PSYC317 overall notes

Lecture 1:

Biopsychology

Biopsychology can be defined a merge of all these disciplines (neuroanatomy, neurophysiology etc). it is founded on the idea that there is a reciprocal relationship between the nervous system and behaviour/cognition.

Timeline of the development of biopsychology

Rene Descartes did not understand how the physical aspects of the brain could give rise to the non-physical (thoughts). He needed to account for this discrepancy so came up with an idea that that things have a dual nature duality.

From the late 1800’s to current time there has been a drastic shift in the knowledge surrounding Biology and Psychology. They were considered as two separate domains but in the mid-20^th century there was a combining of these two fields of work.

Brain & Behaviour

Outward behaviours and cognitive processes are generated by neural activity. If neural activity is altered, behaviours and/or cognitive processes may be altered. Learning and development can shape cognition and behaviour.

How might neural activity be altered?

-            Disease, tissue damage or removal, electrical stimulation, drugs, development and learning.

Nature vs. Nurture

Nature looks at the biological and genetic application whereas nurture looks at the environmental or what has been learned.

Comparative model of Nature vs. Nurture

Nature example: (Tyron 1934)

-            Tested rats in a maze; selectively breeding for high cognitive functioning rats (maze-bright) males with females.

-            And selectively bred low functioning rats (maze-dull) males and females.

Conclusions:

-            Maze dull rates who were selectively bred took slightly longer to complete the task.

-            Bio model distribution for selectively bred rats so potential for a genetic predisposition for good/bad learning abilities in a maze. Potential for a genetic factor controlling their ability to learn (nature)?

Uncertainties:

-            Is intelligence being measured or has their behavioural cognition been altered, which meant they are not able to engage with the task. In this case looked into doing further studies in different environments.

Expanding from this original study:

(Searle 1949) fear, not intelligence

(Cooper & Zubek 1958), environmental rescue

Placed them in an enriched environment, there is no change in performance of bright rats, but there is a change in performance for maze dull rats with an increase in performance. There is an environmental effect NOT just genes.

Nurture example: (Watson & Rayner 1920)

“Little Albert experiment”

-            9-month-old infant Albert with no fear to a variety of objects was exposed to the pairings of loud sounds and visual stimuli (rat) resulting in Albert crying and in discomfort.

-            After numerous pairings of the stimuli together Albert displayed a generalised fear to all stimuli. Behaviour can be learnt.

Certain factors can affect how genes are expressed/controlled, without changing the gene sequence.

Genetics: the study of inheritance, including the genes encoded in DNA & genetic variation.

Epigenetics: the study of how certain factors influence gene expression, without changing the gene sequence. Genes will make proteins if they are allowed to (access to the DNA and ability of that part of DNA to be read).

Neuronal activity patterns can either promote or inhibit gene expression. This means your experiences, past and present, can shape what proteins can be produced in your brain.

The DNA is wound around histone, when an epigenetic factor binds to the histone tail causes the DNA to be unwound allowing access to the DNA, therefore it can be read. (a way of gaining access to and boosting the expression of a gene).

Methyl groups can be added to the DNA, which can block access to the DNA. Can block expression of a gene.

Histone modifications & DNA methylation are two epigenetic mechanisms that can allow access to the DNA/or not.

Lecture 2:

Understanding humans as animals gives us the context to how human development as changed over time and what were the determinants of these developments.

The hominin line

-            The idea that we came from monkeys/chimpanzees is somewhat wrong, humans have a separate branch away from the latter.

-            The shape of the skull has changed drastically, brain mass has increase and we have adapted because of this.

-            A huge factor was the shift to bipedalism this appears to have partially contributed for the shift in brain size. Ability to be able to use our hands, manipulate tools.

With increase in brain size comes:

·       Social advancements

·       Decision-making

·       Social survival

·       Reproduction

·       Energy balance

·       Nutrient balance, varied diet (more support for complex physiological functions)

·       Basic functions

Ø  Specific mechanisms become selected for overtime due to being advantageous for our survival.

Ø  The single biggest change amongst different species is the size of the cortex!

Triune Brain Model: Paul Maclean

three key brain regions consisting of brainstem, limbic system and cortex.

1.       The idea that reptiles have no limbic structure or cortex (NOT TRUE).

2.       Each level is self-contained, and they do not interact with each other (NOT TRUE)

3.       All develop in tandem, but the outer layer has developed to a greater degree in primates.

The Nervous System

Divided into the CNS and the PNS.

PNS can further be divided into the somatic/motor system + autonomic system (ANS)

Afferent side- arriving/input

Efferent side- exiting/output

Sympathetic nervous system is counted as the flight or fight nervous system given that it is sympathetic to your needs. (prepares you to act in a certain way).

Parasympathetic nervous system; used for resting and digesting

The nervous system is made of nervous tissue compromised of two main cell types of neurons & glia.

Neurons transmit electrochemical signals. One neuron sends a message to another cell via the release of a neurotransmitter.

Neuronal communication can be:

-            Neuron to neuron

-            Neuron to skeletal muscle

-            Neuron to smooth muscle of the gland  

-            Neuron to smooth muscle of blood vessel

CNS- Spinal cord

Critical for enabling the brain to receive and send information to the muscles, skin, gut, vasculature, heart etc.

-            Peripheral neural information arrives at the spinal cord (afferent signal)

-            Information ascents up to the brain

-            Brain processes information, if warranted, brain sends signal back down the spinal cord (efferent signal) to execute a peripheral response

CNS- Brain

-            The brain receives and processes all sensory information (internal/external)

-            Information processing occurs learning, thinking, remembering, responding

-            Brain executes all outward responses.

 directional terminology (A/P, M/L, D/V)

for the brain dorsal means the upper portion. If we consider the dorsal spine then it would be the back of the spine.

Human brain in early development

The brain and the brain stem

Major structures of the human brain:

Portion of brain stem, articular formation, important for sleep is????

