Behaviour Notes PDF

The Single Neuron Doctrine (Horace Barlow) Barlow: “the best way to study the brain is by single units (neurons)” Direct measures: directly relate to neurons activity eg. EEG, MEG and single unit (spike every time neuron ﬁres) Indirect measures: use a conduit to access neural activity eg. fMRI measures use of oxygen Direct Measures Single unit recordings (extracellular) Functional extracellular (space between the neurons) spiking activity of a neuron Electroencephalography (EEG) Measures electrical ﬁeld o Right-hand rule o electrical ﬁeld vertical spinning Pyramid cells lined up and become like magnets when stimulated (with a positive and a negative side) Advantages: o excellent temporal resolution (ms) o better for deep sources than MEG o lower cost Disadvantages: o poor temporal resolution o skull and tissue not transparent Magnetoencephalography (MEG) Direct Measures magnetic ﬁeld o the right-hand rule o magnetic ﬁeld horizontal spinning Advantages: o excellent temporal resolution (ms) o skull and tissue transparent Disadvantages: o poor spatial resolution o higher cost MEG vs EEG both use the right-hand rule both have poor spatial resolution and good temporal resolution both are direct measures MEG and EEG source localisation challenge o done at the scalp (2D surface), but coming from a 3D brain Do single unit recordings, MEG and EEG measure the same thing? all direct methods all seem to produce similar results Electrocorticography (ECoG) and intracranial electroencephalography (iEEG) Direct recordings in humans (in severe epilepsy) Figure out where seizures are coming from using electrode directly on the brain Brain Damage Structural-functional method Changes to behaviour and action o Then assess brain once deceased Phineas Gage o damage: frontal lobe o problems: inhibitions and HOC HM o damage: hippocampus o problem: memory formation Tan o damage: Broca’s area o problem: speech Brain Structure Measures CT slices of the brain to reconstruct 3D model MRI Water molecules are lined up by magnetic ﬁeld. Radio pulse knocks the molecules and the rate at which they go back to lined up indicates tissue type. measures cortical thickness DiWusion tensor imaging measures white matter tracts how areas connect movement of water in response to magnetic ﬁeld o in white matter, water molecules move in a sort of string Functional Measures PET Inject radioactive material (safe) Determine where radioactive material pooling is in the brain Don’t need to stay in the scanner, allows for naturalist behaviours Good spatial resolution But invasive and radiation exposure Optical imaging video taken of the monkey brain oxygenated blood is red, non-oxygenated is blue measure red to blue ratio bluer then red in active area because neurons are consuming more oxygen fMRI consumption of oxygen overcompensation o rush lots of blood to area of the brain working o more than what is needed by the brain area Neural Disruption/Causal TMS can get some degree of causation because disrupting brain activity strong, short, electrical current magnetic ﬁeld anticlockwise magnetic ﬁeld goes into the brain and creates a mirror electrical loop in the brain Optogenetics introduce a virus into neurons and make them susceptible to light to be able to turn them on or oW Sleep Properties of Waveform Amplitude Frequency Phase Bio Rhythms Controlled by the brain (eg. heart rate, eating, sleeping) Complex waves can be broken down into sinusoids (individual waves) o power spectrum: power of each frequency (ie. power of each wave) Brain Rhythms: Sleeping vs Awake Awake: high frequencies and low amplitude Asleep: low frequencies only, but magniﬁed to higher amplitude Common Brain Rhythms High to low wave frequency: gamma, beta, alpha, theta, delta Alpha o wakeful relaxation o the boundary between sleep and awake o approx. 8Hz Theta o transition between sleep and awake o approx. 5Hz Functions of Brain Rhythms The binding problem o how does the brain connect red ball moving in front of us? o how does the brain put all this information together when they are from diWerent parts of the brain potentially use brain rhythms —> frequency tagging o signature which tags information o neurons ﬁring for individual objects IT neuron RF encompasses smaller V4 neuron RFs o Direct attention two activate 1 of the smaller V4 neurons, IT neuron is more active à potentially activating other V4 neurons Bad rhythms: epilepsy and seizures Seizure: out of control rhythm spreading across the brain (ie. eWect across the body) Symptom of something else going on, not a disease itself Bio Rhythms circannual ~ 365 infradian > 24 hours circadian ~ 24 hours ultradian < 24 hours Core functions: breathing and heart rate controlled by medulla oblongata monitoring radio of oxygen to CO2 in the body Sleep wake cycle regulated by 2 systems: o homeostatic sleep drive o circadian rhythm mutual inhibition of sleep and wake o once one is activated, the other is inhibited Sleep homeostasis neural mechanism Regulated by hormones Sleep promoting chemical increases (eg. adenosine) and/or wakefulness chemical is depleted CaWeine blocks adenosine receptors Circadian rhythms controlled by superchiasmatic nucleus 24 hour cycle the clock is reset by the sun o cell in the eye is light sensitive and recalibrates the clock