UPENN NEUR2600: Wk08 Videos

List examples of innate immunity.

• peristalsis

• mucosal secretions

• coughing

• gastric acid

Modulated by stress hormones and ANS.

List examples of specific immunity.

T cells and B cells. Recognition of specific foreign substances or pathogens.

Where are immune cells generated?

All of them are produced in the bone marrow. T cells mature in the thymus.

List immune cells and their primary function(s).

• B cells .. humoral adaptive immunity

• T cells .. cell-mediated adaptive immunity

• Neutrophils .. eat bacteria, fungi; first responders

• Dendritic cells .. present antigens (Ag) to T cells

• Macrophages .. eat pathogens, debri; present Ag

• Eosinophils .. target multicellular parasites

• Basophils .. assist in killing parasites (histamine, etc)

• NK cells .. destroy virally infected cells; tumour cells

• Mast cells .. histamine; against parasites; again mucosal pathogens

List classes of immunity related messengers and their roles.

Cytokines are small molecules release by (mostly) immune cells. Mediate inflammation, immunity. Include ILs, IFNs, TNFs, TGFs, CSFs (colony-stimulating factors).

Other molecules:

• Chemokines .. induce chemotaxis in nearby cells.

• Growth factors (GFs) .. cell growth, differentiation

• Adhesion molecules

• Hormones

• Antibodies

• Complement proteins

• Neuropeptides, neurotransmitters

• Eicosanoids (prostaglandins, leukotrienes)

Compare immune and neuroendocrine system in terms of their transmitter, receiver, feedback loop, signal amplification, output, long-term effect.

Are we more likely to get sick if we’re stressed? Why?

Yes.

Cortisol suppresses the immune system (evolutionary - to prioritise glucose for brain/muscles for survival).

Explain how our ANS innervates lymphocytes and why?

• lymphocytes are T cells, B cells, NK cells

• lymphocytes are not directly innervated by neurons

• by ANS can release NT in proximity e.g. in the spleen, bone marrow, lymph nodes

• NE binds to beta-adrenergic receptors on lymphocytes

• ACh binds to nicotinic and muscarinic receptors

• SNS influences cytokine production, affects movement and distribution, affects growth and specialisation of lymphocytes

• PNS suppresses pro-inflammatory cytokines, modulates other functions

• Cortisol (HPA) suppresses immune cells

Why

• scales immune system during stress

• conserves energy during rest & digest period

• ANS can prevent overactivation of the immune system

• SNS can increase activation e.g. during infection

In general how does SNS / fight or flight affect the immune system?

• immediate stress response increases the activity of the immune system; e.g. NE (e.g. in the spleen, bone marrow, lymph nodes) can stimulate mobility, growth, specialisation and pro-inflammatory cytokines in lymphocytes

• prolonged stress response activates HPA and increases cortisol which suppresses the immune system; which may be require to conserve energy and to prevent overactivation of the immune system / autoimmunity

Note that PNS activation opposes this mobilisation by reducing pro-inflammatory cytokines, etc.

How would beta blockers affect the immune function?

• beta blockers will block beta-adrenergic receptors on lymphocytes

• this will reduce pro-inflammatory cytokines

• this will reduce lymphocyte activation and trafficking

• it may reduce chronic inflammation

• however this may also impair body’s abilities to fight infections

What neurons does PVN (HT) have? What receptors? Functions of PVN?

PVN neurons

• magnocellular part (ADH and oxytocin)

• parvocellular part (CRH and TRH)

• DA neurons (modulate PRL release, other functions)

• autonomic neurons (to other brain areas, to spine)

Receptors & inputs

• leptin, insuli, GLP-1, OXM => energy, satiety

• CCK (via NTS) => energy, satiety

• ArgRP, POMC (via ARC) => energy, satiety

• Electrolytes, angiotensin, relaxin => control ADH

• Hippocampal inhibition => CRH response

• SCN => levels of lighting => CRH / pineal / food intake

Functions

• Stress response (HPA; spine, brainstem, spleen, etc)

• Autonomic functions (HR, BP, digestion)

• Feeding behaviour

• Syncing feeding / HPA with circadian rhythms

Which brain region controls SNS neurons innervating the spleen?

