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Flashcards in Dysfunction of pathways Deck (30)
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1
Q

What are the 2 types of cells we find in the brain?

What is their percentage within the total population of brain cells?

A

> Glial cells (90% of brain cells)

> Neurons (10% of brain cells)

2
Q

What are glial cells (neuroglia/glia)?

What are the types of glial cells?

A

Glial cells: non-neuronal support cells of the nervous system

  • Astroyctes
  • Oligodendrocytes
  • Microglia
  • Ependymal cells
3
Q

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?

A

Astrocytes = glial cells
> most abundant cell in the brain
> structural network of the brain / framework of neurons
> have ion channels ; communicate via gap junctions

  1. 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
  2. foot processes for connecting blood vessels:
    - physical structures built onto the blood vessels and maintain integrity of the structure
  3. 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)
  4. help with repairs after brain injuries, forming ‘glial scars’
4
Q

What are oligodendrocytes?
What is the purpose of the myelin sheath?
When is the process of myelination complete?

A

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)

5
Q

What are microglia?
What is their role?
What is apoptosis?
When do they activate?

A

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

6
Q

What are ependymal cells?

What is their role?

A

Ependymal cells = glial cells
> line the ventricles (4 cavities)
> secrete and absorb cerebrospinal fluid
-> helps support and buffer the brain

7
Q

What are neurons?
What are ion pumps?
What is the activity of neurons with their dendrites and soma?
What is particular about neuronal receptors?

A

> 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
8
Q

What produces myeline?

What is its purpose?

A

> 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)
9
Q

What are the ionotropic neurotransmitters (NTs)?

What is depolarisation?

A

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

10
Q

What is Dale’s Law?

In consequence, how are neurones named?

A

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
11
Q

What characterises the change in GABA and glutamate across the life-span?
What is pruning?

A

> 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

12
Q

What is the association between psychosis and GABA-Glu ratio?

A

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

13
Q

What are the 3 common mechanisms of intracellular regulation?

A
  1. Self-regulation: cells synthesise components when they need them and recycle them when they don’t
  2. 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
  3. 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
14
Q

What is the difference between metabotropic and ionotropic inputs?

A

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)
15
Q

What are the 4 dopaminergic pathways (origin and destination)?
What is the consequence of the brain regions where neurons have dopamine receptors?

A
  1. Mesolimbic
    - from ventral tegmental area (VTA) (in the brain stem)
    - to Midbrain (striatum / nucleus accumbens)
  2. Mesocortical
    - from VTA
    - to the Prefrontal Cortex (PFC)
  3. Nigrostriatal
    - from Substantia Nigra (in the brain stem)
    - to Midbrain
  4. 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

16
Q

What characterises the mesolimbic pathway and system?

A

> 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)
17
Q

What characterises the mesocortical pathway and system?

To which mental disorder is it associated?

A

> 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
18
Q

What characterises the nigrostriatal pathway and system?
Is it associated to mental disorders?
What are the effects of antipsychotics?

A

> 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

19
Q

What characterises the tuberoinfundibular pathway and system?
Is it associated to mental disorders?
What are the effects of antipsychotics?

A

> 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

20
Q

What characterises the serotonin and noradrenaline pathways?
Where does their pathways lead to?
Is the dysfunction of this system associated to a mental disorder?

A

> 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
21
Q

What are the 2 major acetylcholine (ACh) pathways?
To which mental disorders are their dysfunction associated?
What are the side-effects of anticholinergic medication?

A
  1. From Nucleus Basalis of Meynert
    - to the PFC, thalamus, amygdala -> attention
  2. 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

22
Q

How does acetycholine (ACh) impacts attention?

What are the mechanisms involved?

A

> 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)
23
Q

How does acetylcholine (ACh) impact memory?

A

> 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
24
Q

What does neuroendocrine (neurohormonal) communication refer to?

A

Hormones that influence brain function

25
Q

What is the function of cortisol?
How does cortisol affect the body inside and outside the brain?
What is the implication for chronic stress?

A

> 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

26
Q

What is the action of cortisol to an acute stress response?

A
  1. Increasing NT secretion:
    Cortisol binds to neurons -> changes cellular chemistry
    -> Stimulates the secretion of NTs -> neural signalling is enhanced (helpful at times of stress)
  2. 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
27
Q

What is the action of cortisol to chronic stress response?

A

Long-term secretion of cortisol… the brain is not primed for it

  1. 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
  2. Increasing NT receptor numbers
    - altering cell gene expression causes changes to cell structure
    - > dendrite shrinkage AND inhibition of hippocampal neurogenesis (neurons die)
28
Q

What is the difference between ionotropic, metabotropic, and neuroendocrine communication?

A
  • Ionotropic communication is quick (Glu and GABA)
  • Metabotropic (dopamine, serotonin, noradrenaline, ACh) and neuroendocrine (e.g. cortisol) systems provide lasting regulation of communication
29
Q

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?

A

> 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?

30
Q

Why is the brain primed to receive more cortisol?

A

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)