1. Organization of Neurons in the CNS

2. Nucleus Group of neurons arranged into functional circuits Consists of 3 components 1.Incoming axons that enter the nucleus 2.Intrinsic neurons that are contained within a single nucleus 3.Neurons that project to other nuclei

3. Information Flow Synaptic divergence= a single presynaptic axon terminal synpases on the dendrites of multiple postsynaptic neurons –One-to-many –Especially important for disseminating sensory information Synaptic convergence= multiple presynaptic neurons converge on a single postsynaptic neuron –Many-to-one –Especially important for nervous system output that depends on balancing many potentially conflicting signals –Ex: activities of motor and autonomic neurons

4. Presynaptic Modulation Occurs when the effectiveness of a synapse is altered by an additional neuron that synapses on the axon of the presynaptic neuron –Axo-axonic synapse= a synapse between two axons Presynaptic inhibition –closure of Ca2+ channels –Opening of K+ or Cl- channels –Inhibiting NT release not through alteration of Ca2+ influx Presynaptic facilitation –Closing of K+ channels  longer action potential on the presynaptic neuron  prolongs Ca2+ ion channel opening

5. Feedforward Inhibition From: http://www.cs.stir.ac.uk/courses/31YF/Notes/Notes_CC.html Net result is a depolarization of the postynaptic neuron followed by inhibition of that same nerve cell by the inhibitory neurons.  Limits duration of EPSPs Presynaptic neuron (excitatory)=red Postsynaptic neuron=black Inhibitory neurons=blue

6. Lateral Inhibition Specialized type of feedforward inhibition Narrowly focuses excitation on a small group of neurons by synapsing on inhibitory neurons in adjacent pathways Typical of somatosensory, visual, and auditory pathways where the contrast between the site of excitation and the surrounding area helps the brain to pinpoint the location of the stimulus

7. Recurrent Inhibition Presynaptic neuron synapses on an inhibitory neuron that acts back on the same presynaptic neuron to inhibit further action potentials Ex: Renshaw cells –Lower motor neurons of the spinal cord innervate skeletal muscle and also synapse on inhibitory interneurons called Renshaw cells –Renshaw cells act back on the same lower motor neuron (NT = glycine or GABA) to decrease the rate of action potential firing –Works to coordinate muscle contraction Tetanus toxin interferes with release of glycine and GABA –Hyperactivity of lower motor neurons  muscle spasms Stiff-man syndrome results from antibodies that inhibit GABA synthesis Strychnine poisoning blocks GABA receptors

8. Brain Metabolism and Blood Flow

9. Metabolic Demands Brain requires ~ 15% of cardiac output and is responsible for ~20% of the body’s oxygen consumption Vocab –Ischemia= interruption of blood flow to the brain –Hypoxia= decrease in blood oxygen –Hypoglycemia= decrease in plasma glucose

10. Blood Supply to the Brain Anastomoses= interconnections between blood vessels that maintain blood flow to tissue when a portion of its blood supply is blocked –Ex: circle of Willis http://www.umassmed.edu/strokestop/module_three/base_brain_willis.html End zone= brain regions where blood is supplied by vessels that branch off of the circle of Willis and do not have anastomoses –Damage to these vessels will likely cause injury to brain tissue in the end zone

11. Flow Autoregulation Adjustment of vessel diameter to maintain consistent cerebral blood flow despite changes in arterial blood pressure Myogenic autoregulation= degree of stretch of a blood vessel triggers changes in vessel diameter –Fall in bp  dilate, Rise in bp  constrict –Most important mechanism in maintaining blood flow to brain as a whole Metabolic autoregulation= blood vessel diameter changes in response to alterations in local levels of metabolic products (0 2, CO 2, pH) –Insufficient blood flow  local levels of 0 2 fall  CO 2 levels rise  local increase in H+  fall in pH  vasodilation

12. Interference with Blood Flow Stroke= sudden and dramatic loss of neurologic function caused by an abnormality in blood flow to the brain Ischemic stroke= a blockage stops blood flow to a portion of the brain, typically a thrombus (stationary blood clot) or an embolus (traveling material that lodges in vessel and causes occlusion) ~85% of strokes, often preceded by transient ischemic attacks Incidence increases with age Intracranial hemorrhages= rupture of blood vessel causes blood to leak out into surrounding tissue, results in blood deprivation and intracerebral pressure –~15% of strokes –Hypertension is most important risk factor