Lecture 3: 18^th July

Protecting and Nourishing the Brain

Skull and meninges protect the brain, space relationship is tightly constrained

-            Anything that pushed in on the brain is not good e.g., concussion

-            Anything that causes the brain to push out on the meninges/skull is also not good (encephalitis)

-            CFS (cerebrospinal fluid) internally protects and nourishes the brain

-            CFS filled arachnoid and ventricular system offers ‘shock absorption’ cushion like.

-            It also provides nutrient exchange between CFS and the brain

-            Hydrocephalus: abnormal build up of CFS in the ventricles within the brain

Note: do not want to get blood on the brain tissue as it is toxic to the brain

Vasculature supplies the brain with oxygen and nutrients

-            The brain requires 20% of your blood supply

-            A constant supply of oxygen and glucose is critical for function. Glucose is the only sugar neurons can use.

-            Blood brain barrier controls entry/exit of molecules into the brain (cells that make up the walls of the blood vessels with restrict the flow of certain molecules into the brain)

Research methods in Biopsychology

-            Studying brain structure

-            Studying brain function

-            Linking structure-function to behaviour

Consider pros and cons for each of these research methods!

To look at the structure of the brain we can use:

Visualising structures in the brain:

Gross Anatomy vis dissection

(-) not ethical unless consensual

(-) don’t get to see the brain alive, functioning

(+) able to find some diagnosis (Alzheimer’s)

Gross anatomy via imaging

CT; computerised tomography scan

MRI; magnetic resonance imaging
DTI; diffusion tensor imaging – specific type of MRI that looks at fibre tracts of the brain

(+) can scan a living brain

(+) given someone has a stroke can localise that damage using a CT scan

(-) not getting the function of the brain, only anatomical detail

Microscopic Anatomy via histology (study of tissue)

Shows basic visualisations of cells, no function

Nissl stains to count cell bodies

Golgi stains to illustrate full structures

Immunohistochemistry- for particular protein, or gene of interest, looking at the expression of a particular gene or level of a given protein. Find an antibody that selectively labels that protein. Staining a section, giving idea of an expression of a gene or protein.

In situ hybridisation, used to determine cellular distribution pattern.

Starting to visual connections e.g., Antero/retro grade tracing

Microscopic Anatomy via electron microscopy

(+) highest detail resolution

(-) postmortem, can’t be done vivo

Microscopic Anatomy via 3D imaging

If you’re interested in both form and function of the brain!

e.g., fluorescence microscopy techniques, multiphoton microscopy + genetically encoded fluorescent proteins (XFPs)

- using animal research, inject a virus into the brain so the cells express a fluorescent protein.

(+) allows for anatomical detail

(+) fine level high resolution imaging

(-) expensive and can’t take images deep within the brain

Examining activity patterns in the brain

Two main methods used to image activity in the human brain:

 PET; Positron emission tomography and fMRI; functional MRI

(+) high spatial resolution

(+) non-invasive

(+) functional and anatomical imaging

(-) low temporal resolution

(-) there is delay of a few seconds, this is because you are measuring metabolic activity (changed in blood oxygen levels, occurring in a given region, after cells in that region have been active).

NIRS; Near-Infrared Spectroscopy

-            Same principle as the two-photon imaging, infrared light will penetrate through the skull, sensors in the cap will pick up on changes in metabolic activity in the regions underneath those sensors.

(+) cheaper, can be used on humans

(-) limited for the cortex, won’t reach subcortical structures

(-) no fine cellular detail

Large scale neural activity patterns

-            Magnetoencephalography (MEG)

-            Electroencephalogram (EEG)

(+) good temporal resolution

(+) non-invasive, low cost

(-) poor spatial recognition

(-) not easy to tell what signals represent in terms of cellular activity, and exact location of neural activity.

Smaller scale neural activity patterns

-            Electrode recording using LFPs, multi-unit, single unit

(-) invasive, for animals

Looking at synaptic transmission, understand how cells are wired together using electrophysiology.

-            Single or subcellar activity

-            Patch clamp, field recording (attaching a single electrode to single neuron)

Manipulating neural activity, optogenetics & chemo-genetics:

-            Optogenetics- controlling and monitoring the biological functions of a cell, group of cells, tissues, or organ with high temporal and spatial resolution by using optical systems and genetic engineering technologies. Light sensitive proteins thar respond to specific wavelength of light.

-            Chemo-genetics- manipulate neuronal activity using genetically encoded receptors that can be activated or inhibited by specific chemical compounds.

Chemo = chemical

Opto = light/vision

problem with neuroscience experiments is there is correlation rather than casual influence have to manipulate activity of neurons.

Three basic experimental approaches:

1) correlation study approach, brain measure or the presence or absence of a particular structure, correlates with a given behaviour (weak approach). Doesn’t give causality.

2) two different kinds of intervention: biological, or behavioural

3) behavioural manipulation, roles are reversed. Plasticity experiments often do this, put an animal through learning paradigm, animal learns something, want to know if it has caused any microscopic changes in neuronal structure or function.

Lecture 4: 22^nd July (no readings)

Neuroplasticity

Changeable malleable structure with the capability of reorganisation. Idea with learning is that synapse, points of communication between cells becomes stronger, facilitates transmission of information from one cell to the next. Physiological change that allows information to be stored in the brain i.e., memories.

If our brain is storing new information, then the brains state has changed. Therefore, there must be a biological change to account for this.

1.       What are neuroplasticity mechanisms that allow us to learn?

2.       Where in the brain or in neural circuits do these changes occur?

History behind Neuroplasticity:

Donald Hebb:

“When an axon of cell A is near enough to excite cell B and repeatedly or persistently takes part in firing it, some growth process or metabolic change takes place in one or both cells such that A’s efficiency, as one of the cells firing B, is increased”.

-            In a nutshell cell that fire together wire together.

