Neuromodulation (Food and Serotonin) PDF

Neuromodulation (Food and Serotonin) Neuromodulation Neuromodulation→ the process of inhibition, stimulation, modification, regulation or therapeutic alteration of activity, electrically or chemically, in the central, peripheral or autonomic nervous systems Neurotransmitter→ a chemical substance w...

Neuromodulation (Food and Serotonin) Neuromodulation Neuromodulation→ the process of inhibition, stimulation, modification, regulation or therapeutic alteration of activity, electrically or chemically, in the central, peripheral or autonomic nervous systems Neurotransmitter→ a chemical substance which is released at the end of a nerve fibre by the arrival of a nerve impulse and, by diffusing across the synapse or junction, affects the transfer of the impulse to another nerve fibre, a muscle fibre, or some other structure. - Chemical signals are used for communication between brain neurons. Neurotransmitters involved in mood and affective behaviour→ monoamine neurotransmitter serotonin (5-hydroxytryptamine or 5-HT) - role in affective behaviour and mood disorders, including depression and anxiety disorders. - 5HT→ serotonin Serotonin (5-HT)→ monoamine neurotransmitter - Serotonin and the the brain serotonergic system is involved in a broad range of different behavioural and physiological functions: - Mood - Sleep - Appetite - sexual behaviour - Cognition - Ability to think clearly Serotonin pathways: - Serotonin cell bodies project from the midline raphe nuclei of the brainstem to various regions: - Brainstem - Spinal cord - Forebrain limbic structures - Cerebral cortex serotonin receptors→ Serotonin binds to exert its effects, similar to a docking station: - 5-HT1A Receptors: - G protein-coupled receptor - 5-HT1A, 5-HT1B, 5-HT1D, 5-HT1E, and 5-HT1F - inhibitory receptors→ reduce neuronal activity when serotonin binds to them - Connection to mood disorders and the mechanism of action of antidepressants - regulate the firing of serotonin neurons→ act like a feedback mechanism to control serotonin release.  - 5-HT2 Receptors: - G protein-coupled receptor - 5-HT2A, 5-HT2B, and 5-HT2C - primarily excitatory receptors→ increasing neuronal activity upon serotonin binding. - Connection to mood disorders, - Regulate mood and emotional responses and processing - 5-HT3 Receptors: - ion channels - fast synaptic transmission - role in nausea and vomiting - 5-HT4, 5-HT5, 5-HT6, and 5-HT7 Receptors: - various functions: - Learning - Memory - mood regulation - gastrointestinal function How our diet affects our brain Tryptophan: - Serotonin is synthesized in the brain from tryptophan - an essential amino acid that the body cannot produce on its own - we must obtain tryptophan from our diet through protein-rich foods - plasma tryptophan is converted to serotonin - plasma amino acids tyrosine and phenylalanine are pre-cursors for the catecholamines dopamine, norepinephrine, and epinephrine - tyrosine is also obtained from dietary proteins as well as from phenylalanine hydroxylation in the liver however functional portions are able to enter the systemic circulation and the brain after food intake. - Catecholamines and Their Precursors: - tyrosine and phenylalanine are dietary precursors for the catecholamines: dopamine, norepinephrine, and epinephrine. - Tyrosine can be obtained directly from dietary proteins or synthesised in the liver from phenylalanine. - Phenylalanine, like tryptophan, is an essential amino acid that must be obtained from the diet. - tyrosine and phenylalanine, along with other LNAAs, compete for transport across the blood-brain barrier→ influences their availability for catecholamine synthesis in the brain. The Blood-Brain Barrier Competition: - tryptophan faces competition at the blood-brain barrier and It's one of several large neutral amino acids (LNAAs) that vie for transport into the brain using the same carrier system for uptake into the brain.  - all the large neutral amino acids (LNAAs) tryptophan, phenylalanine, tyrosine, leucine, isoleucine and valine compete for attachment at the same transport carrier located at the blood-brain barrier for uptake into the brain - The Synthesis Pathway - Step 1: Tryptophan Uptake: The process begins with the uptake of tryptophan from the bloodstream into the brain. - Step 2 Conversion to 5-HTP: Inside serotonin neurons, the enzyme L-tryptophan hydroxylase converts tryptophan into 5-hydroxytryptophan (5-HTP). This is the rate-limiting step in serotonin synthesis, meaning it's the slowest step and dictates the overall speed of serotonin production. - Step 3 Decarboxylation to Serotonin: 5-HTP is then quickly converted into serotonin (5-HT) by the enzyme aromatic L-amino acid decarboxylase. The Tryptophan Ratio - It's not the absolute amount of tryptophan that matters, but its