13. Anatomy of a Stroke Lesion resulting from a stroke consists of an ischemic core where cells cannot recover from the prolonged loss of blood flow –Infarction= ischemia that is severe and prolonged to cause cell death (typically occurs within minutes if untreated) Ischemic prenumbra surrounds the core and consists of viable cells –Most promising target of pharmacologic intervention Patterns of neural deficit vary depending on location of lesion –Example: stroke involving the middle cerebral artery often result in contralateral weakness and sensory loss, visual disturbance, impaired language processing/speech, and difficulty with spatial perception

14. Cellular Consequences of Cerebral Ischemia (1) Detrimental cellular changes occur through 1.Loss of ion gradients  release of toxic levels of excitatory NTs 2.Effects of anaerobic metabolism Active transport of ions by Na+/K+ ATPase maintains resting cell membrane potential Requires energy in form of ATP Insufficient blood flow  reduced ATP  failure to maintain ion gradients Anoxic depolarization= intracellular and extracellular ions begin to equilibrate K+ out, Na+ in  depolarization Reuptake of NTs is also impaired (energy dependent process) Result is dangerously high synaptic levels of excitatory NTs

15. Cellular Consequences of Cerebral Ischemia (2) High synaptic levels of excitatory NTs (esp. glutamate) can have toxic effect on nerve cells ↑ glutamate triggers opening of Na+ and Ca2+ channels which leads to 1.Influx of water by osmosis  swelling  cell death 2.Activation of enzymes that ↑ oxygen-free radicals  damage of genetic material, cell membranes, and cytoskeletal proteins  cytotoxicity Can compensate for 0 2 loss to some degree by undergoing anaerobic metabolism –Byproducts (including lactic acid and H+) have toxic effects on the brain Pharmacological strategies to reduce cell death focus on blocking glutamate receptors, blocking Ca2+ channels, or controlling production of oxygen-free radicals

16. Brain Protection

17. Physical Protection (1) Skull protects from physical insults Meninges underlie skull and keep brain from pressing against bone –Dura mater= outermost layer of meninges, contains spaces called sinuses that connect the venous system of the brain with the systemic circulation –Arachnoid mater= below the dura mater, made up of a sheet of fibroblasts with underlying connective tissue –Pia mater= 3 rd layer of the meninges, thin layer that adheres to the surface of the brain and spinal cord

18. Physical Protection (2) Subarachnoid space= between the arachnoid and pia mater –Contains arteries, veins and cranial nerve roots –Filled with cerebrospinal fluid (CSF) Cisterns= pools of CSF –Cisterna magna= largest, between base of cerebellum and dorsal surface of medulla –Lumbar cistern= just below base of spinal cord, contains nerve roots that supply lower extremities Clinically, can draw CSF samples from this space or administer therapeutics

19. Blood Brain Barrier (1) Protects brain from damage by chemical and infectious agents Formed by tight junctions in the capillaries that supply the brain –Reinforced by astrocyte foot processes –Allows passage of only small lipid-soluble molecules (certain drugs, ethanol, nicotine, heroin, diazepam) –Nutrients such as glucose and amino acids pass through the endothelial cells via transporters

20. Blood Brain Barrier (2) Crucial to the maintenance of the integrity of the brain, but clinically challenging because it blocks entrance of many therapeutics to treat brain disorders –Important research into mechanisms to breech BBB and allow drugs to pass through Parkinson’s disease –Death of dopaminergic neurons in the midbrain –Dopamine itself doesn’t cross BBB, but L-dopa (precursor to dopamine) can enter brain via a transporter of amino acids

21. Blood Brain Barrier (3) Glioblastoma (brain tumor) –Leaky, weakening of the BBB –Leads to edema  intracranial pressure Bacterial meningitis –Increases permeability of brain capillaries  vasogenic edema –Clinically beneficial in that it allows penicillin to pass the BBB for treatment Multiple sclerosis –Demyelination of neurons in the CNS and compromised BBB function –Diminished barrier allows immune cells to enter brain and cause damage to nerve cells –Unclear if change in barrier function is due to circulating inflammatory mediators or intrinsic abnormality in the barrier itself

22. Regulation of Intracranial Pressure (1) Skull volume is ~ 1600 mL –80% brain –12% blood –8% CSF Intracerebral pressure (ICP) is normally 5-15 mmHg ↑ ICP  ↑ rate of CSF out of brain + ↓ arterial blood flow to brain –Can lead to ischemia

23. Regulation of Intracranial Pressure (2) Potential causes of increased volume of cranial contents (brain, blood, CSF) –Brain tumor  increase in brain material –Head injury, lead encephalopathy, meningitis, area around brain tumor  vasogenic edema –Hypoxia or myocardial infarction  cytotoxic edema water moves from extracellular to intracellular space due to failure of ATP-dependent transport of Na+ and Ca2+ causes swelling of neurons, glia, endothelial cells –Hydrocephalus  increased volume of CSF