Brain and Behaviour Flashcards
1
Q
Behavioural traits from:
A
- Evolutionary and genetic influences
- Environmental and social influences
- motivational state
- previous experience (learning)
2
Q
hierarchy of organisation
A
- connected levels - manipulations at 1 affects all
- whole brain, brain circuits, brain regions, cells ect.
3
Q
Germinal stage
A
- 1-2 weeks
- egg + sperm → zygote
- zygote divides at 12 hrs via cleavage → morula
- morula → blastocyte (200-300 cells)
4
Q
Embryonic stage
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- 3-8 weeks
- after implantation in the foetus
5
Q
Fetal stage
A
- 9-38 weeks
6
Q
Gastrulation (part of embryonic stage)
A
- Embroyonic disk
- uneven cell development forms the ectoderm, mesoderm and the endoderm
- ectoderm folds in itself to form the neural tube, which becomes the nervous system
7
Q
Neural tube defects:
A
- Spina bifida - failure of the closure of the neural fold at the spinal cord level (1 in 1000 live births)
- small openings can often be surgically corrected, larger can lead to paralysis and limb deformation
- Anencephaly - brain fails to develop - still birth
(can be prevented by folic acid supplements)
8
Q
Cell birth/proliferation
A
neurogenesis and gliogenesis - massive process, neural tube starts as one cell thick, widens and elongates
- stem cells divide to form progenitor (precursor cells) - neuroblast (neurons) /glioblast (glia cells)
9
Q
Cell migration
A
newly formed cells moving to outer layers, cortex made in inside out manner - predisposed via primitive map
- help from chemical signals and physical support from radial glia (like vines)
10
Q
Differentiation and maturation
A
once they arrive at their destination, cells mature and differentiate
- form an axon (grows a few mm a day) and dendrites (grows a few um a day)
- dendritic development - dendritic arborization (branching), growth of dendritic spines (means they can take more information)
- induction - cells influence fate of neighbouring cells via secreting chemicals
11
Q
Synaptogenesis and Synaptic Pruning
A
guided by cues (chemicals from target sites, cell adhesion molecules and tropic molecules), growth cone at end of axon (battering ram - Santiago Ramon y Cajal, 1890)
- filopodia (extensions) - contact or chemotropism (chemical) guidance
- attracted/repulse to growth cone
- unsuccessful (non maintained) synapses are pruned - rearranged throughout life - lots of pruning in adolescence (more white matter)
- environmental influence important
12
Q
Cell death
A
- part of normal development - apoptosis (quiet death - cascades) - have more neurons and connections than we need
- necrosis - loud death - from injury
13
Q
Which cells die/live?
A
- Rita Levi-Montalcini: proteins secreted by target cells promote the survival and growth of neurons – survival signals - Nerve Growth Factor (NGF) (won a nobel later)
- family of survival factors - neurotrophic factors
- to survive a neuron needs (neurotrophins and active communication with other neurons)
14
Q
Myelination
A
- glia form fatty sheath to cover axons (slow progress)
- saltatory conduction
back to front - spinal cord -> hindbrain -> midbrain -> forebrain - Schwann cells
- Oligodendroglia - wrap around sections of different axons - provide myelination to many different neurons
- motor behaviour correlation between myelination and ability to grasp
15
Q
Nottenohm - 70s + 80s
A
- In songbirds - steady seasonal replacement of neurons in ‘singing’ area (every bird producing thousands a day
- Generated in the lining of the ventricles, migrated to their final destination, differentiated and then responded to auditory stimuli - neurogenic
16
Q
Rostal Migratory Stream (RMS)
A
- newborn cells from SVZ (subventricular zone) migrate to the olfactory bulb and become interneurons
- astrocytes wrap around the migrating neurons to create a ‘pipeline’ that keeps them on the right parth
- occurs throughout life
17
Q
Neurogenesis
A
new neurons formed
e.g.
- hippocampus - granular layer of denate gyrus
- induced by injury (recovery better in younger and in periphery)
- olfactory epithelium (Rostral Migratory Stream)
18
Q
Collateral Sprouting
A
- new branches formed by non-damaged axons attach to vacant spots of dendrites and cell bodies - the cells secrete neurotropins - allow collateral sprouting
- new synapses fast especially in first 2 weeks after damage
- filling ‘gaps’ in brain
- e.g. blind people better at hearing - neuroplasticity
19
Q
Reorganisation in monkey cortex
A
amputated a monkey’s finger - looked at brain before and after - brain part corresponding to fingers
- area initially for amputated finger (3) - reallocated to digits 2 and 4 - collateral sprouting
20
Q
Blindness - sighted and blind people to feel braille letters/other objects - had to say whether the same or different
A
- PET scans showed substantial activity in occipital cortex of blind people during this task - collateral sprouting? (Sadato)
- fMRI study with blind participants showed robust activity in the visual cortex while reading Braille, despite complete absence of vision (Burton et al 2002)
- Blind people recruit brain areas used for vision to perform auditory localization tasks (Weeks et al 2000)
21
Q
Critical periods of collateral sprouting - study examples
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- Bateson 1979 - sensitive periods - can be conceived of as a brief opening of a window of vulnerability, need and opportunity
- Richard Tees - ‘train ride’ - 3 broad waves of brain’s sensitivity to learning - senses wave → language wave → higher cognition wave (increasingly complex skills)
- Blakemore and Cooper 1970
- Case of Genie - case study of a girl growing up in deprivation and chronic malnutrition in California
22
Q
environmental impacts of collateral sprouting
A
- maternal adversity - epigenetic
- childhood outcomes
- conditions traced back - autism eg
- rats with more vs fewer experiences - enriched environment -> more dendritic branching
23
Q
structure of a neutron
A
Dendrite - receives info from other neurons - large receptive field
Soma - cell body - contains machinery controlling processing and integrates info
Axon - carries info from soma to terminal boutons, branch
terminal boutons/axon terminals - where cells talk, location of synapse
24
Q
neuronal membrane
A
