5 6 7 8
TACTILE
0
50
100
150
200
b1 b2 1 2 3 4 5 6 7 8
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How do generalized arousal mechanisms influence particular
arousal states, thus to facilitate specific
behaviors?
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Histamine Receptor Signal Transduction Pathways
Gi/Go
H3
HVACC
Ca2+AC ATP
cAMP
PLA2
AA
H2
GsAC
ATP
cAMP
PKA
CREB
H2
Gq
PLC
IP3
Ca2+
HVACC
Kca
K+
Ca2+
Ca2+
Gq/11
AA
IP3
PKCgK+
leak
PLA2
PLC
cGMP
DAG
NMDA
H1
Gs
ACATP
cAMP
+
K+
H2/A2
NO
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Generalized Arousal Transmitters on VMN Neurons
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800000600000400000200000
T im e (m s)
IN 2 (mV)
-100
-80
-60
-40
800000400000Time (m s)
IN 2 (mV)
-100
-80
-60
-40
600000400000200000Tim e (m s)
IN 2 (mV)
-100
-80
-60
-40
Sodium channel blocker, TTX, had no effect on histamine-induced depolarization
Pre-TTX During TTX Post-TTX
Pataky et al.
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Histamine depolarization was abolished by potassium channel blocker TEA
HA on
600000400000200000Tim e (m s)
IN 2 (mV)
-80
-60
-40
-20
TEA off
HA on
16000001400000Tim e (m s)
IN 2
(mV)
-80
-60
-40
-20
Pataky et al.
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Jin Zhou et al: Potassium current blocker (TEA, 4-AP), but not sodium (TTX) and/or calcium (Cd2+) current blocker abolished histamine-induced depolarization in VMH neurons.
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Calcium chelator (BAPTA) and Calcium-free ACSF did not block histamine-induced depolarization.
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Estrogen treatment increased both HA-induced depolarization and inward current in VMH neurons. Significantly higher percentage of neurons showed action potential firing during depolarization in E2-treated group compared with oil-treated group (Zhou et al).
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(IV.) Idea: Information theory maths shed light on CNS arousal
mechanisms
)(1log)()( 2 xpxpxH
Where H is the total amount of “Shannon” information and p(x) is the probability of event x.
•Arousal-related neurons respond best to high-information (salient, surprising, unpredictable) stimuli (Harvard Univ. Press, 2005)
•Claude Shannon devised an intuitively pleasing, mathematically precise definition of information as follows:
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Arousal / Information theorythinking naturally yields a universal
phenomenon: HABITUATION.
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Laureys, S.L., Owen, A.M., and Schiff, N.D. (2004) Brain function in coma, vegetative state and related disorders. Lancet Neurology 3(9):537-46.
Schiff, N., Ribary, U., Moreno, D., Beattie, B., Kronberg, E., Blasberg, R., Giacino, J., McCagg, C., Fins, J.J., Llinas, R. and Plum, F. (2002) Residual cerebral activity and behavioral fragments in the persistent vegetative state. Brain 125(6): 1210-1234.
Schiff, N.D., Ribary, U., Plum, F., and Llinas, R. (1999) Words without mind. Journal of Cognitive Neuroscience 1(6) 650-656.
Schiff, N.D., and Purpura, K.P. (2002) Towards a neurophysiological basis for cognitive neuromodulation. Thalamus and Related Systems 2(1): 55-69.
Papers on impaired consciousness
Nicholas Schiff, MD
Department of Neurology
Weill Medical College of Cornell University
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MCS
Cognitive function
Motorfunction
Normal
Total functional loss
PVS
Coma
Full CognitiveRecovery
Severe to
Moderate Cognitive Disability
LIS*
Conceptualizing global disorders of consciousness
Total functional loss
Functional Communication
( Schiff, ND, The Neurology of Impaired Consciousness, Cognitive Neurosciences III, MIT Press)
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Penfield, WG, Jasper, HH, (1954) Epilepsy and the functional anatomy of the human brain
Vegetative state EEG patterns are typicallysimilar to coma
Minimally conscious stateEEG patterns may be similar to normal wakefulness
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Minimally Conscious State Patient Normal Subject
Forward Speech
Reversed Speech
Overlap
Schiff, N, Rodriguez-Moreno, D, Kamal, A, Petrovich, N, Giacino, J, Plum, F and Hirsch, J. fMRI reveals large-scale network activation in minimally conscious patients. Neurology (in press)
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Overall Summary
1) We understand neural, hormonal and genetic mechanisms for a specific hormone-driven behavior: VMN Hypothalamic neurons expressing ERs influence several genomic modules to control a spinal-midbrain-spinal behavior circuit.
2) Underlying all mammalian behaviors is CNS arousal: Newly precise operational definition features sensory alertness, motor activity and emotional reactivity. We have a high throughput assay.
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Overall Summary, Continued
3) We understand how generalized arousal forces impact specific arousal states: e.g. HA, NE and ACh, themselves hormone dependent, increase electrical activity in behavior-controlling VMN hypothalamic neurons.
4) Information theoretic treatments of arousal mechanisms lead to new questions: Shannon-Weaver equations offer potential insight to arousal-related neurons?