everyday SLEEP PART 2 Why do animals sleep for diWerent periods of time? - anticipate diWicult periods (eg. extreme environmental conditions) - reduce metabolism to save energy - avoid risk (eg. injury, predators) - vulnerable species appear to sleep less - predators sleep more Human Sleep Patterns REM sleep: memory consolidation, cognitive revitalization? (more REM in childhood) Non-REM sleep: muscle growth, hormones... Sleep Cycle Stages - Stage 1 lasts about 5 mins - Stage 2: - sleep spindles: memory consolidation - k-complexes: reawakening (sleeping with one eye open) - able to hear a noise in the room - make sure that your safe - stage 3: - growth hormone released during this stage for repair - less important for older people - people over 65 rarely enter deep sleep - after sleep deprivation people spend a greater proportion of time in deep sleep - REM sleep - consolidation of memory and assists in problem-solving - occurs in 90-120 minutes - rapid eye movement, vivid dreams, muscle paralysis Why sleep is important Psychomotor vigilance task (PVT) - click the screen when the dot blinks - when people are sleep deprived, perform worse at this task (miss the blinking light) - sleep deprivation is additive Hormonal Function - glucose to be cleared out of our system - glucose clearance is less for those with restricted sleep Immune Function - development of antibodies to the hepatitis vaccine - those which were denied 1 night of sleep after the injection - roughly half the antibodies compared to the normal sleep control Cleaning your brain - beta amyloid - plaques in the brain linked to alzheimers - greater clearance of AB plaques during sleep Emotional Balance - sleep group had greater ability to remember pos/neg images compared to the sleep deprived group - positive images recognition signiﬁcantly decreases compared to the negative images in the sleep deprivation group Mental Health - apnea: throat relaxes and closes, resulting in the body waking them up - does depression cause apnea or does apnea cause depression - depression given sleep apnea (apnea causing depression) - CPAP: small pressure in airway to prevent collapse - depression scores go down after CPAP INFORMATION PROCESSING SYSTEM Claude Shannon: Information Theory and EWicient Coding Low information o receiver knows what will be sent High information o receiver unsure what will be sent Some signals can be eWiciently encoded as there are elements that can be compressed Encoding sensory information rod photoreceptors o grey scale cone receptors o colour o blue, red and green extremely sensitive to the diWerence between red and green o adaptive function to distinguish between red and green o take in information to have maximum utility (eg. Apple on tree) EWicient Encoding: Receptor Density higher cone density in the fovea o high deﬁnition is restricted to gaze undergoes compression before entering the optic nerve (125 million inputs, 1.1 million axons in the optic nerve) simple retinal circuit (1:1, receptor to neuron) convergent retinal circuit (7:1, receptor to neruon) Bayesian Framework for Understanding Perception Thomas Bayes what we see = input and HOC evidence + knowledge about the world —> what is being perceived Example: knowledge that light comes from above Fovea is reliable, but the peripheral is not as much o uses priors to clean up representations Marr’s Levels of Explanation Computational theory: what is the goal of the system Representation and algorithm: what are the steps to reach this goal Hardware implementation: how to physically accomplish this task biologically and mechanically Representations and Processes Eg. Mental rotation o people were mentally rotating the object it in their head (ie. the process) Representation: stored information in a particular format o not all representations are the same (eg. array of number for computer vs light intensity for humans) o good ones make information explicit: Process: an algorithm that changes the form of the representation Reconstructing brain representation from behaviour o eg. similarity between girl, boy and man varies § representational space: construction of a map about closeness/distance o can measure representational structure in the brain using fMRI o time varying representational structure with MEG § how change as a function of time MAPS AND MODULES Receptive Field and Features Features = what the brain is encoding Physical features o orientation o spatial frequency and contrast o speed and motion direction Higher order features o face identiﬁes o emotions o biological motion Retina à LGN à V1 à V2 à V3 à V4 à IT Receptive ﬁeld larger as you go up the visual hierarchy More high-level features as moving up visual hierarchy Wiring of Receptors Convergent circuit More neurons stimulated à greater ﬁring rate Centre surround circuit à SPOT DETECTORS Some neurons are inhibitory à reduce ﬁring rate when stimulated Centre surround organisation in LGN and retina Building features (edge detectors) from features (dot detectors) Many spot detectors (using centre surround organisation) to build edge feature (edge detectors) Spot detectors (in LGN) to edge detectors (V1) o V1 neurons create image of + detecting area and - detecting area at a particular orientation (eg. 45 degrees) Orientation coding eWect (tilt after