boundary, separated extracellular environment from intracellular - lipid bilayer
- protein structures detect substances out of cell and let certain substances into the cell (chemical/electrical gated)
- cytoskeleton
25
electrical vs chemical synapses
Electrical synapse - very rare, retina - small junction (synaptic cleft) (3nm) - direct connection as proteins (connexins) - move freely to communicate
Chemical synapses - more common - chemicals released to connect - neurotransmitters - 20-50nm (longer gap)
26
First experimental evidence for chemical synapse
- Loewi in 1959
- application of fluid following vagus nerve stimulation slowed heart rate
- substance was sufficient to change heart activity, acceptance as primary means of community
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difference synapse locations
Axodendritic - on dendrite (most common)
Axosomtic - on soma
Axoaxonic - on axon
28
Ionotropic vs metrbotrophic receptors
Ionotrophic receptors - opening of an ionic channel
Metamorphic receptors - activates more molecules (second messengers) in neuron + amplifies signal
29
Receptors vary in
pharmacology - what transmitter binds to the receptor and how drugs interact
Kinetics - rate of transmitter binding and channel gating determine duration of effects
Selectivity - what ions are fluxes
Conductance - rate of flux
30
Receptor pharmacology - agonist vs antagonic
- Agonist - a drug that can combine with a receptor on a cell to produce a cellular reaction
- Antagonic - blocks agonist/endogenous ligand, no effect after or on its only
31
Excitatory vs inhibitory transmission
Excitatory = positive ions in + depolarisation + Excitatory post synaptic potential (EPSP)
Inhibitory = negative ions in + hyperpolarisation + inhibitory post synaptic potential (IPSP)
32
Metabotropic receptor - G-protien coupled receptors
- transmitter binds and couples with G-protien and activates it
- G protien splits and activates other molecules
- series of chemical reactions leads to an amplification of the signal - second messenger system (slow but bigger effects - each turns on more molecules)
- activate G-protiens - membrane spanning (more complicated)
33
Neurotransmitter deactivation
- must be inactivated after use to remove them from the synaptic cleft
- reuptake by transporters to pre-synapic
or
- deactivating enzymes - brake down neurotransmitters chemically
34
Autoreceptors (regulating synaptic transmitters)
- on presynaptic terminals - respond to neurotransmitters in the synaptic cleft (generally G-protien coupled)
- regulate internal processing - controlling synthesis and release of neurotransmitters
- negative feedback system
(NOT SAME AS REUPTAKE SITES)
35
Categories of neurotransmitters
**Classical** - amino acids (fast transmission, GABA + Glutamate), Monoamines (dopamine, serotonin), Acetylcholine
- local synthanization, stored in synaptic vesicles, released due to calcium
**Neuropeptides** (eg. endorphins) - pain relief
- synthecised in soma and transported to terminal, stored in secretory granules, need intense stimulation
**Other small molecule transmitters** - nitric oxide
36
Glutamate (ionotrophic)
- ionotropic receptors in general flux Na+ - causes excitatory and depolarization (receptors differ in pharmacology)
- widespread, synthesised by glucose/glutamine
- released by exocytosis
37
AMPA (a glutamate one) - excitatory
glutamate attatches, opens channel, sodium comes into the cell, lower/weaker threshold than NMDA
- sodium and potassium
38
NMDA (a glutamate one) - excitatory
once AMPA opens, triggers depolarisation from sodium
- then causes NMDA to open
(has magnesium which stops it opening but the magnesium is de-lodged via +depolarisation* from AMPA and *glycine* being present)
- sodium, potassium and calcium
39
Dysregulated NMDA
gluatmate excitotoxicity - (cell death) - caused by excessive calcium into cell - activates calcium dependent proteases and phosphlipases that damage the cell - occurs after a stroke and chronic stress
40
GABA
- releases chlorine not sodium (inhibitory)
- synthesised from glutamate
- loaded on vesicles and released - acts on inotropic and metabotropic receptors on post synaptic, reuptake by transporters
41
GABA inotropic vs metabotrophic
GABA ionotropic recepetors - ligand gateded chlorine channel.- fast IPSPs
GABA metabotrophic receptors - slow ISPS - G protien coupled receptors - indirectly coupled to protien or calcium
42
GHB
date rape drug - breaks down and makes more GABA - more inhibition - too much = coma
42
GABA pharacology
Muscimol - agonist, Biciculine/picrotoxin - antagonist
- other drugs bind elsewhere on the receptor - no competition eg. ethanol (alcohol)
- Anxiolytic - increase GABA and reduces anxiety
- anxiogenic - decrease GABA and increase anxiety
- all mean more chloride in, stronger IPSPs
43
Benzodiazepines
- first was chlordiazepoxide (librium)
- diazepam (valium) - major anxiety treatment - sedative - fast acting and large therapeutic window, can cause dependence and potentiated by alcohol
44
Neuromodulators and the diffuse modulatory systems
affect response properties of a neuron - do not themselves carry primary information (e.g. dopamine)
The diffuse modulatory systems - affect glutamate and GABA neurons in their target areas
45
Dopaminergic system
- cell bodies in the midbrain, project into the forebrain
Nigrostriatal system - movement - dysfunction can lead to Parkinsons/Huntingtons
Mesolimbic system - reinforcement - dysfunction can lead to addiction
Mesocortical system - functioning of working memory and planning - dysfunction can lead to schizophrenia
46
Dopamine synthesis
Tyrosine (essential amino acid obtained in diet) (catalysed by tyrosine hydroxylase) (rate limiting - slowest)
→ L-Dopa (cataylsed by dopa decarboxylase)
→ Dopamine
- Catechloamine storage - loaded into vesicles
47
Drugs affecting dopamine synthesis
Reserpine - impairs storage of monoamines in synaptic vesicles - so remain empty
L-DOPA - precursor of dopamine - treatment for parkinsons
( bypasses rate-limiting TH step - Dopa decarboxylase converts it into dopamine and increases the poor of releasable transmitter)
48
Drugs affecting dopamine release and reuptake modulate behaviour:
**psychostimulants - e.g. cocaine, amphetamine**
- all block reuptake of monoamines into terminals - more dopamine in synaptic cleft
