Midterm 1 Flashcards
Motor Control
Motor control systems exist at every level of the nervous system
Spinal cord, Brain stem, Midbrain, cortex
New ways of ordering, sequencing behavior
The story of behaviour is the story of the brain
Behaviours are produced by many different levels of the nervous system
Each layer or region adds a new dimension (levels of complexity) to the behavior
I.e. evolution led not to new behaviors but rather nuance and flexibility
Rat grooming pattern
sophisticated and do not rely on the cortex
Different causes of movement
Top-down
Supplementary eye field (frontal lobe) - guides movement of eyes
Frontal eye field (frontal lobe)
Voluntary behaviours are more cortical in nature
Movement: guided voluntary movement with an expectation for something (e.g. looking for keys)
Sensation: Looking or searching for patterns in the environment (Expectations)
Different causes of movement
Bottom-up
Superior colliculus (midbrain) - visual center: takes in visual infromation and directly integrates it into motor output (e.g. something salient, or flashy)
Involuntary behaviours are much more likely to be driven by subcortical areas
Sensation: Generate perceptions starting at the information coming in and then puting that to more complex organizations until perception
Movement: guided by salient features of the environment (e.g. eyes are drawn to flashy TVs)
Loss of function/ disconnection experiments
Reflexes
responds by stretching, withdrawal, support, scratching, paw shaking, etc. to appropriate sensory stimulation (spinal cord)
Stepping response (to movig treadmill), limb approach or limb withdrawal to tactile stimuli
human version of the spinal animal -> spinal cord damage that diconnected the spinal cord from the rest of the brain -> quadraplegia/paraplegia
Awake, alert, cognitively intact, entire brain left in tact, reflexes, no voluntary movement
Cannot move voluntarily but can behave
E.g. weight on hand, reflex to counteract force (happens without any conscious control)
Loss of function/ disconnection experiments
Postural support
performs units of movement (hissing, biting, growling, chewing, lapping, licking, etc.) when stimulated
shows exaggerated standing, postural reflexes
elements of sleepwalking behaviour
Unable to react to any sensory information coming in
(Hindbrain - low decerebrate) -> surgery between midbrain and hindbrain (mesencephalon and metencephalon)
Pons, cerebellum all connected to the spinal cord which can all control muscles, everything above from the midbrain and onward can no longer do motor control
Low decerbrate animals (spinal cord + hindbrain)
Loss of function/ disconnection experiments
Postural support
Low decerbrate animals
(spinal cord + hindbrain)
Postural reflexes - sit in place even when pushed
Great difficulty maintaining consciousness -> may demonstrate different types of waking and sleeping (quiet and REM sleep) but not normal sleep-wake cycles
Persistent vegetative state (may be conscious in some ways but not able to express it)
Loss sensory info - fundamental change in conscious experience
Some sensory stimulation is reaching the spinal cord and hindbrain which can affect behaviour and elicit movement
Decerebrate rigidity - the animal has stiff and excessive level of muscle tone
Able to hold posture more rigidly
Loss of function/ disconnection experiments
Spontaneous movement
responds to simple features of visual and auditory stimulation
performs automatic behaviours such as grooming
Performs subsets of voluntary movements (standing, walking, turning, jumping, climbing, etc.) when stimulate
Midbrain (high decerebrate) including dopamine producing regions (tegmental, substantia nigra), periaquaductal grey (jumping, freezing, increase in heart rate), red nucleus (esp important for species specific behaviours)
High decerebrate animals
Loss of function/ disconnection experiments
Spontaneous movement
High decerebrate animals
(spinal cord + hindbrain + midbrain) -> forebrain is disconnected
Orientation toward stimuli
No evidence of seeing (conscious visual perception - no ventral pathway)
Automatic movements
voluntary movement (e.g. grooming- relatively automatic but voluntary)
not spontaneous movement (e.g. animal will not start going around looking for something sweet to eat)
example of Loss of function/ disconnection experiments of spontaneous movement
instances where humans are born with relatively little or no cortex
Show relatively little spontaneous movement
Does not show any evidence of conscious perception
E.g. jackson
Affect and motivation
voluntary movements occur spontaneously and excessively but are aimless
shows well-integrated but poorly directed affective behaviour
Thermoregulates effectively
Diencephalon (Hypothalamus, thalamus), mesencephalon (midbrain), and hindbrain (diencephalic)
These regions can recieve sensory info and send motor info
No telencephalon (cortex)- complex discrimmination and learning, complicated movements and sequence of movements
Affect and motivation
Dicephalic animals
Little spontaneous eating or drinking
Sham rage and sham motivation
Behavior is emotional but it is excessive or exagerated
Not necessarily feeling
Sham rage: hiss and rage for hours for small inconvenience
Sham motivation: motivated type behavior, not directed at stimuli and excessive behaviour, and search aimlessly -> less meaningful
Driven by the hypothalamus
Purposeless, energetic behavior
Can walk around and navigate through environment
Self-maintenance:
Links voluntary movements and autonomic movements sufficiently well for self-maintenance (Eating, drinking) in a simple enviornment Basal ganglia (descorticate)- movements that are already learned
Self-maintenance:
Decordicate animals
(no cortex, but everything else (everything below cortex), i.e. incl. Basal ganglia), thalamus hypothalmus, midbrain, hindbrain, spinal cord: surprsingly capable
Can eat/drink to sustain although must need recovery time
Normal sleep/wake cycles
Sequence complicated movements (e.g. rat mating behaviors)
Can learn simple tasks (e.g. discimmination of simple sounds)
Dont make nests or hoard food
Can’t perform complex behaviors
Perform semimotivated type behaviors
Basal ganglia is important for voluntary movement, esp habit based
Control and intention
Performs sequences of voluntary movements in organized patterns
Responds to patterns of sensory stimulation
Contains circuits for forming cognitive maps and for responding to the relationships between objects, events, and things
Adds emotional value
Cortex (normal)
Function of cortex
Complex discimmination learning and learning
Complex movements and sequencing of movement
Basic behaviour -> sophisticated behavior
Flexibility adaptivity (e.g. Angry behavior can manifest in variety of ways)
Future planning - must integrate past experience and imagine the future
Prospective stimulations
Cortex allows increased set of complex behaviour (not new behaviors but the complexity is emerged)
Disconnection to parts of the CNS would change the sensory inputs to influence
the motor outputs
Adaptive output to a constant stream of input coming in
Motor movement flowchart
intention/decision/goal -> motor plan -> motor signal -> movement -> sensory info (e.g. somatosensory, stretch receptors, etc.) -> motor plan or motor signal
Sensory input will govern or change motor plan
exception to Motor movement flowchart
ballisti responses, which are open loop
Some movement are so fast and intense that they cannot reasonably be adapted by sensory info
Case study: patient G.O. Damage to somatosensory nerves on his arms
Numerous problems with movement
Cannot perform movements properly without any sensory response
Cannot adjust behavior automatically and must manually adjust by eye
Holding something needs a certain level of grip to prevent it from slipping out of hand but with no sensory info to help guide movement, the task is much more difficult
Heircarchical control of movement
Top: association cortex (most abstract)
2nd: secondary motor cortex - intention/goal and starting to develop a motor plan - sequencing
May bypass the primary motor cortex and send signals down
3rd: primary motor cortex - pattern of nervous system activity is being activated (generating motor signal)
4th brain stem motor nuclei - sending motor signals
Last: spinal motor circuits: movement is sent to muscles and sensory info is coming back
Functional segregation
The signal can be send directly to spinal motor circuit from higher up in the heirarchy
Functional segregation
different units with different functions
The different levels of hierarchical control suggest a different way in which the brain functions
basic level:
higher level:
even higher level:
Basic level: control of certain muscles
Higher-level: control patterns of certain movements
Even higher level: patterns of patterns of movement
Central sensorimotor program theory
Three main assertions:
- The lower levels of the sensorimotor system hierarchy possess “sensorimotor programs”, and those programs represent particular patterns of activity (basic movement)
So much of our motor input needs no conscious input
Once program is activated, the pattern will run with not much conscious control - A particular movement is produced by activating the appropriate combination of these sensorimotor programs
- Once a particular level of the sensorimotor hierarchy is activated, it is capable of operating on the basis of sensory feedback without direct control by the higher levels
Planning out movements
Motor equivalence
Motor plans are independent of the muscle group - if you learn a motor plan, it can be applied to various parts of the body not just one part
The motor plan independent of muscles exists in the secondary motor cortex
Practice makes chunk-fect
Practice can create and/or modify sensorimotor programs
Learning a new skill requires higher level associations
Larger pattern of activity when learning a new task
