Nervous System and Nerves PDF

**Nervous System and Nerves** **The Brain** **The Nervous System** - **CNS** composes the **brain (in the cranium)** and **spinal cord (in the vertical column)** - **PNS** composes of all **nerves** **CNS** - **Elongated** in vertebrates - **Rostral is anterior**, **caudal is post...

**Nervous System and Nerves** **The Brain** **The Nervous System** - **CNS** composes the **brain (in the cranium)** and **spinal cord (in the vertical column)** - **PNS** composes of all **nerves** **CNS** - **Elongated** in vertebrates - **Rostral is anterior**, **caudal is posterior** **(down the spinal cord)** --- quadrupeds, **horizontal CNS** - **Neuroaxis** is vertical in humans but **rotates anteriorly at the rostral end (bend)** --- **cephalic flexure** **Cells of the CNS** - **Neurons** are the **functional units** of the NS and **glial cells hold the NS together** - **Glial cells:** - **Astrocytes** are involved in **synapse transmission (tripartite synapses)** and the **blood brain barrier** - **Oliogodendrocytes** form **myelin** that coats the axon and **promote action potential transmission** - **Microglia** are **immune cells** that survey the NS to **remove dead or dying cells** **Major Parts of the CNS** **The Brain** 1. **Cerebrum:** Bulk of the brain 2. **Diencephalon:** Deep in the brain, containing the **hypothalamus (homeostasis), thalamus (sensory role), and the pineal gland** 3. **Brain stem:** Attached to the diencephalon, containing the **midbrain, pons and medulla** 4. **Cerebellum:** Role in **motor control** **Gyri, Sulci, Fissures** - 2 hemispheres, separated by the **longitudinal fissure** - Ridges are called the **gyri**, grooves called the **sulci**, **increasing the SA for neurons** - **Central sulcus** divides the anterior and posterior brain, **separating the frontal and parietal lobes** - **Precentral gyrus** in **in front of the central sulcus**, containing the **primary motor cortex** which coordinates the muscles - **Postcentral gyrus** is **behind the central sulcus**, containing the **primary sensory cortex** which processes sensory information - **Parieto-occipital sulcus** **separates the parietal and occipital lobes** - **Transverse fissure** separates the **horizontal axis of the brain**, and defines the position of the **temporal lobe** - **Cerebellum** also has folds called **folia** - **Deep in the transverse fissure** lies the **insula**, involved with the **limbic system** **Wrapping of the Brain --- Meninges** - 3 membranes - Outer-most layer is called the **dura mater**, and is **tough for protection**, and has **dural folds** that **sit in the fissures**/folds of the brain - **Falx cerebri** sits in the **longitudinal fissure** - **Tentorium cerebelli** sits in the space **between the cerebellum and cerebrum** - **Falx cerebelli** sits **between the 2 hemispheres of the cerebellum** - 2nd layer is called the **arachanoid membrane** - Inner layer is called the **pia mater**, a thin membrane that **lines the sulci and gyri** - **Subdural space** is **between the dura mater and arachnoid membrane** which has **many blood vessels** - **Subarachnoid space** is **between the arachnoid membrane and the pia mater** which is **filled with CSF** - **Superior sagittal sinus** is a **large blood vessel** in the **dura mater**, and some parts of the **arachnoid membrane protrude** into this are called **arachnoid villi**, where **CSF is reabsorbed** into vasculature **CSF** - Inside the brain and **surrounds the brain and spinal cord** - **Capillaries** filter blood through the **ventricles** to form the CSF - **Production** occurs in the **ventricular system** of the CNS, the **choroid plexus**, mainly in the lateral ventricles but also in the third and fourth - Lateral ventricles → Third ventricle → Fourth ventricle → Spinal cord - CSF flows through the **subarachnoid space**, **increasing the pressure**, and resulting in **reabsorption into the vasculature** via the **arachnoid villi** - **Production and reabsorption are balanced** - **Hydrocephalus** is where the **sutures** of the skull are **not fused**, causing the **skull to expand** when **CSF builds up without arachnoid granulations** **Organisation of the Cerebral Cortex** - Left and right hemisphere are **not symmetrical**, and have **different functions** - **Primary cortices** are around **deeper sulci/fissures** like the central sulcus, lateral fissure, and the calcarine sulcus - **Secondary cortices** are located **near the primary cortices** **Corpus Callosum** - Allows **communication** between the **left and right hemispheres** - Many **myelinated axons** make up the **white matter**, and allow **communication** **The Brainstem** - Between the