Selegiline - Monoamine oxidase B inhibitor
- prevents breakdown of catecholamines and increases the releasable pool
- can have antidepressant activity and can be used for treating Parkinsons
49
Serotonergic system
- Nine raphe nuclei (in brain stem) with diffuse projections - each projects to a different part of the brain - descending projects to a different part of the brain
- descending projections to cerebellum and spinal cord
- mood, sleep, pain, emotion, appetite
49
Serotonin synthesis
Tryptophan (essential from diet - rate limiting) (catalsed by Tryptophan hydroxylase)
→ 5-hydroxttryotophan (5-HTP) (catalysed by aromatic amino acid decarboxylase)
→ serotonin (5-HTP, 5-HT)
50
tryptophan and mood
- first step of serotonin synthesis
depletion died (experimentally inducing a depression state), enrichment can improve mood)
51
drugs increasing serotonin
Fluoxetine (prozac) - blocks reuptake of serotonin (SSRI selective serotonin reuptake inhibitor) - anti-depressant/anti-anxiety
MDMA - ecstacy - increased empathy and euphoria and makes serotonin, transporters (SERT) - to work in reverse so more serotonin from synapse - monoamine oxidase inhibitors boost monoamines
52
Physiology of the stress response-SAM system
- Sympathetic-Adrenal-Medullary (SAM) system
- Hypothalamus and sympathetic nervous system stimulate adrenal medulla (kidneys) to release the catecholamine transmitters epinephrine (**↑**blood glucose) and norepinephrine (**↑** blood pressure)
- Norepinephrine also secreted in brain during stress
53
Physiology of the stress response-HPA axis
- Hypothalamic-Pituitary-Adrenal (HPA) axis
- Paraventricular nucleus of the hypothalamus (PVN) releases the peptide **corticotropin-releasing hormone/factor** (CRH/CRF)
- CRH -> adrenocorticotropic hormone (ACTH) -> adrenal cortex to secrete glucocorticoids (e.g. cortisol)
→increases glucose, decrease pain sensitivity
54
Evidence for stress-induced neurotoxicity (Diamond et al 1999)
- rats exposed to cat smell + presence (75 minutes) → blood glucocorticoids increased (evidence for neurotoxicity)
- impaired primed-burst potentiation (similar to Long term potentiation) in hippocampus
- impaired in spatial task requiring hippocampus
55
Stress effects on the brain
- can be neurotoxic
- chronic exposure to glucocorticoids destroys hippocampal (learning and memory) neurons via too much glutamate in synapse (excessive calcium influx and toxicity)
56
PTSD and brain changes - Hippocampus
- reduced hippocampus size in those with PTSD
- risk factor - genetic factor (MZ twin study from Vietnam war)
- hippocampus plays a role in distinguishing contexts - threat generalisation
57
PTSD and brain changes - Amygdala and medial prefrontal cortex
- PFC involved in impulse control and thought to normally inhibit amygdala + emotional expression
- PTSD → greater amygdala and reduced PFC activation than control for fearful face (opposite for happy - less amygdala + more PFC)
- excessive emotional response and reduced inhibitory control from PTSD
58
Treatments for PTSD
- Psychotherapy - associated with decreased amygdala activity and increased PFC, hippocampus activity
- antidepressants (SSRIs) → increased hippocampal volume
- exposure therapy - philosophy of extinction learning
59
Brain changed from anxiety disorders
- functional imaging - changes in the prefrontal cortex, anterior cingulate cortex and amygdala
- increased amygdala activity when anxious (no suppression from PFC)
- Adolescents with GAD exhibit increased amygdala and decreased prefrontal cortex activation (Monk et al., 2008)
60
treatment drugs for anxiety
- GABAergic drugs - Benzidiazepines - Binds to the inhibitory GABAA receptor as ‘agonist’.
reduces anxiety and similar behaviours in animals (rats spend more time on open arm (plank) of cage with drugs)
- Flumazenil (antagonist) disinhibits action at GABAA receptor and produces panic in panic disorder patients (Treats BDZ overdose, acute alcohol intoxication)
- side effects - Abuse potential, withdrawal, sedation
60
Increasing neurosteroid synthesis for anxiety treatment
- Neuroactive steroids ‘neurosteroids’ synthesized in periphery and CNS → increase activity of GABAA receptor.
- neurosteroid synthesis is suppressed in anxiety attacks -> suppression of GABAA receptor function.
- XBD173 enhances neurosteroid synthesis and reduces panic
61
compounds affecting serotonin and glutamate system
- fluvoxamine (an SSRI) reduces panic attacks
- similar findings for D-cycloserine(an indirect NMDA receptor agonist) -facilitating in extinction of conditioned fear in animals
62
Brain circuits of aggression
- brain stem programs
- electrical stimulation - of **periaqueductal gray** (PAG) elicited aggressive attack and predation in cats ([Gregg and Siegel 2001]
- Medial Hypothalamus→Dorsal PAG: defensive rage
- Lateral Hypothamaus→Ventral PAG: Predatory attack
- **Amygdalar nuclei control these pathways**
63
Aggression and serotonin - Animals
increasing serotonin transmission reduces aggression - reducing serotonin transmission (via destruction of serotonergic axons) (reducing increases aggression)
→ serotonin inhibits aggression and controls risky behaviours
64
Aggression and serotonin - humans
- serotonergic neurons play an inhibitory role in aggression
- low 5-HIAA in CSF linked with aggression and antisocial behaviour
- SSRI (fluxetine) - has shown to reduce aggressive behaviour in some cases
65
one treatment working for PTSD, anxiety and aggression
SSRIs (antidepressant - fluvoxamine, fluoxetine)
66
Aggression as a reward
- certain people exhibit appetitive agression - reward
- adaptation to violent environments - war - elevated social status
- animal models let us study this
67
Conditioned place preference (CPP)
- drug, food, social reward in mice/rats
- neutral chambers at first
- one room paid with drug reward, after several reward-chamber pairings the reward-paired side achieves motivational significance → conditional stimulus
- a reward develops a preference
68
Conditioned place preference (CPP) with aggression
- resident vs intruder males (males territorial after mating)
- During conditioning: Resident attacks the intruder in the ‘Paired’ side, no intruder on the ‘Unpaired’ side
- After conditioning: Resident mouse that exhibited aggression spends more time on the Paired side in the absence of the intruder mouse.