PVN, which is involved in the regulation of the autonomic function including the SNS.

How does septic shock cause circulatory collapse?

• infection => cytokines (TNFa, IL-6)

• widespread vasodilation

• increased vascular permeability

• as a result severe hypotension

• blood also shunted to non-vital areas leaving vital organs hypoxic

• heart itself may be affected / depressed

• coagulation issues (microclotting aka DIC)

How do we treat the septic shock?

Septic chock is caused by cytokines e.g. IL-1, IL-6, TNF-alpha and includes severe drop in BP due to vasodilation, vascular permeability, cardiac depression; may include DIC which can include both excessive clotting and excessive bleeding as clotting factors are depleted. Treatment includes:

• large amounts of IV fluids to restore blood volume

• vasopressors (typically norepinephrine)

• broad-spectrum antibiotics

• steroids to treat refractory septic shock or adrenal insufficiency

• anticoagulants (heparin) are used only on case by case basis

Why steroids?

• increase sensitivity of blood vessels to catecholamines

• dampen immune activation by pro-inflammatory cytokines

• improve adrenal insufficiency (septic shock may cause the adrenals to produce insufficient cortisol)

Steroid dampen the immune response

• steroids reduce expression of pro-inflammatory cytokines ..

• .. including IL-1, IL-6, TNF-alpha, COX2 (that produces PGE2)

• reduce migration of immune cells

• reduce activation of T cells and macrophages

Why norepinephrine?

• NE acts on a1 adrenergic receptors and has a limited action ..

• .. it constricts most blood vessels and slightly increases HR

• E acts on a1, b1, b2 ARs, significantly increase HR and can dilate some blood vessels

• therefore NE is preferred as a more limited and controlled intervention

• if NE doesn’t work, E can be used instead

Difference in the HPA / immune system in the Lewis vs Fischer rats.

• Lewis rat => low HPA but highly reactive immune system => susceptible to autoimmune

• Fischer => high HPA => low immune activation => no autoimmune but more infection

Is there a link between chronic stress and cancer?

Weak link.

• stress => suppress immune system => cancer cells evade detection

• cortisol, adrenaline => angiogenesis => helps cancer

• cortisol, adrenaline => reduce apoptosis => helps cancer

• stress => overeating, lack of exercise, poor sleep => cancer risk

How do cytokines (when we’re sick) affect our behaviour?

• fever

• slow wave sleep

• social isolation

• decreased eating

• slow digestion

• taste aversion to novel foods

• hyperalgesia

Can immune cells penetrate BBB?

Yes they can. Old concept was that they can’t. Now we know they can but its just the brain rarely gets an infection. Also it was found neurons express MHC.

Wha is the role of MHC-I vs MHC-II?

• MHC-I are found on all nucleated cells

• MHC-II are found on dendritic and B cells, macrophages

• MHC-I present intracellular pathogens (e.g. virus)

• MHC-II present extracellular pathogens (bacteria, parasites)

• MHC-I present pathogens to CD8 (cytotoxic T cells)

• MHC-II present pathogens to CD4 (helper T cells)

Why do neurons have MHC-I complex?

• found pre- and postsynaptic at glutamate synapses

• standard role of presenting intracellular pathogens to CD8 (cytotoxic T cells) and NK cells .. though immune system goes very easy on neurons to avoid inflammation

• MHC-I modulate synaptic plasticity and LTP

• involved in synaptic pruning (w/o pruning - autism, schizophrenia)

• help during development e.g. guiding axons to their targets

• interacting with glial cells

What is synaptic pruning?

• selective elimination of neurons

• allows to fine-tune neuronal circuits

• occurs in children

• w/o pruning connections are slower and noisier

• w/o pruning there’s cognitive overload, difficulty focusing, slow learning

W/o pruning => autism, schizophrenia.

Explain the immune role in schizopherina.