eWect) When you stare at one orientation, neurons sensitive to that tilt get tired, you see the other image tilt the other way are they don’t have the energy Maps Various types of maps o eg. visual, somatosensory, auditory Organisation of information in the brain (ie. what is encoded in which location) tells us what information is important Vision gets a lot of real estate in the brain à important o 17-22 retinotopic maps in the visual cortex V1 Map Right or left eye Orientation Beyond V1 Complexity and size of visual ﬁeld increases as moving to more higher order representations Modular areas become more prevalent in higher order areas o maps more prevalent in lower levels Map = cluster of neurons with similar functional properties o gradual progression of stimulus across the cortical sheet??? Module = cluster of neurons with similar functional properties o discrete regions with clear boundaries o eg. modules relating to faces, scenes, food o still can contain maps of the visual ﬁeld § retinotopically organised but more aligned with function Visual Processing of Objects fMRI Adaption Normal fMRI o area will activate whether shown big or little car because neurons for big and little cars coded in the area § does it care about the size of the car? = size invariance o how do you determine whether size is considered by a subsection of the area when spatial resolution is bad in fMRIs? —> fMRI adaption fMRI adaptation o repeated exposure to stimulus will result in neural adaptation o little car —> little ca: area will show less activity as “small car” neurons are tired o small car —> big car: area will show same activity if neurons are diWerent to “small car” fMRI adaptation allows us to determine whether neurons within areas have multiple functions despite limited spatial resolution of fMRIs Object Representation in LOC Do diWerent areas of the brain care about diWerent (aka invariant) features? o location in visual ﬁeld o size o image format o visual or tactile input Lateral occipital complex (LOC) processes high level object shape representation o LO (lateral occipital) subdivision: sensitive to changes in location and size § more sensitive to 2D shape features o VOT (ventral occipital temporal area) subdivision: sensitive to changes in location § more invariant to location and size than LO § bigger receptive ﬁelds and more abstract concepts § sensitive to perceived 3D shape § VOT closely linked to recognition/perception § eg. activity in V1 not related to ability to recognise a cat, but VOT is § ie. category labels of cat, boat, dog, house etc. o VOTV (ventral occipital tactile visual area) subdivision: activated by both visual and haptic input § multimodal Experiment Trained people to use auditory cortex to identify things in images Recognise visual images by soundscapes (OIC objects) o can identify novel images LOTv activated by vOICe objects (haptic and visual convergence) Disorders of Object Processing Visual agnosia = a failure to make sense of visual information (to know what it represents) Elementary visual function intact Can’t recognise objects Apperceptive agnosia (construction issue) Damage to perceptual processing system o can physically see shapes but can’t make sense of the input Bilateral damage in occipital lobes o can’t: § copy drawings § match objects § read § recognise faces § judge size or orientation Case of DF o Lesions above LOC o Can: change hand shape and orientation to correctly grab an object § Indicates dissociation between perception and vision for action (eg. can’t “tilt envelope to ﬁt the slot” but can “post the envelope”) Associative Agnosia (labelling issue) Damage to recognition system o can physically see shapes and make sense of input but cant label/recognise (eg. dog) Can copy drawings, discriminate shapes Cannot identify objects Cause? o disconnection between intact perceptual input and memory (peripheral) o loss of stored object representations (central)? Types o visual object agnosia: inability to recognise objects o prosopagnosia: inability to recognise faces o alexia: inability to recognise words o topographical agnosia: inability to recognise familiar environments Lesions tend to be bilaterally in VOT o objects and words more in the left hemisphere o faces more in the right hemisphere The Logic of Dissociations in Neuroscience Simple dissociations o patients can do A but not B o could conclude that A and B tap into diWerent (and independent processes) o BUT this could be due to diWerence in task diWiculty Double dissociations o one patient can do A but not B o one patient can do B but not A o much more powerful evidence that A and B are independent Cognitive Neuroscience vs Cognitive Neuropsychology Cognitive neuroscience = aims to understand the relationship between brain and mind o what are the neural substances of cognitive processes? Cognitive neuropsychology = aims to understand the architecture of the normal cognitive system o functional systems in the brain Language Studying Language Phonemes: individual smallest meaningful sounds/letters o eg. fox/socks/box Phonology: patterns of speech and language sounds Syntax: combining words into sentences o eg. subject + verb + object Semantics: meaning of words Pragmatics: social aspect of language interaction o eg. do you know what time it is? § yes OR