Harder to multitask two tasks when the higher-level association cortex is focused on a specific task
As you learn and getting better and better at actions the control shifts from higher levels of motor control to lower levels
More automatic and unconscious
Free to do other tasks and multitask easier by freeing up higher levels
Most theories talk of two sorts of processes that influence the learning of sensorimotor programs
- Response chunking- grouping things for efficiency (e.g. learning to read - recognize letters and eventually read/ recognize words without needing to focus and go through each letter)
- Shifting control to lower levels- frees up higher levels to do other tasks
Sensorimotor association cortex
Posterior parietal cortex + dorsolateral prefrontal cortex
Involved in most abstract level of behavior
Dorsolateral prefrontal cortex
Posterior parietal cortex
There are a variety of subareas for these areas but are considered the sensorimotor association cortex
Provides information on where body parts are in relation to the external world
Receives input from visual, auditory, and somatosensory systems
Output goes to secondary motor cortex
Stimulation of this area makes the subject feel they are performing an action
Dorsolateral prefrontal cortex
involved in working memory, decision-making, other aspects of cognition but also motor region
Posterior parietal cortex
sensory processing, body awareness, proprioception but also motor region
Posterior parietal cortex damage
Involved in a variety if cognition, sensation perception, and behavior -> some part of dorsal stream
Knowing where you are in space (starting point) for whatever actions
Lots of sensory inputs (somatosensory, auditory, and body awareness/ proprietary)
Sending signals to the dorsolateral prefrontal cortex and the secondary motor cortex
There are subregions that are easily to outline than the dorsolateral prefrontal cortex
Damage has a strong lateralizing effect
I.e. see one type of deficit with damage to one side vs. the damage to the other sid
If you stimulate the posterior parietal cortex
- at low currents
- at high currents
at low currents, patients experience the feeling that they are going to perform a behaviour
“I feel like im going to move my arm”
At higher currents, patients feel that they have performed a behavior
“I feel like i just moved my arm” even if action did not happen
Posterior parietal cortex damage
Apraxia
(inability to perform movements on command)
Occurs when posterior parietal association cortex is lesioned
Great difficulty imitating a gesture especially if the gesture or movement is meaningless, like pretending to hold something
Difficulty performing gestures on command
Difficulty using tools outside its use (e.g. painting on canvas is fine but not on a rock)
Associated with left hemisphere damage (posterior parietal cortex)
Spontaneous movements tend to be fine
Symptoms are bilateral
Posterior parietal cortex damage
Contralateral Neglect
(fail to respond to visual, auditory, or somatosensory stimuli)
Produced by very large right parietal lesions
Some of the world is mapped bilaterally (i.e. if you damage the left parietal, the right parietal can take over and pay attention to the right side, but not the other way around)
Attentional impairment NOT visual impairment
Individuals only attend to right side of body or items in environment
They will not pay attention to the left side of the world (e.g. shave right side the face, eat the right side of the plate)
Egocentric left is not payed attention to (not an issue with vision) without realizing they are not paying attention to the left side of the world
Individuals are capable of unconsciously perceiving objects on the left
Not interfering with other aspects of cognition (e.g. puts all number on a clock on clock face but only on the right side of the clock)
Dorsolateral prefrontal cortex (DLPFC) Receives projections from..
projects to…
Receives projections from posterior parietal cortex (finding out info on where we are in space and our orientation, and appetitive/motivational info)
Evaluated all the different types of stimuli and decides what to do (behavioral choices)
Projects to secondary motor cortex, primary motor cortex, and frontal eye field
Dorsolateral prefrontal cortex (DLPFC)
If you record activity from the DLPFC, some of the neurons are firing when performing certain actions, or to the characteristics of an object that leads to an action
Involved in assessments of external stimuli
Lots of areas have activity that precedes a behavior or movement - predicts whether a movement is going to occur
May work with posterior parietal cortex in decisions regarding voluntary response initiation
dlPFC fires first in motor chain - when a particular action is being decided, the earliest activity in the DLPFC
Decision making, voluntary movement (top-down)
But also critically involved in so many other functions (e.g. problem-solving, math, working memory, learning)
Dorsolateral prefrontal cortex (DLPFC) damage
Variety of types of errors in cognition or motor can occur
Damage depends on the extent of damage, the extract subregions damaged, whether the interactions between posterior parietal or other regions are damaged
Secondary motor cortex
At least Eight areas of secondary motor cortex
Two areas of premotor cortex
Externally guided behaviour (e.g. dancing with partner)
Not exactly bottom-up
Three supplemental motor areas
Activity recoded in these areas seems to be internally guided (top-down) in motor planning
Voluntary spontaneous behaviours
Three cingulate motor areas
Secondary motor cortex
They receive inputs from the posterior parietal and the dorsolateral prefrontal
Projects to primary motor cortex, each other, and brainstem
Sometimes completely bypass primary motor cortex entirely
Produce complex movements (before and during voluntary movements) - motor
Separation of specific subaspects of movement
Exact role of these areas is unclear
SMA: planning, internally guided
Premotor: externally guided
There are mirror neurons in these areas
Premotor areas encode spatial relations
Both premotor and SMA contain mirror neurons
Mirror neurons
Likely the basis of mimicry/learning
some learning perhaps related to theory of mind (firing for intentionality of movement), empathy, not just the secondary motor cortex
Monkey fired neurons in the same way that when they were doing the action as watching someone perform the same action
Mirror neurons fired for our and other animal’s movements
But when it is a meaningless gesture (e.g. picking up the box or action of picking up a box but without the box) the mirror neurons fired much less
The intentionality of the gesture is important
Lot of speculation- maybe more than just for micry but for emotional reactions
Watching someone else learn the action helps us learn the action
Not just in secondary motor cortex, 11% of all the neurons recorded were in the hippocampus
Primary motor cortex
aka the (anterior) precentral gyrus, M1
While Somatosensory cortex (postcentral gyrus)
Somatotopic organization: motor homunculue
A lot of our motor cortex is devoted to our hands, and lips
Receives feedback from muscle and joints (sensory input) - not solely motor about
Neurons code for preferred patterns of movement/direction, not muscles per se even though muscles are the last step
Primary motor cortex Damage
Damage to M1 is not as disruptive as you might think
Manifest in different ways
Loss of limb separation or Independent movement (e.g. can open and close their hand but may have difficulty moving one finger)
Astereognosia - sensory impairment
Losing the ability to use touch and movement of object to identify object
Reduced speed/ accuracy/force - less efficient movements, slower movement
Not too great of an effect on voluntary behavior - there are multiple levels of control of the system that bypassed by the M1
Suggests SMA/premotor control
Motor control hierarchy cannot account for the following disorders
Alcohol effect
Cerebellar disorders
Parkinson’s disease
Stereotypy and impulsivity in psychostimulant addiction
The cerebellum
- receives inputs from:
Receives inputs from:
Sensory inputs (somatosensory system, vestibular system, proprioceptive info)
Primary and secondary motor cortex
Information about descending motor signals from the brain stem nuclei
Feedback from motor responses via the somatosensory and vestibular systems
The cerebellum
Part of motor control system
The primary cortical neurons send another axon (branches/calateral) to the cerebellum
Cerebellum receives somes of the motor signals
Compares our intended movements to our actual movements, and then corrects our motor behaviour
Cerebellum corrects movement, coordination, and course correction and improves motor output
Critical for timing and sequence (both motor and cognitive)
Ipsilateral control of body -> i.e. left half of the body is responsible for the left half of the body, unlike most of the brain
Damage to the cerebellum
loss of ability to precisely control the direction, force, velocity, and amplitude of movements
loss of ability to adapt patterns of motor output to changing conditions
difficulties in maintaining steady postures (e.g., standing) - often how to recognize people have cerebellum damage
The hand may be wobbly to grab glass of water
disturbances in balance, gait, and the control of eye movement
impairments on measures of attention and executive control, procedural memory, working memory, language and visual-spatial processing
They must manually adjust by eye
Impairments in closed-loop movements where there is feedback and movement and sensory input over and over
impairments in the learning of new motor sequences
Impairments in coordination and control and motor learning
Not much impairment in ballistic movement
Cognitively, some impairments in attention and executive control (normally there would be bold activity in the cerebellum during these tasks)
Damage to the cerebellum