• maternal infection is risk factor for SZ

• SZ associated with changes to the MHC portion on ch.6

• in SZ patients acute psychosis is associated with elevated cytokines (possibly affecting the brain via circumventricular organs or vagal receptors)

How could cytokines affect the brain (esp. in schizophernia, etc)

• in schizophernia elevated cytokines are accoiated with acute psychosis

• possibly affecting via circumvetnroicular organs or vagal receptors

What do we need to consume to survive if we’re sick?

• when we sick, our survival is prioritised

• we need O2, glucose, water, salt

• vitamins, minerals, amino acids are LESS important

• all other things are EVEN LESS important

What is a learned taste aversion (when we’re sick)?

• learned taste aversion is a classical conditioning

• if we eat something and get sick (vomit, nausea, etc) we begin to associate that food with unpleasant feelings

• develops with a single exposure and even if that particular food didn’t actually cause the problem

• time gap can be quite long (e.g. we eat something hours before we get sick - the brain still makes a connection)

Example:

If you eat a particular dish, like seafood, and then get food poisoning a few hours later, your brain may associate the seafood with the unpleasant experience of being sick, causing you to feel nauseated or avoid seafood in the future.

How do rodents eat new food introduced to them and why?

If the food is new and unknown, they just nibble on it. This allows them to understand if it’s poisonous.

What is the “wisdom of the body” concept and why it may be wrong?

“Wisdom of the body “ concept by Curt Richter

• rats given deficient diet A

• then can choose b/w deficient diet A and good diet B

• they choose diet B

• Richter thought rats can “tell” that diet B has nutrients they needed

Rozin Experiments

Rozin showed that’s likely not true.

Experiment 1
- give deficient diet A but later inject nutrient A
- they still like diet B despite not needing nutrient A
- so perhaps they prefer B b/c it’s new and exciting?
Experiment 2
- give deficient diet A but later inject nutrient A
- choose b/w fortified diet A or deficient diet B
- they still like B - new & exciting? or perhaps A is old & boring?
Experiment 3
- give fortified A, then deficient B
- then choose b/w fortified A, deficient B and new diet C
- rats choose A (!) so it’s not about exciting new diet or boring old diet

The conclusion was that rats somehow sense which diet made them unhealthy and avoid it; at the same time they prefer the diet they’re familiar with it so long as it provides the necessary nutrients.

How does the immune system contribute to taste aversion?

• nutrient deficiency leads to general malaise

• causes release of cytokines IL-1, TNF-alpha

• cytokines may alter food preferences; may make us more tuned to foods we’re deficient in

• poor food may cause low grade gut inflammation which would cause the effect describe above

• animal can also directly associate feeling sick with the usual diet and that would produce aversion

• animals deficient in specific elements required by the immune system (zinc, iron) may seek those out

What are exogenous pyrogens? How do they work?

Substances that cause an increase of body temp. Could be bacterial toxins (e.g. lipopolysaccharides), pathogen-associated molecular patterns (PAMPs) e.g. flagellin, viral RNA, fungal cell wall components.

Pyrogens => macrophages/DCs/monocytes => endogenous pyrogens (e.g. IL-1, IL-6, TNF-a) => anterior hypothalamus => increases temp set point => fever => reduces pathogen survival and increases activity of the immune system and tissue repair.

Difference b/w endogenous and exogenous pyrogens.

• pyrogens increase body temperature

• exogenous pyrogens are anything body recognises as a pathogen / foreign substance (bacterial toxins e.g. LPS, PAMPs e.g. flagelling, viral DBA, fungal cell wall componets

• endogenous pyrogens are cytokines e.g. IL-1/6, TNF-a

• exogenous pyrogens => macrophages / dendritic cells => endogenous pyrogens => anterior HT => fever

How do pyrogens produce fever and why? Explain step by step starting with pathogens entering the body.

