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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 CPG Friesen et al, 1976 CPG signal propagation • Generalized “descending” excitation • Segmental coordination by inhibition Inhibitory connections run opposite direction of signal propagation Friesen et al, 1976 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 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. Gossard et al, 1994 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 Dorsal Root Spinal cord Sympathetic Paravertebral Ganglion • Sympathetic trunk – Postganglion – Ionotropic rcptrs • Perhipheral effectors – Metabotropic receptors Ventral Root Sympathetic Trunk Autonomic signaling Co-Transmission and Co-localization with neuroactive peptides Tyrosine derivatives Tryptophan derivative Sympathetic neurotransmitters (adrenergic) Norepinepherine Parasympathetic neurotransmitters (cholinergic) Acetylcholine Dopamine Serotonin ATP Somatostatin Neuropeptide Y Calcitonin related peptide Neurotensin Vasoactive instestinal peptide NO Cerebrovascular Anatomy • Redundant – Carotid artery – Subclavian – Circle of Willis Anterior Cerebral A Internal Carotid A • Pressure regulation – Myogenic – Neurogenic Middle Cerebral A Basilar A Posterior Cerebral A Vertebral 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 NE a1A-AR Gi/o Gq 5-HT 5-HT1 PLC Ca2+ Contraction Gi Adayev et al, 2005 Lincoln 1995 Spitzbarth-Régrigny et al 2000 Innervation mediates proliferation and differentiation of smooth muscle • Sympathetic denervation reduces cell # • Denervation reduces contractile proteins Untreated artery Sympathectomized Growth-associated serotonin signaling 5-HT Rho-GEF 5-HT 1B/1D PI3K 5-HT 2A PLD PC PA Rho Kinase Cytoplasm mTOR ROCK RSK1 ERK S6 Elk1 Egr1 Hypertrophy Proliferation GATA4 ERK Extracellular Cyclin D1 Nucleus Liu &Fanburg (2004,6,8) 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
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