- →aggression is rewarding because the attacker prefers the side ‘paired’ with aggression
69
Operant/instrumental task for aggression reward
- learn to press level for food reward (Skinner chamber) - reward self-administration + reward seeking
- animals will learn to lever press for ‘intruder’ (aggression self-administration)
- Trained animals press lever even in absence (aggression-seeking)
70
Does aggression activate brain reward system
- nucleus accumbens (NAc) and ventral tegmental area (VTA) (reward and motivation)
-> sends dopamine projections to NAc and part of ‘mesolimbic pathway/system’ (e.g. Food and drug-seeking)
- Activated by rewarding experiences
- Measured by the activity-sensitive protein ‘Fos’
71
Fos - a protien expressed in activated neurons
- can detect activated neurons in the brain using a biochemical assay called ‘immunohistochemistry’
- more neurons activated in the nucleus accumbens when animals exposed to rewarding stimuli - aggression too?
- correlational evidence - more activated neurons that contain Fos (Golden et al 2019)
72
Important names for DNA
Francis Crick and James Watson, Rosalind Franklin, Maurice Wilkins
73
single nucleotide polymorphisms (SNPs)
- natural variations - we inherit unique combinations from our parents
74
Mendel’s Law (Mendelian Inheritance)
Law of Segregation - each individual has 2 versions (alleles of a gene) - these segregate during reproduction - each gamete only gets one
Law of Independent Assortment - genes for different traits are inherited independently (unless linked on a chromosome)
Law of Dominance - some alleles are dominant and some are recessive
75
Huntingtons Chorea
- neurons in part of the brain gradually broken down and die, attacks area helping to control intentional movement (abnormal body postures ect.)
- single gene disorder on chromosome 4 - autosomal dominant inheritance
- chromosome 4 mutated HTT gene → 35 or more CAG repeats → more polyQ regions → neuron degeneration → atrophy of basal ganglia, enlargement of lateral ventricles
76
Phenylketonuria
- recessive inheritance - mutation in PAH gene (phenylalanine hydroxlase) - enzyme that breaks down dietry phenylalanine
- phenylalanine can build up to harmful levels → intellectual disability, behavioural difficulties, epilepsy ect.
- screening at birth - symptoms can be prevented by diet
77
Chromosomal abnormalities
- Monosomy - single copy of a chromosome - embryonic lethal e.g. Turner syndrome
- Trisomy - 3 copies of chromosome - very highly rate of embryonic lethality e.g. downs syndrome - trisomy in chromosome 21, 47 chromosomes
78
X-inactivation in females
- X-inactivation ensures that dosage of activations maintained in all individuals
- inactivated X chromosomes condenses into a compact structure - **Barr body**, stably maintained in a silent state
- an adult female is a mosaic of clones, within a clone all the cells inactivate the same X, but between clones the choice is random - carrier of an X-linked recessive disease → implications
79
Rett syndrome (X-linked)
- progressive neurodevelopmental disorder - almost exclusively affecting females → profound disabilities (rare)
- mutation (spontaneous) in the MeCP2 (methyl CpG binding protein 2) - transcriptional repressor → turns off the expression of unwanted genes during synapse formation
- X-inactivation → variable penetrance, sometimes see milder symptoms
- affected males → embryonic lethal or die soon after birth- do not have good copy
80
Fragile X (X linked)
- most common form of learning disability, reasonably common, symptoms predominantly in males (eg. large ears ect.) (daughters as carriers)
- mutation in 5’ UTR end of the FMR1 gene (fragile X messenger ribonucleoprotein 1), consisting of an amplification of a CGG repeat (200+ copies; normally between 6 and 40 repeats) - FMR protein thought to take select mRNAs between cytosol and nucleus
81
Epigenetics - mechanisms
binding of epigenetic factors alter the extent to which DNA is wrapped around histones and availability of genes in DNA to be activated (protiens around which DNA can wind for compaction and gene regulation)
- Transgenerational e.g. smoking/drinking = influence on parent affecting offspring (disrupting sperm histones)
eg. rats maternal licking - affecting glucocorticoid receptor - methylation affected for whole life
82
Genetics of Alzheimers:
- mutations in PSEN1, PSEN2, APP - mutations in these genes cause AD, amyloid precursor protien (on chromosome 21)
- Risk genes identified in Gene association or genome wide association studies of late onset AD
- One SNP difference between APOE3 (common allele) and APOE4 (changes an amino acid in protein)
83
concordance
the degree to which a trait is seen in 2 individuals (polygenic factors of twin studies)
84
Genetics of schizophrenia (Gottesman)
- a 48% concordance rate in MZ and 17% in DZ twins
- so schizophrenia has a large genetic component - high correlation - other factors must play a part as not 100% though
- genetic wide association study of over 150k people (36,000 with schizophrenia)
- Genes associated with synaptic transmission, glutamate and dopamine (Dopamine D2 receptor)
85
Animal models
- gene and biological function similarity
- conservation of behaviour with humans
- inbreed strain of animals genetically identical
- control environmental conditions
- manipulate genes
86
Mouse as a model organism
- cost effective, easily bred, short life cycle, genetic tractability and well understood genetics, similar to human biology and disease manifestation, amenable to experimental manipulation
- synteny between human and mouse chromosome
- inbred strains will have different genetics neurobiology and behaviour - comparisons
- how to map these differences to genes? - which mice have alcohol preference, which C57 genes?, activity mapped to chromosome, knockout genes - impact drinking?
87
knock-out mice vs knock in
knock out = remove a gene, knock in = introduce
88
Arnold Berthold - chicks
castrating and moving testes led to normal male development, could even be swapped with another chick, not connected to blood supply or neuronal networks - effect was mediated by chemicals released to the blood stream
89
Hormone
signaling molecular that can carry messages to distant targets through the blood stream (e.g., testosterone). (produced by glands)
90
Neurohormone
a hormone released by neurons. Targets neighboring or distant cells (e.g., oxytocin).
91
Target
cells that detect the hormone (express a specific receptor) and it is affected by it.
