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Long term potentation (LTP)
LTP is a process by which synaptic connections between neurons become stronger with frequent activation. It is thought to be a way in which the brain changes in response to experience and thus may be a mechanism underlying learing and memory.
Long term depression (LTD)
LTD is a process by which synaptic connections between neurons are weakend. It may be important for memory formation → by resetting previous synaptic changes to allow for new memories to be formed via long-term potentation (LTP)
The case of patient H.m_
The bilateral removal of the hippocampal formation and allied structures in H.M. had important implications for the understanding of the neurobiological basis of learning and memory:
- It supports the theory of different forms of memory: short term vs long term
- It indicates that the temporal lobe, is a critical neuronal substrate necessary for specific forms of learning and memory
- Hippocampus is not the ultimate structure for long-term storage of declaratice memories
- Medial temporal lobe structures are important for the formation of new memories
Emergency circuits that stimulate feedining
- In response to conditions of acute energy deficiency or chronic energy deficiency the brain initiates behavioral, autonomuc and neuroendocrine response to increase availability of fuel to the CNS
- Response may be: Increase in feeding an hepatic glucose production, in parallel the body conserves energy by inhibiting growth and reproduction while reducing metabolic rate through the suppression of the HPT axis
Effetcs of stress on food intake
- Stress activated both anorexigenix and orexigenic pathways
- Balance between the pathways shift to anorexigenic if high calorie food is not available, and shifts to orexigenix if high calorie food is available
- Both is possible: People that eat less in stressful times and people that eat more in stressful times
3 ways in which alterations of the leptin regulatory loop could lead to obesity
- Failure to produce leptin would result in obesity
- Low leptin secretion for a given fat mass. The fat mass would expand until normal leptin levels are reached, resulting in obesity
- Obesity could result from insensitivity to leptin at its site of action
Stages of addiction cycle
- Preoccupation/anticipation phase: Where there is exaggerated motivation fo drug use
- Binge / intoxication phase: Characterized by the downregulation of positive responses and a subsequent increase in the level of drug intake → dose needs to be increased to get the positive effect
- Withdrawl: Negative effect phase where addictive substances become the driving force for contiues drug seeking and intake
The differences between controlled and uncontrolled drug use
- Drug self-administraton: Availablinity play a role in determining the pattern of druf intake
- Restriction of drug access a few hours a day produces a regular and stable pattern of consumption
- Escalation of drug intake may set the stage for addiction
The role of brain dopamine in obesity
- Weight gain, DA response becomes insensitive
- Leads to overeating which leads to even lower DA response
- People at high risks for obesity have a hypersensitive DA respnse
- Additional factors: Stress, poor nutrition, genetics, environmental toxins
Axonal sprouting
Healthy axons sprout nre nerve endings that connect to other pathways in the CNS
Could be used to strengthen existing conncections ot the repair damaged parts of the CNS by repairing damaged pathways
Synaptic pruning
Synapses start to form around the \(36^{th}\)week of gestation and it gets denser for about 2 years, converging to a fully connected neural network
After it gets as dense as it possibly can, some synapses that do not conduct action potential on a frequent basis starts to disappeat and the number of connections start to decline
As we age, old connections are deleted
Synaptic pruning eliminates weaker synaptic contracts while stronger connections are kept and strengthend
Types of trauma / memory loss: amnesia
- Retrograde amnesia: event for a period of time before the traume are forgotten, but memories from the distant past and the period following (future) are in tact
- Anterograde amnesia: Events before the trauma can be remembered but there are no memories for the period following the trauma
Case of Patiend H.M: conclusion
The bilateral removal of the hippocampal formation and allied structures in H.M has important implications fro the understanding of the neurobiological basis of learning and memory
- It supports the theory of different forms of memory: Short and long term
- It indicates that the temporal lobe is a critical neuronal substrate necessary for specific forms of learning and memory (declarative)
- The hippocampus is not the ultimate structure for long-term storage of declarative memories
- Medial temporal lobe structures are important for the formation of new (declarative) memories, which are then imprinted on the other brain structures
Working memory and attention
- With age it becomes harder to ignore irrelevant information
- It also becomes harder to switch between tasks with different requirements
- These difficulties can make it more difficult to hold relevant information in mind and switch between different task requirements
Brain aging
Characteristics of brain aging is loss of brain volume (white matter > gray matter) especially in the hippocampus and frontal lobes → loss of myelin, synpases and dendritic arbor, cystoskeletabl changes (accumulation of neurofibrilarry tangles and deposition of amyloids in the brain and blood vessels)
Aging is associated with progressive losses in function across multiple systems (sensation, cognition, memory, motor control and affect) and they occur with increasing age.