diencephalon and spinal cord - **Mid brain** - **Pons bridges** the brain stem, cerebellum, spinal cord, and cerebrum - **Medulla** **Grey and White Matter** - **White matter** is made up of **myelinated axons** - **Cerebral cortex** has many **neuron cell bodies** which are **non-myelinated**, making up **grey matter**, with axons extending into the white matter - **Grey matter nuclei** are **deeper in the brain**, and make up the **basal ganglia** which deteriorates in **PD** due to its role in **motor control** - **Oligodendrocytes (CNS)** and **Schwann cells (PNS)** are **glial cells** that **myelinate axons** **The Spinal Cord** - Parts of spinal cord are named by the bones that encase them - The **meninges and CSF** in the sub-arachnoid space **protect the spinal cord** **Cervical and Lumbar Enlargements** - **Diameter is larger** in the **cervical and lumbar cord** due to their role in **nerve transmission to the limbs (upper and lower)**, since they require **more nerves (motor neurons)** **Ending** - Ends at the **conus medullaris --- L2** - Nerves extend down the vertical column, the bundle being called the **cauda equina** - Final filament is called the **filum terminale**, **attaches the spinal cord to the coccyx**, an **extension of the pia mater** **Spinal Cord Development** - **Musculoskeletal** **development** occurs **faster** than **spinal cord development** - **Nerves** are **stretched and elongated** to give rise the **cauda equina**, eventually **extending into peripheral tissue** to act as **peripheral nerves** **Lumbar Puncture** - Can collect CSF between **L3 and L4** due to low risk of spinal cord damage **White and Grey Matter** - **Grey matter** is deep **within white matter** - **Grey matter** are **'horns'**, posterior, lateral, and anterior - **White matter** are **'columns' or 'funiculus'**, posterior, lateral, and anterior **Spinal Cord --- White Matter Tracts** - **Motor/efferent** pathways control **movement** --- **CNS → PNS (descending)** - **Sensory/afferent** pathways communicate **sensation** --- **PNS → CNS (ascending)** **Nerves** - Collection of **axons** enclosed in **connective tissue sheath** - **Endoneurium → Perineurium → Epineurium (Fascicles)** - **Motor** or **sensory** axons - **Spinal nerves** arise from the **spinal cord** - **Cranial nerves** arise from the **brain or brainstem** - **Cell bodies** of **motor neurons** are within the **CNS**, and **sensory neurons** are **just outside** - **Sensory neurons** are **pseudo-unipolar** neurons since they have a **single cell body** and a **single axon** that extends from it - **Sensory axons** join the **CNS** at the **dorsal root to the dorsal horn**, and **motor axons** at the **ventral root to the ventral horn** --- segregate - **Dorsal root ganglia swells** because it has the **cell bodies** of the **sensory neurons** **Spinal Reflexes** - Sensation → Sensory neuron → Interneuron → Motor Neuron → Muscle reflex **The Peripheral Nervous System** - **31 pairs** of **spinal nerves** - Nerves correspond to **vertebrae/bone**, exception is the **1 extra cervical bone** **Rami** - Rami are **branchings** of **mixed spinal nerves** - **Dorsal ramus** wraps around the **posterior of the body** - **Ventral ramus** wraps around the **anterior of the body** - Contains **motor and sensory axons** **Segmental Innervation** - **Dermatome** is an area of the **skin** supplied by a **single spinal nerve** --- **sensory** - **Myotome** is the **group of muscles** a **spinal nerve innervates** --- **motor** - Body is divides into slices - **Face** is **not supplied by spinal nerves**, rather it is **cranial nerves** - Can be helpful for **sensitivity tests** to see **where spinal cord damage** has occurred - **Plexus** is where **axons are shared between adjacent nerves**, and so a **peripheral nerve** can have **multiple spinal nerves** --- aids in **protection of functionality** **Cervical Plexus** - C1 - C5 - **Phrenic nerve** projects to the **diaphragm for breathing**, controlled by axons from **C3 - C5** **Cranial Nerves** - 12 pairs - **Cerebral hemisphere** - **Olfactory:** Smell - **Optic:** Vision - **Midbrain** - **Oculomotor:** Eye movement - **Trochlear:** Eye movement - **Pons** - **Trigeminal:** Face sensation - **Abducens:** Eye movement - **Facial:** Facial muscles - **Vestibulocochlear:** Balance and hearing - **Medulla** - **Glossopharyngeal:** Tongue and pharynx sensation - **Vagus:** Autonomic regulation of organs - **Accessory:** Neck muscle movements - **Hypoglossal:** Tongue movements - **Sensory, motor, or mixed nerves** **Somatic vs Autonomic Nervous System** - **Somatic** controls **voluntary** muscle movement - **Autonomic** controls **visceral/involuntary** movement - **2 neurons** in the pathway to control the tissue --- **pre-** and **post-ganglionic neurons** that communicate and the **ganglion** - **Parasympathetic:** **Long pre-ganglionic neuron** since ganglia are localised in the target tissue - **Sympathetic:** **Short pre-ganglionic neuron** **ANS** - **Sympathetic** has **thoracolumbar outflow**, where **pre-ganglionic neurons** arise from the **thoracic or lumbar parts of the spinal cord** - **Parasympathetic** has **craniosacral outflow**, where **pre-ganglionic neurons** arise from the **cranial or sacral nerves of the spinal cord** **Sympathetic Outflow** - Pre-ganglionic neuron from lateral horn → Ventral root → Mixed spinal nerve → White ramus → Sympathetic ganglion → Post-ganglionic neuron → Grey ramus → Mixed spinal nerve → Target tissue - **White ramus** is myelinated pre-ganglionic neuron - **Grey ramus** is unmyelinated post-ganglionic neuron - Sympathetic chain of ganglia for integration of functions **Parasympathetic Sacral Nerves** - Pre-ganglionic neuron from lateral horn → Ventral root → Parasympathetic ganglia → Post-ganglionic neuron → Target tissue - **Pre-ganglionic neuron** usually extends **within target tissue** **Parasympathetic Cranial Nerves** - **Occulomotor nerve**: Narrowing and dilation of pupils - **Facial nerve**: Tears, nasal secretions, and salivary glands - **Glossopharyngeal nerve**: Salivary glands - **Vagus nerve**: Visceral muscle regulation **Action Potentials and Graded Potentials** **Gated Ion Channels** - Can **open and close** in response to **stimulus** to **change conductance** of ions across the membrane - Changing the **shape** of the protein to switch from **open to closed state** **Types of Channels** - **Voltage-gated ion channels** respond to changes in membrane potential via **voltage sensors (positively charged amino acids)**, **closed** when **intracellular charge is negative** and **open** when **positive due to repulsion** - **Leak channels** are **always open** - **Ligand-gated ion channels (receptor mediated)** open in response to a **ligand binding to a receptor** - **Mechano-gated ion channel** is where **mechanical stimulus** opens or closes the ion channel, **e.g.**, stretch receptors, touch receptors, barroreceptors, and proprioceptors **Voltage-Gated Ion Channels** **Action Potentials** - Depend on the presence of **voltage-gated ion channels** - **Threshold potentia**l is the membrane potential value for which **voltage-gated ion channels can open** and **action potentials can be generated** - **V-gated ion channels are restricted to**, and **action potentials can only occur through** the **axon hillock (trigger zone), axon, and axon terminals (neurotransmitter release)** **Types of V-gated Channels** - **Voltage-gated Na+ channels** - Fast dynamics - **Voltage-gated K+ channels** - Slow dynamics - **Voltage-gated Ca2+ channels** - **Na+ and K+** involved in **action potentials** - **Ca2+** involved in **neurotransmitter release** - Region of amino acids with a positive charge in the channel act as voltage sensors - **Hyperpolarised (negative) --- close** - **Depolarised (postive) --- open** - **Inactivation gate** can **block** the ion channel **V-Gated Na+ Channels** - Opens and closes **fast** - **3 shapes:** - **Closed** at **resting potential** but can open - **Open** when **threshold potential** is reached, allowing **depolarisation** - **Inactive** when **inactivation gate closes** the channel and makes it **unable to be opened** (**refractory period**), allowing **repolarisation** to occur **V-Gated K+ Channel** - Opens and closes **slowly** - **2 states:** - Closed - Open **VNa and VK Conductance Dynamics** - Driving membrane potential to the **EK** for **hyperpolarisation** **Threshold Potential** - **Resting potential** = -70 mV - **Threshold potential** = -50 mV - Triggers a **positive feedback cycle** of **opening VNa, influx of Na+, and depolarisation** **The Action Potential** **Membrane at Rest** - **75x more permeable to K+** compared to Na+ due to presence of **K+ leak channels** **Depolarisation** - Reaches **threshold potential (-50 mV)** - Rapid **opening of VNa** - Rapid **conductance of Na+** and therefore **positive membrane potential** - **VK closed** **Repolarisation** - **VNa** become **inactive** due to **inactivation gate** - **VK open** - **Greater K+ conductance**, causing **efflux** and **reducing membrane potential** **Hyperpolarisation** - Membrane is **3x more permeable to K+** than at **rest** - **Slow closing of VK** - **Over-shooting** of membrane potential, **closer to EK** **Refractory Periods** - **V-gated channels** unable to generate new action potentials - **Absolute refractory period** follows