shooting dart study
No cerebellar damage: accurate
With glasses that change the angle of vision: less accurate but over time they adapt and hit the target
Take glasses off and angle shifts back and they have less accuracy again until they adapt back to accuracy
Cerebellar damage: relatively accurate
With glasses: less accurate and they do not adapt
When they take prism goggles off, they do not overshoot, they go back to shooting relatively accurate
Cerebellum is important in adjusting with feedback happening moment to moment and on a larger scale
Basal ganglia
2 regions:
Striatum (with 2 subregions: caudate nucleus, putamen) Ventral surface of the striatum -> nucleus accumbens - important for addiction and motivated behaviours globus pallidus (pale globe - white matter) with 2 components: internal segment (GPI), external segment (GPE)
Basal ganglia
2 Other regions intimately connected to the basal ganglia
- Subthalamic nucleus
2. Substantia nigra - Midbrain region that produces dopamine
Basal ganglia
Modulates motor output (classical view)
Critical to habit formation “Muscle memory”
Many cognitive roles
Motivated behaviours - seeking out rewards
Promotes skill learning
Two pathways of the basal ganglia
Direct pathway: GO: facilitates disinhibition of frontal cortex; increasing activity
Indirect pathway: STOP: maintains the tonic inhibition of frontal cortex; decreasing activity
Basal ganglia must decide which circuit or which patterns of activity should be elicited at any given moment
Piano: some fingers must move and some not (coordinate patterns of activity)
How brain regions interact to produce different types of output
Frontal cortex include secondary motor areas, association cortex like dorsolateral prefrontal
Various parts of the cortex = sensory cortex, dorsolateral, secondary motor, etc
Whether we move or not has to do with the
frontal cortex (secondary motor areas) If the thalamus is sending lots of glutamate signal to the cortex, then elicit lots of voluntary spontaneous movements
Motor/premotor areas in frontal cortex are normally tonically inhibited
Result: no movement
The default is to have a low level of spontaneous movement
indirect/STOP pathway: maintains the tonic inhibition of frontal cortex
DEFAULT: The globus pallidus internal sends this gabaergic signal to the thalamus tonically -> strong inhibitory signal
Inhibits the thalamus -> the thalamus does not send its glutamate signal to the frontal cortex -> relatively low amount of spontaneous voluntary movement
Increase the amount of tonic inhibition coming from the GPi
Motor/premotor areas in frontal cortex are normally tonically inhibited
Increase the amount of tonic inhibition coming from the GPi
chain of events
(2 pathway)
Parts of the cortex synapse on another cell of the striatum part of indirect pathway -> send glutamate onto cells of the indirect pathway -> those striatal neurons fire lots of action potentials -> release lots of GABA onto GPe (inhibits) -> GPe is not inhibiting the GPi -> GPi has no inhibition on it -> GPi is free to sends a strong gabergic signal to the thalamas -> inhibits thalamas -> thalamas send excitatory signal to the frontal cortex -> less movement
Parts of the cortex synapse on another cell of the striatum -> send glutamate onto cells of the indirect pathway -> those striatal neurons fire lots of action potentials -> release lots of GABA onto GPe (inhibits) -> GPe is not inhibiting the subthalamic nucleus STN -> STN sends sends strongs excitatory signal in the GPi -> GPi more strongly sends inhibitory signals to the thalamas -> thalamas sends less glutamate sent to frontal cortex -> less movement overall
Net result: more go, less stop -> movement
Direct pathway (fewer steps): To activate motor cortex, we need to inhibit the inhibition: this is called disinhibition (release inhibition)
Tonic inhibition is removed
Direct/Go pathway: facilitates disinhibition of frontal cortex
Cortex sends a glutamatergic signal to the striatum (excited neurons) -> send more action potentials to release GABA onto the globus pallidus internal -> inhibition of the GPi -> not gonna have many AP -> removing tonic inhibition -> thalamus free to send glutamate signals to frontal cortex without inhibition by GABA from the GPi
Result: movement; more activity in particular circuit
Dopamine’s role in these pathways
Dopamine releasing region is the substantia nigra par compacta (SNc), releasing dopamine onto the striatum
Monoamines are not super targeted -> the whole striatum receiving dopamine
Neurons in the go and stop pathway are recieving dopamine
The two pathways have different dopamine receptors
Primarily D1 receptors in the go/direct pathway -> excitatory
Dopamine D1-family receptors have a positive modulatory role -> increases activity within neurons
D1R activity increases transmission in the direct/GO pathway
Primarily D2 receptors in the indirect/stop pathway -> inhibiting
Dopamine D2-family receptors have a negative modulatory role -> more inhibition of activity
D2R activity decreases transmission in the indirect/STOP pathway (indirect pathway)
The release of dopamine leads to what of the pathways of the basal ganglia
The release of dopamine leads to more GO/direct and less STOP/indirect -> leads to more movement
Parkinson’s disease
In PD, most of the dopaminergic neurons of the SNc die
Lack of voluntary spontaneous behavior
Death of SNc -> no activity in the D1 and D2 receptors
As such, dopamine is not released onto the striatum
This decreases transmission in the GO pathway
This also increases transmission in the STOP pathway -> increase in tonic inhibition (inhibiting the thalamus)
Net result: less go, more stop -> diminished movement
Parkinson’s disease
Treatment
Restoring dopamine signal on the striatum should hopefully restore the movement (L-dopa)
L-DOPA (precursor to dopamine) is the gold standard
Deep brain stimulation (DBS) of the STN
Parkinson’s disease
Treatment
L-DOPA (precursor to dopamine) is the gold standard
Dopamine pill does not cross the BBB but L-dopa does cross the BBB
Enzymes in the brain will convert L-dopa into dopamine, increasing dopamine in the striatum and all across the brain -> restore some of the activity in the GO and reduce activity in the STOP
Parkinson’s disease
Treatment
Deep brain stimulation (DBS) of the STN
Generally inhibits brain region -> improve symptoms seen in Parkinson’s disease
Reduce activity of STN -> less excitatory signals to the GPi -> less GABA released from the GPi -> less inhibition of the thalamus -> more glutamate released from the frontal cortex
Huntington’s disease
Tremors, inability to stop spontaneous voluntary movement, constantly moving or clenching
Constantly moving exhausts the muscles even when tired -> huge build-up of lactic acid -> painful
Purely genetic in nature- we know who has the genotype in infancy
Opposite of Parkinson’s disease
damage within the basal ganglia circuitry
HD affects neurons across the brain, but especially the striatum
Net result: no stop -> excessive movement
Huntington’s disease
damage within the basal ganglia circuitry
Damage neurons especially in the indirect pathway
This decreases transmission in the indirect/STOP pathway
In particular, the striatal neurons that project to GPe die (i.e. neurons in the indirect pathway - normally more tonic inhibition, reduction in movement)
Freeing the direct pathway to remove tonic inhibition
Huntington’s disease
Treatment
Unfortunately very little
Must find out the way to prevent the gene from being expressed into a protein
Fatal disease 100% of the time
Can only ease symptoms
Increasing dopamine transmission
Drugs
All drugs of addiction increase the amount of dopamine functioning of the brain indirectly or directly
All the drugs are going to increase the amount of dopamine being released
Drugs are considered habit/habitual (basal ganglia circuit)
Excessive drug use -> increase dopamine release -> bind to D1 (strong positive modulatory effect- more activity in the direct pathway, increasing movement) and D2 (block activity in indirect pathway -> disinhibition)
Drug users are behaviourally more active
At low doses, it can help you stay motivated or on task
At higher doses, rats will perform more rat-like behavior (more grooming); in humans, more primate like behavior (e.g. biting nails, picking skin, tweaking)
biggest change to brain when drug addiction develop
The ventral tegmental area has another basal ganglia circuit that is more related to motivated behaviors
Dopamine and reward
All drugs of addiction directly or indirectly increase dopamine transmission from SNc and the other main dopaminergic region, the VTA
change in behavior to seek out more of the drug by shaping the way in which our basal ganglia work
Effects of prolonged use is that they fundamentally change how the basal ganglia are working
these drugs can shape our behaviors such that we seek out more of them (e.g. addiction)
psychostimulant drugs like cocaine or amphetamines increase goal-directed behaviours, impulsivity, and (at higher doses) repetitive behaviours (called stereotypy or punding)
~_% experienced drug addiction in the past year
4
~__% experienced drug addiction in their lives in North America
10
If >__% of individuals try illegal illicit drugs in their life, then >__% do not struggle with addiction
50;80
addiction- types of stigma
Self stigma (low self esteem, feeling ashamed) social stigma (the way others are treated them, saying it is a choice rather than biological change in brain) structural stigma (policies, social services)
People at Risk of Addiction
Dependent on the drug, but generally, usually men (the gap is closing over time)
Any age– Higher risk of drug addiction if drug use begins in adolescence
But this could be due to longer total exposure time to a drug, which is the biggest correlate to drug addiction
High rates of drug use and drug addiction (depending on particular drug) in 18-25 y.o.