92
Hormones and sexual behaviour in male and female rodents
male rodent - mounts, intromission, ejaculation
- depends on testosterone levels, castrated male rats injected with testosterone reinstate sexual behaviour (Whalen et al)
female rodents - lordosis (sexual behaviour in female rodents) - females initiates copulation
- depends on estradiol and progesterone, Ovariectomised rats (ovaries removed) display no sexual behaviour
92
Hormone classes:
Steroid hormones - derived from cholesterol - travel across cell membranes (cortisol and progesterone)
Amine hormones - derived from amino acid tyrosine, cannot cross the cell membrane (thyroid hormone)
Peptide and protien hormones - amino acid chains - cannot travel through cell membrane but activate membrane receptors (oxytoxin, vasopressin)
93
Hormonal control of sexual behaviour
- control sexual development and interact directly with nervous system
- menstrual cycle: FSH→estradiol→LH→ovulation→estradiol and progesterone (from corpus luteum)
- in non-primate females sexual behaviour linked to ovulation, primate females can mate at any time during menstrual cycle
94
Neural control of sexual behaviour - experimental tools
- retro-tracing to define the circuit that control sexual organs - injection of psuedorabies virus in sexual organs
- activation of Fos, a marker of neuronal activity in key brain regions
- identify of neurons containing sex hormone receptors - estrogen and progesterone or testosterone
95
Male neural control of sexual behaviour
- spinal mechanisms - men with complete spinal cord transection above the 10th thoracic segment can ejaculate,
- a group of neurons in the lumbar region (spinal ejaculation generator), lumbar spinothalamic (LSt) cells control ejaculation, destruction of LSt cells abolishes ejaculation, but not mounts or intromissions
95
removed ovaries and injected mothers with hormones
restores maternal behaviour, pups through birth canal triggers maternal behaviour
96
Maternal behaviour
- hormones can influence maternal behaviour - do not control it
- Medial preoptic area - crucial for maternal behaviour.
- The VTA-NAC pathway (reward system) - activated when mothers encounter pups.
- Encountering pups more rewarding than cocaine in lactating females (Ferris et al., 2005).
- Human mothers show activation of the reward system when presented with pictures of their babies (Bartels & Zeki, 2004)
97
Affiliate behaviours
- positive social behaviours with the same or difference species
- neuropeptides oxytocin (OXT) and vasopressin (VP) are key for complex social behaviours → produced in hypothalamus → released from posterior pituitary gland as hormones/from axons projecting to specific brain regions (as a neuromodulator or neurotransmisser)
98
Paternal behaviour
- Monogamous prairie voles share offspring care, whereas polygamous male meadow voles leave the female after mating.
- Size of MPA (Medial preoptic area) is less sexually dimorphic in prairie voles than in meadow voles.
- MPA lesions disrupt paternal behaviour in rats and prairie voles.
99
Pair bonding
- only 3-5% of mammals are monogamous
- bi-parental species - males and females raise the young (prarie voles but not meadow voles - have been extensively studied)
100
Hormones influence pair bonding
- exposure to a partner when injected with VP or OXT increased preference
- male and female paired for 1hour, one recieves VP or OXT
- partner preference test - can choose to spend time alone, with a stranger or with partner from when they were exposed to drug
- when exposed to drug spent more time with partner
101
why meadow voles polygamous
over expression of VP receptor in the ventral pallidum enhanced male preference in meadow voles (more monogamous)
101
Neurobiology of pair bonds
- pair bonds associated with the density of VP receptors in the reward areas of the brain
- After mating and cohabitating with female, a male prairie vole spent more time with partner than stranger
- OXT receptors are highly expressed in PFC and Nacc in prarie voles -> disrupted after blocking
102
Formation of pair bonds in humans
- OXT and VP seem to influence pair bonds in humans
- OXT intra-nasal caused relaxation and anxiety reduction in humans, maternal and romantic love activated regions of the brain rich in VP and OXT receptors
103
Prosocial behaviour
- associated with positive social behaviours - trust, cooperation, care, empathy, altruism
- OXT subtle effects on prosocial behaviour and fear and reward processing
- interest in OXT for treating anxiety and ASD ect. - effects influenced by individual and contextual conditions
- OXT more complex than just increasing one dimension
104
Oxytocin and trust
investor and trustee given money, investors chose to give money and trustee could give it back- placebo or OXT given - higher MU transfer levels after OXT → mediating trust?
- also correlated with altruism, empathy and social approach (physical distance)
105
male sexual brain mechanisms
- olfactory bulb → medial amygdala (info from others)
- medial amygdala destruction disrupts sexual behaviour, activates medial preoptic area (part of hypothalamus)
- medial preoptic (larger in males than females) inhibits Nucleus paragigantocellularis - normally inhibits mating behaviour
- Periaquductal grey matter - normally excited nPGi
- some connections inhibitory
106
female sexual brain mechanisms
- female all to do with brain (no spinal circuits)
- medial amygdala shared - activated when in sexual behaviour
- MA will activate ventromedial nucleus of hypothalamus → activates Periaquductal grey matter → activates medulla
- destruction of any of these areas stops all (with males some is inhibitory)
107
Learning
response of brain to environmental events - adaptive changes in synaptic connectivity - will alter behaviour -
- Donald Hebb: - Cells that wire together fire together
- memories formed via strengthening and weakening synaptic connections
108
The Hippocampus
- in temporal lobe, part of limbic system
- most researched part for learning
- spatial memory, STM→LTM, verbal memory, emotions
109
Long term potentiation
- a persistent strengthening of synapses based on recent activity patterns → long lasting increase in signal transmission (a key mechanism of underlying learning and memory) (following tetanic stimulation)
- recorded within denate gyrus, high frequency electrical stimulation (HFS) of axons in prefrontal pathway
- temporal
110
Recording electrical signal
high stimulation of A (Schaffer collateral commissural pathway), temporal summation, high frequency on A so when back to low frequency it fired more, reached threshold and strengthened connections
111
Morris Water Maze - Animal experiments - LTP and learning
- how an animal can learn where a hidden platform is in water, will learn and find platform quickly
