Fundamental CNS Arousal Moods, Molecules, Maths'

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Fundamental CNS Arousal Moods, Molecules,
Maths.

• Donald Pfaff
• The Rockefeller University
• Laboratory of Neurobiology and Behavior
• pfaff_at_rockefeller.edu

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• Looking backward It is possible to explain
  mechanisms for a mammalian behavior.
• 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 ERa, ERb). P
• Determine neural circuit for lordosis behavior.
  P
• Establish which neurons accomplish E/ERs g
  Lordosis facilitation. P
• Show requirements for new mRNA, protein
  synthesis. P
• Discover certain E gr gene transcription
  inductions. P
• 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.
Individual-specific olfactory cues
Non volatile
volatile
Hypothalamus PVN and SON
Main Olfactory Bulb/System
Vomeronasal Organ
OT
b
ER
OT
E
Accessory Olfactory Bulb/System
OT
Blood Stream
OTR
Amygdala
E
a
ER
E
Ovaries Estrogen (E) production
Social Recognition
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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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EMOTIONAL FUNCTION
FEELINGS
(minutes)
MOODS
(hours)
TEMPERAMENT
(lifetime)
AROUSAL
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Fundamental Arousal of Brain and Behavior
Applications

• 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)

• Stupor, vegetative, coma
• Aging
• Alzheimers
• ADHD
• Autism
• Anesthesia
• Sleep Disorders

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Operational Definition of Arousal

• A more aroused animal or human is
• More alert to sensory stimuli in all modalities.
• Emitting more voluntary motor activity.
• More reactive emotionally.

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Re Inputs
Re Operations
Re Outputs
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.
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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 Potenti
ation
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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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Microarray Confirmation
Northern Blot
OB
MBH
CTX
POA
V
V
V
E2
E2
V
E2
E2
PGD2S
Blotted total RNA was probed with a P32-labeled
DNA probe for PGDS. The same blot was
re-probed with a DNA probe for 18s ribosomal RNA
as a measure of RNA quantity per lane
18s
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Poly-D,L-lactide-co-glycolide Microspheres
(PLGA)
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MIN
n6
n5
n6
n5
n5
n7
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EFFECT OF AN H1 RECEPTOR ANTAGONIST ON SENSORY
RESPONSIVENESS
MALES
HACT
FEMALES
time (minutes)
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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
AA
cAMP
HVACC
PLA2
Ca2
AC
ATP
NMDA
gKleak
H3
PKC
K
H1
H2
DAG
Gq
H2
IP3
PLC
PLA2
Ca2
AC
HVACC
AA
IP3
ATP
H2/A2
Ca2

cAMP
Ca2
NO
PKA
K
Kca
cGMP
CREB
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Generalized Arousal Transmitters on VMN Neurons
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Sodium channel blocker, TTX, had no effect on
histamine-induced depolarization
Pataky et al.
Pre-TTX
During TTX
Post-TTX
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Histamine depolarization was abolished by
potassium channel blocker TEA
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

• 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

Where H is the total amount of Shannon
information and p(x) is the probability of event
x.
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Arousal / Information theorythinking naturally
yields a universal phenomenon HABITUATION.
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Nicholas Schiff, MD Department of Neurology Weill
Medical College of Cornell University
Papers on impaired consciousness
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., and Purpura, K.P. (2002) Towards a
neurophysiological basis for cognitive
neuromodulation. Thalamus and Related Systems
2(1) 55-69.
Schiff, N.D., Ribary, U., Plum, F., and Llinas,
R. (1999) Words without mind. Journal of
Cognitive Neuroscience 1(6) 650-656.
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Conceptualizing global disorders of consciousness
Cognitive function
Total functional loss
Normal
Full Cognitive Recovery
Severe to Moderate Cognitive Disability
Functional Communication
Motor function
MCS
PVS
Coma
LIS
Total functional loss
( Schiff, ND, The Neurology of Impaired
Consciousness, Cognitive Neurosciences III, MIT
Press)
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Minimally conscious state EEG patterns may be
similar to normal wakefulness
Vegetative state EEG patterns are
typically similar to coma
Penfield, WG, Jasper, HH, (1954) Epilepsy and
the functional anatomy of the human brain
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Minimally Conscious State Patient
Normal Subject
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

• 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.
• 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?