-             

Engram- biological memory trace

Karl Lashley conclusions; equipotentiality & mass action

-            Equipotentiality- all areas of the cortex have the same potential

-            Mass action- as the size of the lesion seemed to matter, he figured the whole cortex was acting in unison to guide learning and store information.

Not entirely sure if either of these things are true

H.M (Henry Molaison)

- early childhood was in a bicycle accident

- aged 10 has onset of severe TLE (temporal lobe epilepsy)

- age 27 was the last person to receive bilateral TL resection

Effects:

-            Lost his ability to form new memories

-            Had much of anterior campus removed

-            Was not just the removal of hippocampus

Human and rodent hippocampi share similar organisation

The Tri synaptic circuit of the hippocampus:

EC > DG; DG > CA3; CA3 > CA1

Unidirectional flow of information in the hippocampus

1.       FV= Fibre volley (presynaptic action potential firing)

2.       fEPSP = field excitatory postsynaptic potential (synaptic activity)

3.       “Pop spike” (postsynaptic action potential firing)

Hippocampal slice experiment

Using rodent brain, used to study electrophysiological properties of individual neuron/circuits.

LTP- note:  not everything when it comes to plasticity

1)       Single pulse evokes a single fEPSP. Do this to get baseline value of synaptic transmission. Typically, we record a baseline about 30 minutes for stability.

2)       High frequency stimulation can be used to trigger burst of synaptic events. Induce LTP.

3)       Go back to single pulses to see how synaptic transmission has changed, and for how long. Still above baseline sometime later, does decay but only slowly overtime.

(HFS= high frequency stimulation, LFS = low frequency stimulation)

-             potentiation & depotentiation.

High frequency stimulation produced LTP, but low frequency stimulation erases/reverses it.

Can we induce synaptic plasticity?

-            Activity dependent

-            Rapid onset

-            Long-lasting

-            Reversible

Just like a memory!

Does learning induce synaptic plasticity?

-            LTP looks like a memory. But does learning induce LTP?

Inhibitory Avoidance Paradigm using Shock chamber

Has electros implanted in rodent’s hippocampus. Place animal in chamber with two sides. Used this mechanism to test the latency to enter the chamber when the doors open. Given the rodent enters the other portion of the chamber it will receive a mild electric shock.

-            After the shock the inhibitory avoidance trained animals, have a latency to enter the chamber increases.

-            Rodent has learnt to avoid that area, suggesting there is a memory there.

Forced Swim Test

Place rodent in chamber of water. Then in a similar chamber with a raised platform. Afterwards put subjects in chamber that does not have the platform and see how long it takes before they become immobile and give up.

-            Animals with previous exposure to tank without platform learn to give up and stop earlier on.

-            Hippocampus animals who had gone through forced swim test showed potentiation of synapses in the hippocampus.

Issues: ethics, just because you’re seeing synapse changes does not mean those synapses are storing the relevant information regarding this example.

Lecture 5: 24^th July

Mechanisms of LTP

Coincidence detection- allows us to detect when process A is occurring at the same time as process B.

Glutamatergic synapse

Glutamate is the most abundant excitatory neurotransmitter. It acts on several receptors, the mains ones AMPA receptors and NMDA receptors.

AMDA: mainly pass Na+ ions

NMDA: mainly pass Ca2+ ions

The NMDA receptors channel only opens when glutamate is bound, and the postsynaptic cell has already been depolarised. NMDA receptor is only active during high levels of coincidence pre- and postsynaptic activity.

MPA receptors in blue; permeable to sodium ions 

NMDA receptors in red; permeable (doesn't always open easily Mg ion blocks it) 

EPSP (excitation post-synaptic potentials); vast majority of depolarization measured is a reflection of sodium passing through the AMPA receptors channel. Glutamate is released from the pre-synaptic cell, binds to the AMPA receptor, opening the channel and sodium flows into the post-synaptic cell. 

When cell is sitting happily at regular membrane potential, resting (-70) NMDA receptor does not open channel even if glutamate is bound to it. NMDA is blocked by magnesium ion. 

Need post-synaptic cell to be depolarized first, therefore inside of the cell is a little less negative, pushes magnesium ion away (positively charged) heavily attracted to the negativity inside of the cell. 

• Given that you make the cell less negative there is less of that attractant force. 

NOW magnesium is out of the way, calcium can flow into the cell. 

-            Calcium is important as it activated many enzymes that can act on receptors and change their properties or trigger synthesis of new proteins. Also gives depolarization of post-synaptic cells.

Could NMDA be the coincidence detector that triggers LTP?

Yes, by blocking NMDA receptors (with AP5) can block LTP. Aswell as spatial learning.

Two conditions: 

1. Regularly experimenting, measuring slope of field potential  

2. Repeat experiment injecting LTP into the brain of this animal. (Now when you apply high frequency stimulation to active those hippocampal synapses you do not get LTP). 

*Prove that LTP requires the NMDA receptor 

Tetanic stimulation- high frequency stimulation 

Morris Water Maze 

• Idea that you have large tank of water, colored water making it less clear with a hidden platform under the level of water 

• Spatial memory tasks, cues so that the animal can orient itself 

• After a while the animal learns the location of the platform so the next time you put it in, beelines straight for the platform (spatial memory component) to this task. 

Measure: latency to get to the platform, time spent in the quadrant of the platform (looking in the right area). Spend more time in this quadrant as the trials go on. 

Do the same thing but this time inject AP5 into the animal’s brain. Spatial learning and memory have now been lost. Good evidence that the NMDA receptor is the coincidence detector, that triggers LTP and therefore triggers certain forms of memory (spatial). 

Presynaptic = more glutamate release

Post synaptic= more AMPA receptors

Hebb’s idea of cell assemblies: bunch of reciprocally connected neurons are networks of cells that are already connected with one another. Presentation of a particular cue sets of some cells in the cell assembly, if they are heavily connected will drive each other to fire.

Does learning always involve LTP?

