10. NERVOUS SYSTEM HEALTH Flashcards
This module covers: • Nervous system health. • Neurotransmitters. • Gut-brain axis. • Supporting nervous health. • Depression. • Bipolar depression. • Anxiety. • Insomnia. • Addictions. • Migraine. • Neuralgia.
What are some key factors affecting nervous system health?
- Lifestyle ― environment and our response to it.
- Nerve cell structure and function ― cell membrane integrity via EFAs, phospholipids, myelin, antioxidants, removal of toxins, minerals.
- Hormonal and immune ― oestrogen, testosterone, thyroxine, cortisol, adrenaline, cytokines (inflammation), neurotrophic factors.
- Energy ― relies on a steady flow of glucose and rich in mitochondria.
- Gastrointestinal health ― the ‘second brain’ and the bidirectional communication between the central and enteric nervous system (GBA).
What is the Gut-brain axis (GBA)?
The GBA is the bidirectional communication between the central and enteric nervous system.
The vagus nerve connects the GIT and brain, and contains 80% afferent (sensory) and 20% efferent fibres.
In which ways can gut microbes interact with the GBA?
- Modulating NT production ― e.g., serotonin which functions as a key NT in the GBA at both its terminals.
- Bacterial metabolites ― e.g., SCFAs support the intestinal barrier, mucosal serotonin release and influence memory and learning processes.
- Modulation of afferent sensory nerves ― e.g., L. reuteri has been shown to enhance neuron excitability, modulating gut motility and pain perception.
- BDNF production ― gut microbiota can modulate BDNF function in the CNS via changes in NT function or by changes in brain SCFAs.
Interaction also occurs via the immune system (i.e., GALT)
How does gut barrier function influence the GBA?
- Diet-induced changes in the gut microbiome can lead to a compromised mucus layer, allowing access of luminal microbes to extensions of dendritic cells, resulting in activation of these cells by both pathogens and commensals.
- This local immune activation can lead to ↑ permeability of the tight junctions that further compromises the intestinal barrier.
- This can result in ‘metabolic endotoxemia’, where immune activation in different organs occurs, including the brain.
- Elevated levels of LPS have been associated with neuro-inflammation and conditions such as depression.
Key factors influencing general nervous system function
- Inflammation, oxidative stress, toxic load: E.g., infection, environmental toxins, glycaemic variability, obesity, ↑ intestinal permeability, stress (↑glucocorticoids), ageing (↑exposure to cellular stressors), nutritional factors (high sugar, damaged fats, processed foods; low antioxidant-rich foods and omega-3s.
- Decreased expression of neurotrophic factors such as BDNF and nerve growth factor (NGF). Influences include physical and psychological stress, ageing, lack of physical activity.
- Mitochondrial changes: Relate to inflammation and oxidative stress, reduced neurotrophic factors, ageing, nutritional deficits.
Possible underlying causes of Neurotransmitter (NT) imbalaces
Often multifactorial issues, such as inadequate nutrition, high stress, toxicity, SNPs, poor digestive health, drug use, etc.
- NT synthesis is from specific substrates (e.g., amino acids) using nutritional co-factors (e.g., vitamin B6).
- Methylation ― Methyl folate for biopterin (BH4 ― co-factor for serotonin and dopamine). SAMe (methyl folate and B12) for melatonin and adrenaline.
Why is the reuptake of NTs an important mechanism?
List two key enzymes here.
To maintain neurotransmitter balance, NTs need to be inactivated and removed via enzyme breakdown, diffusion or reabsorption.
Key enzymes include:
- Monoamine oxidase (MAO) ― breaks down monoamines: serotonin, adrenaline, noradrenaline and dopamine.
-
Catechol-O-methyl transferase (COMT)
― breaks down adrenaline, noradrenaline and dopamine using a methyl group from SAMe.
[SNP rs4680 (G472A) A allele associated with reduced activity.]
Which amino acid is essential for serotonin and melatonin synthesis?
List four good food sources.
Tryptophan
Brown rice, quinoa, pumpkin
seeds, oats, bananas, turkey, fish, eggs
Where is the majority of serotonin in the body produced?
Serotonin is produced by enterochromaffin cells and bacteria in the GIT (95%).
and also in the CNS
What are the Functions of serotonin?
Serotonin is a GI signalling molecule (motility patterns and epithelial secretions incl. mucus).
It also regulates mood, appetite, sleep (melatonin synthesis), blood clotting.
Which co-factors are necessary for the conversion of tryptophan to 5HTP by Tryptophan Hydroxylase?
Vit B3
5-MTHF
Ca
Fe
Vit D3
Which functional test can give an indicator of serotonin levels?