the opening of VNa, whereby **VNa must re-enter closed state** to generate a new action potential - **Relative refractory period** is where **K+ permeability is still high,** so it is **more difficult** to generate an action potential **Properties of Action Potentials** - **All or none:** Will always depolarise to the **same peak value** - **Self-generating/regenerative:** Depolarisation travels down the axon from **one segment to the next** in **one direction** - **Greater stimulus activation** does not correlate to greater action potential amplitude, it **increases number of action potentials** **Graded Potentials** - Changes in membrane potential **below threshold potential** - Occur because **gated ion channels open and close**, causing **influx or efflux** of ions - Those that occur due to **synaptic activity** are called **post-synaptic potentials** - **Localised at stimulus point** - **Excitatory** and **inhibitory** potentials **EPSP and IPSP** - **EPSP (Excitatory post-synaptic potential)** is membrane **depolarisation** that moves it closer to threshold - **IPSP (Inhibitory post-synaptic potential)** is membrane **hyperpolarisation** that moves it further away from the threshold **Movement is Passive** - As current passes along, **amplitude of depolarisation decreases from stimulus point** **Summation** **Temporal and Spatial Summation** - **Temporal** occurs in **time** --- **same synapse, different times** - **Spatial** occurs when **PSPs at 2 different synapses summate** - **Summation** can bring the membrane to threshold to generate an action potential **Summation Occurs at the Trigger Zone** - Triggers action potential at the **axon hillock** **Neurotransmitter Release** **(1) Action Potential Invades the Axon Terminal** - **Neurotransmitter filled vesicles** are present and **ready** to be released - Action potential **depolarises** the **axon terminal** **(2) Depolarisation of the Axon Terminal Opens VCa** - **Opens VCa** and **Ca2+ enters** the cell - **Calcium-mediated exocytosis** of **neurotransmitters** into the **synaptic cleft** **(3) Diffusion From High to Low Concentration** - Drives movement of neurotransmitter **across the synaptic cleft** **(4) Neurotransmitter Binds to Receptors** - Neurotransmitter binds to the **post-synaptic receptor**, **activating it** - **2 types of receptors:** - Open ion channel/Ligand-gated ion channel - Activated GPCR and secondary messenger system **(5) Neurotransmitter Function is Terminated** - **Enzyme** degradation - Uptake by **astrocytes** - **Re-uptake** into releasing cell via **re-uptake transporters** **How Drugs Work --- Agonists** **Binding** **Pharmacodynamics** - The **effect of drugs on the body** - **Mechanism** and **dose-response relationship** **Binding and Activation of Receptors** - **Cell surface** or **intracellular** - Must **bind** to target to have an **effect** - **Reversible binding** means the drug can **bind** to the receptor and **dissociate** **Binding Determination** - **Forces:** - Ion-ion (strongest) - Ion-dipole - Dipole-dipole - Hydrogen - Hydrophobic (weakest) - **Receptor and ligand concentration** - **Likelihood of ligand binding** is determined by ligand **affinity** - **Likelihood of ligand activating** a receptor is determined by ligand **efficacy** **Affinity** - **Attraction of a ligand for a biological target (receptor)** - Equilibrium dissociation constant **(KA)** - Equilibrium is **dynamic** - **Greater affinity, lower KA** - **High affinity** ligands bind **rapidly**, for **longer**, and **more bound at lower concentrations** compared to low affinity ligands **Receptor Occupancy** - **Law of Mass Action**: Rate of **chemical reaction** is proportional to **reactant concentration** - **Forward:** \[A\]\[R\]\*k+1 - **Backward:** \[AR\]\*k-1 - **Forward = Backward** at **equilibrium, KA = k-1/k+1** - **Fractional receptor occupancy:** \[AR\]/\[R\] = \[A\]/(KA + \[A\]) - When **\[A\] = KA**, fractional receptor occupancy is **0.5 (half)** **Efficacy and Potency** **Efficacy** - Likelihood of bound ligand to **activate** a receptor - Strength of an **agonist-receptor complex** in **evoking a tissue response** - Depends on **intrinsic efficacy, receptor density, and coupling factors** - **Zero efficacy** = No ability to activate receptor **(antagonists)** **Relationship Between Drug Concentration and Effect** - **Dose** determines drug **benefits and harm** - **Log scales** when plotting drug concentration **Relationship Between Agonist Concentration and Effect** - **Emax** = Maximal response the drug can produce - **Potency** is the drug concentration required to elicit an effect **Efficacy of Full vs Partial Agonists** - **Partial agonists** can have **higher, equal, or