Methods, hormones & development

Methods, hormones & development

1. How do we study the brain?

   • Measure/manipulate brain & behaviour
     • study the direct relation between brain & behaviour - healthy or unhealthy
     • first they just observed behaviour, now advanced technique can measure specific functions - fine movements, memory, emotion
     • manipulated by altering brain function, electric/magnetic current, optogenetics
     • chemogenetic stimulation combines designer receptors & synthetic drugs to excite targeted cells in living tissue
     • Measure the brain's electrical activity
       • cell recording - neurons employ a code, cortical neurons organized into functional groups work as coordinated networks
       • neurons respond to specific characteristics of stimuli
       • EEG & ERP measure electric/magnetic activity from thousands of neurons at once, eeg can reveal gross behavior, erp change location increased behaviour
       • egg erp noninvasive methods, electrodes on scalp, ECoG & single-cell recording is invasive
       • EEG
         • changes as behaviour changes
         • recorded from cortex displays an array of patterns, some rhytmical
         • brain's electrical activity is never silent, even asleep or comatose
         • ERP
           • complex electronencephalographic waveform related in time to specific sensory event
           • mapping brain function, must repeat several times bc distortion
           • brief changes in eeg signal, regions participation, activated zones knowing route info takes, clinical work
       • Single-cell recording
         • could kill the cell, cannot do awake freely moving animals
         • invasive method
         • ECoG
           • graded potentials recorded with electrodes placed directly on the brain's surface
     • Histological
       • brains sectioned postmortem, tissue stained with dyes
     • Neuropsychological testing
       • memory - corsi block tapping test, mirror drawing test, test of recent memory
       • of rats - place learning, matching to place learning, landmark learning
       • Brain lesions/stimulation
         • stereotaxic apparatus,  compensation, 
         • deep-brain stimulation, electrical/chemical stimulation
       • Drug manipulation
       • Optogenetics
         • transgenetic technique that combines genetics & light to control targeted cells in living tissue
         • lights can activate certain proteins that occur naturally & have been inserted into cells of model organism
         • can activate a single cell
       • Chemogenetics
         • transgenetic technique that combines genetics & synthetic drugs to activate targeted cells in living tissue
         • activate only genetically modified receptors
   • Anatomical imaging techniques
     • CT & MRI - sensitive to density of brain structures, ventricles, nuclei & pathways
     • ct three dimensional x-ray, quicker & less expensive
     • mri - hydrogen atoms behave like spinning bar magnets in presence of magnetic field, time & money consuming, clear image
     • diffusion tensor imaging is a form of mri, discover abnormal fiber tracts/myelin in the brain - mrs detects brain metabolites
     • Functional brain imaging
       • metabolic imaging shows every behaviour requires collaboration of widespread neural circuits
       • positron emission tomography records blood flow/other changes 
       • fmr  + mri can locate changes in individual brain & complement erp results - fmri resting state connectivity across regions
       • fnirs is a form of optical tomography, brain tissue can be reconstructed by gathering light transmitted through the object
       • fnirs simplier than fmri/pet but cannot go deep so only used for cortical function studies
       • fMRI
         • changes in elements such as iron & oxygen are measured during the performance of a specific behaviour
         • used to measure cerebral blood flow
       • PET
         • detects changes in blood flow by measuring changes in the uptake of compounds such as oxygen or glucose
         • can detect decay of hundreds of radiochemicals, 
         • can detect relative amounts of a given neurotransmitter, density of receptors, metabolic activity
         • injected radioactive water before
     • MRI
       • portrays density differences among the hydrogen atoms
       • DTR
         • image fiber pathways in the brain by detecting the directional movements in water molecules
       • MRS
         • uses hydrogen proton signal to determine the concentration of brain metabolites
     • CT
       • x-ray technique that produces a static three dimensional image of the brain in cross section
       • radiation
   • Chemical/genetic measures
     • analysis of changes in genes/neurochemicals gives insight into molecule correlates with behaviour
     • Using animals
     • Microdialysis
       • determine chemical constituents of extracellular fluid in freely moving animals
     • Cerebral voltameter
       • identify the concentration of specific chemicals of the brain as animals behave freely

