Dysfunction of pathways Flashcards
What are the 2 types of cells we find in the brain?
What is their percentage within the total population of brain cells?
> Glial cells (90% of brain cells)
> Neurons (10% of brain cells)
What are glial cells (neuroglia/glia)?
What are the types of glial cells?
Glial cells: non-neuronal support cells of the nervous system
- Astroyctes
- Oligodendrocytes
- Microglia
- Ependymal cells
What are astrocytes?
What are their 4 roles?
What is the blood-brain barrier?
What is the potassium buffer after depolarisation?
Why is it important that glutamate NTs are recycled?
Astrocytes = glial cells
> most abundant cell in the brain
> structural network of the brain / framework of neurons
> have ion channels ; communicate via gap junctions
- help maintain the blood-brain barrier: tight junction around blood vessels that go into the brain
- > it’s hard for bacteria to get into the brain -> few infections - foot processes for connecting blood vessels:
- physical structures built onto the blood vessels and maintain integrity of the structure - maintain an optimal microenvironment around the neurones
- buffer potassium after depolarisation : ions like potassium (K) are released after depolarisation -> extracellular K increases
(astrocytes consume K -> astrocytic K modulates neuronal excitability)
- metabolise and recycle neurotransmitters (NTs) - especially glutamate (most common and is toxic extracellularly -> can kill neurons) - help with repairs after brain injuries, forming ‘glial scars’
What are oligodendrocytes?
What is the purpose of the myelin sheath?
When is the process of myelination complete?
Oligodendrocytes = glial cells
> they ‘myelinate’ axons -> myelin sheath
- insulates axon, stops cross-conduction between neurons
-> stops neurons affecting each other, unless intended
- speeds up the conduction of transmission along neurons (20 to 50 times faster)
> in utero, wrap around axon in concentric lamellae
largely finished after first year
not complete until approx. 20 years old, especially with PFC cortices: individuals are more prone to damage during this time (illicit drugs)
What are microglia?
What is their role?
What is apoptosis?
When do they activate?
Microglia = glial cells
> Central Nervous System (CNS) macrophages
- white blood cells that kill anything recognised as foreign in the body (i.e. processes without antibodies: microbes, cellular debris, cancer cells)
(only type of macrophage found in the brain: in neurons, brain blood vessels, meninges surrounding the brain)
> in utero: clear waste material, apoptosis (programmed cell death)
in adults: immunosuppressed stable population
only activate in response to specific immune conditions (e.g. infections)
secondary immune response: assist activated T cells
What are ependymal cells?
What is their role?
Ependymal cells = glial cells
> line the ventricles (4 cavities)
> secrete and absorb cerebrospinal fluid
-> helps support and buffer the brain
What are neurons?
What are ion pumps?
What is the activity of neurons with their dendrites and soma?
What is particular about neuronal receptors?
> Electrically-excitable cells
- constitute 10% of brain cells
- specialised ion pumps establish an electrical gradient
(ion pumps = highly specialised transmembrane channels)
- neuronal membranes are polarised (charged) and depolarise spontaneously BUT can be stimulated and inhibited by NTs -> action potential
> Collect chemical information via their dendrites
- various receptors that bind specific NTs (primarily ionotropic, but also metabotropic and neuroendocrinal)
- different neurons have different numbers and locations of receptors (for dopamine, or acetylcholine, or serotonin)
- However, all neurons have glutamate and GABA receptors (inputs)
> Assimilate information in their cell body (soma, perikaryon)
- ionotropic info. from glutamate or GABA can alter their electrical charge -> tells whether to depolarise or not
- assimilates metabotropic input (i.e. serotonin, dopamine, acetylcholine NTs)
- assimilates neurendocrinal (hormonal) input (e.g. cortisol)
> Depending on this info. the neuron may depolarise
- depolarisation wave travels along axon
- myelinised axon insulates the axon and speeds transmission by x20-50
What produces myeline?
What is its purpose?
> Oligodendrocytes (type of glial cell)
> Myeline sheath:
- insulates axon, strops cross-conduction between neurons
- > stops neurons affecting each other, unless intended
- speeds up the conduction of transmission along neurons (20 to 50 times faster)
What are the ionotropic neurotransmitters (NTs)?
What is depolarisation?
Ionotropic NTs excite or inhibit neurons via movement of ions across membrane
> Glutamate (Glu) = ubiquitous excitatory NT -> makes neurons depolarise
> GABA = ubiquitous inhibitory NT -> stabilises neurons
> Sum of continuous Glu and GABA activities determines likelihood of depolarisation
Depolarisation is an “all-or-nothing” action
- no ‘half-firing’ and can’t be stopped once started
Depolarisation wave reaching the end of the axon triggers NT efflux
> Most neurotransmission involves Glu and GABA
What is Dale’s Law?
In consequence, how are neurones named?
Dale’s Law: a neuron can have multiple NT input types. BUT can only have one output type
- > neurons are named according to their output NT
e. g. ‘dopamine neuron’ only releases dopamine
What characterises the change in GABA and glutamate across the life-span?
What is pruning?