it is 10am Comprehension Acquisition Production Theories of Language Nativism: Noam Chomsky Humans are born with an innate ability to learn language through language acquisition devices (LAD) Universal grammar: certain grammatical structures and rules are innate in all human language Example of Nativism Fake/impossible language Broca’s area activation for the real language condition higher than for the fake language conditions when accuracy was high Linguistic Relativity: Sapir-Whorf Structure of a language aWects its speakers’ cognition and worldview Two main versions o strong: language determines thought and cognitive processes o weak: language inﬂuences thought Examples of Linguistic Relativity Colour perception: Russian speakers, who have separate terms for light and dark blue (goluboy and siniy), are faster at distinguishing between these shades compared to English speakers, who use a single term for blue. Spatial orientation: In some cultures, languages rely on absolute directions (north, south, east, west) rather than relative terms (left, right). For example, speakers of the Guugu Yimithirr language in Australia use cardinal directions for all spatial references, which inﬂuences their navigation and spatial cognition. Embodied Cognition The mind is inﬂuenced by the physical and sensory experience of the body o cognitions, including language, are activated in the brain as if they were occurring § eg. thinking about running activates these areas in the brain (motor neurons) § eg. feel diWerent when thinking about relaxing compared to thinking about climbing or running Understanding language involves simulating the sensory and motor experiences associates with the words and phrases we hear Examples of Embodied Cognition Action Words: When people hear or read words related to physical actions (e.g., "kick," "grasp"), there is activation in the motor areas of the brain associated with performing those actions. Spatial Metaphors: Language often uses spatial metaphors to describe abstract concepts (e.g., "up" for happy, "down" for sad). Understanding these metaphors can involve bodily simulations, such as physically leaning forward when thinking about the future. History of Language in the Brain Paul Broca Patient could only speak a single word (”tan”) but could understand language perfectly o lesion in the left frontal lobe (Broca’s area) Non-ﬂuent, expressive Broca’s aphasia (video) o major disruption is speech production § problems with syntax (not able to produce a correctly structure sentence) o comprehension intact o main retain some use of nouns and verbs o loss of pronouns Carl Wernicke Patients could speak ﬂuently but the speech was nonsensical and could not comprehend/understand language o lesion in posterior part of the super temporal gyrus (Wernicke’s area) Wernicke’s Aphasia o major disruption in auditory comprehension o comprehension NOT intact § not answering questions asked o ﬂuent speech, normal rate, rhythm and intonation o disturbances of sounds, structures of words o semantic substitutions or paraphasia § eg. television to velitision o poor repetition and naming Electrophysiology N400: The Neural Marker of Semantic Processing What is N400? o event-related potential (ERP): brain activity at time of semantically non/sensical word § compared with one another o reﬂects the brain’s response to semantic abnormalities § eg. she spread the bread with socks When does N400 occur? o ~400 ms after the presentation of the non/sensical word or stimulus —> ERP Features: o latency: ~400 ms after stimulus onset o location: usually left centro-parietal electrodes P600: The Neural Marker of Syntactic Processing What is the P600? o event-related potential (ERP): brain activity at time of synaptically non/sensical word § compared with one another o reﬂects brain’s response to syntactic abnormalities and garden path sentences § eg. the cat will eating the food § eg. the horse ran past the barn fell When does the P600 occur? o ~600 ms after the presentation of the non/sensical syntactic or grammatical structure violation —> ERP Features o latency: ~600 ms after stimulus onset o location: usually centro-parietal electrodes Current Models of Language in the Brain Left hemisphere is dominant for language in 90% of people o small % of left handed people have right hemisphere dominant Cortical Regions Occipital cortices (visuospatial): handle attention and recognition language and speech input Parietal regions: angular and supra-marginal gyrus work in concert with auditory, visual and motor inputs Frontal and temporal regions: provide linking of words to form sentences and coordinate motor functions such as moving the arms, legs and mouth Subcortical Regions Basal ganglia: role in phonological processing Putamen: rhythm with speech and sounds and semantic access facilitation Globus pallidus: conscious movements working in concert with other corticostriatal loops (IMPORTANT) Caudate: syntax and working memory Thalamus: phonetical and morphology or words o e.g. the core root of a word Language Process Control Bottom-up processing o response to external environment o updated response to environment once information is interpreted o occipital and parietal brain regions involved § eg. reading text or listening to words Top-down processing o internal