Organic acid testing:
5-Hydroxyindolacetic acid (5-HIAA) is a metabolite of serotonin and acts as an indicator of serotonin levels.
Low serotonin ― causes / risk factors
- Insufficient nutrient status ― i.e., tryptophan, cofactors (e.g., Zn, Fe, Mg, B9, B6 etc.)
- Chronic stress ― hyper-secretion of ACTH and cortisol may alter chaperone proteins which maintain 5HT receptor integrity, reducing 5HT uptake.
- Negative outlook / thinking; a sense of lack of purpose / goals; financial problems, problems at work etc.
- GI dysbiosis ― can impact tryptophan metabolism and gut serotonin production which in turn can both impact brain serotonin metabolism.
- Poor digestive health
- Lack of sunlight ― in periods of darkness, more serotonin is used to synthesise melatonin.
- Caffeine ― inhibits tryptophan hydroxylase.
- Long-term alcohol use ― shown to lower 5-HT.
- Being sedentary ― exercise increases 5-HT.
- Statin use ― chronic cholesterol depletion using statins impairs the function and dynamics of serotonin 1A receptors.
What is the ‘tryptophan steal’?
Tryptophan can be metabolised by either the 5HTP or kynurenine pathway. Upregulated by stress/inflammation, enzymes shunts tryptophan down the kynurenine pathway to produce NAD+ and ATP at the expense of serotonin.
Quinolinic acid is a by-product produced in the kynurenine pathway. This excitotoxin (↑glutamate), hinders neuronal function, causes cell death and is linked to mood disorders and neurodegenerative diseases.
Which dietary and lifestyle recommendations can be given to reduce quinolinic acid neurotoxicity?
Consume foods rich in Catechins and ECCG. Also curcumin, pomegranate, garlic, saffron, broccoli sprouts and do regular exercise
How could the following SNPs impact serotonin?
- TPH1
- TPH2
- FKBP5
- 5-HTT 5-HT1 & 2A
- IFNG & TNF
- MAO-A
- VDR
- TPH1: Tryptophan hydroxylase 1 ― peripheral serotonin synthesis (e.g., gut). SNP/slower can result in constipation.
- TPH2: Tryptophan hydroxylase 2 ― CNS serotonin synthesis. SNP / slower can impact serotonin.
- FKBP5: Cortisol dysregulation ↑ kynurenic acid pathway.
- 5-HTT 5-HT1 & 2A: 5-HTT (SERT / SLC6A4) transporter and 5-HT receptor SNPs reduce the effects of serotonin.
- IFNG & TNF: IFNG (Interferon gamma), TNF (Tumour Necrosis Factor) upregulate inflammation (same effects as FKBP5).
- MAO-A: Monamine oxidase ― high activity SNP leads to more enzymatic breakdown and lower serotonin.
- VDR: Lower sensitivity to vit. D. Potentially less support for serotonin synthesis.
How can heavy metals and oestrogen possibly impact serotonin?
-
Heavy metals ― e.g., arsenic disrupts serotonin metabolism;
linked to mood disorders, cognitive decline and can induce neuronal death. Mercury inhibits serotonin receptor binding. - Sex hormone imbalances e.g., low oestrogen, as oestrogen normally ↑ tryptophan hydroxylase and inhibits MAO.
Which conditions are associated with low serotonin?
- Mood disorders
- anxiety disorders
- panic disorders
- insomnia
- anger
- discontentment
- eating disorders
- OCD
- alcohol / substance abuse / addictions
- IBS and functional constipation
- migraines.
What are the characteristic functions of Glutamate and GABA that ensures their Yin-Yang relationship?
Glutamate is a major excitatory NT that plays a role in memory and learning whilst GABA is an inhibitory NT which increases BDNF levels (neuroprotective). GABA also regulates epinephrine release directly from the adrenals so acts centrally and peripherally.
Which condtions can be linked to excess glutamate?
Neuronal injury and neurodegenerative diseases, e.g., Alzheimer’s, MS, epilepsy.
GABA deficiency ― signs and symptoms
Anxiety, insomnia, alcohol craving, panic attacks, palpitations, cold or clammy hands, seizures, carb cravings, tinnitus.
GABA deficiency ― causes / risk factors
- Alcohol ― inhibits GAD (glutamate decarboxylase - converts glutamate to GABA).
- Co-factor deficiencies ― e.g., vitamin B6, magnesium etc.
- Dysbiosis ― intestinal bacteria including several strains of Lactobacillus and Bifidobacterium synthesise GABA and influence Vagus activity.
- Chronic stress ― can reduce GABA activity, possibly through decreased expression of GAD and GABAA receptor subunits.
