CNS: depression, BPD and anxiety disorders (spring) Flashcards
what are the three broad categories of brain function?
Input (perception): The process of handling data transmitted to the CNS from sense organs. e.g. sensory cortex, thalamus and reticular formation.
Processing: Integration of new data and association with existing information (memory), cognition, emotional components. e.g. cortex and limbic system
Output: The consequential output following cognitive function. Can be voluntary or involuntary, such as movement or homeostasis. e.g. Cerebellum, basal ganglia, motor cortex, hypothalamus.
what are the three Anatomical Brain Planes?
Coronal (frontal)
Horizontal (transverse)
Sagittal
what is grey matter and white matter?
Grey matter: the areas dense in neuronal cell bodies (as well as glial cells and neuropil).
White matter: the areas dense in myelinated axonal tracts (with fewer cell bodies)
the cerebral cortex:
which species is the cerebral cortex largest in?
what percentage of neurons in the brain does it contain?
what is the cerebral cortex responsible for?
Evolutionary young area, proportionally larger in humans than other mammals
Contains 90% of total neurons in the brain
Responsible for abstract thought, judgement, memory and interpretation and integration of sensory input.
name the cortical lobes and a briefly state what each is involved in
frontal lobe: higher, executive functions
parietal lobe: integration sensory information
temporal lobe: processing sensory information
occipital lobe: visual processing
The Limbic System
what regions does it include?
what is the Limbic System responsible for?
what are the overall behaviors of the Limbic system determined by?
what does limbic system dysfunction manifest as?
Includes hypothalamus, amygdala, hippocampus, thalamic nuclei, olfactory and other regions
Responsible for the application of emotion (feelings) to cognitive functioning: e.g. fear, love, rage, pleasure etc.
Overall behaviors are largely determined by balance between cortical and limbic functions.
Limbic system dysfunction often manifests as emotional disturbance
describe the roles of the Thalamus, Hypothalamus, Hippocampus and Amygdala
Thalamus acts as pre-processor and relay for sensory information - dysfunction can result in perceptual symptoms e.g. hallucination
Hypothalamus helps coordinate NS with endocrine system (via pituitary) and sympathetic NS (PNS) - fight or flight
Hippocampus is important for learning and memory
Amygdala is involved in fear processing and emotional memories
Basal Ganglia
what are they?
what are they responsible for?
main components of the Basal Ganglia?
what is Basal Ganglia dysfunction associated with?
interconnected nuclei within the cerebrum
Responsible for coordinating voluntary motor activity and for aspects of cognition, learning and memory and emotion.
Main components:
- Striatum (dorsal: putamen & caudate nucleus; ventral: nucleus accumbens & olfactory tubercule)
- Globus pallidus (GPe, GPi)
- Subthalamic nuclei (STN)
- Substantia nigra (SNc, SNr)
Dysfunction is associated with many disorders, including Huntington’s and Parkinson’s disease.
The Brainstem
what are the main components?
what three centres does the brain stem contain?
what is the brain stem responsible for?
which amine neurotransmitters does the brain stem contain?
Main components: midbrain, pons and medulla
Contains visual, auditory and motor centres
Responsible for many involuntary functions:
- Respiration, cardiovascular control, pain sensitivity control
- alertness, consciousness (reticular formation, throughout the brainstem)
Contains the majority of cell bodies for amine neurotransmitters
- dopamine: substantia nigra & ventral tegmental area (midbrain)
- noradrenaline: locus coeruleus (in reticular formation)
- 5-hydroxytryptamine (serotonin): Raphé nuclei (in reticular formation)
- cholinergic neurons in the medial septum
what do ascending and descending pathways in the relay station do?