- rats with hippocampal lesions did not learn (so hippocampus important - same with NMDA antagonist)
- probe trials (no platform) - go towards where the platform was (spends most time in quadrant where platform was), hippocampal lesion rat did not
112
Calcium through NMDA receptor →
- → activation of Calcium calmodulin-dependent protein kinase II (CaMKII):
1) phosphorylates existing AMPA receptors increasing their effectiveness
2) stimulates the insertion of new AMPA receptors into the membrane
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Dendritic spine structural changes
dendritic spines receive information, in a normal condition the spines don’t have projections on them, when more synaptic connections they form projections - more projections = stronger connections, but very plastic (projections can recede eg. if you’re not thinking of a memory enough + not firing enough)
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Presynaptic events in LTP:
- postsynaptic neuron can feed back to presynaptic neuron by retrograde neurotransmitter (Nitric Oxide (NO))
1) Ca2+ through the NMDA channel activates Nitric oxide synthase
2) NO diffuses from site of production and activates guanylyl cyclase in the presynaptic terminal
3) Guanylyl cyclase produces the second messenger cGMP
4) Signal transduction cascade leads to increased glutamate release from the synaptic bouton
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CaMKII has autocatalytic activity
- becomes phosphorylated by itself - when active no longer needs calcium, maintains phosphorylation ect. even after depolarisation has ended
molecular switch - maintains increased excitability of neuron for minutes to hours
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Late phase LTP:
- protein synthesis required for long lasting LTP (days, months)
- protein synthesis inhibitors prevent consolidation of LTMs and LTP (injected just post acquisition (training) inhibits recall - necessary for consolidation
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Early vs Late phase LTP (short vs long term events)
- early phase LTP (a minute to an hour) - explained by actions of calcium through NMDA receptor and subsequent enhancement of AMPA receptor efficiency
- Late phase LTP lasts hours, days or months... requires new protein synthesis and can involve morphological changes and the establishment of new synapses
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Long term depression
- low frequency stimulation → a decrease on further stimulation
- NDMA dependent process, AMPA receptors are dephosphorylated and removed from membrane
- but low level rises in calcium activate phosphate rather than kinase
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Theta rhythms
- a neural oscillation - one of the most regular EEG oscillations
- key brain signal implicated in memory, spatial navigation, and coordinating brain-wide neuronal networks
- LTP physiological - waves of neuronal activity - hippocampal theta rhythms - involved in arousal, alertness ect.
- depolarising stimulation coincident with peak of wave → LTP but trough → LTD
- disruption in theta waves causes deficits in learning tasks
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Enhancing LTP
- genetically - Tang et al - increasing NMDA receptor type
- decreased age
- enrichment
- associations (linked to lateral amygdala)
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Pain
“An unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.”
- promotes avoidance of situations which may decrease biological fitness, promotes resting behaviour
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Nociceptors
- sensory neurons specific to pain, free nerve endings, synapse in spinal cord to ascending neurons to brain
- Activated, send signal to spinal cord → brain
- free nerve endings contain receptors sensitive to noxious stimuli
- high threshold mechanoreceptors
- vanilloid receptor, TRP channels (temperature-gated channels), damage (ATP release) (purinergic receptors)
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Primary afferents
- As fibres - lightly myelinated, medium diameter - first share pain
- C fibres 0 unmyelinated, small diameter - continuing dull ache after, poorly localised
secondary: A alpha and beta fibres - normal proprioceptors, myelinated, large diameter
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Two paths into brain:
1 - somatosensory cortex via the thalamus - encode the sensory components, sensory discrimination, where it hurts
2 - emotional cortex via the thalamus, encode the emotional components, unpleasant, negative effects (insula and cingulate)
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peripheral sensitisation of pain
- inflammatory response in and around injured tissue, peripheral nerve endings (nociceptors) become more responsive to stimuli, lowering threshold for pain perception
- Hyperalgesia - noxious stimuli → exaggerated pain sensation
- Allodynia - non-noxious stimuli produce pain sensation
- neuropeptides - substate P and CGRP - (calcitonin gene related peptide), released from nociceptor neurons
- triggers vasodialiation, plasma extravasion (leakage of protiens and fluid from capillaries), activation of Mast cells and neutrophils
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Central sensitisation of pain - "wind up pain"
neuroplastic changes in the CNS, neurons become more excitable and respond ot stimuli that wouldn’t normally cause pain, persistent pain, nerve injury or inflammation (repetitive firing -> neuroplastic changes in spinal cord - strengthening synapse)
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Chemicals released after pain - inflammatory soup:
- histamine (mast cells) - caused vasodialation and increased permeability → swelling and redness
- nerve growth factor (mast cells)
- serotonin (platelets)
- Proteases (cleave extracellular peptide to bradykinin (peptide sensitised nociceptors)
- COX enzymes (cyclo-oxygenase) covert arachidonic acid (lipid) to prostaglandin
- neurotransmiters - substance P and CGRP
- Cytokines
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Modulation of nociceptor activation
- Bradykinin, NGF and Prostaglandin - send feedback to neurons → hypersensitisation - bind to receptors and opening channels - more sodium and calcium, depolarises membrane ect. - more excitable (components of inflammatory soup)
Vanilloid receptor 1 - VR1 receptor is phosphorylated and threshold changes → opens at lower thresholds
Sensory nerve specific (SNS) Na+ channel - phosphorylated → threshold voltage for firing is decreased → nociceptor more excitable
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Why increase pain sensitivity?