Higher risk for people struggling with Depression – Anxiety – PTSD, personality disorders (bipolar disorder), other
Depression and anxiety increase risk of drug addiction, and drug addiction increases rick of depression and anxiety
Higher rates of drug addiction in people who identify as white and indigenous
Some evidence for predisposition to addiction
Individuals who are better able to metabolize a drug are at higher risk of disorder -> leading to using more of the drug
Higher risk of addiction family history of addiction
Low SES are more likely to never use drugs and yet they are more likely to struggle with drug addiction
Individual higher in socioeconomic status (SES) use more drugs but less likely to struggle with addiction than low SES
Poverty / low SES
Chronic stress
Early childhood adversity- maternal/paternal neglect, social isolation, trauma, abuse
Being single / divorced in men
Measurement of how long it took for drug addiction to develop
and comparison between men and women
time between first use and time when they seeked help
This time is much shorter in women than men
Women move through the stages of drug addiction faster than men do, which is known as “telescoping”
What changes occur with drug addiction
Prolonged use of drug leads to observable and persistent neurobiological changes in the brain, especially the dopamine system in the basal ganglia
Changes in the structure and function of the brain
These drugs act on the brain
Alter our motivation, leading to increased drug-seeking behaviour -> drugs hijack motivational system
Addiction is not a “failure of willpower”
Drug abuser: less lighting up, fewer places for radioactive ligands to bind to the dopamine transport
Prolonged drug use has led to the hypofunctional dopamine system
This person was abstinent, but the changes to the brain are persistent
Features of drug addiction
Pleasing effects - the elevated sense of well being
Diminish effect over time
Pleasing effect not necessary for drug addiction to develop (e.g. tobacco)
Craving - illicit drug-seeking behavior
Tolerance - cells adapt to the presence of the drug
Dependence - your cells that have adapted to the drug will experience withdrawal
Does not function normally without the drug
Relapse- difficult to maintain abstinence
Continued use despite adverse effects on life -> in work, relationships, finance, etc.
can someone be addicted to coffee
coffee does NOT satisfy this criterion but checks off all other criteria -> not considered drug addiction
Would be considered drug dependence
does not check off Continued use despite adverse effects on life
Adenosine (produced by mitochondria)
Remember: ATP is cellular energy
ATP can be broken down to ADP and then to AMP and then to A (adensosine)
Adenosine is ATP by product
Build up of adenosine while we are awake
Adenosine can signal how sleepy you are
Found across entire brain and body
Inhibitory effect
Adenosine receptors - more active throughout the day
accumulation of daytime sleepiness driven by adenosine
Not a NT system, only a byproduct of energy use throughout the day but sends signals to the brain
Caffeine/theophylline: adenosine receptor antagonist
Trying to block activity of adenosine receptors -> feel more awake
Over time tolerance will develop more caffeine
Body recognize that adenosine is not binding to receptors-> body adds more adenosine receptors so adenosine can bind
Extra adenosine receptors binds to adenosine -> we feel more tired without coffee
Must drink more coffee to have the same effect as coffee (as when beginning to use coffee)
With more adenosine receptors-> more sensitive to adenosine (adenosine withdrawal in the morning)
After 3-4 weeks of abstinence, the adenosine receptors will go back to the initial state without use of coffee
Opponent Process Theory of Drug Addiction
AKA withdrawal theory (Koob)
The opponent-process is seen for emotion
Explains some (e.g. opioids)
From “taking drugs to feel good” to “taking drugs to feel normal”
Tolerance and withdrawal
Development of withdrawal is what drives the use of drug use
E.g. opioid users -> taking drugs in order to prevent withdrawal effects
Tolerance and withdrawal mechanism
stages of drug addiction (a common framework) as related to opponent process theory
- Intoxication/binge
- Development of dependence (withdrawal)
- Preoccupation and anticipation (craving)
Development of dependence (withdrawal) mechanism
Driven by the activity in the amygdala (esp nucleus accumbens) increases
Withdrawal drives continual use of the drug
Withdrawal goes away -> some part of you will return to baseline or near baseline
The amount of withdrawal does not line up with addictive potential -> example evidence
Many people who were abstinent and relieves withdrawal symptoms still relapse -> must understand mechanism of relapse
Associative Learning Principles Used in Addiction Models
Operant conditioning – Reinforcement
Outcomes of an animals behavior will shape animals behavior in the future
Positive reinforcer
Dopamine projects from
Ventral Tegmental Area (VTA) to Nucleus Accumbens (NAcc; the ventral part of the striatum)
Stimulation of electrode whenever the animal pressed the lever onto the axon towards NAcc
Causes AP to fire in bundles of axon -> release NT (dopamine) onto NAcc
Animals would press lever thousands of times until exhaustion even if there are other rewards are available
The animal is intensely motivated to do this behaviour -> not necessarily that they like it
Drugs that directly increase dopamine transmission - and how
methamphetamine, amphetamine -> these drugs bind to dopamine transporters and cause them to work in reverse
Normally transporters remove NT from the synapse (cleanup mechanism)
Amphetamine causes transporter to push dopamine out of the cell (no reuptake)
And interacts with transporters on the vesicles and pushes dopamine out of vesicles
Lots of dopamine is released into synapse - causing an increase in dopamine transmission
Cocaine acting similarly
Drugs that indirectly increase dopamine transmission - and how
opioids bind to opioid receptors, which are found in many different locations Opioid receptors (GPCR; metabotropic; have an inhibitory effect) found on a number of GABA neurons both in the VTA and NAcc GABA neurons in the VTA are normally inhibiting dopamine neurons Heroin, fentanyl, morphine binds to the opioid receptors and inhibits GABA neurons in the VTA, releasing these dopamine neurons from inhibition (disinhibition) -> dopamine neurons are free to release dopamine at their axon terminals in the NAcc
Dopamine and Parkinson’s Disease Dopamine
Caused by the loss of neurons in the Substantia nigra pars compacta (SNc)
Thin dark region of the brain
PD -> low levels of dopamine
One of two major dopamine-producing regions
Great difficulty initiating spontaneous voluntary movement
Does not have decreased level of pleasure (e.g. good food)
Tremors are a common symptom
Dopamine and Parkinson’s Disease Dopamine -> treatment
L-DOPA (will cross BBB) as PD treatment
Enzymes transform L-DOPA (precursor of dopamine) into dopamine in the brain and relieve symptoms of Parkinson’s disease - easier voluntary movement due to restoration of dopamine levels
But does not increase pleasure
Schizophrenia medications
dopamine D2 (receptor antagonists)
Drugs that bind strongly to the dopamine receptors (D2) and block them -> small dose
Better they work at alleviating symptoms of schizophrenia
Lower levels of y-axis -> bind more strongly (e.g.spiroperidol)
Binds most weakly to D2 receptors (e.g. promazine)
Drugs that bind weakly to the dopamine receptors (D2) and block them -> higher dose
schizophrenia
People with schizophrenia have hyperfunctioning dopamine systems
Positive symptoms: hallucinations, delusions, mania, disorganized thought speech and behaviour
Not necessarily different levels of pleasure
Separating Pleasure from Motivation
Taught a rat to make decisions in a T maze task (decision-making task)
Low effort, low reward vs. high effort, high reward
baseline:
with dopamine antagonist:
In baseline: animals would put in more effort for a higher reward
Decrease motivation but not pleasure
Shift behavior: choose low effort and low reward option
Can be systemic or directly injected into VTA or NAcc
But without the barrier that makes it high effort for high reward the same level of effort to the low reward option, the animals take the higher reward
The animals are more than willing to obtain a larger reward, but they do not want to put in the extra effort
Dopamine is more related to
motivation, movement, and behaviour
All drugs of addiction are increasing
motivation levels -> drugs shape our motivation
Incentive sensitization theory
artificial motivational signal
Separates liking (pleasure) vs. wanting (motivation)
All addictive drugs hijack DA (dopamine) system, increase DA (well above natural circumstances)
The increase in dopamine is causing an increase in motivational value to the stimuli
Drug use adds incentive salience to drug stimuli
Explains important elements that withdrawal theory can not
Food will cause a __% increase in dopamine
50
Cocaine will cause >__% increase in dopamine
150
Meth has shown up to ___% increase in dopamine
1800
how does Drug use adds incentive salience to drug stimuli
Via artificially increased DA levels
Drug-related stimuli is everything related to the use of the drug (e.g. time, location, smell, lighter, people, etc)
Brain becomes “hyper-reactive to the incentive motivational properties of drug cues”
Sight of drug cues facilitates motivation (i.e. craving drug) -> RELAPSE potential
Dopamine increases the relationship with drug and all the other cues related to the drug
Incentive sensitization theory (becoming sensitive to the motivational cues of drug use)
Berridge and Robinson gave 6 (OHDA) hydroxy dopamine lesions -> destroy dopamine neurons in rats
what happened?