Does plasticity also recruit other forms of plasticity?

Examples of other learning mechanisms:

1)       Plasticity of Intrinsic Excitability (PIE)

2)       White matter plasticity

3)       Neurogenesis

Intrinsic excitability – how likely the cell is to fire an action potential intrinsic to that cell.

PIE (Plasticity of Intrinsic Excitability)

-            Separating early learners from trained rats

-            Test excitability at these time points using single cell electrophysiology

-            Looked at the brain tissue from early learning rats and the overtrained groups

-            Responsivity of these cells in the hippocampus, how likely they are to fire action potential in response to depolarization.

Results:

-            Early learning groups, if you stop, cells have become more excitable

-            When you depolarize these cells a little, more likely to produce action potentials in response to the same amount of input.

-            Post synaptic cells have become more responsive to the same amount of input

-            More excitable

-            Transient (not long lasting)

White Matter Plasticity

White matter = axons

White matter tracts- bundles of axon fibres

-            Cognitive training enhances white matter density which can be seen using DTI (diffusion tensor imaging)

NB?????NB in rodents blocking white matter plasticity blocks memory consolidation, motor learning and drug reward learning. Blocking the white matter tracts from getting thicker. These three things are dependent on synaptic change as well as changes to white matter.

White matter is formed by myelin, wrapped around axons, myelin sheaths formed by oligodendrocytes, a type of glial cell. When axons are highly active, the myeline sheath wrapped around them become thicker speeding up action potential.

Neurogenesis

New neurons are born in the dentate gyrus (part of hippocampus) throughout life, but this process slows with age. Can be boosted via exercise, environmental enrichment. New neurons can become integrated into existing DG circuitry. New cells integrate into existing cells and replace old cells.

There is competition between new and old cells, new cells are more excitable therefore outcompete old cells (mature cells reduce their number of synaptic inputs from EC).

Does this equate to forgetting, losing memory?

Hippocampus

Back to H.M.

-            Hippocampus is not storage for long-term memories as H.M has his removed but could still recall old memories. Damager to anterior parts of hippocampus.

-            H.M implicit memory was intact but his explicit was not

Implicit memory (procedural) - unconsciousness and effortless “knowing how”

Explicit memory (declarative) - consciously, previously learned information “knowing that”

H.M showed deficits in both semantic and episodic memory, but most people with specific hippocampal damage only show deficits in episodic memory. Semantic requires more extensive temporal lobe damage.

Controversies about H.M.:

Ø  50% of H.M hippocampus was still present. Adjacent structures such as entorhinal cortex was completely destroyed.

Ø  Autopsy of H.M. brain revealed a pre-surgery lesion of the OFC, memory deficits before surgery. Areas involved in memory formation.

Ø  Ventral hippocampus in rodents in analogous to anterior hippocampus in humans, effectively the same lesion that H.M. received.

Lecture 6: 25^th July

Specifically lesioned the ventral hippocampus in rats, corresponds to anterior hippocampus in humans. Lesioning the ventral hippocampus in rats reduces anxiety but doesn’t affect learning/memory in the Morris Water Maze. (Bannerman et al, 2003)

What about anterior hippocampus damage in humans?

Frontotemporal dementia: damage either to the frontal cortex, leading to behavioural issues (e.g., lack of inhibition), or to the temporal cortex leading to language difficulties (e.g., aphasia)

-            Damage to temporal lobe tends to effect language.

In the frontal (behavioural) variant, there is specific atrophy of the anterior hippocampus, but memory deficits are not commonly seen. Indeed, significant episodic memory impairments is actually an exclusion criterion under current diagnostic criterion for bvFTD (behavioural frontal temporal dementia)

-            People with FTD get atrophy and shrinkage of anterior hippocampus

The hippocampus is not just a memory-related structure. It is also part of an emotional-social anterior network (connecting the anterior CA1 and subiculum with the prefrontal cortex, amygdala and nucleus accumbens).

The Papez circuit:

-            Papez (1937) injected tracer dye into hippocampus, traces projection of fibres to next structure so forth.

*fornix = white matter tract

Papez mapped out a circuit of what came to be known as the limbic system

This circuit was originally conceived as an emotion circuit, was also thought to be a memory circuit.

Key findings that have changed this view:

1.       Damage to the ATN (anterior thalamic nuclei) produces semantic memory deficits (Nishio et al., 2011)

2.       Damage to the cingulate gyrus causes amnesia for episodic memory (Yoon et al., 2006; Gallardo-Tur et al., 2014)

3.       Damage to mammillary bodies produces amnesia for semantic and episodic memory (Hildebrandt et al., 2001; Beglinger et al., 2006)

*Damage to the circuit results in specific deficits

Conclusion: the hippocampus is one part of a circuit that control explicit/declarative memory.

Is the hippocampus involved in forming, storing or recalling memory?

Aggleton et al. (2004): KN has extensive hippocampal damage, and anterograde amnesia, cannot recall nearly learnt info. However, can pick out things familiar to them.

Hippocampus is heavily connected with areas involved in cognition and emotion. These circuits tend to involve either the septal (posterior) hippocampus or the temporal (anterior) hippocampus.

These circuits allow the hippocampus to process information related to situation (septal HPC) and motivation (anterior HPC) and produce desirable outcomes. Information about place in space, emotional state/internal state.

Behavioural States

As an organism interacts with its environment, its nervous system transitions between states that influence how sensory information is processed and how actions are generated.

Arousal states: sleep and wakefulness

Motivational states: high or low

Emotional states: anxiety, euphoria, depression

Cognitive states: attention, vigilance

With a learning paradigm you have to consider the state of the animal going into the task

Value? Reinforcers give a particular value to behaviour

Biological state? How motivated is the animal to learn this task

Reinforcement & motivation

-            Positive or negative valence, rewards give positive valence and punishment has negative valence.

