Integration of neural plasticity

• Multiple mechanisms per synapse

• Multiple synapses per cell

• Multiple cells per function

• Examples– Tritonia escape response– Aplysia gill withdrawal reflex– Leech central pattern generator– Autonomic control of hypertrophy

Neural pattern generation

• Tonically firing neurons– Pacemaker cells– Persistent Na+ leak

• Rhythmic neural circuits– Sensory feedback

Central pattern generator

• Rhythmic assembly of neurons– Coordinate cyclic movement patterns

• Flexion-extension• Parystalsis

– Self-organizing, independent of external feedback

• Hierarchical• Entrainment

– Sensory feedback– Higher neural process

CPG Organization

• Leech swimming by dorso-ventral flexion

• Independent control of 32 segments

Motorneurons

CP

G

Friesen et al, 1976

CPG signal propagation

• Generalized “descending” excitation

• Segmental coordination by inhibition

Friesen et al, 1976

Inhibitory connections run opposite direction of signal propagation

Coordination• Intersegmental

– Parallel PA inhibition as within segment– Conduction delay between segments

Coordination

• Sensory feedback– Nervous system needs state information– Subject to habituation, sensitization, etc

Gossard et al, 1994

PSPs in LG or sol motorneuron due to synergist afferent.•IPSP in “resting” state•EPSP after dopamine

This is a monosynaptic connection. Reversal with dopamine suggests that some dopaminergic interneuron changes the character of state feedback. EPSPs would extend the flexion half-center; IPSPs would shorten it.

Autonomic control of arterial tone

• Neuroanatomy

• Neural signaling– Transmitters– Receptors

• Secondary signaling

Autonomic neuroanatomy

• Principal effector system

• Competitive– Sympathetic– Parasympathetic

• Except skeletal muscle (somatic)

Neuroanatomy

• Spinal cord– Preganglion

• Sympathetic trunk– Postganglion– Ionotropic rcptrs

• Perhipheral effectors– Metabotropic

receptors

Spinal cordDorsalRoot

VentralRoot

SympatheticTrunk

SympatheticParavertebralGanglion

Autonomic signaling

Sympathetic neurotransmitters

(adrenergic)

Parasympathetic neurotransmitters

(cholinergic)

NorepinepherineDopamine

Serotonin

ATP

Somatostatin

Neuropeptide Y

AcetylcholineCalcitonin related peptide

Neurotensin

Vasoactive instestinal peptide

NO

Tyrosine derivatives

Tryptophan derivative

Co-Transmission and Co-localization with neuroactive peptides

Cerebrovascular Anatomy

• Redundant– Carotid artery– Subclavian– Circle of Willis

• Pressure regulation– Myogenic– Neurogenic

Internal Carotid A

Anterior Cerebral A

Basilar A

Vertebral A

Middle Cerebral A

Posterior Cerebral A

Netter 1989

Cerebrovascular innervation

Sympathetic axons (white) surround various chick cerebral arteries. Hayashi et al. 2002

Cerebral arteries

• Myogenic and neurogenic regulation– Not all arteries are innervated– Peripheral vs Cerebral

• Innervated via cerebral ganglion– Norepinepherine, serotonin, dopamine– Reduce flow during extreme stresses

Tension

30 s Electrical stim Neurotransmitter bath

Adrenergic vasoconstriction

• G-Protein coupled activation of TRPC3 & PLC

• IP3 mediated Ca2+ release

• Parallel serotonin pathway• NE mediates bronchodilation, also via Gi

a1A-ARNE Gi/o

5-HT 5-HT1 GiAdayev et al, 2005Lincoln 1995Spitzbarth-Régrigny et al 2000

Gq PLC Ca2+ Contraction

Innervation mediates proliferation and differentiation of smooth muscle

• Sympathetic denervation reduces cell #

• Denervation reduces contractile proteins

Untreated artery Sympathectomized

Growth-associated serotonin signaling

Liu &Fanburg (2004,6,8)

5-HT

PI3K PLDRho-GEF

Rho Kinase

ROCK

S6

PA

PC

ERK

ERK

mTOR

RSK1

GATA4

Elk1

Egr1

Cyclin D1

Proliferation

Hypertrophy

5-HT 1B/1D 5-HT 2A

Extracellular

Cytoplasm

Nucleus

Physiological consequences

• Vasoconstriction promotes hyperplasia– Wall thickening vs lumen dilation– Postnatal growth

• Genetic polymorphisms– Adrenergic receptors

• Exercise tolerance• Hypertension

– G-Proteins• Hypertension• Body composition

– GRK• Heart failure

Pathology

• Stroke– B-adrenergic receptor polymorphism may be a risk

factor for ischemia

• Other cerebrovascular incidents– Lower NE associated with intracerebral hemorrhage in

brown Norway rats– High NE associated with aneurysm during

experimental hypertension or hyperperfusion in Long Evans rats

• Statins– Cholesterol reducing drugs also reduce farnesyl and

geranyl-geranyl fatty acids– Rho acylation is essential for its function– Statins reduce VSM proliferation