response, perception and understanding o feedback to bottom-up areas for response o temporal and frontal brain regions involved § eg. comprehension of words, test and subsequent reactions Duel Stream Model: Frederici Two streams (dorsal and ventral) each with two pathways Dorsal pathway 1: connects temporal cortex with premotor cortex o function: map sound to motor action (for speech repetition) and phenological processing Ventral pathway 1: connects temporal cortex to the anterior inferior frontal gyrus o function: semantic processing Ventral pathway 2: links the anterior superior temporal gyrus (STG) to the frontal operculum o function: local structure building Dorsal pathway 2: connects the posterior of Broca’s area with the posterior STG o function: complex hierarchical sentences Computational Brains Reductionism = the practice of analysing and describing a complex phenomenon in terms of its constituents (ie. smaller parts), especially when this is said to provide a suWicient explanation o Barlow’s neuron doctrine: best to study brain in terms of single neurons and what they do Explanation Explanation often requires an account of how the parts work together o reductionism does not do this To understand behaviour or experience we do need to know something about what the brain is doing, but do we need to know what every ion is doing? o consider what scale should be assessed depending on the question o neuroscience vs psychology level questions § psychology —> explaining behaviour and conscious experience (eg. how can you recognise a smell) § neuroscience —> (eg. how to strop hyperactivity in seizures) Emergence = what the parts are made of is not very important, rather, it is the relations/interactions among parts that is important o eg. what the cogs on a bike are made of doesn’t matter, it is the relative size of the cogs that does Computational neuroscience is based on the idea that behaviour and experience are emergent Unpredicted emergence = when the interactions among may parts yield behaviours that are hard to anticipate o eg. cyclone would be hard to predict as a possibility based one what is known about air molecules o eg. large language models § initially programmed to determine which word i most likely to come next § researchers realised it can be asked questions —> unpredicted emergence Computational Modelling Assumes behaviour and experience are emergent We should be able to build something that accomplished the target behaviour Seeks simple explanations of behaviour and experience o as simple as possible whist still satisfying #2 Copies aspects of the brain as its building blocks o typically uses a simpliﬁed neuron as its basic building block Modelling and Simulation Build something which mimics the thing we are trying to understand Strips away irrelevant detail o eg. rather than focus on how long the wires are on a computer board, focus on connections o eg. rather than making model of plane from actual material, using a scale model of an airplane made of plastic in a wind tunnel Metaphors to Model the Mind 1st Century: wax tablet —> memory o impressionability 17 Century: Coo-coo clock o how parts interact to produce an action 20th Century: Computer o Programmed with a series of steps and diWerent functions done by diWerent modules § eg. attention § enhance § inhibit § engage § disengage § move o Problem: neurons have multiple functions, thus, does not represent the brain function 21st Century: Connectionist Networks o Invented to mimic aspects of the brain § eg. large language models like chat GPT Level of Simplicity Modelling how brains complete tasks not how they can be completed o example: alphabetising a word list can be done in various ways, but we want to explain how we do it Explaining Behaviour One or two neurons can allow reﬂex or Pavlovian learning Several neurons can form connectionist (PDP) networks for word or concept recognition Simple Neuron Connections Synapses between neurons are modelled by “weights” or “connections” Important for information processing o Excitation or inhibition at synapse o Threshold activation rule (whether the neuron becomes active and send a signal to another neuron) Linear activation rule: simply pass on the overall votes/stimulation Linear is not enough for decisions Threshold activation rule: stimulation > threshold —> activation a function emerges from activity of many units interacting Parallel Distributed Processing (PDP) Network There is no “bird” category in the brain, rather it emerges from the overlap of all bird type instances Strengthening of connections o by learning statistical relationships o birds strongly associated with having feathers but less strongly with running Brain vs PDP o brain has interference (eg. previous grocery lists eWecting current grocery list) and generalisation (eg. generalise to new grocery list based on regularities previously) o PDP computer has no interference (eg. only works with input) and no generalisation Connectionist vs Computer Models Connectionist Model o memory stored in connections o computing occurs in connections o prone to interference o generalises o ﬂexible capacity limit (interference as memories accumulate) § you don’t realise the neuron memories/connections that weaken as you absorb new ones. You maintain the key ideas from