Healthy brain aging
- Maintenance or improvement of cognitive performance
- Larger brain and hippocampal volumes were associated with preserved cognitive function
- Ability to make decisions and remain independent
- Avoidance of disease and disability by maintenance of physical, cognitive and sustained social engagement
Alzheimer's Disease (AD)
- Chronic neurodegenerative disorder
- Progressive dementia (= group of symptoms affecting thinking and social abilities)
- Loss of memory
- Cognitive decline
- Changes in personality
Blood supply in body
- Depending on activities there is more or less blood flow through certain body parts: When doing sports → blood supply to skeletal muscle increases, blood supply to kindeys/ gut system decreases
- When resting: Blood supply to skeletal muscle decreases
Depression facts
- Common mental disorder
- Leading cause of disability world wide and is a major contributor to the overall global burden of disease
- More women affected by depression than med
- There are psychological and pharmacological treatments for depression
AD genetic risk factors
- The most important genetic risk factor for AD is the apoE4 gene
- ApoE4 is one of three variants of the apoE gene
- If a person carries the apoE4 (for one parent) --> three times the risk to develop AD
- If a person carries 2 apoE4 genes the risk increases to ten times
Functional basics of heart (drawing)
Pericardium
- Is the membrane enclosing the heart, the heart floats in fluid inside pericardium
- Prevents overstretching
- Reduces friction during contractions
The heart is an autonomous pump
- It generates its own beating and doesnt need nerves to beat
- However the heart beat rate is controlled by nerves (autonomic nerves system)
The heart is a pump. Pumps blood from body to lungs and back to body (circulation cycle). While passing through lungs, the blood acquires oxygen and gets rid of CO2 (which were used up and produced by body metabolism)
Basic electro --> chemical --> mechanical events in a heart cell (Drawing)
For a heart muscle cell to contract, a membrane potential is required. The ultimate contraction is Ca2+ concentration dependent. (voltage gated Ca2+ channels → calcium increase causes force)
blue controls green
green controla red
An isolated heart without calcium will stop beating, with calcium the beating will continue
Necessity of calcium for heart contraction
In muscle cells, there are actin and myosin fibres inside. Myosin paddles along actin in an ATP-dependent manner. This sliding of actin and myosin relative of each other = contraction.
Myosin can only bind to actin (and thus do contractions) when the calcium concentration is high.
The Ca2+ for the contractoin comes from the extracellular space and from sarcoplasmic reticulum
Excitation --> contraction coupling in a heart cell (Drawing)
- Depolarization of the muscle cell membrane (caused from neurotransmission) leads to opening of the \(Ca^{2+}\)voltage gated ion channels
- \(Ca^{2+}\)ions flow in (\(Ca^{2+}\)usually high outside and low inside the cell), \(Ca^{2+}\)binding to sarcoplasmatic reticulu also causes \(Ca^{2+}\) storage to flow out ⇒\(Ca^{2+}\)concentration gets even higher
- \(Ca^{2+}\)act on myosin / actin → contraction
How do heart cells generate the membrane potential waces, which make contraction happen?
Drawing: molecular biophysics of heart AP pacemaking
- Voltage gates Ion channels: activated in certain ranges of membrane voltage.
- Current through these channels changes membrane voltage
- So voltage-gated channels influence each others gating / opening by influencing voltage
This and different activation speeds of different channels (Na+ fast, K+ slow), produce self-sustaning cycling/oscillations in membrane voltage --> pacemaking
What does ECG (electrocardiogram) measure?
Because heart cells generate electrical waves roughly in sync with eachother, the combined waves of electricity are large enough to be recorded from the outside of patient's chest. This enables physicians to record ECG, from which they can look at rhythm abnormalities etc.
A graph of voltage versus time of the electrical activity of the heart using electrodes placed on the skin. These electrodes detect the small electrical changes that are a conseqeunce of cardiac muscle depolarization followed by repolarization during each cardiac cycle.