2. How the nervous system develop/adapt

   • Three perspectives on brain development
     • development a complex dance between genes & environment, fit in a cultural/environmental context
     • 1) correlating emerging brain structures with emerging behaviours
     • 2) correlating new behaviours with neural maturation
     • 3) identifying influences on the brain & behaviour
     • Neurobiology of development
       • long process of brain maturation, late as 30
       • neurons develop phenotype, migrate, as process elaborate, establish connections with other neurons even before birth
       • the developing brain produces more neurons/connections than it needs, prunes back, early adulthood stable level maintained by some neurogenesis
       • experiences throughout development can trigger epigenetic mechanisms, such as gene methylation that alter gene expression
       • Using emerging behaviours to infer neural maturation
         • we develop through similiar stages around the world, Piaget
         • from gross poorly directed movement to controlled grasps - cognition stages of logic & problem solving
         • behaviours emerge as the neural systems that produce them develop, happens synchrony,
         • maturation of cognitive behaviour as neural circuits in the frontal/temporal lobes mature in early adulthood
         • motor behavoiurs in synch with maturing motor circuits in cerebral cortex, basala ganglia, cerebellum, connections spinal cord
         • Motor behaviours
           • changes take place especially in the development of dendric arborizations & in fiber connections between neocortex &  spinal cord
           • myelin formation & ability to grasp
         • Language development
           • start vocabulary at 12m, 6yrs 2500
           • motor skill develop befire
         • Piaget
           • sensorimotor - object permanence & stranger anxiety
           • preoperational - pretend play, egocentrism, language development
           • concrete operational - conservation, mathematical transformations
           • formal operational - abstract logic, potential mature moral reasoning
       • Gross development
         • zygot, fertilization 2w - embryo, 2-8w - fetus, 9w+
         • formation of neural tube, forebrain, midbrain, hindbrain
         • 7w miniature person, 
         • Cells
           • neural stem cells - progenitor cells - neuroblast/gliablast - specialize
           • cell birth (neurogenesis/gliogenesis) - cell migration - cell differentiation - cell maturation - synaptogenesis - cell death & pruning - myelogenesis
           • maturation = growing dendrites to provide surface area for synapses + extending axons to initiate synapse formation
           • glia starts develop after most neurogenesis is complete, keeps develop through life, cortical till 18
           • Teratogens
             • full-term birth more sensitive than during neurogenisis
             • adult tumours & lack of neurogenesis vs children
           • Neurogenesis
             • largely complete about 5 months of gestation
             • hippocampus exception, grow thorugh life
         • Synaptic development
           • specific synapse contacts is guided into place by local environmental cues/signals
           • simple synapse contacts in fith gestational month, by seventh synaptic development on cortical neurns are extensive, increase at birth..
           • Synaptic pruning
   • Brain development & environment
     • plastic during development, neural structures/connections can be affected
     • brains sensitivity to external events, quality of environment, tactile stimulation, drugs, gonodal hormones, injury
     • critical periods for specific brain regions - anoxia toxins trauma can alter the brain, disorders
     • neurological & hormonal abnormalities - deprivation
     • How do any of us develop a normal brain
       • the brain has substantial ability to repair or correct minor abnormalities
     • Experience & cortical organization
       • stimulating environment & intellectual development
       • increase of synapses numbers from sensory processing
       • richer in synapses, changes neural structures in cortex
       • tactil stimulation improves recovery - before, during after pregnancy
       • Critical periods
         • developmental window for a specific ability, critical for typical development
         • Gondal hormones & brain development
           • testosterone vs androgen - alike till these come in
           • female better at discrimination task - men better at object reversal learning
           • gondal hormones alter basic neural development, shape experienced-dependent changes in the brain