older knowledge/memories and add them to new ideas o more units (ie. neurons) o continually adaptive o graceful degradation Computer Model o memory stored in one area o computing occurs in one area o no interference o no generalisation o once its full, its full o speed or messages and computation is faster o catastrophic failure from minor injury Example: computer must consider all 200 million chess positions per second to beat grand master at chess o brain works smarter not harder o computer now wins, but does task in diWerent way than humans Why do our brains never seem to be full? Individual memory distributed across thousands or millions of synapses You don’t realise the neuron memories/connections that weaken as you absorb new ones o you maintain the key ideas from older knowledge/memories and add them to new ideas Thus, you never have a limit, rather your constantly degrading/losing old while making new We also make new synapses and neurons Moravec and Polanyi’s Paradox Moravec’s paradox o Perception, movement: Easy to us, Hard for computers § sensorimotor skills require enormous computational resources o Reasoning: Hard for us, easy for computers Polanyi’s paradox o Our brains know a lot about perception and locomotion, but “we” don’t. Result: We’ve been slow to be able to make robots that can perceive the world and walk around. Rodney Brooks: we must start with sensing and action and leave out the “intelligence” part Representing Space Coordinate Frames Hippocampus important for memory of large scale areas Allocentric: things are relative to an external reference o eg. north pole Egocentric: things are relative to you Need diWerent coordinating frames for diWerent actions o Eye-centred o Body-centred o Head-centred o Hand-centred Constantly need to update coordinated as map changes often o various parietal areas which are not retinotopic are involved Looking: Move eyes 15 degrees to left object relative to eyes (15 degree diWerence) o retinotopic map o angle speciﬁed by which neurons stimulated by cube Walking: Rotate body 30 degrees to right object relative to eyes (15 degree diWerence) eyes relative to head (0 degree diWerence) head relative to body (45 degree diWerence) = 30 degrees to right Reaching: Move hand 22 degrees to right object relative to eyes (15 degree diWerence) eyes relative to head (0 degree diWerence) head relative to body (45 degree diWerence) hand relative to body (8 degree diWerence) = 22 degrees to right Calculating Eye Angle Relative to Head Gaze Angle Needed for direction of pointing, walking etc. When retinal motion detected, did eyes or object move? o direct sensing of eye position (via proprioception) o remember where you told your eyes to move (eWerence copy) § most evidence suggests this is how we know this Eye Movement Commands Eye movement command (eWerence copy) gets sent to parietal cortex to: o Update representations of where things are o Compensate for retinal motion, so you don’t perceive world to move when your eyes move Space and Body Location calculated on-the-ﬂy each time object is attended? Using cues in visual ﬁeld (eg. hand location) may reduce need to calculate orientation of eyes relative to head Parietal Lobe Function Uses sensory signals for o Calculating position of body parts relative to objects o Representing space for consciousness Uses location information for o Calculating position of body parts relative to objects o Location information for awareness o Location information for action (dyspraxia) § Ocular apraxia = does not scan visually § Optic ataxia = deﬁcit of reaching under visual guidance Brain Injury Injury to left lobe —> right side eWects Stroke —> Hemiparesis o weakness of one entire side of body o neurons unable to tell side of body what to do Stroke —> Hemispatial neglect o can see visual ﬁeld but unable to process it o deﬁcit in attention o patient does well on standard vision tests (not hemianopia) Stroke —> Hemianopia o blindness of one visual ﬁeld in both eyes Bilateral parietal injury o Simultanagnosia § only one object perceived at a time o Motion creates stronger visual signal § able to reach more accurately Dyspraxia = disorder of movement o Due to perceptual problem § reduced ability to coordinate movement § ie. plan for how to get hand to a visual location o Not due to weakness, inability to move, abnormal muscle tone, motor deﬁcits Spatial Memory Dorsal Stream: egocentric (where/how) Uses parietal and visual areas Ventral Stream: allocentric (what) Uses allocentric memory Memory stored in allocentric coordinates but is projected into ego-centric coordinates. When allocentric, all information is intact (eg. can remember shops on both sides) but when projected to ego-centric, hemispatial neglect can continue (eg. can only name shops on left side but when standing opposite direction can name shops of right side) Visual Processing Without Parietal Function eg. house on ﬁre o but is smoke recognised as smoke? Or do they just prefer the more symmetric house? Stroop Experiment (Berti, Frassinetti, & Umilta, 1994) o normal people § slower for incongruent o Hemispatial neglect § report nothing on the left § still slower for incongruent —> processing words Brain imaging of processing of unperceived stimuli o unseen faces activated right visual cortex (V1) and