Special features of the heart muscle
- Heart cells are connected to each other mechanically and electrically (syncytium)
- This is an essential feature that enables the heart to work. Otherwise each cell would beat in isolation and there will be no overall contraction of the pump
Coupling between heart cells:
- Electrical = gap junction proteins
- Mechanical = desmosome proteins
Eletromechanical coupling between heart cells produces coordinated contraction of the whole heart. This is critical for blood pumping
Sino-atrial node
The heart cells that set/entrain the whole heart are located in the sino-atrial node (SAN- in right atrium wall)
SAN = natrual pacemaker of the heart
The rate is transferred through all cells via electrical connection
Heart valves
Heart valves ensure one way flow of blood. This is necesary for sending blood flow in the correct direction during contractions of atria and ventricles.
- Atrio-Ventricular Valces: prevent blood from flowing from ventricles to atria
- Semilunar valves: Prevent the return of blood to the heart
Innervation of heart
The heart beats autonomously (self-generated). The rate of this beat is modulated by autonomic motor nerves (ACh, NA)
Sympathetic nerve activity --> releases NA on heart --> accelerates heart rate
Parasympathetic nerve activity --> releases ACh on heart --> slows down heart rate
Control of heart rate by autonomic nerves (Drawing)
Regulation of heart pumping - Frankling Starling mechanism
FS mechanism: the more blood enters the heart, the stronger the heart contracts (intrinsic regulation of heart pumping)
Coronary vessels: heart arteries and veins
Coronary arteries supply heart with blood. Their clogging leads to heart attack (damage to heart muscles)
There are 2 key functions a heart has to deal with in order to work properly and supply the body with nutrients and oxygen: amount of workload (amount of blood) and contractility (ability to contract in the way it should). Therefor heart failure has to do with either one of those or both of these factors
Heart failure
= Output insufficient to provide enough O2 for tissue
Cardiac glycosides
- Classic heart-force-increasing agents
- Cardiac glycoside drugs increase force by increasing cytosolic Ca2+
- Cardiac glycoside drugs: Block Na/K pump. This makes more Calcium enter intracellular Ca2+ stores. So stronger contraction during electrical stimulation
How do cardiac glycosides increase cytosolic Ca2+?
- Block Na+ pump, so Na+ goes up
- Less Ca2+ leaves via Na+/Ca2+ exchanger
- More Ca2+ into SR
- More Ca2+ release!
ACE inhibitor drugs
Block blood vessel adaptations (constriction) that are normally caused by reduced cardiac output. This prevents failing heart from being destroyed further by its work load
It makes blood pressure decrease and therefore work load decrease, so that the failing heart can still pump without getting too stressed
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Flashcards
Factors affecting the rate of gas diffusion through respiratory membrane
- Thickness - reduces rate - can increase eg due to edema
- Area - increases rate - can reduce eg due to removal of lung
- Diffusion gradient
Transport of oxygen and carbon dioxide in blood and tissue fluids
- Oxygen diffuses from blood to tissue, because tissue O2 levels are kept low by tissue metabolism thus creating a constant diffusion gradient
- Increased blood flow to tissue increases extracellular O2 levels in tissue theoretically up to those in blood
- CO2 diffuses from tissue to blood, because tissue CO2 levels are kept high by tissue metabolism thus creating a constant diffusion gradient
- Increased blood flow to tissues reduces extracellular CO2 levels in tissue, theoretically up to those in blood
Role of Hemoglobin (Hb)
Hb is a red blood cell protein that binds O2. This increases O2 carrying capacity of blood about 70-fold
Hemoglobin and trabsport of oxygen and carbondioxide in blood
- H+ (CO2) increases O2 dissociation from Hb --> Bohr effect. This allows tissues that make more CO2 to get more O2 from blood.
- CO combines with Hb in a way that competes with O2. High CO levels can therefor displace a lot of O2 from Hb. This can be lethal
- CO2 / H+ and O2 can all bind to Hb. These bindings influece each other. H+ / CO2 binding makes Hb bind less O2 → so O2 can diffuse into tissue
O2 binding to Hb reduces CO2 binding = Haldane effect - Increased O2 levels, when blood passes through lungs, increase dissociation of CO2 from Hb. This property of Hb promotes CO2 removal from body during breathing.
Regulation of respiration according to H+/CO2
- Brain stem respiratory control neural networks sense H+/CO2 levels and adjust breathing reate accordingly.