- Also consider: limited exercise; impaired digestion / absorption.
Which two strains of bacteria play a role in the synthesis of GABA?
a. Saccharomyces and L. reuteri
b. Bidifobacteria, and Akkermansia spp.
c. Lactobacillus and Bifidobacterium
d. Roseburia and Lactobacilli
c. Lactobacillus and Bifidobacterium
How could the following SNPs impact GABA?
* GABRA2
* GAD 1 & 2
* ALPL
-
GABRA2: SNPs lower sensitivity to GABA, so creates feeling of less GABA. Strongly associated with anxiety and use of alcohol to
relief anxiety / feel calm (as alcohol binds with the GABA receptor and has a similar effect as GABA, so people with a GABRA2 SNP are more inclined to misuse alcohol to get the GABA relaxation effect). - GAD 1 & 2: Impacts glutamate to GABA conversion, so less active GAD genes can result in lower GABA (with similar effects to GABRA2).
- ALPL: Degrades B6 which is a co-factor for the GAD genes (faster degradation of B6 means potentially lower B6 co-factor and lower GAD activity).
List three catecholamines
Dopamine
Adrenaline
Noradrenaline
What are the functions of dopamine?
- Motor control
- curiosity
- working memory
- cognition
- motivation
- Reward seeking behaviour - linked to addiction.
- Acts as a (neuro)hormone released by hypothalamus to inhibit prolactin.
Which marker in Organic acid testing can be an indicator of dopamine (DA) levels?
DA is metabolised to homovanillic acid (HVA)
Why is B6 contraindicated in patients on L-dopa?
Vit B6 converts L-dopa it to DA which does not cross the BBB (losing its effect).
What are the signs & symptoms of low dopamine levels?
anxiety / depression,
low libido and
restless leg syndrome
What are the signs & symptoms of elevated dopamine levels?
OCD and hyperactivity
Outline four possible causes / risk factors for dopamine (DA) imbalances.
- Insufficient dietary intake of phenylalanine / tyrosine and co-factors, e.g., B6, folate, iron, etc. Also consider poor digestion / absorption.
- Chronic stress ― increases adrenaline (SNS), reducing DA.
- Sleep deprivation ― downregulates DA receptors.
- High sugar diets.
- Recreational drug use (e.g., cocaine).
- Poor gut health and dysbiosis ― about 50% of DA is produced in the GIT by enteric neurons, epithelial cells and bacteria, where it normally supports GI motility.
- High saturated fat ― can alter DA-related gene expression.
List three key SNPs that could cause dopamine imbalances
-
Tyrosine Hydroxylase (TH)
Converts Tyrosine to L-DOPA. SNPs ↑ TH activity resulting in ↑ DA, which can be good (supporting DA levels, and cognition; ↓ risk of cognitive decline) or bad —excess DA. -
MTHFR
provides 5-MTHF for biopterin cofactor to support TH. SNPs — ↓ methyl-folate can impact dopamine synthesis. -
SLC6A3 / DAT (Dopamine Transporter)
Dopamine reuptake — SNPs increase resulting in lower DA, increasing risk of addiction, ADHD, and cognitive decline. -
DRD2/4
Dopamine receptor SNPs ↑ likelihood of addictive behaviours. DRD2 ↑ impulsiveness. DRD4 ↑s risk taking behaviour. -
COMT
Breaks down DA. Fast SNPs lower DA, slow can increase DA. -
Monoamine Oxidase B (MAOB)
Breaks down DA. SNPs decrease activity — slower breakdown of DA.
What is the major neurotransmitter in the parasympathetic nervous system?
Acetylcholine (ACh)
What is acetylcholine synthesised from?
Acetylcholine (ACh) is formed from mitochondrial acetyl-CoA and dietary choline. It is essential for mood, memory and learning.
What can increase acetylcholine release?
A healthy diet, lifestyle and BDNF increase ACh release through Vagus nerve stimulation.
What can downregulate brain ACh by inhibiting acetyltransferase?
Cortisol
What are the functions of serotonin?
- Mood
- sleep
- attention
- motivation.
From which amino acid is serotonin synthesised?
Tryptophan
What are the co-factors for serotonin synthesis?
B3, B6, B9 (folate), D3, Vit C, Mg, Zn, Ca
What are the functions of GABA?
Sleep & relaxation
What are the co-factors for GABA synthesis?
B6, Mg, Zn, C
From which amino acid is GABA and glutamate synthesised?
Glutamine
What are the functions of Glutamate?
Reward, attention, learning
Which amino acids are needed for catecholamine synthesis?
- L-Phenylalanine
- Tyrosine
catecholamines = Dopamine, Adrenaline, Noradrenaline