Rats would not show appetitive responses to food (they liked the food)
They did not seek out food (motivation)
Motivated behaviour do not always lead to _____
pleasure
Wanting and liking are slowly separating with more drug use
VTA (DA) neurons
Dopamine and reward prediction error
When something unexpectedly good happens -> increase in DA firing
When something unexpectedly bad happens -> decrease in DA firing
When something expected happens -> baseline level of DA firing
Dopamine effect
Some stimuli have innate or learned incentives
Incentives facilitate dopamine release onto NAcc
Teaching signal
Motivational signal
Other functions
NAcc gets many inputs, guides behaviour (valuation)
Increase in likelihood that you will repeat behaviour that lead to increase in dopamine
Dopamine is shaping and facilitating our motivated behaviours
Drug Addiction and Changes to Learning and Memory Systems
These changes to brain regions are often persistent:
- Dorsolateral prefrontal cortex
- Dorsal striatum
- Orbitofrontal cortex
- Reward circuit
- Amygdala
- Hippocampus
- VTA (one of the 2 main dopamine producing regions)
Dorsolateral prefrontal cortex: planning and reasoning altered by drugs - drugs disrupt impulse control
Dorsal striatum: mediates implicit behaviors such as habit learning
Orbitofrontal cortex: assigns value to stimuli paired with drug effects
Reward circuit: elicits reinforcing effects from acute administration
Amygdala: Pain stimuli with reinforcing drug effects
Hippocampus: stores contextual information related to recreational drug taking
VTA (one of the 2 main dopamine producing regions) -> projects to the NAcc
Projects to areas that lead to structural changes when there is prolonged drug use
Psychological and Pharmacological Therapies
Detoxification
remove the presence of the drug from system
Go through withdrawals and readjust body to prior to drug use
Psychological and Pharmacological Therapies
Drug replacement therapy
replace the drug with a less dangerous version but satisfies the same need
Psychological and Pharmacological Therapies
Behavioral therapy
identify certain patterns of thought and intervening them
Psychological and Pharmacological Therapies
Twelve-step programs
group therapy with mentors that support each other (e.g. alcoholics anonymous)
Psychological and Pharmacological Therapies
Deep brain stimulation of the NAcc
block activity in the NAcc but it affects motivational pathway as a whole
treat/cure drug addiction
Heroin
Across all the treatments - only 30% of individuals are abstinent after 5 years later
70% of individual will continue to use the drug even after treatments
Methadone: durg replacement therapy- another opioid drug, administered orally (safer admistristrstion and supply)
Effects last for ~36hr
Most successful for opioid than other methods
Long term/short term residential (rehab) - living at the hospital - detox
Outpatient (not living in hospital) drug free - detox and rehab
The rate for detox and other therapies working together are not effective
1 year abstinence ~5%
5 year abstinence ~10%
why does Getting through withdrawal effect for therapy not work
as there are strong motivational cues still in environment
Environment is shaping and acting a cue for motivational behaviour for drug use
treat/cure drug addiction
Cocaine
Bit easier to get recover from than heroin
- all methods around 20% will be abstinent
In all individuals who struggled with drug addiction -> what happens to the functioning of the dopamine system
there is hypofunctioning of dopamine system, which persists (semipermanently)
Part of the trouble in treating addiction: Feedforward mechanism
Early childhood adversity and other risk factors -> changes how dopamine and NAcc functions -> more impulsive and less behaviourally sensitive -> more likely to try drugs and lead to addiction
Addiction then leads to more impaired functioning of the dopamine system and leads to more drug-seeking behaviour
Behavioural Addictions
e.g. Food, gambling, internet
Share some similarities with drug addiction
Pleasing effects
Tolerance - used to be more excited when they first start than later
Dependence
Cumulative negative effect
Act on the same system (i.e. dopamine)
Pathological gambling is the only behavioural addiction that is added to the DSM
Quantified better -> financial toll
Patients who struggle with gambling are much more likely to have a substance use disorder
Reward circuits are active for natural rewards as well as drug rewards
Dopamine agonists and Parkinson’s Disease
Some individual do not respond well to L-DOPA - causes side effects
They tried DA receptor agonist
DA receptor agonists can cause “impulse control disorders”
Problem gambling
Hypersexuality
Compulsive shopping
more
Impulse control disorders manifest due to increasing dopamine receptor function
dopamine really is fundamental in our motivational system
the major component of addiction seems to revolve around
how drugs hijack the dopamine system
successful treatment for addiction likely requires large changes in
social, economic, and mental health conditions
Cannot treat with detox
The environment will causes exposure to cues and risk factors for drug use
incentive-sensitization theory posits the essence of drug addiction to be
excessive amplification specifically of psychological ‘wanting’, especially triggered by cues, without necessarily an amplification of ‘liking’.
due to long-lasting changes in dopamine-related motivation systems of susceptible individuals, called neural sensitization
many studies had found that brain dopamine systems were activated by most ____, and further that manipulating dopamine altered ________ + example
rewards; ‘wanting’ for rewards
for example changing how much animals preferred, pursued, worked for, or consumed the reward
reported that suppressing dopamine neurotransmission in people did not reduce their ___ ____ of drug
pleasure ratings
This type of ‘wanting’ is often triggered in pulses by
reward-related cues or by vivid imagery about the reward
incentive salience ‘wanting’ is less connected to cognitive goals and more tightly linked to reward cues, making those cues attention-grabbing and attractive
The cues simultaneously become able to trigger urges to obtain and consume their rewards
Wanting’ is mediated largely by
brain mesocorticolimbic systems involving midbrain dopamine projections to forebrain targets, such as the nucleus accumbens and other parts of striatum
This interaction allows ‘wanting’ peaks to be amplified by brain states that heighten dopamine reactivity, such as
stress, emotional excitement, relevant appetites or intoxication
State-dependent amplification of incentive salience is one reason why many addicts find it so hard to stop at ‘just one hit’
Incentive salience ‘wanting’ in opposition to cognitive wanting, for example
occurs when a recovering addict has a genuine cognitive desire to abstain from taking drugs, but still ‘wants’ drugs, so relapses anyway when exposed to drug cues or during vivid imagery about them.
fearful salience
generated by the same mesolimbic circuitry as incentive salience.
This dopamine-related fearful salience has been suggested to contribute to human paranoia symptoms in schizophrenia and in psychostimulant-induced psychosis
hedonic hotspots
‘liking’ system comprises a collection of interactive hedonic hotspots, and this hedonic circuitry may be shared by diverse pleasures ranging from sensory food and drug pleasures to human cultural and social pleasures
The pleasure-generating hotspots are anatomically tiny, neurochemically restricted, and easily disrupted
Each hedonic hotspot is nestled within its larger limbic structure
The hotspot constitutes only 10% of total nucleus accumbens volume: the remaining 90% of the nucleus accumbens lacks any ability to enhance ‘liking’, though still robustly causes intense ‘wanting
hedonic hotspot located in the ventral pallidum
at the base of the subcortical forebrain
this ventral pallidal hotspot is the only known site in the brain where a small lesion conversely also eliminates normal pleasure, and reverses the hedonic impact of sweet sensation from ‘liked’ to instead ‘disgusting’
Mesolimbic sensitization happens especially if the drugs are
taken repeatedly, and at high doses spaced apart
drug sensitization
drug sensitization also alters glutamate neurons that project from cortex to nucleus accumbens
Sensitization also changes the physical structure of mesolimbic neurons, such as altering the shape and number of tiny spines on dendrites of neurons in nucleus accumbens, which act as their ‘receiving antennae’ for incoming signals
mesolimbic sensitization renders brain ‘wanting’ systems hyper-reactive to drug cues and contexts - more intense incentive salience on those cues or contexts
Sensitized ‘wanting’ can persist for years, even if
even if the person cognitively doesn’t want to take drugs, doesn’t expect the drugs to be very pleasant, and even long after withdrawal symptoms have subsided
addiction becomes compulsive when
mesolimbic systems become sensitized and hyper-reactive to the incentive motivational properties of drug cues
compensatory suppressions of drug-elicited reactions due to over-stimulation does not contradict incentive-sensitization because
primary mechanism for the compulsive craving in addiction, consistent with incentive-sensitization
incentive-sensitization under abstinence
neural changes that cause incentive-sensitization do not fade over months of drug abstinence → sensitization grows for some time during abstinence
a phenomenon sometimes called ‘incubation of drug craving’, which is an increase in relapse vulnerability after a month or so of drug abstinence
drug taking context and sensitization
Early animal studies showed that giving the drug in a test environment where it never before was experienced can completely prevent the expression of behavioral and neural sensitization, even when it clearly has been induced, whereas a previously drug-associated context enables the sensitized response to fully reappear again when drug is retaken- context of drug use is important
better recreate drug-related contexts and cues in order to reveal sensitized hyper-reactive brain responses to drugs that would occur in real-life drug situations
important determinants of susceptibility to sensitization
Genetic factors are important determinants of susceptibility to sensitization in rodents, and genes also contribute strongly to addiction vulnerability in humans
Other determinants of sensitization vulnerability include gender and the presence of sex hormones, and whether the individual has had major stresses in life before taking drug
important situational factors can facilitate incentive-sensitization
These include how long drugs have been taken, whether dose has escalated, and whether the person took drugs by routes that resulted in drug rapidly reaching the brain (i.e., inhalation or intravenous use)
sign-trackers
will work avidly to get the cue that predicts drug reward
- Studies in the T.E. Robinson lab have found that discrete cocaine or opioid cues acquire greater incentive salience in sign-trackers than in goal-trackers
- in some situations sign-trackers are also more likely than goal-trackers to show cue-triggered relapse of drug-taking behavior
goal-trackers
go directly to the location of the impending delivery of a food reward when its predictive cue appears
Neural sensitization of ‘wanting’ mechanisms may in some cases occur without drugs.