• exogenous pyrogens (LPS, flagelling, viral RNA) appear

• macrophages or dendritic cells detect them

• they release endogenous pyrogens (IL-1, IL-6, TNF-a)

• these travel to the preoptic area of anterior HT

• there endogenous pyrogens activate COX2

• COX2 produces prostaglandin PGE2

• PGE2 activates pyrogenic neurons

• these neurons

  • activate brown fat

  • constrict blood vessels in extremities

  • cause rapid mucles contractions to induce shivering

• this raises fever

• fever makes the body inhospitable for pathogens

• fever increases activity of leukocytes, speeds up tissue repair, improves production of antibodies

What is COX1 and COX2?

COX1/2 are cyclooxygenase enzymes. They convert arachidonic acid into thromboxane (COX1) prostaglandin PGE1/2.

COX1

• COX1 is a “housekeeping” enzyme

• expressed normally in many tissues

• converts arachidonic acid into thromboxane-2

• COX1 induces GI mucus

• COX1 induces platelet aggregation to clot blood

• COX1 regulate blood flow to kidneys

COX2

• enzyme induced by cytokines

• produced in response to infection or tissue damage

• converts arachidonic acid into prostaglandin-2

• in HT PGE2 induces fever

• in other tissues PGE2 induces pain and inflammation

How do COX2 inhibitors work?

• COX2 (cyclooxygenase) inhibitors are a type of NSAIDs

• NSAIDs are non-steroidal anti-inflammatory drugs

• COX2 converts arachidonic acid into prostaglandin PGE2

• PGE2 activate vlPOA in the HT to induce fever

• PGE2 in other tissues induce pain and inflammation

• COX2 inhibitors prevent that

What are COX inhibitors? Difference b/w COX1 and COX2 inhibitors.

• COX inhibitors inhibit cyclooxygenase

• COX1 is required for normal “housekeeping” (kidney function, blood clotting, GI tract mucus / protection)

• COX2 is induced in response to infection / inflammation

• COX inhibitors are non-selective NSAIDs (non-steroidal anti-infloammatory drugs)

• called non-selective b/c suppress both COX1 and COX2

• aspirin, ibuprofen, acetaminophen, diclofenac

• reduce fever, inflammation, pain

• aspirin also reduces blood clotting

• side effects: GI bleeding, stomach ulcers, gastritis, risk of bleeding

• there are COX2-specific inhibitors e.g. celecoxib

Why does infection promote hyperalgesia?

To promote social isolation, inactivity, care of sites of injury, to reduce energy use and promote recuperation.

How doe infection promote hyperalgesia?

Brain

Infection => IL-1 and TNF-alpha => activates CN X => NTS => Raphe => Dorsal Horn. This enhances pain transmission.

Tissue

• lowers activation threshold of nociceptors (via PGE2)

• activates nociceptors directly (substance P)

What is primary and secondary hyperalgesia in response to infection?

• infection activates the immune system (IL-1, IL-6, TNF-a)

• these stimulate PGE2 in tissues and brain

• primary hyperalgesia: due to peripheral sensitisation by PGE2 when pain threshold of nociceptors is lowered

• secondary hyperalgesia: due to central sensitisation (as pictured) in the spinal cord and brain

Which three cytokines activate the HPA axis?

IL-1, IL-6, TNF-alpha.

IL-1 stimulates both CRH and ACTH.

IL-6 also stimulates CRH neurons to release ADH causing hyponatremia.

What are the synergistic abilities of IL-6 when it acts on CRH neurons? What role does ADH play?

Il-6 / CRH neuron synergy is critical for stress response to inflammation.

• during immune response immune cells produce IL-6

• IL-6 cross the BBB and actives CRH neurons in the PVN

• IL-6 not only activates them but also enhances their sensitivity

• this creates a +’ve feedback loop responding with stress to inflammation

Role of ADH:

• CRH neurons co-release ADH as well

• ADH enhances action of CRH on production of ACTH

• note that IL-6 (and other cytokines) cause vasodilation

• ADH can counteract that by constricting blood vessels systemically (restoring BP) while at the site of infection IL-6 will keep blood vessels dilated

Note that normally AVP is produced by magnocellular neurons in the PVN in response to the stimulation by neuronas in the circumventricular organs e.g. subfornical organ.