3. Principles of psychpharmacology

   • produce effects by acting on neural receptors/chemical processes in nervous system - agonist vs antagonist
   • drugs administrated by mouth, inhalation, absorbation through skin, rectally by suppository or injection 
   • drugs must pass through numerious barriers by digestation/dilution, blood barrier & cell membrane to reach nervous system target
   • drugs don't act specifically & consistantly, learning affects response - body become tolerant must higher dose - or sensitized same dose stronger each time
   • Grouping psychoactive drugs
     • grouped by major behavioural effect - five groups
     • antianxiety agents & sedativehyponotics, antipsychotic agents, antidepressants & mood stabilizers, opioid analgesics, psychotropics
     • each contains natural or synthetic drugs or both - they may produce their actions in different ways
     • Factors influencing individual responses
       • a drug no uniform action on every person - body weight,sex, age, genetic background, learning, cultural & environmental contexts
       • influence varies with the situation & as a person learns drug-related behaviours 
       • behavioural myopia ex can influence person to only focus on prominent environmental cues, may encourage uncharacteristic behavour
       • females more sensitive to drugs, may become addicted faster to lower doses
     • Antianxiety agents & sedative-hypnotics
       • benzodiazeptines: diazepam, alprazolam vs alcohole or barbiturates
       • seductive-hypnotics increase GABA binding - maximize pore opening
       • antianxiety drugs influence the frequency of pore opening - tips don't use together
       • GABA - inhibitory neurons firing rate
     • Antipsychotic agents
       • chloropromazine can lessen schizophrenia symptoms, occupies the dopamine site on D2 receptor, preventing activation
       • amphetamine & cocaine block the reuptake of dopamine - amphetamine promotes the release of dopamine
     • Antidepressants & mood stabilizers
       • MAO inhibitor inhibits the breakdown of seratonin -> more seratonin is available for release
       • selective seratonin block transporter protein for seratonin reuptake: stays in cleft longer
       • MAO, the trycyclic antidepressants, second generation antidepressants
       • mood stabilizers for bipolar disorder - mutes intensity of one pole, making the other pole less likely to recur
     • Opiod analgesics
       • morphine, codein, heroin
       • sleep inducing & pain relieving properties
       • results in both tolerance & sensitization - overdose possibility always - increased dose within a few weeks
     • Psychotropics
       • amphetamine, cocaine, LSD, ecstacy
       • blocking the dopamine reuptake transporter - amphetamine/cocaine
       • psychedelic drugs = alters sensation & perception, LSD
       • acetylcholine psychedelics, anandamide, glutamate, norepinepherine, seratonin psychedelics
   • Explaining & treating drug abuse
     • neural mechanisms implicated in addiction are the same for liking & wanting more generally - develops in stages
     • initially it produces pleasure (liking) - repeated use the behaviour becomes conditioned to other things - eventually wanting seekout - drug seeking promotes craving - like decrease want increase
     • treatment varies with the drug, whatever approach lifestyle change must occur
     • all can get addicted, but some are more vulnerable bc genetic/epigenetic
     • alcohole damage thalamus, hypothalamus, poor nutrition before the drug - cocaine can reduce bloodflow, ecstacy result in loss of axons impairment cognitive, marijuana/LSD psychotic behaviour
     • Hormones
       • steriod/peptide hormones produced by endoctrine glands circulate in bloodstream to affect various targets -
       • brain stimulates pituitary gland through hypothalamus to regulate hormone levels - stimulates or inhibits
       • homeostatic hormones regulate the balance of sugars, proteins, carbohydrates, salt & more - gonadal hormones regulate sex characteristics - glucocorticoids stress
       • hippocampus important for ending the stress response - failure to turn down PTSD - may modify expressions of genes, hormones
       • synthetic anabolic steroids mimic the effects of testosterone, increase muscle bulk, stamina & agression but can have deleterious side effects
     • Tolerance
       • aka habituation - repeated intake - cross tolerance
       • 1. metabolic tolerance, enzymes that break down toxins increases - quicker metabolized - blood alcohole levels fall
       • 2. cellular tolerance, brain cell activities adjust to minimize the effect of toxin in the blood
       • 3. learned tolerance, ppl learn to cope with the demands & appear sober tho not
     • Sensitization
       • increased effect, periodic intake
       • change in synapse, changes in receptor numbers on postsynaptic membrane, rate of transmitter metamolism, transmitter reuptake, number size synapses
       • conditioned to environment
     • Wanting-liking theory
       • stages - first repeated use liking (pleasure) then decrease - higher dose for liking - & wanting increase
       • explanation holding that when a drug is associated with certain cues, the cues themselves elict desire for the drug
       • activates opiod systems in the brainstem - wanting spring from actiity in the mesolimbic pathways of dopaminergic activation system
       • learning, dorsal stratum, region in the basal ganglia
       • Damage
         • the developing brain particularly sensitive
         • MSG killed neurons, as PCP & ketamine
         • domoic acid produces hippocampal damage - ecstacy degeneration of very fine seratonergic nerve terminals
   • Routes
     • oral - to reach bloodstream drug must be absorbed in stomach
     • gases - respiratory tract absorbed across these membranes when inhaled, reach bloodstream by circumventing the barriers in digestive system
     • into brain is the best, lower dose no barriers - next into bloodstream few barriers must be hydrophilic
     • drugs contained adhesive patches are absorbed through the skin & into bloodstream
     • Blood brain barrier
       • capillaries in most of the body allow for substances to pass between capillary cell membranes, but those stimulated by actions of astrocytes form a tight junction of blodd brain barrier
       • transporter proteins specialied to convey a particular substance 
       • pineal glad entry of chemicals that affect day-night cycles - pituitary gland entry of chemicals that influence pituitary hormones - area postrema entry of toxic substances that induce vomiting 
       • Antagonist
         • substance that blocks synapse function
       • Agonist
         • substance that enhances synapse function