- High pH /low CO2 is negative feedback signal for breathing
Regulation of respiration according to O2 levels
- Carotid and aortic bodies are cell clusters that act as O2 sensors
- They send stimulatory signals to brain stem respiratory centers, when O2 is low
Regulation of respiration summary
- Brain stem respiratory neurons stimulate breathing
- Carotid body cells send stimulatory signals to brain stem respiratory neurons
- H+/CO2 --> increase action potential firing in brain stem respiratory neurons --> more breathing
- O2 --> Inhibits carotid body cells --> less stimulation of brain stem respiratory cells --> less breathing
- So low O2 or high H+/CO2 will stimulate breathing
- Breathing in turn increases O2 and reduces H+/CO2 levels thus closing the feedback control loop
The role of leptin
Leptin acts as a hormone that modulates the size of the adipose tissues in the body. It increases the metabolic rate expenditure and decreases food intake.
Leptin regulates energy intake and fat stores so that weight is maintained within a relatively narrow range.
Model for negative feedback regulation of food intake in response to changes in body fat content
- In response to reduce body fat storage
- Adaptive changes occur in neuronal systems governing food seeking behavior and satiety perception
- Both motivation to find food and size of individual meals tend to increase until energy stores are refilled
- Reduction of leptin levels increases rewarding properties of food while diminishing satiety
Non metabolic factors play an important role in:
- Environmental cues
- Reward
- Cognitive
- Emotional factors
Non metabolic factors are mainly processed in cortico limbic structures.
Importance of food reward and cortico-limbic structures
- In humans, initiation of meal starts often as a cognitive/executive decision from the cortex.
- Even at satiety and replete energy stores, the cortex and limbic system can overpower the hypothalamus into an ingestive mode
Hedonic processing: integral part of homeostatic regulatory system
- Signals of short- and long-term internal nutrients availability such as leptin, gut hormones and metabolites are sensed by hypothalamic nutrient sensor and
- hedonic/reward processing centers → dependent on environmentm patalatble food available?,
- / 4. and these circuits communicate bidirectionally with each other to unconsciously affect eating.
Psychological basis of emotion and motivation
Motivation plays and important tole in the control of food intake.
Environmental cues that acquire motivational properties through Pavlovian conditioning can subsequently override satiety and promote eating in sated rats.
Neurobiology of food reward: psychological components of reward
- It is necessary to learn about relationships among stimulu and about the consequences of actions
- Reward consumption can produce hedonic consequences
- Individual has to be motivated to learn and acts
- Reward can be subdivided into different categories: learning, motivation and emotion → Each of these categories contain different psychological aspects which could be affected by neurobiological manipulations
Inducing "wanting" without "liking"
- Electrical stimulation of LH --> consume much more than normally
- Wanting enhancements caused by hypothalamic stimulation or by dopamine elevation
Hunger and satiety signaling during intake of a standard meal
Signals are transmitted from the GI to the brainstem --> energy content and taste is registered. In the absence of strongly attractive tatse, hypotalamus performs the integrated energy sensing through the interaction of various appetide signals and their receptors in the hypothalamic nuclei. Termination of food intake occurs.
Hunger and satiety signaling during intake of palatable food
- With palatable food the attractive taste of food is registered. This leads to the activation of reward center, releasing various reward signals (NAC: important site). The reward center has close connections to the hypothalamus → influeces the hypothalamic energy homeostasis mechanism.
- The end result in prolongation of food intake
Adiposity negative feedback
Circulating signals inform the brain of changes in body fat mass. In response to this input, the brain mounts adaptive adjustments of energy balance to stabilize fat stores.
- Signal is circulating at levels proportionate to body fat content
- Signal is able to enter the CNS and regulate homeostatic neurons
- Signal is able to reduce food intake and increase energy expenditure
- If deficient, this signal leads to hyperphagia
The dual center hypothesis
Discrete neuronal pathways, which are integrated into a complex neural network in which specific orexigenic and anorexigenic neurotransmitters are released from specific neurons to influece food intake.