Problem with using male rats in studying mental health.

Sex differences seem to influence mental health and most other aspects of the neuro/endocrine systems.

E.g. in the US / Europe / Asia women are at a higher risk of developing Alzheimers.

Sex differences in hippocampus. What causes these differences?

• men: better at spatial navigation

• women: better verbal memory and social perception

• hippocampus shows stronger activation in women during memory tasks

• also stronger connectivity b/w hippocampus and amygdala in women

Differences likely influenced by estradiol b/c it promotes neurogenesis, dendrites growth and spines, as well as hippocampal volume.

Why does hippocampus makes its own estrogen?

Hippocampus has very high neural plasticity and this is aided by estrogen. Estrogen also protects neurons from damage e.g. ROS, inflammation.

Which hormone affects the onset of Alzheimer’s?

Lack of estrogen increases the risk. Low estrogen increases systemic inflammation. Inflammation contributes to Alzheimers.

What explains the fact that women are more at risk of Alzheimers.

• it’s not known what causes Alzheimer’s

• one hypothesis is that it’s due to neuroinflammation

• women have stronger immune system response

• estrogen is neuroprotective and anti-inflammatory and therefore post-menopausal women are at an especially high risk

• while men have lower estrogen than women of any age; men benefit of testosterone aromatised to estrogen

• women live longer than men

• these factors explain why women are at higher risk for Alzheimers than men

Are symptoms of Alzheimers worse in men or women?

The symptoms of A’s are worse in women. Semantic memory is worse in women.

How does estrogen replacement therapy affect Alzheimer’s?

One study showed ERT sped up the onset of AD. However in this study they gave ERT to women in their 60s, so 15 years after the drop in estrogen. So possible causes:

• brain already adapted to low E and ERT disrupted this

• artificial E is different from real E

• they may have used progestins which can be damaged

Other studies showed beneficial effects of ERT especially if started early.

Autism has heritability of about 70%. If 100 couples where one of parents have autism have one child (i.e. 100 children) how many children will have autism?

Impossible to say. Heritability in this case is how much autism can be explained by genetics (in this case 70% by genetics, 30% by other factors e.g. environment).

Imagine if ASD had 0% heritability. We can’t say that just because it has heriability of 0%, then 100 autistic parents will produce 0 autistic children - other factors (environment, etc) may still cause a child to develop autism.

Is autism heritable?

• ASD is highly heritable

• 90% concordance in MZ twins

• heritability in 55-80%

• polygenetic condition

• parents tend to be emotionally aloof and/or scientists

Is there drug treatment of autism?

No.

• anti-psychotic drugs may reduce aggressive behaviour

• antidepressants and anti-ADHD drugs don’t help

What does that mean that autistic children have impaired social cognition / theory of mind? How can we test this?

They don’t understand what other people experience, can’t put themselves in their shoes. Simple test:

• tell a child being tested a story

• in a story there are two kids in a room

• one kid puts a toy in a basket and leaves

• the other kid moves the toy behind the curtain

• the first kid returns and starts looking for the toy

Ask your child where would the kid look? If the child has a theory of mind, they will understand that the first kid will first look in the basket, because this kid wasn’t in the room when the toy was moved.

How are patterns of neuronal activation different in autism?

• cerebellum

• striatum

• amygdala

• hippocampus

• insular cortex

They have reduced activation in social cognition areas (PFC, tmpoeral-parietal junction, fusiform face area)

What

How are brains of autistic people different?

• abnormal head growth (it’s larger early in development)

• maaaybe low IGF-1 (needed to cerebellar growth)

• early brain overgrowth; poor pruning => overstimulation

• reduced connectivity b/w brain region (white matter)

• PFC, amygdala, temporal lobe, cerebellum, corpus callosum are different

What are approaches to study autism in animal models?

• find animals with social avoidance (but doesn’t truly mimic autism)

• find animals that mimic Rett or fragile X syndrome in humans (both have typical autistic symptoms)

Rett => girls, child regresses, loses motor skills, ability to speak, anxiety

Fragile X => boys, intellectual disability, anxiety, long face, prominent jaw, big ears

Connect oxytocin and autism.