Reinforcement, Motivation and Dopamine

Monkeys with electrodes in brain, seated in front of two levers. Present monkeys with visual start cue (light) then present reward (juice) if monkey presses correct lever.

-            Measure midbrain dopamine neuron activity

-            At first: dopamine neuron activity spikes when reward arrives

-            Later: dopamine neuron activity subsides when reward present, instead surges earlier- when cue present.

There is a surge in activity of dopamine after rewarded, but with continuous training of the animal the dopamine surge stops.

Reward (and punishment) prediction is essential, without it we don’t learn to seek goals. Motivated behaviours are not learnt. e.g., dopamine-deficient mice do not learn to seek food even if hungry. Restoring dopamine in these mice restores motivation to engage in goal-directed behaviours such as eating.

The Dopamine System

2 pathways of interest:

1)       The mesolimbic pathway (VTA > NAc, then continues to other limbic systems)

2)       The mesocortical pathway (VTA > PFC and other cortical areas)

VTA responds to sensory/contextual cues that a reward may be present. PFC processes salience of the dopamine signal and mediates decision to approach the reward. NAc is involved in acquitting (learning) the behaviour if there is a reward.

Important to note:

-            Dopamine mediates “Wanting”

-            But wanting does not = liking

Hotspot- bits off the brain that light up in unison when you see something you like.

How do rewards help us learn?

Diffuse dopaminergic projections throughout the cortex and limbic system are powerful modulators of plasticity & learning. LTP in hippocampus of freely moving rats is facilitated by exposure to a novel environment. This effect is blocked by a dopamine D1 receptor blocker.

Dopamine is critical for learning motivated behaviours in a number of ways

Arousal circuits (MUST KNOW)

-            Locus coeruleus: noradrenaline

-            Raphe nuclei: serotonin

-            Tuberomammillary nucleus: histamine

-            Lateral hypothalamus: hypocretin (orexin)

-            VTA and periaqueductal grey: dopamine

Lecture 7: 29^th July EATING

Obesity has become a global epidemic

-            Tremendous socioeconomic burden

-            Significant morbidity and mortality

-             Age of onset getting younger and younger

Definitions:

Hunger vs Eating: The purpose of hunger is to prompt eating (hunger is the driver/motivation and eating is the behaviour).

Homeostasis

The tendency towards a stable equilibrium (preferential set point/optimal point that gives optimal function).

Cells need energy to function. Energy can come in the form of glucose, fatty acids, amino acids. These energy forms can come from the diet and/or stores within the body. The brain preferentially (& selfishly) uses glucose.

GI Tract

 Stomach – starts protein breakdown, largely churns food and acidifies it

Small intestine-majority of nutrients are broken down here, as well as absorbed

Large intestine- some vitamins, minerals and remaining water is absorbed here

Accessory organs part of the gastrointestinal system include:

Ø  Gall bladder- squirts bile into the SI to help break down fats

Ø  Pancreas- secretes insulin into the blood stream. Insulin signals cells to uptake glucose from the blood & use it. Insulin causes blood sugar to drop.

1940’s & 1950’s

(Short-term) Glucostatic Theory- body aims to maintain blood glucose at a set-point.

Ø   When blood glucose drops, meal initiation

Ø  When blood glucose rises, meal termination          

(long-term) Lipostatic Theory- body aims to maintain body fat % at a set-point

Ø  When body fat drops, eat high calorie foods to replenish reserve

Ø  When body fat rises, reduce high calorie foods to maintain set reserves

There set-point theories are logical but there are major issues:

Glucostatic theory is saying that low blood sugar should drive hunger not high blood sugar. Yet in diabetics they have high blood sugar but feel very hungry. This is the opposite of what the Glucostatic theory proposes.

Hedonic  feeding- pleasure as opposed to maintaining homeostatic set point.

-            We have developed reward systems that signal the value of getting pleasure from eating, topping up energy reserves.

The hypothalamus is involved in an array of homeostatic mechanisms. Is well placed to exert profounds behavioural effects through its connectivity with the limbic system, midbrain, spinal cord etc.

Also receives many hormonal signals produced elsewhere in the body. Hormones enter blood, can then enter HYPO from blood or be taken up into the CSF in choroid plexus and enter HYPO via 3^rd ventricle. Hormones can enter blood supply.

lesions to ventromedial hypothalamus (VMH): ventral meaning lower and medial meaning inner. Results in hyperphagia (overeating)

lesions to lateral hypothalamus (LH) lateral meaning outer, resulted in aphagia & adipsia (lack of hunger/lack of thirst): no interest in food, but partial recovery if tube fed.

Potential for paraventricular nucleus to be damaged when electrode is inserted for lesioning.

*If you stimulate LH rodent starts feeding. Lateral=let’s eat!

*If you stimulate VMH the animal stops eating.

low blood glucose (Hypoglycaemia)

-            Glucodetectors in liver send info to the hypo

-            Glucodetectors in NST (nucleus of the solitary tract) brainstem to the hypo

Low blood fatty acid (Lipoprivation)

-            Lipodetectors in liver send info to hypo

Maybe the brain monitors…

·       Signals based on nutrient and energy levels- low/high?

·       Signals from stomach- empty/distended?

Sel-report of hunger: ‘empty’ gastric signals might be: somatosensory (auditory?) endocrine.

Cannon and Washburn (1912) Hunger Pangs; Washburn swallowed a balloon and then had it inflated whilst it was in his stomach. When his stomach contracted, this would press against the balloon and the contraction thus recorded. Washburn pressed a key each time he felt hungry.

Hormones

Substances produced and released from endocrine glands; travel via blood to reach target tissues & exert effects

Three classes: amino acid derivatives, peptide hormones, & steroid hormones

-Hormones must be bind to the right hormone receptor to work

Hormones can signal the brain in two ways:

1.Secreted into the blood, travel to target brain regions

2.Activate afferents of Vagus nerve (CNX), which signals to hindbrain (NST). Here, they synapse onto cells that project to many brain regions (including HYPO).