- good pain - you know you are hurt - protect area to prevent further injury
- congenital disorders where people have no pain perception - no signals to indicate to avoid painful stimulus → low life expectancy
- case study - SCN9A channelopathy - no pain - no Na+ channel on nociceptors, street performer died before 14, put knives through arms, jumped off a building
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Central sensitisation explanation of “wind up pain”
- repetitive firing → neuroplastic changes in spinal cord strengthening synapse - less stimulation = larger signal
- nociceptor afferents release glutamate and substance P in spinal cord - activate the spinothalamic neurons
- NMDA receptor activation → influx of calcium
- substance P activates NK1 receptor (metabotrophic) - phosphorylation of NMDA and AMPA receptors, receptors more responsive to glutamate, neurons more excitable
- Substance P diffuses to other synapses
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Gate control theory
- a gate in the spinal cord - can modulate/block pain signals from reaching the brain
- Stimulation of A⍺ or Aβ fibres in vicinity of injury activates interneuron in dorsal horn which inhibits spinothalamic neuron from firing
- Competition between excitation (from nociceptor) and inhibition (from proprioceptors)
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Distraction from pain
- internal mechanisms to decrease pain
- blowing/rubbing site of injury
- central correlate - biting finger to block pain from stubbed toe
(VR treatment in burn units (use a snow world - pain rating reduced))
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Other internal mechanisms
- stress induced analgesia - adaptive response to down-regulate pain
- central mechanisms triggers descending regulation of pain circuity to inhibit pain signals arriving in the brain
- release of endogenous opioids (naloxone challenge (opiods antagonist) blocks the analgesic effect)
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Descending inhibitory pain modulation
- brain sends singals down to spinal cord - to reduce/block pain signals
- key brain regions - periaqueductal gray (PAG) and rostral ventromedial medulla (RVM)
- Activate the endogenous opioid system (endorphins and other opioids)
- brain overrides pain signals, switches them off in spinal cord, opioids acting at inhibitory metabotrophic receptors
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Acute pain:
- lidocaine can block sodium channels
- ibuprofen - NSAID blocks synthesis of prostaglandin
- oxycodone, morphine - opiate/cannabinoid receptors (G coupled) - activated leading to inhibition of adenylyl cyclase
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Capsaicin
active ingredient in chilli, agonist of TRP channels - max out pain if eat enough, stops fluxing ions, massive release of Substance P in spinal cord, depletion of substance P (neuropeptites) and blocks central sensitisatio
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Opiates
- morphine, codeine, fentanyl
- agonists of endogenous opioid system - taps into same pathway (bodies own system of pain regulation)
- peripherally, spinal cord, centrally
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Other methods to reduce pain
- electrical stimulation of PAG - clinially significant
- acupuncture - can be blocked by naloxone implicating opioid system
- placebo - effects blocked by naloxone
- non-opioids mechanisms
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Cannabinoid system and stress-induced analgesia
- opioid independent mechanism
- Endocannbinoids, 2 arachidonoylglycerol (2-AG) and anandamide, act at CB1 receptor
- Injection of CB1 agonist into PAG is analgesic
- Injection of CB1 antagonist into PAG blocks stress induced analgesia
- multiple ways to target pain
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Mechanisms leading to chromic pain
- pain lasting longer than 12 weeks/beyond natural healing time
- Peripherally - sensitisation of peripheral neurons, increased activity of damaged axons and sprouting
- Centrally - hyperexcitability of central neurons, reorganisation of synaptic connectivity in spinal cord, disinhibition (removal of tonic descending inhibitory control)
- could be nerve damage causing chronic pain - causes resprouting and new synapse formation in dorsal horn
- Excess glutamate release during painful stimulus results in excitotoxicity, loss of inhibitory interneurons, no brake on excitation
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Biological factors explaining ID of pain
- genetics - disorders have genetic components - congenital pain disorders, migraine
- Genetic variability in components of system - failure to increase levels of analgesis peptides (NPY), marked decline in GABAergic function, accentuated sympathetic responses
- interactions with other systems - irritable bowel syndrome - brain-gut dysfunction
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Sex differences in pain and why
- men more likely to have cluster headaches, women more likely to have migraine
- pain thresholds differ
- women report more intensive acute pain, more chronic pain ect. but higher thresholds
Why?
- genetic differences, sex hormones, how the brain looks and functions
- psychosocial - negative emotion, coping strategies, social influences
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Sex differences in opioidergic mechanisms
- females need less morphine
- women may show less endogenous analgesic effects, different receptor distribution
- kappa opioid receptor agonists have stronger analgesic effects in women (influenced by melanin)
- women with red hair and fair skin - greater analgesic response than men with same or women with other variants
- need for sex specific treatments, pharmacogenetics, other descending control mechanisms
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2 Drives of Sleep:
Homeostatic (S) - if we do not sleep, we accumulate sleep debt
Circadian (C) - sleep tends to happen at a particular time during the 24 hour cycle
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Study of sleep - Polysomnography
- gold standard - Hans Berger (1929)
- used first in cats - now for research and clinical purposes
- involves recordings of electrical activity - from multiple sources - ‘poly’ sonography
- recordings revealed sleep architecture
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recording sleep
- EEG (electroencephalogram) recordings - recording activity of neuons in brain
- EOG (electrooculogram) recordings - recordings of activity of muscles around eyes - decipher eye movement
- EMG (electromyogram) recordsings - recording of mucles in the body
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Brain activity:
Wakefulness
- Beta waves - irregular activity - 13-30 Hz - when the brain is processing information, alert and attentive to events in environment or engaging in cognitive processes
- Alpha waves - activity of 8-12 Hz 0 resting quietly no strenous mental activity
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Brain activity:
Sleep
- Stage 1 - Theta activity - transition between sleep and wakefulness - 3.5-7.5 Hz
- Stage 2 - Sleep begins - irregular activity and sleep spindles, K complexes (K only in 2) 12-14 Hz
- Stage 3 - high amplitude and low frequency delta activity - synchronized regular waves, slowing of brain activity and other functions - slow wave/deep sleep
- REM sleep - increased brain activity, like wakefulness - facial twitches, vaginal secretions, dreaming, erections
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Michel Juvet, 1959 REM
deep sleep, in terms of muscle activity but light sleep, in terms of brain activity - Paradoxical sleep
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Dreams
- Dement and Kleitman 1957 - more vivid dreams in REM
- important in Psychoanalysis - Freud (dreams as ‘royal route to unconscious’) Jung (dreams as a glimpse into collective unconscious)
- most dreams are related to events that happen in life
- Calvin Hall et al 1982 - analysed 10,000 dreams - most sadness and anger, less happy, least sexual
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Activation Synthesis Hypothesis of Dreams
- J Allan Hobson 2004 - no meaning in dreaming even though based on experiences
- brainstem activated in REM → signal to cortex → creates images with actions and emotions