> Ratio of GABA-Glu changes dramatically throughout life, especially 15 and 20
> Pruning: during its development, the brain loses synapses to refine its pathways and balance Glu and GABA
What is the association between psychosis and GABA-Glu ratio?
Psychosis associated with reduced GABA and Glu synapses and reduced myelination
= difference in the ratio of inhibitory (GABA) and excitatory (Glu) synapses in psychotic illnesses
What are the 3 common mechanisms of intracellular regulation?
- Self-regulation: cells synthesise components when they need them and recycle them when they don’t
- External / environmental Input
- e.g. exercise strains muscle cells and causes growth, damage to cells releases chemicals that invoke healing (protein expression)
- > if a cell is damaged it’ll try to repair itself - Neuron-specific Mechanisms of Regulation
- Metabotropic communication (e.g. serotonin, dopamine, acetylcholine)
- Neuroendocrine (hormonal) communication (e.g. cortisol)
- These 2 communications alter complex intracellular chemical pathways, and can affect the differential expression of cellular proteins through signalling to DNA
- > communication inside the cell, keeping the neurons healthy
What is the difference between metabotropic and ionotropic inputs?
Metabotropic and ionotropic NTs both bind to neuron receptors
Metabotropic NTs
- Activate secondary messengers
- Trigger changes in cellular chemistry
- which may cause changes in gene expression (DNA) and protein expression
(through signals sent to nucleus: DNA)
-> change the configuration of the neuron receptor so the inside of the receptor opens new surfaces that send chemical cascades through the cell and alters its expression
- they are specific and few in number: approx. 1/4 million neurons of each type (e.g. dopamine, serotonin, noradrenaline, acetylcholinergic cells)
- However, impact of metabotropic neurotransmission is quite profound inside the cell and on its functioning
Ionotropic NTs
- Activate ion pumps
- Trigger changes in ion concentration
- which may cause depolarisation
- ubiquitous: all 100 billion neurons have them (glutamatergic and GABAergic)
What are the 4 dopaminergic pathways (origin and destination)?
What is the consequence of the brain regions where neurons have dopamine receptors?
- Mesolimbic
- from ventral tegmental area (VTA) (in the brain stem)
- to Midbrain (striatum / nucleus accumbens) - Mesocortical
- from VTA
- to the Prefrontal Cortex (PFC) - Nigrostriatal
- from Substantia Nigra (in the brain stem)
- to Midbrain - Tuberoinfundibular
- from Hypothalamus
- to Brain Stem
> Neurons in these areas have dopamine (D_1-5) receptors -> they expect dopamine input and need dopamine to work well
-> areas with dopamine input rely on it
Occipital, temporal and parietal cortices don’t have dopamine input, don’t need dopamine and won’t have dopamine receptors
What characterises the mesolimbic pathway and system?
> Pathway:
- from Ventral segmental area (VTA) (in the brain stem)
- to Midbrain (striatum / nucleus accumbens)
> Regulates Limbic system: involved in
- reward processing -> pleasure
- salience -> threat evaluation - rapid decision making (can be overriden by PFC after)
What characterises the mesocortical pathway and system?
To which mental disorder is it associated?
> Dopamine Pathway:
- from ventral tegmental area (VTA) (midbrain)
- to the Prefrontal Cortex (PFC)
> Regulates prefrontal cortex (PFC): involved in
- cognition
- motivation
- social expression
(PFC needs metabotropic input of dopamine for self-regulation)
> Psychosis: dysfunction of the mesocortical system
- it’s hypoactive
- > reduced stimulation of the PFC causes negative symptoms of psychosis (e.g. cognitive impairment, social withdrawal)
- this dopamine pathway is hard to treat with medication, and some medication actually make it worse
What characterises the nigrostriatal pathway and system?
Is it associated to mental disorders?
What are the effects of antipsychotics?
> Pathway:
- from Substantia Nigra (in the brain stem)
- to Midbrain
> Regulates the basal ganglia: involved in movements
- especially initiation of movements
> No mental disorders associated, BUT antipsychotics can interfere, causing impaired movements
What characterises the tuberoinfundibular pathway and system?
Is it associated to mental disorders?
What are the effects of antipsychotics?
> Pathway:
- from Hypothalamus
- to Brain Stem
> Regulates the Hypothalamic Pituitary Axis (HPA): involved in control of the endocrine system (including sex and growth hormones)
- turberoinfundibular dopamine neurons help this area function well
> No mental disorders associated, BUT antipsychotics can interfere, causing hormonal problems
What characterises the serotonin and noradrenaline pathways?
Where does their pathways lead to?
Is the dysfunction of this system associated to a mental disorder?
> They’re separate, yet intertwined:
- they innervate similar regions and affect each other’s outputs
- > serotonin can affect noradrenaline outputs and vice-versa
> Metabotropic pathways:
- only 1/4 million neurons each
- originate in the brain stem
- project to specific locations: spinal cord, amygdala, hypothalamus and thalamus, PFC, basal forebrain, striatum
- > involved in:
- sleep
- appetite
- libido
- higher cognition
- mood
> Dysfunction of theses sites is associated with depression
- clinical profile: difficulty with sleep, appetite, libido, making decisions, fear processing, mood
- > common innervation from serotonin and noradrenaline
What are the 2 major acetylcholine (ACh) pathways?