Ascending pathways carry information to the brain
Descending pathways carry information to the periphery
label the parts of the brain stem
What’s the difference between Psychiatry and Neurology?
cell types that comprise the CNS
Neurons
- Principal signalling units
- Connections and properties underlie higher behavioural functions
- 100,000,000,000 in humans
Glia
- As many glia as neurons
- Oligodendrocytes: make myelin
- Astrocytes: homeostasis, synaptic modulation, blood brain barrier (BBB)
- Microglia: brain’s immune system
- (there are also ependymal cells)
Other relevant non-neural cells
- Endothelial cells, pericytes (BBB)
describe the roles of Astrocytes, Oligodendrocytes, and Microglia
Astrocytes
- Stellate (fibrous and protoplasmic)
- Physical support for neurons
- Neurotransmitter uptake and Ionic homeostasis
- Signalling to neurons
- Release gliotransmitters (response to Ca2+)
- Respond to CNS injury: formation of glial scar, repair
- End feet interact with capillaries: support formation BBB
Oligodendrocytes
- Myelinating cells of the central nervous system
- Each cell myelinates several axons
Microglia
- Macrophage-like cells, cells of the immune system resident in CNS
- Respond to CNS inflammation and injury
- Can engulf (phagocytose) “foreign” bodies
- Contribute to repair, but also to injury
Blood Brain Barrier
what is the Blood Brain Barrier?
how is it formed?
how are different molecules transported?
Highly selective, semipermeable membrane acts as a barrier to protect brain from the periphery
Endothelial cells form tight junctions (TJ). Adherens junctions (AJ) stabilise. TJs make the brain inaccessible for polar molecules unless actively transported. Can pose a problem for getting therapeutic compounds into the brain.
crossing the barrier:
- Some large molecules enter CNS by receptor-mediated transcytosis (e.g. insulin) or non-specific adsorptive-mediated transcytosis (e.g. albumin)
- Some molecules have specific transporters (e.g. glucose, amino acids, nucleosides)
- Some water-soluble factors cross by paracellular transport, some lipid-soluble can diffuse
- Efflux transporters actively pump some molecules OUT (e.g. P-glycoprotein)
- Most drugs pass by diffusion: need low MWt and high lipid solubility (also affected by e.g. charge, protein binding…)
give structural features of Neurons
Dendrites
- Basal
- Apical
Cell body
- Nucleus
Axon
- Initial segment
- Hillock
- Myelin Sheath
- Node of Ranvier
Nerve terminals
- Presynaptic terminal
what differences in neurons can you get?
Morphological differences:
- Shapes
- Spines
- Myelinated or unmyelinated
Chemical differences - use different neurotransmitter systems
- Glutamate (50% of neurons)
- GABA (30% of neurons)
- Amines: dopamine or 5-HT (serotonin) or noradrenaline
- Acetylcholine
- Neuropeptides
Physiological differences
- neurotransmitter receptor and ion channel repertoires
how are neuronal signals carried in the body?
what causes the neuronal signal?
The neuronal signal is electrical and Electrical signals in the body are carried by charged ions.
These ions can be positively or negatively charged
- Positive: cations (Na+, Ca2+, K+)
- Negative: anions (Cl-, protein anions)
The neuronal signal is caused by ions moving across the cell membrane of a neuron.
The Cell Membrane
function?
is the cell membrane lipophilic or hydrophilic and what properties does this give?
what is the voltage?
Separates the inside of the cell from the outside environment- Separates intracellular and extracellular solutions that have different ionic concentrations (i.e. concentration gradients)
Cell membrane is lipid-based: high electrical resistance, Intrinsic capacitance properties.
These properties prevent the movement of most substances across the membrane (e.g. water, ions, proteins)
At rest, the inside of the cells is slightly negative compared to the outside (approx -70mV for a neuron, typical cell ranged from -40 to -80 mV)
How are Ions Distributed in the cell?
All ions are present on both sides of the membrane, but at different concentrations which leads to the resting membrane potential of -70mV in the neuron
How do Ions Cross the Membrane?
Neuronal function is a dynamic state
Ion channels:
- Are selective for specific ions (e.g. Na+ channel)
- Allow movement of ions across the membrane down their concentration or electrical gradient (electrochemical)
- Can be open or closed
- Can be opened by: Ligands- specific chemicals (ligand-gated channels), or Changes in the membrane potential/voltage (voltage-gated channel)
describe the movement of Sodium (Na+), Potassium (K+), and Chloride (Cl-) ions into and out of cells.