evidence is emerging that individuals with these behavioral addictions may have some sensitization-like patterns of brain hyper-reactivity to cues related to their own personal addictions
sensitization-related brain changes arise in some highly susceptible individuals to produce these addictions without need of drugs
Opioid blockers (e.g., naltrexone)
Opioid blockers (e.g., naltrexone) conceivably help somewhat blunt ‘wanting’ as well ‘liking’ peaks
Obesity is correlated with health risks
Cardiovascular disease (CVD), diabetes, sleep apnea, some cancers Does not assess someone’s health with BMI
BUT disentangling the effects of obesity, diet, and physical exercise is necessary
e.g. >50% of all considered overweight, and >30% of all considered obese, are healthy (e.g. not at risk of CVD)
Some people are staying active and treating their body well - individuals are healthy
E.g. sumo wrestlers -> healthy from exercise although they consume a lot of calories
Then there’s paradoxical “obese survival”, and natural selection
In Individuals who suffer from major life threatening situations (e.g. surgery, cancer), people who are obese have a higher chance of survival -> they can lose weight and still stay relatively healthy
Why do we eat?
Most common Hypothesis:
We start/stop eating to maintain “balance” in our bodies.
Given energy supply- > recharge battery when depleted, and hungry
Not necessarily true in terms of energy level we have
e.g. We eat to satisfy a deficit in our body’s energy reserve
Homeostasis
Homeostasis is “the wisdom of the body”: Cannon (1939)
“The necessary condition for free life is constancy of the internal environment”: Bernard (1865)
Common examples: temperature, glucose, salt, water, temporary, ions
The goal: maintaining a set point (cf. thermostat) - when set point is matched, not much happens
At low levels of moving away from homeostasis (e.g. start to get cold), there are internal changes (e.g. shiver, and retain heat -> vasopressin- hormone that retains water in body, urinate less)
Beyond a certain point of the range of homeostasis, external (i.e. behavioral - thirst, hunger) changes are necessary
Homeostasis as related to eating
Two basic proposed mechanisms:
Glucostatic (shorter term) - set point protecting is blood glucose levels and trying to maintain ideal level
Lipostatic (longer term) - set point for amount of body fat on body and trying to maintain ideal level of body fat
Implications of homeostatic theories of eating
Hunger/eating triggered by changes in blood sugar / body fat
Satiety/cessation of eating triggered by changes in blood sugar / body fat
There must be accompanying body/brain mechanisms for initiation/cessation of these motivated behaviors
We should “know” what to eat and when - if we notice deficit, we should be counteracting the defecit by eating or not eating
Body weights should be stable
Unrelated stimuli should not influence eating
Taste/flavor is relatively unimportant- food should only be more restoring our level of glucose and body fat
Is hunger/eating triggered by changes in blood sugar?
Prior to a meal, blood sugar levels decrease
Modest to strong correlation of blood glucose level and subjective experience of hunger
If you skip a meal, blood sugar level returns to normal
Blood sugar level changes likely due to your body preparing for the meal
Eating food is physically stressor to body so body prepares for meal by lowering blood glucose levels
Response to food in anorexia -> they find act of eating to be stressful
Insulin - released by pancreas and causes blood glucose levels to go down
Triggers body to store energy instead of using glucose
Using insulin to artificially stimulate eating
But the amount of blood sugar level that drops from insulin does not happen in nature and not in normal physiological range
Having a high-calorie drink before dinner
Is hunger/eating triggered by changes in body fat?
Leptin - hormone secreted by fat cells which can enter brain
Lots of fat cells -> satiety signal
Leptin-related mutations (leptin production is reduced) can cause obesity and cannot stop eating
Correlation in leptin level and eating
There was hope it would be a great therapeutic target for obesity…
They wanted to target leptin system to change how people eat
Increase in leptin: increase metabolism and decrease in hunger
But not true: but with more leptin -> healthy individuals do not change their weight or hunger/eating
Leptin has many targets (e.g. fertility, reproduction) -> wide variety of roles
Consider the average obese individual’s leptin levels, as related to their weight
Ghrelin
released from stomach when stomach is empty to induce hunger
If you knockout production of ghrelin via genetics -> these animals eat less
Can administer ghrelin to underweight people - does induce hunger and eat more
Blocking ghrelin receptors -> the ghrelin antagonists were safe and do block ghrelin signaling but there was no effect on eating and hunger in animal models that were obese - NOT EFFECTIVE
Orexin
(aka hypocretin - NT, Hormone, signaling molecule) - will trigger and induce hunger
Cannot target system as it will cause changes in eating and sleeping
Related to sleep
Peptide YY (PYY)
Released by digestive tract - satiety signal in brain to reduction in body weight
weak evidence for PYY in treating obesity (c.2003-2006) - PYY agonist to treat obesity
They have adverse effects on the heart
Hormones are distributed across the body
Are there other body/brain mechanisms for initiation/cessation of eating? The hypothalamus: Stimulation vs. lesions Lateral hypothalamus (LH)
Placed electrode for electrical stimulation
With stimulation (gain of function) -> animals start eating and will continue to eat until stimulation stops (stimulus bound eating)
With electrolytic lesion -> lead to aphasia (stops eating) and adipsia (Stops drinking water)
The animals need to be tube fed and over time they will accept highly palatable food
But they can recover partially over time although adipsia somewhat persists
Are there other body/brain mechanisms for initiation/cessation of eating? The hypothalamus: Stimulation vs. lesions Ventromedial hypothalamus (VMH)
Placed electrode for electrical stimulation
With stimulation (gain of function) -> stops animals from eating and everything else
With electrolytic lesion -> hyperphagia (eating a lot to obesity)
The dual hypothalamic theory of hunger
LH -> excitatory and drives feeding (start mechanism)
VMH -> inhibitory (stop mechanism) of hunger
VMH damage
huge insulin increase -> blood sugar levels are low - need to eat more to retain healthy physiological function
LH lesions
Lead to impairments in responding to food and and other sensory functions
Damage to medial forebrain bundle (MFB), i.e. axons from VTA to NAcc
Damage to MFB interrupted DA passage leading to impairment in motivation behaviour in general
Evidence for intelligent and/or homeostatic eating: cafeteria diet
Early cafeteria diet studies in animals and children -> provide a wide variety of food options and let people choose
Overall animals and children will choose foods a well rounded diet
Cafeteria diets with high-preference food -> all intelligence eating is gone
Desert: children and animals will eat a heavy high desert and yummy foods
Protein-deprived animal models -> offer animals variety foods and they will choose high protein diet
BUT if there are highly palatable foods - they will lean towards highly palatable (high sugar) foods intense
They would rather continue to be protein derived to have high sugar content
We can maintain a balanced diet as long as there are no highly palatable foods available
evidence that we eat in an intelligent way
diabetes insipidus
related to less vasopressin (release causes water retention)
Salt loss in diabetes insipidus, salt-deprived animal models (will shift to eat salty foods instead of other foods)
They must eat a lot of salt to compensate for salt less
Free-feeding vs. caloric restriction in humans and animals
Caloric restriction - reducing calories
Eating 80% full instead of full - longer lifespan
Generally major benefits - increases lifespan in many animals even invertebrates
Delays age related decline
Lower levels of obesity
Some studies find that mild caloric restriction is related to higher working memory and long term memory scores
Mattison et al. 2017 -> rhesus monkeys in 1980s and went through entire lifespan
Caloric restriction was related to longer lifespan, delays in age related decline, lower rates of cancer, lower rates of insulin resistance, lower rates of cardiovascular disorders, lower rates of diabetes
free-feeding - eating until full
Are body weights stable?
individual:
societal
Individual: some relative stability short term though not as stable as a lipostatic mechanism would suggest
Societal: obesity is pervasive and on the rise - no reduced rate of obesity in any country studied
Do stimuli that are not physiologically relevant influence our eating?