inferior temporal areas § weaker than seen faces Coordinate Systems for Cognition and Recognition “What” requires spatial information o object recognition sometimes requires translation of retinotopic sensory signals into a stimulus-centred or object-centred representations § eg. recognise feet event when person upside down o processing shapes § stimulus-centred: direction of arrowhead relative to centre to determine which direction pointing o processing words § object-centred: which letter is ﬁrst § unconsciously process left side of mirrored word even when cant process left side of normal word § eg. words: need to know which letter is ﬁrst, second ect. even for unusual orientations Synaptic Plasticity: Mechanisms of Learning Hebbian synapse models how connections between a conditioned stimulus and a unconditioned response are strengthened when there is co-occurrence of the US and the CS resulting in the UR. This is the basis of which LTP is modelled oW. Synaptic plasticity in the hippocampus hippocampal formation = hippocampus proper (CA1, CA2 and CA3) and the dentate gyrus o critical for learning and memory neural circuitry in hippocampus segregates inputs and throughputs o easy to measure stimulation of single neuron from a single synapse o ie. if measuring output in perforant path and input in dentate, you can know it is monosynaptic Entorhinal cortex à perforant path à dentate gyrus à hippocampus proper Long term potentiation (LTP) LTP is a physiological example of synaptic plasticity o potential as a model for neural mechanism of learning Step 1: weak stimulation of presynaptic input (in performant path) which causes little to no activity in post-synaptic neurons (in dentate) Step 2: strong high-frequency stimulation of pre-synaptic input causes long lasting increase in sensitivity of post-synaptic neurons Step 3: weak stimulation of the pre-synaptic input now produces action potentials in the post-synaptic cells LTP is “dose dependent” weak HFS in step 2 —> short-lived potentiation (10 mins) strong HFS in step 2 —> long-lasting potentiation (hours) HFS is usually continuous but can also get result using patterns of short bursts (ie. theta burst stimulation, TBS) o duration of LTP depends on number of TBSs Long term depression (LTD) plasticity is bi-direction low frequency stimulation can reduce synaptic eWicacy may be mechanism of inhibition? but can contribute to excitatory behaviour Properties of LTP suggesting it as a model for learning and memory 1. persistence o long lasting and enduring 2. synaptic speciﬁcity o only stimulated pre-synaptic inputs show potentiation o ie. no increased sensitivity to other pre-synaptic input o —> learning is speciﬁc 3. associativity Associativity of LTP can get LTP when weakly stimulate one pre-synaptic input at the same time as strong stimulation to a seperate but converging neurons resembles Hebb’s model for how associations are acquired by the NS Do LTP and learning share a common mechanism? 1. Correlations between LTP and learning o Age-related decline in learning correlates with age-related decline in induction of LTP in hippocampus. o Similar correlations between LTP and learning in mouse model of Alzheimer’s Disease. 2. Saturation of LTP o Evidence of saturation of LTP in hippocampus impairs learning 3. Learning and LTP share common neurochemistry o Pharmacological interventions that prevent LTP (block NMDA receptors) also disrupt learning. § Conditioned Taste Aversion; § Conditioned Fear; § Conditioned Eyeblink; § Maze learning. Neurochemical Basis of LTP LTP and Glutamate 1. Glutamate binding to AMPA receptors o glutamate released from pre-synaptic terminal o binds to AMPA on post-synaptic neuron o causes excitation (depolarisation) § fast excitatory post-synaptic potentials (EPSPs) 2. Glutamate binding to NMDA receptors o receptors are both ligand gated (glutamate) and voltage gated (depolarised) - dual gated § allows for SYNAPSE SPECIFICITY o release Ca2+ into the neuron which increased AMPA activity and number of AMPA receptors § more likely to produce an AP Intracellular Changes Triggered during LTP Initial Learning into Long-term Memory Process 1. Generating synaptic change 2. Stabilising synaptic change 3. Consolidating synaptic change 4. Maintaining synaptic change Generating synaptic change (~1 min) Post-translational changes underlying LTP Post-translational = rapid changes Use existing proteins to create association but unless other processes are activated, association will be lost (ie. it is transient) May explain why recent memory traces can be disrupted by head trauma o eg. concussion causes amnesia for events that occurred a few minutes before an accident Constitutive tra^icking and recycling of receptors Constitutive traWicking = receptors (AMPA and NMDA) on dendritic spine are recycled constantly and form new receptors Calcium ions (released from NDMA receptors when glutamate binds) activate protein kinase enzymes which increase rate of constitutive traWicking o enzymes are also activated which break down existing protein structure (the cytoskeleton made of actin ﬁlaments) and then rebuild it - help to maintain elevated traWicking o eventually return to normal rate Stabilising synaptic change (~10-15 mins) Cell Adhesion Molecules Cadherin monomers (weak adhesion form) align