2 regions in the hypothalamus control feeding:
- VMH (ventromedial hypothalamus) lesions cause animal to eat and become obese → VMH produces condition of appetite (satiety center)
- LH (lateral hypothalamus) lesions cause refusal to eat → LH produces an anorexic condition (feeding center)
Neurocircuits involved in the homeostatic regulation of feeding
- AGRP neurons in the ARC stimulate feeding when they are activated
- AGRP neurons are inhibited by insulin and leptin and activated by ghrelin (hunger hormone)
- POMC inhibits food intake by binding and activating melanocortin receptors
- POMC neurons are stimulated by leptin (higher body fat → high leptin → lowers POMC → inhibits hunger)
Interactions between emotions and metabolic regulation
The balance between food intake and energy expenditure is not alone in contributing to energy homeostasis. → influeced in a higher level by emotions and stress situations and by learned feelings
Emergency circuits that stimulate feeding
- Response to stressful stimuli can override the homeostatic control of energy balance
Stress activated anorexigenic and orexigenic pathways. Balance between the pathways shifts to anorexigenic if high calorie food is not available and shifts to orexigenic if high calorie food is available.
Drug addiction defenition
Chronically relapsing disorder that is characterized by a compulsion to seek and take drugs, loss of control in limiting intake and emergence of a negative emotional state when access to the drug is prevented
Drug addiction - reward transmitters implicated in motivational effects of abuse
Developing addiction
- Escalation in dose
- Habituatio / Tolerence
- Resistance to extinction when behaviours no longer deliver drugs but deliver punishment instead
Reward pathway: Neurotransmitters acting on reward pathway
Dopaminergic involvent in reward pathway
- Dopamine is released in the NAc following electrical stimulation
- Dopamine antagonists will block self-stimulation
- Dopamine agonists will be injected into the NAc by rodents (self-administration)
- Dopamine is releades in NAc following natural rewards
Direct drug action
- Drug of abuse may work via direct action on a receptor
- Magnitude of the effect will primarily depend upon the nr of existing receptors
- e.g. Dopamine agonists will bind directly on the dopamine receptors
e.g. Cocaine: Cocaine binds DAT = ↑ extracellular dopamine.
Cocaine modifies the action of dopamine in the brain
Normally dopamine is released into the synaptic cleft, and a re-uptake happens via DAT-binders, so that not too much dopamine is left in the cleft. Cocain binds to the re-uptake transporter → re-uptake of dopamine is blocked→ way too much dopamine is released → Highly increased dopamine levels
Indirect drug action
- GABA-gated chloride channel is embedded in cell membrane of certain neurons
- Channel has multiple receptor sites where alcohol binds
- Binding of these molecules opens the chloride channel → negatively charged chloride ions can enter neurons cell body
- Changing its charge in negative direction pushes neuon pathway from firing and activating a GABA neuron
Summary Drug action and reward pathway
Withdrawal
- Following physiological adaptation to the presence of an agent → tolerence occurs
- Withdrawal is the result of an abrupt termination of the drug
Syndrome:
- Disturbance of the Autonomic Nervous System
- Activation of thalamus
- Release of corticotroph releasing factor
- Activation of locus coreuleus
Development of addiction
The use of the drug is increased to maintain euphoria or to avoid dysphoria. The number of receptors gradually increases to counter for the continual presence of the drug abuse. The amount of neurotransmitter gradually decreases through depletion and feedback inhibition → reinforcment properties of drug gradually decrease (tolerance) → need for drug is therefore increased
Genetics may influence how neuobiology interacts with environment. Reward neurons may respond more strongly to uncertain rewards
DA agonist and antagonist effects on ICSS
- DA Antagonist: Drug that blocks the effetcs of DA → reduce ICSS potency
- DA Agonist: Drugs that enhance the effects of DA → increase ICSS potency
Neuobiological substrates for the acute reinforcing effects of drugs abuse
Overweight and obesity according to WHO
Overweight and obesity are defined as abnormal or ecessive fat accumulation that may impair health
Metabolic parameters: Insulin resistance
Insulin resistance is a physiological condition in which cells fail to respond to the normal actions of the hormone insulin. The body produces insulin but the cells in the body become resistant to insulin and are unable to use it as effectively
Metabolic parameters: Glucose intolerance
Glucose intolerance is a term for metabolic conditions which results in higer than normal blood glucose levels (hyperglycemia)
Metabolic parameters: Metabolic syndrome
Metabolic syndrome is a combination of the medical disorders that, when occurring togetehr, increase the risk of developing cardiovascular disease, stroke, diabetes.
Metabolic parameters: Metabolic risk factors
Abdominal obesity, high triglyceride levels, high cholesterol level, high blood pressure, high fasting blood sugar
Facts about overweight and obesity (WHO)
Overweight and obesity are linked to more deaths worldwide than underweight. 65% of the world's population live in countries where overweight and obesity kill more people than underweight (includes high-income and middle-income countries)