Stomach hormone (Ghrelin) Ghrelin is a peptide hormone produced by endocrine cells in the stomach. Hunger = grrrr= Ghrelin!

-            Ghrelin levels rise during fasting, and immediately drop after a meal (hunger hormone) In some cases of obesity ghrelin does not drop post-meal and remains elevated.

-            Ghrelin injections in rats or humans rapidly increase appetite.

-            It does not readily cross BBB; mostly signals to the brain via vagus nerve.

-            Ghrelin will activate specific receptors on specific target cells.

-            Only hunger hormone

Feelings of satiety, fullness and stopping feeding: the brain relies on multiple signals to generate the feeling of satiety. (high gluc+insulin, distended GI tract, high PYY, high CCK, high leptin).

Insulin

-            is a Peptide hormone

-            Insulin is produced by the pancreas and travels via blood stream. Must bind to the insulin receptor to elicit its effects whereby signals cells to uptake glucose + signal glycogen formation

-            insulin prompts cells to utilise circulating glucose for energy; if there is extra glucose circulating around, then insulin prompts glycogen formation.

Insulin release in multiple phases: (pre and post eating)

1.       Cephalic phase- meal related sensory stimuli processed by brain, causes conditioned release of insulin in anticipation of meal. Conditioned hunger

2.       Digestive phase- Food in GI tract stimulates pancreas to release insulin

3.       Absorbed phase- Glucodetectors in liver detect glucose in circulating blood and stimulate pancreas to release insulin.

What if you don’t make enough insulin?

Diabetes: metabolic disorder whereby you can’t regulate levels of blood sugar. Either blunted insulin response or genetic issue inability to synthesis enough insulin.

31^st July

Peptide YY3-36 (PYY3-36)

PYY3-36 is a peptide hormone produced by cells in the large intestine, released in response to ingesting food. Post-meal peaks in PYY closely relate to feelings of satiety in humans, PYY injections, systematically or into hypothalamus, curb appetite.

Cholecystokinin (CCK)

CCK is a peptide hormone produced by cells in the small intestine, released in response to ingesting food.  (especially protein)

Ø  Short-term release = rapidly satiety

Ø   longer-term release = nausea

CCK decreases food intake, blocking CCK increases food intake. CCK can reach brain via blood but mostly blocks effects of ghrelin on vague nerve.

Protein rich foods are associated with higher feelings of satiety, carbohydrate rich meals are not. High protein meals will trigger ^ in CCK release.

Ø  PYY & CCK signal to the brain “you are absorbing a meal”

Ø  Low levels of PYY have been correlated with obesity tendencies. CCK is significantly lower in people with bulimia nervosa.

Leptin

Leptin is a hormone produced by fat cells (adipocytes).

-            Binds to ObReceptors, found in several HYPO nuclei, plus cortex, hippocampus and choroid plexus.

-            Choroid plexus ObReceptors take up leptin from blood and transport into CSF, from there reaches HYPO via 3^rd ventricle.

-            Leptin signals to the brain that “you have energy reserves”

-            Defects in leptin production or receptor activation lead to overeating and weight gain.

Signal integration

-            The brain relies on multiple signals to generate satiety feelings

-            The brain relies on multiple signals to general hunger feelings

Need to know key nuclei of HYPO: LH, OVN, Arcuate

The Arcuate Nucleus

Receives projections from NST.  A major entry point into hypothalamus for many hormones.

Cells of the arcuate nucleus: POMC and NPY neurons.

-            POMC neurons, act as satiety neurons, inhibit appetite, promote metabolism

-            NPY neurons, acts as hunger neurons, stimulate appetite, reduce metabolism “No Pudding Yet”

Needs to be studied!

Common Themes:

Two pieces of stress response CRH and cortisol. Released in response to stress yet CRH is involved in reduced feeding and cortisol is associated with increased feeding.

In response to acute stress, you get a spike in CRH. In short term will reduce food intake. chronic stress= tendency to eat more, chronically elevated CRH levels producing more downstream cortisol exerts negative feedback which shuts of CRH production, secretion.

Cross over between stress response and neurons responsible for giving you hunger and satiety.

The Ultimate Diet Drug

If ghrelin is one physiological signal that makes you feel hungry, then if you block or reduce ghrelin then it should make you feel less hungry.

-            There is a lot of interest in developing GOAT inhibitor (GOAT= ghrelin O-acyltransferase)

-            GOAT is an enzyme that is needed to make ghrelin ‘active’ in the body

-            GOAT inhibitors do reduce food intake in lab animals

However,

-            Ghrelin is involved in heaps of central and peripheral processes

-            With the pancreas ghrelin up regulates insulin sensitivity. GOAT inhibitor with increased sensitivity to insulin that you get with ghrelin is going to be lost. (less sensitive to insulin).

-            Ghrelin receptors throughout the brain (taste, smell, learning and memory) ghrelin promotes LTP, facilitates the abduction of LTP. Also promotes neurogenesis. If you block ghrelin learning may be stumped.

Reinforcement via the hypothalamus and dopamine system

Start with the HYPO
NPYAGRP neurons of the arcuate nucleus are ‘hunger neurons’ but stop firing when eating commences. They provide a negative valence signal. This is a form of punishment. We learn to avoid this signal (and thus hunger).

Out from the HYPO

DA release from VTA to NAc primes ‘wanting’ & salience (mesocortical)

DA release from VTA primes motivated action planning (mesolimbic)

The LH (lateral hypothalamus) has distinct populations of taste sensitive neurons

-            ‘High palatability’ neurons (respond to high fat, sweet & salty foods)

-            ‘Low palatability’ neurons (respond to sour & bitter foods)

LH sends projections to the VTA that trigger DA release.

VTA also sends projections back to the LH, activating cell that promote overconsumption of highly palatable food.