To which mental disorders are their dysfunction associated?
What are the side-effects of anticholinergic medication?
- From Nucleus Basalis of Meynert
- to the PFC, thalamus, amygdala -> attention - From medial septal nucleus
- to hippocampi -> memory
> Acetylcholine has both ionotropic and metabotropic receptors
> Core feature of Alzheimer’s dementia (AD) is degeneration of acetylcholine
Schizophrenia associated to acetylcholine dysfunction
- negative symptoms: attention and memory deficits
> Some psychiatric medicines are ‘anticholinergics’
- side-effects of anticholinergics impair memory and concentration
How does acetycholine (ACh) impacts attention?
What are the mechanisms involved?
> Pathway: Nucleus Basalis of Meynert to PFC, thalamus, amygdala
> Some of the neural activity taking place in the PFC, is noise
ACh reduces the PFC signal-to-noise ratio
- makes transmission in PFC more efficient
-> enhanced attention (more focused)
Mechanisms:
> Synchronising PFC depolarisations
-> makes it more efficient
> Regulating relative sensory input from thalamus to PFC
-> ACh stops some competing stimuli
> Inhibiting recurrent collateral PFC depolarisations (‘cross-talk’: numerous connections between neurons)
-> larger highways of communication
> Synchronising mesocortical dopaminergic pathways (VTA-midbrain to PFC)
- > making them more efficient
- makes dopamine neurons depolarise in synchrony
- > helps cognition (PFC)
How does acetylcholine (ACh) impact memory?
> Pathway: Medial septal nucleus -> Hippocampi
- medial septal nucleus is the primary source of hippocampal ACh
> ACh regulates hippocampal function by oscillating the hippocampus at 5-12 Hz
> These vibrations appear crucial to memory formation
- but only partially understood
- > Acetylcholine allows learning memories to do their jobs
What does neuroendocrine (neurohormonal) communication refer to?
Hormones that influence brain function
What is the function of cortisol?
How does cortisol affect the body inside and outside the brain?
What is the implication for chronic stress?
> Emotion of stress -> signals from PFC and limbic system got to the hypothalamic pituitary axis (HPA) and increase cortisol
- the PFC and limbic system are associated to cognition and emotional processing, so are affected by stress
- > more stress = increased secretion of cortisol
> Increases blood pressure and heart rate
Diverts resources away from inflammatory areas
- stress associated to infections: cortisol is secreted to answer to immediate needs of stressful response
-> body shuts down immune system
Increases neural plasticity (e.g. thinking and memory)
=> These effects can be acutely beneficial, but chronic stress can cause a toxic build-up
What is the action of cortisol to an acute stress response?
- Increasing NT secretion:
Cortisol binds to neurons -> changes cellular chemistry
-> Stimulates the secretion of NTs -> neural signalling is enhanced (helpful at times of stress) - Increasing NT receptor numbers:
Cortisol enters postsynaptic neuron -> alters gene expression -> more receptors are synthesised -> more NT can bind to the postsynapse (better primed to receive excess NTs) -> neural signalling is enhanced
What is the action of cortisol to chronic stress response?
Long-term secretion of cortisol… the brain is not primed for it
- Increasing cortisol NT secretion
- glial cells consume and recycle NTs shortly after secretion
- NTs like glutamate (Glu) are toxic and normally regulated by astrocytes (glial cells)
- chronic cortisol causes excess build up, which glial cells can’t control - Increasing NT receptor numbers
- altering cell gene expression causes changes to cell structure
- > dendrite shrinkage AND inhibition of hippocampal neurogenesis (neurons die)
What is the difference between ionotropic, metabotropic, and neuroendocrine communication?
- Ionotropic communication is quick (Glu and GABA)
- Metabotropic (dopamine, serotonin, noradrenaline, ACh) and neuroendocrine (e.g. cortisol) systems provide lasting regulation of communication
To which mental disorder is the dysfunction of the mesolimbic system associated, including drug-induced? How?
What is the first therapeutic target in medication in this context?
> Psychosis: in many cases, mesolimbic (dopamine) system is hyperactive
- neurons in this region receive too much dopamine (metabotropic)
- cells become chronically dysregulated (internally)
BUT can still depolarise (ionic - Glu and GABA don’t depend on dopamine - metabotropic)
-> people become less effective in rapid decision making, assessing situation ‘appropriately’
- e.g. paranoid interpretation (core symptom of schizophrenia)
> Drugs affect reward processing system (mesolimbic)
- BUT Chronic drug use can lead to dysregulation of the salience part of mesolimbic system
- > Drug-induced psychosis
=> First therapeutic target in medication: can we stop the overreaction of the mesolimbic system?
Why is the brain primed to receive more cortisol?
Only 10% of cortisol receptors are occupied -> 90% are waiting for a stress response
-> brain is primed to receive more cortisol than it does in non-stress responses
(stress -> secretion of cortisol)