• OTR knockout mice have impaired social memory

• intranasal oxytocin enhances trust in NT individual

• OTR expressed in frontal cortex, olfactory nucleus, amygdala, hypothalamus

• individual with overexpressed OTR show generous behaviour, are pro-social, show empathy, less stressed, are better parents

• some children with autism have lower levels of OT

• there’s increased rate of mutation in OTR

• intranasal OT improved autistic children’s emotion recognition, recognition of social cooperation, preference and time gazing at pictures of faces

Sexual dimorphism of autism?

More common in males.

“Extreme male brain” theory - more systematic, less empathetic brain.

There seem to be androgen receptor mutation in females with autism.

Digit ratio suggest excess T exposure in autism.

Describe cognitive dysfunction in T2DM.

Reduced:
- intelligence
- psychomotor efficiency
- cognitive flexibility
- processing speed
- exectuvie function
- memory

Diabetes increases the risk of demetia by 19%

Atrophy of white matter.

Specific brain regions affected in T2DM.

• hippocampus: reduced contextual memory

• NAcc: explains reduced reward responsiveness

• PFC: loss of cognitive control

• Amygdala: high anxiety, less social affiliation

Improved BGL does not reverse these changes, but GLP-1 improves the brain. Intranasal insulin improves hippocampus.

What does higher IGF-1 do in aged rats?

IGF-1 seems to improve hippocampus and related memory tasks; improves denritic branching. Perhaps indicative of T2DM related decline in hippocammpus. Perhpas insulin resistance in the brain contributes to cognitive decline.

Is insulin resistance in the brain possible?

T2DM is known for various cognitive deficienices (hippocampus -memory; NAcc - anhedonia; amygdala - anxiety; PFC - poor cognitive control).

Insulin receptors are found in many areas of the brain. Insulin modulates LTP. While neurons take up glucose in insulin-independent manner, astrocytes and oligodendrocytes require insulin - so they may be vulnerable.

What is migraine?

• headache disorder

• moderate to severe headaches

• throbbing and pulsating

• last hours to days

• can also have nausea, photophobia, phonophobia

• neurological condition

Phases include prodrome, aura (some ppl), headache, postdrome.

What triggers migraine?

• hormonal changes esp. female cycles

• stress

• certain foods

• caffeine, alcohol

• sleep deprivation

• weather changes

• bright lights, loud noises, strong smells

• dehydration or fasting

Prevalence of migraines.

• 15% of population

• typically ages 22 to 55

• most common debilitating brain disorder

• 3:1 female to male

• runs in families

Mechanisms of migraine.

Cortical spreading depression
Wave of electrical activity; followed by neuronal inhibition. This triggers changes in NT and inflammatory substances. This wave activates trigeminal nerve system (leading to headache) and sometimes aura.

Trigeminal vascular system
Trigeminal nerve activated => releases calcitonin gene-related peptide (CGRP), substance P => vasodilation and inflammation of meningeal blood vessels => trigeminal ganglion carries pain signal => brainstem and HT / reward system.

In what condition do we find cortical spreading depression? Why does it happen?

Migraine is preceded by cortical spreading depression. Wave of electrical activity; followed by neuronal inhibition. This triggers changes in NT and inflammatory substances. This wave activates trigeminal nerve system (leading to headache) and sometimes aura.

It happens due to predispoision to neuronal hyperacitity, possibly due to mutations in Ca channels, Na/K ATPase, VG-Na channels, glutamate related proteins, etc.

What changes does migraine cause in the brain, structurally?

• thicker somatosensory cortex

• more gray matter in caudate

• less gray matter in amygdala and various cortical areas

Though these changes may be related to pain as a symptom, rather than migraine itself.

Novel tx for migraine.

• CGRP (calcitonin gene-related peptide) antibodies (one injection lasts months)

• vagal nerve stimulation

• anticonvulsants

• botox (reasons not understood; maybe less signalling via trigeminal nerve)