YES PEOPLE
Friends and food (social facilitation) - eat 60% more when eating with other present
Friends and bitterness - bitter foods are never preferred over water
Bitter foods become more palatable when introduced in social context
Culture and food preference
Children enjoy foods that people they admire eat
Culture dictates the types of foods we eat and the ways we eat
How about other observations/research that contradicts homeostatic theories of eating?
The bottomless bowl of soup
- People will eat far more soup when the bowl is refilled from the bowl not given bowl after bowl
The appetiser effect
- Appetisers cause you to eat more
Eating in anterograde amnesia (cannot create new memories)
- They will eat more far more meals when given consecutive meals with no memory
- Homeostatic mechanisms for hunger is not affected until they have eaten far more than necessary
The significance of serving size
- In countries where serving sizes are bigger -> eat more
- In countries where serving sizes are smaller -> eat less
- Not due to homeostatic mechanism
Lots of types of noodles
- If there are lots of types, people will eat more
So how did the homeostatic theory do?
Controlling cessation of eating did not line up well
X Hunger/eating triggered by changes in blood sugar / body fat
Cannot use leptin to stop people from eating
X (Mostly) Satiety/cessation of eating triggered by changes in blood sugar / body fat
X (Mostly) There must be accompanying body/brain mechanisms for initiation/cessation of these motivated behaviors
E.g. dual hypothalamic theory - not bad theory but more complex than this
X (Sometimes we do, but usually not) We should “know” what to eat and when
X Body weights should be stable X Unrelated stimuli should not influence eating
X Taste/flavor is relatively unimportant
consider the evolutionary pressures on eating
Food goes through huge abundances and scarcity
Agriculture is less than 12,000 years old, and absent in virtually all other animals
The norm was food scarcity - eat when food is available, and not when not available
Bears will start off skinny in spring and then super big during september -> for hibernation
Not following homeostasis
Eating for pleasure
The positive-incentive theory of eating:
we are motivated to eat not by internal energy deficits, but rather by the anticipated pleasure of eating
Not reliant on homeostatic theory although homeostatic mechanisms are present
The degree of hunger you feel depends on the interaction between a large variety of factors:
Flavour of the food
What you have learned about the food
Time since last meal
Type and quantity of food recently consumed
Presence of other people who are eating or not - motivational property
Whether your blood-glucose levels are within a normal range - homeostatic
Taste types
sweet, sour, salty, bitter, umami (high aa content)
Eating is driven by a combination of
evolutionary pressures and simple learning
Evolutionary pressures of eating:
Avoid dangerous foods
Choose trustworthy foods
Eat a variety of foods
Eat far more than you need - eat in abundance because eventually food will be scarce
Eating driven by Simple learning: (incentive and motivation - operant learning)
Eat what brings pleasure
Eat what has been associated with pleasure in the past
Seek food at times when we’ve learned food will present
Do we avoid dangerous foods and choose trustworthy foods?
In the short term, yes -> Generally, flavour corresponds to nutritional value/safety (e.g. bitterness)
Things that are poisonous are bitter in flavour -> high correlation
Social transmission of food preference -> rat observes another rat that ate something
The observer rat is more likely to eat the food that the other rat ate when given a variety of option of new food
Rats are conscious about eating new foods as they cannot vomit
Bitter foods taste better with social facilitation
Infants rats have preference for foods that mothers ate -> social transmission to help trustworthy foods
BUT Modern access to highly palatable food is dangerous…
Do we eat a variety of foods?
Yes, as described before (cafeteria diets)
This is undermined by highly palatable foods like sugar
Mechanism: sensory-specific satiety
sensory-specific satiety
as you continue to consume a specific thing, the value of the food goes down and down but can eat other foods
SSS can’t easily be explained by homeostatic theory (but is understandable in light of evolution and learning) - we can eat well beyond what we need if the foods are different (even different pasta shapes)
SSS likely operates on both peripheral (at taste buds, up or down regulation of receptors) and central levels (motivation may be shifted - pasta example, food taste is same but the different “type” of food causes motivation to eat more)
Interesting: personal preference affects SSS -> different foods can be consumed more for some people than others due to food preferences
Do we eat far more than we need?
YES (In any given moment)
See previous: appetiser effect (although more food, appetisers make us eat more even for caloric drinks), social factors, buffets, and on and on
In feast-or-famine conditions, this is an optimal strategy
Graphs below:
Cafeteria diet - caloric intake goes up
Do we eat what brings pleasure?
Yes. Taste: sweet, sour, salty, bitter, umami
Species predispositions for taste (sweet, fatty, salty foods for humans, i.e. high-energy or high-salt foods)
we rapidly learn food aversions (evolution), i.e. what doesn’t bring pleasure (single-trial learning)
6-OHDA lesion and naloxone have dissociable effects on motivation and expressions during tasting
i.e. Dissociating pleasure and motivation again
With 6-OHDA (dopamine) lesion
they will still enjoy food and dislike bad foods BUT not be motivated to seek food
Naloxone
(opioid receptor antagonist- blocking effects within the opioid NT system) - no effects on motivation to seek food but does respond with pleasure or aversion to the food
Do we eat what has been associated with pleasure in the past?
YES
Without socialisation: bitterness is tolerated but never better than neutral (water)
With socialisation: bitterness can be better than neutral
Many social factors, as above (e.g. preference for spicy food)
Other associations of pleasure? (e.g. coffee - has psychoactive ingredients)
Do we anticipate/seek/eat food at times when food is predicted to be present? STUDY
CS+: buzzer & light -> present food only when stimulus was present (operant learning for food prediction)
- They learn to eat when stimulus is present
- They eat within 5 seconds
US: food -> can eat whenever they want
CS-: tone/control -> the tone doesn’t predict anything
Training phase
Testing phase
So is eating driven by evolution and positive incentives?
Evolutionary:
✓(at small timescales) Avoid dangerous foods
✓(at small timescales) Choose trustworthy foods
✓ Eat a variety of foods
✓ Eat far more than you need - eat when food is present due to food scarcity
So is eating driven by evolution and positive incentives?
Simple Learning
✓ Eat what brings pleasure
✓ Eat what has been associated with pleasure in the past
✓ Seek food at times when we’ve learned food will present
Under most conditions, eating behaviour reflects learning for
positive incentives
- Dopamine plays a key role in motivation and learning in eating, whereas the endogenous opioids play a key role in the pleasure of food
Clear evidence suggests that the perception of thirst occurs in higher-order centres
the anterior cingulate cortex (ACC) and insular cortex (IC), which receive information from midline thalamic relay nuclei
Small changes in ECF volume
well tolerated owing to dynamic compensatory changes in vasomotor tone that modulate the compliance and capacity of the vascular system
Thirst has a key role in the maintenance of
body fluid homeostasis by driving water intake to compensate for losses incurred as a result of breathing, sweating and the production of urine
Two distinct types of thirst emerge under different circumstances
homeostatic thirst is evoked in response to an existing water deficit, whereas anticipatory thirst occurs before an impending deficit
Homeostatic thirst is induced in response to
hypernatraemia, hyperosmolality and hypovolaemia, whereas anticipatory thirst occurs in response to food intake or hyperthermia or before sleep
oropharyngeal afferents and thirst
Thirst is rapidly inhibited by oropharyngeal afferents in response to water intake; inputs from gastric distension sensors can also provide feedback signals that suppress thirst
Anterior cingulate cortex ACC
The anterior part of the cingulate cortex, which is a midline structure that lies dorsal to the corpus callosum. The ACC has a role in regulating body homeostasis and higher-order functions such as reward anticipation and decision making.
Affective motivation
Motivation to complete a task driven by a particular emotion
Primordial emotions
Instinctive processes that drive behaviour to maintain optimal body homeostasis (for example, thirst, hunger and pain).
Insular cortex (IC)
The portion of the cerebral cortex within the lateral sulcus. It is believed to have roles in consciousness, emotions and regulating body homeostasis
Interoceptive sensory modalities
Sensory signals related to the internal state of the body and viscera (for example, stomach distension, temperature and acidity).
Cortex
The outermost portion of the brain, thought to mediate consciousness, memory, attention, awareness, language and thought.
a series of Volume-regulated homeostatic mechanisms maintains
ECF volume near a desired set point
Pathological symptoms can also be induced by
changes in the solute concentration (that is, osmolality) of ECF
Acute changes in extracellular tonicity are poorly tolerated because
they cause swelling or shrinking of cells and organs due to osmosis
acute decreases in ECF Na+ concentration (hyponatraemia) or osmolality (hypoosmolality) cause significant increases in brain volume, whereas acute hypernatraemia or hyperosmolality causes shrinking
intense thirst caused by systemic infusion of hypertonic saline or exercise-induced dehydration is consistently linked to
activation of the ACC and other regions such as the insular cortex (IC)
The ACC and IC are immediately deactivated when
thirst is satiated by the ingestion of water, well before water absorption from the digestive tract corrects the affected physiological parameter
Autoradiographic metabolic trapping
A method of visualizing glucose utilization in the brain. It is used as a surrogate to indicate that neurons have been electrically activated
Organum vasculosum lamina terminalis (OVLT)
A midline brain structure located in the ventral part of the lamina terminalis and contained within the preoptic area of the hypothalamus
Subfornical organ (SFO)
A midline brain structure that is located at the dorsal aspect of the lamina terminalis and attached to the hippocampal commissure.