ratio to the other LNAAs in the plasma (the TRP/LNAA ratio) - Plasma→ Plasma is the liquid component of blood. - A higher TRP/LNAA ratio favours tryptophan entry into the brain, leading to increased serotonin synthesis - An increased plasma Trp/LNAA ratio increases the influx of tryptophan into the brain and causes a subsequent rise in brain serotonin levels, - A declining Trp/LNAA ratio has the opposite effect. Carbohydrates vs. Protein: - Carbohydrates→ Increase TRP/LNAA ratio - An increase in brain tryptophan is produced by a carbohydrate-induced elevation of glucose and insulin  - Carbohydrates (glucose and insulin) boost insulin release, which promotes the uptake of LNAAs (except tryptophan) into skeletal muscle tissue (for conversion into protein) - A higher proportion of tryptophan is the available for transport into the brain - Increases in insulin causes the free fatty acids to be stripped away from albumin circulating in the blood by promoting their uptake by adipocytes. - Proteins→ decrease TRP/LNAA ratio - a source of tryptophan BUT contain a higher proportion of other LNAAs - Consuming protein, therefore, leads to a decrease in the TRP/LNAA ratio, potentially reducing brain serotonin synthesis - Alpha-lactalbumin: - A Potential Ally - a whey protein with a relatively high tryptophan content→ contrary to other proteins - a promising dietary method for increasing brain serotonin→ increases in the TRP/LNAA ratio and improves mood and stress adaption and response in vulnerable individuals Acute Tryptophan Depletion (ATD): - a procedure used to investigate the role of serotonin in various psychopathologies, including affective disorders like depression→ drastically reducing the building blocks for serotonin → only affects people with a history of mood disorders or those with a genetic predisposition to them (short-allele 5-HTT genotypes) - Disrupting the Ratio: ATD manipulates this crucial ratio by introducing a tryptophan-free amino acid mixture into the system. This mixture contains all the essential amino acids except tryptophan - Depleting Tryptophan: Consuming this mixture triggers protein synthesis in the body. Since tryptophan is absent in the provided mixture, the body is forced to  draw upon its existing tryptophan stores to support protein production. This leads to a significant drop in plasma tryptophan levels, further decreasing the TRP/LNAA ratio. - Impact on Serotonin: The reduced TRP/LNAA ratio limits the amount of tryptophan available for transport into the brain. This, in turn, reduces brain serotonin synthesis, leading to a state of serotonin depletion The inverted U-Shaped Curve→ both low and excessively high Trp levels impair mood/cognition, while moderate to high Trp levels are beneficial Fig. 1. Relationship between brain tryptophan (Trp) levels and cognition/mood. In both healthy and vulnerable subjects too low and too high brain Trp levels result in impaired cognitive ability. This indicates that in the case of cognition, brain Trp levels should lie within an optimum range (a). The effects of small increases or decreases in brain Trp levels on the mood of healthy subjects is negligible (b, ). Only large increases in brain Trp levels are able to improve mood significantly in these subjects. Conversely, in vulnerable subjects (b, ) relatively small increases in brain Trp result in an improved mood. Unphysiologically high increases in brain Trp lead to negative effects on mood in both healthy and vulnerable subjects. Impact on Mood and Stress: - Altering brain serotonin levels via dietary manipulation has implications for mood, stress response, and cognitive function. - Effects of carbohydrates on mood affect specific people: - Mood disorders: are almost exclusively found in affected or sub-clinical subjects, whereas dietary effects on mood are rather inconsistent in healthy non-affected subjects. - Genes: In healthy subjects with a genetic 5-HT vulnerability like short-allele 5-HTT genotypes (More vulnerable and susceptible to stress) - in sub-clinical subjects suffering from carbohydrate-craving obesity, late luteal phase syndrome or seasonal affective disorders - Personality: Neuroticism (anxious, worrisome, emotional) → more likely to experience mood changes after eating carbohydrates - Stress-induced serotonin vulnerability→ serotonergic system becomes more sensitive to fluctuations in tryptophan availability during times of stress - Stress Response and Serotonin: - Stress triggers a cascade of physiological responses, primarily mediated by the hypothalamic-pituitary-adrenal (HPA) axis.  - The brain's serotonergic system plays a critical role in regulating this stress response, influencing coping mechanisms. - Initial Serotonin Boost: - In the initial stages of stress, serotonin synthesis and function are often increased. - This increase helps regulate HPA activity and dampen the sympathetic nervous system's stress response, promoting a return to homeostasis. → Seretonin helps to adapt to stress - Chronic Stress Depletion: - Prolonged or chronic stress, however, can lead to a decline in brain serotonin levels and function. - This depletion occurs due to various factors, including reduced tryptophan availability and alterations in serotonin receptor function→ our body supply runs low→ why Carbs and ATD have more impact on people with chronic stress - limited Availability: The rate of serotonin production in the brain is directly influenced by the availability of tryptophan in the plasma. - This availability is not solely determined by the amount of tryptophan consumed but is also affected by its competition with other large neutral amino acids (LNAAs) for transport across the blood-brain barrier. Other forms of Serotonin Neuromodulation: - Exercise→ Triggers the release of tryptophan into the bloodstream making it more available for the brain to convert into serotonin - Sleep→ Serotonin is a precursor of melatonin - When sleep is disrupted→ unbalances neurotransmitters such as serotonin in the brain - Social interaction→ release of oxytocin→ indirectly supports serotonin function Ketodiet→ people don't eat carbs only meat (decrease the levels of neurotransmitters such as dopamine or serotonin) How neurotransmitters influence our mood and emotions Serotonin: - role in mood and emotion - feel good neurotransmitter - association with our well-being→ Low levels are linked to mood disorders - linked with emotional stability Dopamine: - governs the brain's reward system, motivation, and pleasure, helps focus - high dopamine is actively linked to feelings of euphoria, motivation and reward. - Low levels can contribute to disorders like Parkinson's disease and addiction behaviours. - Produced from tyrosine. Adrenaline: - regulates arousal, and alertness, and gives us stress response. - Low levels can cause depression and anxiety. GABA: - primary inhibitory neurotransmitter - adequate GABA levels can produce stability of moods, - low levels of Gaba mood disorders and shifts. Genetic Brain (5HT) Vulnerability, Stress, Depression and the Influence of Food Stress, brain biochemistry and depression - Stress & Depression - Stress→ the energy we require to maintain mental-emotional homeostasis Dysfunctional stress, disease and psychopathology→ Affective disorders - Releasing an excess of stress hormones Mental emotional homeostasis - Scale balancing Realistic environment (Demands, requirements → objective actual world ‘As it is’ on one side and We as a person ( Wishes, capacities, preferences→ subjective ideal world ‘As we want’ - This scale is frequently challenged to continuously regain homeostatic balance and synchronicity between subjective vs objective world) → We require mental-physiological energy to balance - Stress is good when we use it to face our daily challenges or when we use it to protect ourselves - Stress is bad when it becomes chronic → Stress, disease and psychopathology→ can lead to depression Mental health→ sufficient resilience to daily stress - Individual differences - Adaptive response→ Resilience to stress disease - Maladaptive response→ Predisposition to stress disease - Individual differences in stress→ flight/fight→ HPA dysfunction (Brain-stress mechanism (HPA) stress responsiveness) → due to reduced PFC-amygdala connectivity vs Cognitive therapy addresses negative automatic thoughts & responsiveness. Biochemistry of Stress Vulnerability and Depression: - NA - DOPA - 5-HT Serotonin (5-HT), Stress ‘resilience’ and depression Diathesis-stress model→ Depression results from Biological x Environment interactions Serotonin vulnerability→ Having a susceptible brain for serotonin alterations - Gene 5-HTT polymorphism (5-HTTLPR) → Assumed to promotes 5-HT vulnerability - 5-HT vulnerability for stress and related disorders - Epidemiology - Genes are contributing but not determining factors in stress-disorders - Alleles always in pairs - Short allele (5-HTTLPR)→ more vulnerable to stress - Long allele→ less vulnerable to stress Brain Regions: Pre-frontal cortex (PFC) Hypothalumus→ bodily homeostasis ( hormones Pituitary glands → hormones Hippocampus→ memory Amygdala→ fight or flight response HPA Axis→ The hypothalamic-pituitary-adrenal (HPA) axis is a communication system between three organs. It's crucial for your body's stress management. These endocrine system organs create a feedback loop of hormones to enact and regulate your body's stress reaction Neurotransmitters involved in stress: Serotonin Cortisol Dopamine Depression → 5HT receptor changes → receptor upregulation due to reduced NT concentrations - Its not about a shortage of serotonin its about the serotonin receptors