Sodium (Na+)
- High concentration outside the cell
- Pumped out of the cell in exchange for K+
- Na+ channels are closed at the resting membrane potential (-70mV)
- When channels open, Na+ will enter the neuron along the concentration gradient
- Vm becomes more positive
Potassium (K+)
- High concentration inside the cell
- Pumped into the cell from the outside
- Many K+ channel types are open at rest to fine tune the resting potential
- When voltage gated K+ channels open, K+ flow along the concentration gradient out of the neuron
- Vm becomes more negative
Chloride (Cl-)
- High concentration outside the cell
- Pumped out of the cell by a co-transporter
- Most Cl- channels are ligand gated (e.g. GABA and glycine receptor types)
- When ligand gated Cl- channels open, Cl- flows along the concentration gradient into the neuron
- Vm becomes more negative
what is The Action Potential and what is it responsible for?
what is an action potential reliant upon?
Binary unit of information transfer in the nervous system
Responsible for conveying information intracellularly (within a neuron)
Responsible for initiating electrochemical transmission intercellularly
Reliant upon voltage-activated ion channels
how does a Post-synaptic Potential work?
Dendrites receive signals from other neurons
Open ion channels in the dendrites to produce “graded responses”
Grading dependent upon volume of NT and receptor present
Responses can either be inhibitory or excitatory
compare Excitatory and Inhibitory Responses
Excitatory:
- Excitatory post-synaptic potentials (EPSPs) are due to an influx of Na+/Ca2+ ions.
- Makes inside of cell less negative (depolarisation)
Inhibitory:
- Inhibitory post synaptic potentials (IPSPs) are due to an influx of negative ions (Cl-)
- Makes inside of cell more negative (hyperpolarisation)
what determines whether an action potential (AP) will fire or not?
Overall contribution of EPSPs and IPSPs
Temporal summation (when two or more PSPs coincide in time). Two EPSPs together have a much greater effect than one alone, IPSPs have the opposite effect
Each neuron can receive thousands of inputs from other neurons, each of which may be inhibitory or excitatory. Gives rise to spatial summation that also determines whether AP fires or not
describe what happens in an Action Potential using glutamate as an example
- Resting neuron membrane potential at -70mV
- Glutamate released from presynapse
- Activates AMPA/kainate receptors, influx of Na+ leading to depolarisation
- Cell depolarises (NMDARs slower and voltage-dependent)
- Resulting depolarisation called an excitatory postsynaptic potential (EPSP)
- Subsequent APs can occur before Vm returns to rest and summate
- If/when summated EPSPs reach the threshold for voltage-gated Na+ channel activation (~-55mV), allowing rapid entry Na+ and an action potential will fire, propagating the signal
- All or nothing
- For inhibitory NT (e.g. GABA), instead get inhibitory PSPs (IPSPs)
summarise an Action Potential
After temporal and spatial summation, if there is a large enough depolarisation at the axon hillock, AP fires
Action potentials are “all or nothing”
APs propagate from dendrite to axon terminals where presynapses are located
Arrival of APs at the presynapse triggers a sequence of events that result in neurotransmitter release into the synaptic cleft where they can act on pre- or post-synaptically located receptors
Which brings us to the chemical synapse
what does electrochemical transmission tranduce?
neurotransmitter is released into the synaptic cleft.
Activates receptor postsynaptic cell
- Ionotropic (fast-acting, channels/pores)
- Metabotropic (slower, prolonged, via 2nd messengers)
Downstream cellular effects
what type of neurotransmitter is glutamate?
what receptors does glutamate act at?
most common excitatory neurotransmitter in the CNS (~50% of neurons)
acts at ionotropic (fast, ion conducting: AMPA, NMDA and Kainate) and metabotropic (slower, G-protein coupled: mGluR) glutamate receptors
what is another name for GABA??
what type of neurotransmitter is it?
which receptors does GABA act at?
g-amino-butyric acid
principal inhibitory neurotransmitter
acts at ionotropic (GABAA) and metabotropic (GABAB) receptors
apart from glutamate and GABA, name neurotransmitters/ receptors
endocannabinoids, adenosine, glycine, acetylcholine, dopamine, noradrenaline, serotonin (5-HT), peptides, hormones etc.
what happens after Ionotropic receptor activation?