Circumventricular organs
Regions of the brain that lack a blood–brain barrier, such as the organum vasculosum lamina terminalis, subfornical organ and area postrema. Neurons in these regions are directly exposed to circulating substances in the blood
functional imaging studies in humans have shown that medial thalamic nuclei become activated following stimulation of
thirst by infusion of hypertonic saline or exercise-induced dehydration
Homeostatic mechanism of thirst
specialised molecular and cellular systems have evolved to enable sodium-sensitive, osmosensitive and volume-sensitive neurons to encode quantitative changes in these parameters by altering the rate of action potential firing, thereby regulating the electrical activity of thirst-promoting neurons via negative feedback
Natraemic thirst
The molecular mechanisms responsible for sodium detection
Presumably involve proteins that can mediate an increase in the rate of action potential firing of specialized neurons that are exposed to small increases in extracellular Na+ concentration
organum vasculosum lamina terminalis (OVLT) and subfornical organ (SFO) — a pair of midline circumventricular organs that have key roles in the control of fluid balance
Electrophysiological recordings have shown that neurons in the OVLT and SFO can be depolarized or excited by increases depolarized in extracellular Na+ concentration
Anatomical studies have shown that neurons in the MnPO, OVLT and SFO are extensively and reciprocally interconnected and functional studies have shown that activation of neurons in any of these areas by Optogenetic or chemogenetic approaches can stimulate thirst
Osmotic thirst
Dilution of the ECF (hypotonicity) was recognized as an inhibitory factor for thirst
lesions of the SFO fail to prevent water intake induced by systemic hypertonicity
activation of SFO neurons under such conditions might not be essential for the induction of osmotic thirst
lesions encompassing the OVLT and MnPO were found to cause adipsia and prevented water intake induced by a hyperosmotic stimulus
fMRI studies in humans have shown that the ventral portion of the lamina terminalis, which encloses the OVLT, is activated in response to systemic hyperosmotic stimuli
The lamina terminalis is not the only source of systemic osmosensory information and that the thirst-promoting ACC/IC network might also receive such signals via vagal or spinal afferents that project via the brainstem
the activation of thirst by systemic hyperosmotic stimuli might involve the osmotic excitation of OVLT neurons and interconnected neurons in the MnPO and SFO, as well as neurons in brainstem nuclei, which together engage the medial thalamic–ACC/IC network
Volaemic thirst
hypovolaemia, a term that designates a net loss of ECF volume regardless of its composition
hypovolaemia can be caused by haemorrhage, a condition that leads to a loss of isotonic ECF.
Experiments in rats have shown that haemorrhage is a potent stimulus for thirst
it is now well established that mammals have evolved sensitive systems that monitor ECF volume independently of osmolality or natraemia and that these systems can either promote or inhibit thirst via negative feedback
Changes in ECF volume are monitored indirectly by pressure receptors that detect stretch forces within the walls of the vasculature
Decreases in vascular stretch forces associated with an ECF volume deficit (that is, hypovolaemia or hypotension) induce a number of compensatory responses that maintain blood pressure and ECF volume, including an increase in the perception of thirst
an increase in stretch forces associated with overfilling (hypervolaemia or hypertension) induces opposite responses, including a suppression of thirst
Study has demonstrated that baroreceptors play a greater role than volume receptors in the suppression of thirst during hypervolaemia or hypertension
Efferent signals from the lamina terminalis target the paraventricular nuclei of the thalamus and could therefore activate thirst via the thalamic–ACC/IC circuit
optogenetic inhibition of glutamatergic thirst-promoting MnPO neurons is sufficient to suppress water intake in mice that have been water deprived for 48 h
Hypovolaemia can also stimulate thirst through the release of renin from the kidney
Hypervolaemia associated with excess ECF volume can also inhibit thirst through humoral mechanisms, whereby stretching of specialized cardiac myocytes causes the release of atrial natriuretic peptide (ANP) into the bloodstream
Thirst-promoting anticipatory mechanisms
A host of feedforward responses are now understood to drive water intake in anticipation of impending systemic solute loads or water deficits associated with various behavioural and environmental conditions
These types of mechanisms are important because they can blunt the impact of physiological perturbations before they occur
Prandial thirst
The existence of preprandial thirst implies the influence of a learned behaviour, or perhaps of a subconscious learned anticipatory benefit
Prandial water intake is directly proportional to the salt content of a meal, suggesting the presence of solute sensors in the upper gastrointestinal tract, the liver or the interposed hepatoportal system, which can provide ascending feedforward information to stimulate prandial thirst in accordance with prevailing water requirements
hepatic osmoreceptors that send ascending signals to the brainstem via dorsal root ganglia, indicating a possible contribution of spinal pathways to the control of prandial thirst
projections that ascend from the NTS could mediate prandial thirst by activating the ACC or IC via projections to the OVLT, MnPO or medial thalamus
lesions of the SFO reduce prandial thirst in rats, whereas thirst-promoting SFO neurons are activated at the onset of feeding in mice.
Thermal thirst
Hyperthermia caused by exercise or heat exposure inleads to a loss of ECF solutes and water due Homeotherms to the evaporation of fluids during cooling responses such as sweating, panting or the spreading of saliva
rodents exposed to high ambient temperatures drink considerable quantities of water before ECF osmolality or volume is increased– and that the magnitude of the – observed water intake is proportional to the change in core body temperature.
hyperthermia can provoke a feedforward anticipatory stimulation of water intake that could mitigate the dehydrating effect of thermoregulatory cooling
Sensors responsible for the detection of core body temperature might therefore be particularly relevant to the control of thermal thirst
POA as the main locus of the central thermostat
POA warming activates heat-dissipating mechanisms, whereas cooling drives thermogenesis
Structures within the POA and other areas of the hypothalamus orchestrate the thermoregulatory responses induced by heating or cooling of the periphery
we showed that thirst can be induced by optogenetic activation of OVLT neurons that express the heat-sensitive channel DN-Trpv1
Neurohypophysis
The posterior part of the pituitary gland that contains axon terminals originating from magnocellular neurosecretory neurons in the supraoptic nucleus and paraventricular nucleus
Circadian thirst
Prolonged sleep is a potential cause of dehydration because fluid losses caused by breathing and urine production at this time are not opposed by regular water intake
studies in humans and rodents have shown that renal water reabsorption is progressively enhanced during the sleep period
caused by an increase in vasopressin release from the neurohypophysis
increased water intake during the active period was not driven by osmotic, prandial, volaemic or thermal thirst, supporting the hypothesis that water intake at this time is an anticipatory behaviour driven by the circadian clock (that is, the Suprachiasmatic nucleus (SCN)
vasopressin-containing neurons located in the outer shell of the SCN serve as the main output neurons that mediate a variety of circadian rhythms
projections from SCN vasopressin-expressing neurons to the OVLT are necessary and sufficient to mediate circadian thirst
the electrical activity of OVLT neurons is significantly increased during the active period compared with the basal period and, specifically, that the firing rate of vasopressin-expressing SCN neurons was significantly increased during the active period.
OVLT neurons are depolarized (that is, excited) by electrical stimulation of the SCN
circadian thirst during the active period is driven by an excitatory effect of vasopressin released by SCN neurons on thirst-promoting neurons in the OVLT
Satiation of thirst
imaging studies in humans have shown that the ACC and IC are rapidly deactivated upon water ingestion
the OVLT remains activated even after the ACC and IC are deactivated upon satiation prompted by water intake in hyperosmotic humans, suggesting that osmosensory OVLT neurons that monitor systemic tonicity continue to signal the hyperosmotic state until it is fully corrected by water absorption and that satiety must occur at another level
activity of thirst-promoting neurons in the MnPO and SFO of thirsty mice can be rapidly suppressed by water intake, suggesting that these sites may mediate satiety signals under some conditions.
glutamatergic MnPO neurons seem to proportionally encode the aversive quality (negative valence) of thirst, and inhibition of these neurons is sufficient to quench thirst in water-deprived mice
gastric distension or dilution signals provide the immediate inhibitory signal to cease drinking once sufficient fluid has been ingested
in the absence of this feedforward effect, postingestive homeostatic signals (for example, ECF hypoosmolality or hypervolaemia) can act to suppress thirst should the ECF become hypoosmotic