lower potency** than full agonists - **Full agonists** have **higher Emax** than partial agonists, with **ΔEmax** being the difference - **Emax** for an agonist can **differ between tissue types** - Drug-dependent component of efficacy is **intrinsic efficacy** **Potency** - Drug concentration required to elicit a given effect - Conc. that elicits **50% response (EC50)**, is used to **compare potency** of drugs - **Lower EC50 = More potent, vice versa** **Differences in Potency and Efficacy** **Receptor Reserve, Desensitisation, and Good Agonists** **Receptor Reserve** - **Agonists** can elicit **maximum effect** at **low receptor occupancy** - Mechanism linking **receptor binding** and **response** has a **reserve capacity** where a system has a **receptor reserve** - **Receptor pool** is **larger than needed** for **maximal full agonist response** **High Potency:** - Effects at **low** drug concentrations **Desensitisation (Tachyphylaxis) and Tolerance** - **Drug effect** can **diminish** due to **repeated administration** - **Desensitisation:** Minutes or less - **Tolerance:** Hours to days to weeks - **Mechanisms like:** - Receptor internalisation - Change in receptor expression - Mediator exhaustion - Physiological adaptation **Good Therapeutic Agonist** - Usually **high affinity/potency/efficacy** - **Salbutamol** → **β2-adrenoreceptors** - Partial agonist - Treat **asthma** by relaxing bronchial smooth muscle - **No desensitisation** of target receptor - **Sumatriptan** → **5-HT1A receptors** - **Migraine** treatment - Vasoconstriction of coronary arteries is less likely so it **reduces heart attack risk** - **Buprenorphine → μ-opioid receptors** - **Pain** treatment - **Less euphoric and addictive effects** - **High selectivity** **How Drugs Work --- Antagonists** **Competitive Reversible Antagonists** **Definition** - Molecule that **interferes** with **agonist interaction** and a **receptor protein**, or **blocks the constitutive elevated basal response of a physiological system** **Types** **Competitive Reversible Antagonists** - **Most common** and **most important** due to **high potency and selectivity** - Binds to **agonist binding site (orthosteric)** without activating - **Prevents agonist binding** and **dissociates** - **E.g.** Naloxone is an opioid receptor antagonist, **e.g.** prevents morphine binding - **Parallel right shift** of the **agonist response curve**, apparent **potency reduced** - Enough agonist can overcome --- **surmountable** - **More antagonist = more antagonism = greater parallel rightward shift** - **Winning depends on concentrations and receptor affinities of both** - **KB** is the **equilibrium dissociation constant** of **competitive antagonists** - **IC50** is the **conc. of antagonist** to **reduce a response** of a fixed conc. of agonist by **50%** - IC50 depends on **agonist conc.** - **Inhibition curves** do not say what **type** of inhibition **Competitive Irreversible Antagonists, Partial Agonists, and Allosteric Modulation** **Competitive Irreversible Antagonists** - Binds to **orthosteric site** and **prevents agonist binding** - **Binds** **covalently** or **dissociates very slowly** - Affects number of **available receptors** - At high conc., can't be outcompeted --- **insurmountable** - **E.g.** Phenoxybenzamene binds to alpha-adrenoreceptors - **Emax reduced** but will not show if there are **spare receptors** - **Reduced potency = greater EC50** **Partial Agonists as Antagonists** - Can **alter agonist** with higher efficacy response - Act as **competitive, reversible antagonist**, **reducing potency** and is **surmountable** - **E.g.** Buprenorphine is a partial opioid receptor agonist **Allosteric Modulation** - Binds to **same receptor** at a **different site** - Can **increase or decrease** agonist **affinity** - Can **increase or decrease efficacy** of agonist --- **biased agonism** by **favouring intracellular pathways** - **E.g.** Benzodiazepines are positive allosteric modulators of GABA **Non-Receptor Agonists** **Chemical Antagonists** - **Binds to ligand or destroys it, preventing ligand binding** - **E.g.** Protamine (cationic) neutralises heparin (anionic) - **E.g.** Mepolizumab stops IL-5 binding to receptor - **Proteolysis-targeting chimeras** are bifunctional small molecules that **induce ubiquitin-mediated protein degradation** **Functional Antagonism** - **Oppose biological effects** of an agonist **acting at a different receptor** as an agonist - **E.g.** Salbutamol used to treat asthma triggers airway smooth muscle relaxation **What Makes a Good Therapeutic Antagonist?** - **High affinity and selectivity** - Used to understand physiology, biochemistry, immunology, neuroscience, etc.