- frontal cortex less activated - no logic in timing/sequences
- bottom up view on dreams - try to make our dreams into a logical story
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Adenosine
accumulates during the day, after prolonged wakefulness and promotes sleep - caffeine antagonises effects of adenosine
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Brain areas involved in sleep and wake (Moruzzi and Mogoun 1949 - (discovered accidentally in cats, stimulated brainstem, woke up when stimulated a specific area)
- Reticular formation (Reticular Activating System - RAS) - responsible for wakefulness
- compromised by a group of nuclei in brainstem - projections to promote arousal
- Locus coeruleus (LC - NE/NA)
- Raphé nucleus (RN – 5HT)
- Tuberomammillary nucleus (TMN-Histamine) * antihistamines
- Nucleus basalis of Maynert (NBM-Ach) * also high during REM sleep
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Constantine von Economo observed patients with encephalitis
- continuous sleepiness - damage of base of brain
- insomnia - damage in anterior hypothalamus
- Anterior hypthalamus - (ventro-lateral preoptic area (vlPOA)) - contained inhibitory neurontransmitters - inhibit areas promoting wakefulness - damage causes insomnia, electrical stimulation of this area causes sleepiness
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Flip-flop switch - Cliff Saper 2001
- cannot be halfway - on/off
- arousal when on, sleep when off - mutual inhibition
- orexin/hypocretin - peptide - arousal chemical - holds flip flop on
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Sleep deprivation in rats - Rechstschaffen et al 1983
- animals looked sick, stopped grooming, weak and lost ability to thermoregulate
- losing weight, even though eating more, eventually died
- human ethical restrictions - sleep deprivation has negative effects
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Sleep is adaptive
- original function - conserve energy - decrease of body temperature, muscle activity, sleep time increases when less food
- brain spends 20% of energy normally - true for NREM sleep but not REM
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Sleep is restorative
- at night, end of busy day, more energy for the next day
- accumulate free radicals (oxidative stress) and potentially toxic waste (amyloid beta)
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Sleep promotes development
- infants sleep more than adults
- REM sleep in adults about 20-25% of total sleep - 50% of total sleep time in infants
- growth hormone released at peak of stage 3 (SWS)
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Sleep facilitates cognition
- enhances learning and memory - task performance better when well rested, neurons replay previous experience to retain information (Wilson and McNaughton 1994)
- problem solving and creativity - during sleep the brain continues to process material and enables the solution to problems - evidence by aha phenomenon upon waking
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Circadian Rhythms
- 24- hour cycle - such as day or night
- humans are diurnal (vs nocturnal)
Endogenous cycles - our brain and body spontaneously generate their own rhythms based on the earth’s rotation - can be annual (migration) or seasonal (breeding)
- 24 hour cycle controls other functions - like body temperature, secretion of hormones, urination ect.
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1979 - french geologist Jean Jacque d’Ortous de Mairan - experimented with mimosa plant
leaves continued rhythmic behaviour even when isolated from light, dark/temperature cues - endogenous (within) cycle
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Aschoff 1965
- humans places in underground bunkers with no external cues
- continued to show daily sleep-activity rhythms - even though drifting to slightly above 24 hour cycle
- humans have an endogenous biological clock - governs sleep-wake behaviour
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Entrainment (setting and resetting biological clock)
- zeitgeber - entrained → cycles - external cycles
- most potent zeitgeber for humans is light - others = meals, activity, temoerture)
- when a zeitgeber resets a biorhythm → entrained
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Jet lag
west = phase delay, east = phase advance (harder)
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Curt Paul Richer 1927 - convinced of a brain area of CR
electrical lesions in rat brains to locate to biological clock - lost rhythmic behaviour after damage to hypothalamus, hypothesised that many disorder may result from disruption to clock
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Suprachiasmatic Nucleus is the clock
- 1972 - Moorer & Eichler and Stephan & Zucker
- primary clock in SCN in hypothalamus - lesions disrupted circadian rhythms of wheel running, drinking ect. → **master clock**
- recording electrons confirm that neurons more active in light than dark periods, single SCN cell raised in tissue cultures continues to function in rhythmic pattern,
transplantation into donor organism → recipient following donor’s rhythm
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How does light reach the SCN
- through the retinohypothalamic tract - formed by special ganglion cells (photosensitive retinal ganglion cells-PRGCs)
- have own photopigment - melanopsin - respond directly to light - especially blue light - don’t rely on rods and cones (blind people remain entrained)
part of this tract terminates in midbrain to control pupil size depending on light
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what makes CR tick
- Hall and Rosbach - 1984 - “per” gene and “PER” protien (period)
- Young - 1994 - discovered “tim” gene → “TIM” protien (timeless)
- fruitflies - same mechanism is conserved across species
- SCN drives slave oscillators - each responsible for the timing of a different type of behaviour - all in sync and happening at the right time
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SCN effects on other brain areas
secretory glands like pituitary (glucocorticoid - light phase - arousal) and pineal gland (melatonin release - dark phase - rest activities)
- also control breeding of animals, disease treatment, cognitive performance
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Sleep hygiene principles
- use your bed only for sleep and sex
- steady schedule of bedtime and waketime
- appropriate atmosphere to promote sleep - lighting, colours
- sleep in total darkness
- reduce intense activities before bedtime
- avoid napping close to bedtime
- avoid using screen right before bedtime
- avoid caffeine, heavy meals, alcohol and drugs, exercise, excessive liquid consumption in the pm
- no sleeping pills
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negative symptoms of Schizophrenia
absence of normal behaviour, flattened emotional response, lack of initiative, social withdrawal, anhedonia (lack of pleasure)
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Cognitive symptoms of Schiz
- difficulty sustaining attention, low psychomotor speed, learning and memory deficits, poor problem solving
- neurocognitive deficits associated with frontal lobe hypofunction (Weinberger 1998) - lower activity in frontal lobes - especially dorsolateral prefrontal cortex (e.g. attentional deficits like Stroop task, working memory deficits like Wisconsin Card Sorting Test)
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postive symptoms of Schiz
- (in addition to)
- thought disorders - disorganised irrational thinking, difficulty to arrange thoughts logically
- delusions of persecution, grandeur and control
- hallucinations - auditory and olfactory (smells) - link to delusions
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when do symptoms of schizophrenia show
- early adulthood usually - appear gradually (3-5 years), negative -> cognitive -> positive
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Structural differences in Schiz
Weinberger and Wyatt - CT scans
- relative ventricle size more than twice as big as that of normal control subjects
- reduced brain volume (less grey matter) in temporal, frontal lobes and hippocampas
- faulty cellular arrangement in cortex and hippocampus
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