Chen et al (2020) Chow test in mice

Measured different chow intake in mice, in control group has no effect on intake 

• Sign light to activate neurons in hypothalamus with the ChR2 group it does not have much of an affect with standard chow consumption. 

• High fat or higher sugar causes consumption to increase. Activating these cells selectively prompts these animals to consume more high palatability foods. 

LH > VTA projections can provide a reward learning mechanism due to big dopamine release signalling reward value. Also, sensory/contextual cues can trigger food seeking.

What “nature” factors influence when you eat?

What “nurture” factors influence when you eat?

-            Learned social structure of X number of meals a day

-            Learned timing of those X amount of meals

This can lead to conditioned hunger = cephalic insulin release in preparation of meal

-            Pre-meal hunger pains is not indicative of energy deficit, rather the body preparing for an expected meal. Often conditioned hunger pangs/pains motivate us to eat, and they are difficult to ignore.

Factors that influence HOW MUCH we’ll eat!

Cessation of eating can be influenced by:

-            Innate and learned taste aversions

-            Satiety signals spurred from volume of food and nutritive density of food

Eating promotion can be influenced by:

-            Innate and learned taste preferences

-            Appetiser effect (entrée effect) small pre-meals can increase hunger

-            Serving size

-            Social eating

-            Variety of food available

-            Marketing, advertisement, product placement & price (contextual reinforcement).

Sensory specific satiety- full of certain tastes/flavours, levels of satiety however would drop with something sweet or fat.

Week 4- August 5^th

Your body needs X number of calories per day for basic functioning, growth, repair and activity levels (BMR- basal metabolic rate)

Ø  If you consume X = balanced

Ø  If you consume > X, you will store the extra energy (weight gain)

Ø  If you consume < X, you will burn some of your energy stores (weight loss) and your body will start to enter ‘conservative mode’.

Body weight does seem to follow a set-point pattern to prevent weight loss. Any sudden drop in weight or energy stores will likely spur compensatory metabolic adaptation. Conservation mode.

Conservative mode- when you start to lose body fat, you’re

Preventing Obesity

Evolutionary pressure – nature. Has set us up to gain weight, in terms of evolutionary fitness the ability to store fat is a good thing ‘thrifty genotype’.

Generational pressure – genetics. Do influence body size potential & hormone levels

-            If your parent has a big skeleton, you are likely to as well

-            If your parent struggles with hormonal imbalance, you may be predisposed

-            If you parent was obese pre/peri conception, this could predispose one to obesity and or related health issues.

Environmental pressure & situational pressures- food availability influences body size materialisation

Genetic vs. Epigenetics

Genetic variation - different sequences of a gene person to person

Genome wide association studies – certain genes or variations of genes associated with diseases. Different types of mutations have been identified that correlate to Type A insulin resistance, Rabson-Mendenhall syndrome, Donohue syndrome.

Inheritance studies- how a gene is passed on to the next generation. Majority of these detrimental mutations are recessive (2 copies are required).

Examples:

(2010) Rat study whereby rats were being overfeed early in development as a result developed metabolic syndrome. Only the overfeed rats showed the metabolic phenotype to persist throughout their lifetime.

(2016) study used epigenetics to see if there were generational influences. By isolating an egg of an unhealthy mouse and planting it into the embryo of a healthy mouse, results showed that the offspring will develop syndromes.

- methylation tags can be passed on to the next generation, what you do in your life can have an effect on offspring.

Obesity is elevated or excessive body fat which presents health risks.

risks: diabetes, high BP, high cholesterol, arthritis, cancer, sleep apnoea et al. together cause metabolic syndrome and greater risk of heart attack, stroke, amputation, kidney problems. as a rough index BMI of >25 is overweight and >30 is obese.

Type 1 diabetes (insulin dependent or ‘juvenile dependent’)

-            Insulin producing cells in the pancreas don’t work correctly meaning body can’t make insulin.

-            Glucose can’t be properly utilised by the cells in the body

-            Glucose remains high in the blood, which can cause extensive damage

A person must inject insulin so that:

1)       Their cells can utilise glucose

2)       Prevent damage associated with hyperglycaemia (high blood glucose)

Type 2 diabetes (insulin resistance or ‘adult onset’)

-            Insulin producing cells in the pancreas are present

-            Body does not make enough insulin for its needs and/or the insulin receptors stop working fully.

-            Glucose remains high in the blood which can cause extensive damage.

Course of treatment.

Step 1) weight loss, diet modification, exercise

Step 2) Glucophage (metformin) medication

Step 3) usually lots of added oral meds

Step 4) insulin injections

Why can’t you take insulin orally? Because the digestive enzymes of the stomach break it down, meaning it will lose its function. Hard to be absorbed into intestines.

-            This has changed, there has been development of orally ingestible tablets.

Although BMI is used, a measure of waist circumference is better as visceral fat is better correlated to obesity related health risks. Ethnicity differences in visceral fat propensity.

Wednesday 7^th August- Eating as a Driver of Obesity

Why are we getting obese?

1) inactivity, sedentary (getting worse in young people)

2) portion size (may have doubled since 1980s)

3) increase in highly processed foods (low nutritional value)

All three are either promoted, advertised or reinforced. Third is generally cheaper

Psychological effects of being overweight, psychological challenges of trying to lose weight.

Food & Mood

1.       High glycaemic index (GI)

foods cycle of reward and punishment, energised for short period of time, followed by lethargy. Psychologically, these can create a viscous cycle of reward and punishment

·        This constant surge of blood sugar levels, followed by surges of insulin release can be taxing on the insulin response system (insulin receptor desensitisation)

·        Animals can develop preferences for vitamin rich foods that make them fell ‘well’ in practice humans don’t do this often.

e.g., thiamine (B1) deprived rats prefer thiamine rich foods. Learn one item is doing something good for them, whilst the other is not.