Ionotropic receptor activation opens channel to allow influx of specific ions
Glutamate receptors allow + ions (above), GABAA allow in Cl- ions (see later)
Can thus lead to depolarisation (e.g. glutamate) or hyperpolarisation (GABA)
what type of receptors are Metabotropic neurotransmitter receptors and what does this mean?
what determines the downstream effect?
Metabotropic neurotransmitter receptors are G-protein coupled (GPCRs)
7-TM pass receptors
On binding ligand, get dissociation and activation of G-protein signalling
Depending on which type G protein (G𝝰X – where X is: s, i/o, q/11 or 12/13) it is coupled to determines downstream effect (second messenger systems).
give examples of small NTs and large NTs
Small NTs
- Amino acids (e.g. glutamate, GABA, glycine), typically fast-acting
- Monoamines (e.g. dopamine, noradrenaline, serotonin), diffuse effects, synthesised from tyrosine and tryptophan, neurons of brainstem
- Soluble gases (Nitric oxide)
- Acetylcholine
Large NTs: Neuropeptides (e.g. endorphins, substance P, neuropeptide Y)
Ionotropic vs Metabotropic Receptors
Ionotropic: Fast, IPSPs & EPSPs, Ligand-gated ion channels
Metabotropic: Slower, receptor activates intracellular signals, may activate or close ion channels, may increase/decrease gene expression
give examples of Ionotropic and Metabotropic Glutamate Receptors
Ionotropic: AMPAR (fast activation, responsible for most fast excitatory NT in CNS), NMDAR (slower, voltage-dependent block at resting), Kainate R
Metabotropic: mGluR1-8 (Class I: mGluR1 & 5, Gq; Class II: mGluR2&3, Gi/G0; Class III mGluR4-8, Gi/G0)
what types of receptors are GABAAR and GABABR?
what does GABA binding cause at the GABAAR receptor?
what does GABABR stimulate and inhibit?
GABAAR is a ligand-gated ion channel
- Other drugs acting at allosteric sites or within the pore can modulate GABA actions at the receptor (e.g. benzodiazepines)
- GABA binding causes opening of the conducting pore that allows Cl- to pass
- Inhibitory as Cl- flows into the cell causing hyperpolarisation
GABABR is metabotropic, GPCR, Gi/G0-coupled
- stimulates GIRKs (GPCR-coupled Potassium channels) and inhibit VGCC (voltage-gates calcium channels)
name NT receptors and their receptor type
GABA: GABAAR (ionotropic); GABABR (metabotropic, Gi/G0)
Glutamate: NMDAR, AMPAR, KainateR (ionotropic); mGluRs (metabotropic, 1-8)
Dopamine: D1-5 (all metabotropic, D1/5=Gs, D2-4=Gi/G0-coupled)
Serotonin: 5-HTR1-7 and sub-types, metabotropic except 5HT-3 (ligand-gated ion channel)
- 5HT1 & 5, Gi/G0-coupled
- 5HT2, Gq/11-coupled
- 5HT4-7, Gs-coupled
Noradrenaline (norepinephrine): adrenergic receptors (adrenoceptors): a1+2, b1-3 (all metabotropic)
- a1 is Gq-coupled, a2 is Gi-coupled
- b1-3 all Gs-coupled
Acetylcholine: Nicotinic nAChRs (ionotropic); muscarinic mAChRs M1-5 (metabotropic, M1,3,5 are Gq-coupled, M2 & 4 are Gi/o-coupled)
what does Activation of presynaptic Neurotransmitter receptors lead to?
Activation of these receptors tends to decrease further release of neurotransmitter from the presynaptic cell. (negative feedback)
compare diagnosis with ICD-10 and DSV-IV
DSM-IV requires at least 5 out of 9 symptoms
ICD-10 requires 4 out of 10 symptoms
Must include core symptoms:
- 1 of 2 from DSM-IV and
- 2 of 3 from ICD-10
give the ICD-10 and DSV-IV scores for different classes of depression (sub-threshold, mild, moderate, severe, persistent sub-threshold)
Persistent sub-threshold - at least 2 and <5 symptoms for at least 2 years (sometimes referred to as dysthymia)
for the 4 stepped care model give the Focus of Intervention and Nature of Intervention for each step