2.       Poor food choices that affect your gut microbiome

Microbiome

Microbiome = all the microbiota (bacteria, fungi, etc.) that live on and in you

Symbiotic microbes – both party’s benefit

Pathogenic microbes – the microbe can hurt the host

Some microbiome is unique to you, some is encoded by DNA. In infancy many of us are exposed to our mum’s unique microbiome through birth canal/breastfeeding. However, environment and lifestyle can progressively change your microbiome.

Prebiotics

-            microbes enzymatically breakdown starches, pectin, insulin, etc.

-            this acidifies the colon (which helps counter bad bacterial growth)

-            produces short chain fatty acids, appears to be beneficial for health.

Probiotics

-            food already containing microbiota (yoghurt, Yakult, kefir, miso, kimchi, kombucha etc.)

things that make microbiome upset include:

-            refined carbohydrates, lack of fruit and vegetables, lack of water.

If your gut bacteria are not happy, this can have negative consequences such as:

-            Flatulence, constipation, diarrhoea

-            Fatigue, lethargy

-            Inflammation

Ø  Inflammatory molecules produced in the gut (cytokines) can enter the systematic circulation, can cross BBB. This can spur microglial activation (i.e., inflammation) in the brain. Growing interests linking inflammation to depression.

Ø  Cytokines signalling proteins that help control inflammation in your body

Ø  Systemic inflammation= whole body, central inflammation = brain

How can inflammation lead to insulin and leptin resistance?

High fat diet consumption and obesity induces a whole-body chronic inflammatory state. Proinflammatory cytokines produced during inflammation are responsible for hypothalamic insulin and leptin resistance.

POMC neurons- satiety neurons

NPY- ‘no pudding yet’ hunger neurons

-            Both projecting to LH and PVN

* PVN (anorexigenic) stop engaging in food eating/seeking

*Remember LH ‘let’s eat’ (orexigenic)

Both cells of arcuate synapsing onto cells of PVN, insulin receptors and leptin receptors on both of these cell types.

Leptin response- similar response on leptin receptors if you continually eat a high fat diet. Or a diet that leads to accumulation of lots of adipose body fat. As you gain additional body fat more adipocytes releasing more leptin. More leptin receptor activation can eventually blunt leptin receptor response.

Ø  Leptin resistance can be facilitation/boosted by inflammation

e.g.,

-            in obese individual increase in adipose tissue, production of inflammatory signals in the gut that can cross lining of gut, head to brain, signals can act on resident microglia

-            Microglia release cytokines of their own, (TN, IL1-B, IL-6)

-            cytokines that come from microglia in hypothalamus blunt activity of insulin and leptin receptor.

-            More of a hunger signal (NPY, less of a satiety signal POMC)

Food & Sleep

Modified diets either high protein or low protein, looked at arousability during sleep by using sensory signals to see how easily they could be aroused from their sleep.

Enrichment of dietary proteins makes flies and mice less arousable from sleep. Need more arousal to wake up.

Dietary proteins activate cells in the gut to secrete the peptide CCHa1. CCHa1 signals to the brain dopamine neurons to modulate sensory responsiveness.

·        In humans’ high fat, sugar diet is associated with poorer sleep quality.

NEXT LECTURE:

Treating Obesity

Caloric reduction (behavioural approach)

Increased activity (behavioural approach)

-            Success/failure of public health interventions tell us either or both approaches must be progressive, long-term, permanent changes.

-            Changing the default environment is a must in terms of preventing obesity

Drugs (pharmacological approach)

What would we want to target?

-            Reduced hunger and food-seeking, reduced absorption of molecules, increased metabolism, increase energy expenditure.

Drug basics:

·       Route of administration – getting drug into the body

·       Absorption – getting drug into the blood stream

·       Mechanisms of action – what the drug does (cellular level) antagonist/agonist/inhibitor

·       Mode of action – what the drug does on large, organism level

All drugs have side effects because they act all throughout the body

Weight loss drugs have had limited success

-            Problematic because of side effects e.g.,

1950-70s: amphetamine derivatives CV risk and abuse potential

1980s: 5-HT-releasing agents, pulmonary hypertension, cardiac valve pathology

1990s: SNRI sibutramine (Meridia): cardiovascular risk

Extra Credit Assessment
Ozempic (semaglutide)- is the newest weight loss drug. Except is not strictly weight loss drug.

Problematic: because of redundancy in appetite circuitry.

-            Often initial anorectic effects plateau after a few months

-            Often modest 12-month weight loss: 1-5kg

Bariatric surgery (surgical approach)

If bariatric approach is going to work it needs to target, why we eat!!

-            Restrictive procedures (gastric band, stomach stapling, sleeve gastrectomy, gastric balloon)

-            Malabsorptive procedures (duodenal switch, intestinal liner)

-            Malabsorptive + restrictive (gastric bypass)

Weight loss is achieved as surgery has one or more effects.

Ø  Forces small meals, reduces absorptions of nutrients or causes hormonal changes.

-            Bariatric surgery reduces comorbidity of type 2 diabetes, hypertension, metabolic syndrome.

-            Target audience for this surgery would be a BMI 35+ with comorbidity

Comorbidity- the presence of two or more diseases or medical conditions

Issues with bariatric surgery:

·       Surgical risks, pre-operatively given BMI & CV status

·       Surgical risks, peri- & post-operatively

·       Surgery is expensive (not a widespread solution)

·       Malnourishment especially vitamins and minerals

·       Forced small meals (nausea and vomiting)

·       Potential weight regain!

Deep brain stimulation (DBS)

-            Shown to reduce food intake but does not affect body weight in mice fed a high-fat diet

Faecal transplantation? (biotic approach)

Subpar microbiome can influence weight gain. E.g., antibiotics that affect gut flora can induce weight gain (Cho et al., 2012)

-            Important to keep a healthy gut flora

-             

Sustainable “lifestyle changes” are habits that can be realistically maintained for the rest of your life.

No lectures next week in preparation for Test 1!! (Week 5)

Further understanding needed:

Anorexigenic neurons

Orexigenic neurons