pre- and post- synaptic terminals Calcium ions (released from NDMA receptors when glutamate binds) cause change into cadherin dimers (stronger adhesion form) o aka calcium dependent adhesion molecules Consolidating synaptic change (2-4 hours) Translational and Transcription Processes (Protein Synthesis) Need to generate new AMPA proteins to maintain constitutive traWicking??? Strong HFS (or theta burst frequency) produces LTP LTP requires translational processes (protein synthesis) o drug that blocks protein synthesis can prevent LTP § no eWect on STP Local translation of mRNA: synthesis of AMPA receptors occurs in the dendritic spine (in ribosomes) o if disconnect soma from dendritic spine, can still get some LTP o thus, translation does not need to come from ribosomes in soma, rather can come from ones in dendritic spine o but most mRNA does come from ribosomes in the nucleus Transcription of mRNA in nucleus: o mRNA from nucleus to supplement mRNA in dendrites o calcium ions (entering voltage-gated ion channels) activate transcription of mRNA in nucleus Spine Growth Sustained synaptic activity leads to enlarged dendritic spine o larger surface area o more receptors o more eWective and spable Triggered by brain-derived neurotrophic factor (BDNF) and transcription of mRNA. New cytoskeleton created supports traWicking of extra AMPA receptors Small spines learn; large ones remember Maintaining synaptic change (4+ hours) Self-Perpetuation AMPA receptor contains GluA1 subunit sustained synaptic activity results in GluA1 being replaced by GluA2 o GluA2 is more stable but doesn’t support further potentiation o GluA2 uses a type of protein kinase which is self-activating to increase constitutive traWicking Where might we ﬁnd changes in strength of synaptic connections underlying leanring? are these changes local or global? in keeping with localisation of function in the brain, diWerent types of leaning. appear to be localised in diWerent parts of the brain Hippocampus and cerebellum Hippocampus and spatial navigation morris maze o using extra maze cues o form representaiton of spatial lay out brain imagind studies in spatial navifation in humans o activation of hippocampus while people nastivagate virtual town on computer Hippocampal Place cells neurons that become active (ﬁre) when rat is in a speciﬁc location in environment allocentric reception ﬁeld: organisational structure of space deﬁned by relations among objects rather than with reference to observer (eg. receptive ﬁeld in visual cortex) o receptive ﬁeld based on external relations o doesnt care which way rat is headed, speed, ie. NOT egocentric place cells in CA1-CA3 region and dentate gyrus INPUT: sensitive to visual input o but place cells continue to show spatial ﬁring in dark, and congenitally blind rats have place cells o olfactory and tactile (whisker) inputs also inﬂuence spatial pattern Location speciﬁcity a single place cell is stable and speﬁc within a particular environment but can be active in >1 environment individuals cells do not uniquely code for a location, patter of activity across multiple cells does place cells tend to be non-directions (active in location regardless of rats direction) place cells form a cognitive map of environment o activity of cells can predict animals navigation through maze and even predict its errors o allows to take novel path on familiar paths Learning about Place place cells establish spatial pattern within few minutes of being introduces to novel environment and can maintain this pattern for dags or even several months place rats into 2 similar enclosures. place cell patters were initally very similar, but after many exposures overl several weeks, the patterns began to diverge o learn discrimination between places Grid cells in medial entorhinal cortex (MEC) inputs to hippocampus come from entorhinal cortex grid cells in MEC: provide building blocks for allocentric representation many neurons in MEC respond to rats position but follow a lattice or grid the grid pattern of a single cell can cover a large area and the cell will show same grid across diWerent environments grid cells keep exact grid layout despite changes in speed or direction of rat therefore, not about encoding particular places, but rather provide coordinate frame for any space pattern arises from in diWerent spacial frequency o small patches —> big patches pattern arises from the ways that the cells are connected in the MEC o eg. short-range excitation between cells and long range inhibition o phasic activity o range determined spatial frequency of the ﬁeld § large —> large compared to a place cell, grid cells provide ambiguous information about location o ie. rat could be at any one of the many locations where activation strength is repeated o ie. wouldn’t be in empty patches but unsure where on grid ambiguity solved if take into account multiple grid cells and how they are ﬁring o due to diWerent spatial frequency and phase o eg. able to tell diWerence between diWerent coloured stars MEC (grid cells) —> hippocampus (place cells) So what does the hippocampus do? creates allocentric maps of space and time episodic memories o spacial and temporal context is fundamentally important for many other types of learning and memory (especially episodic) o allocentric representations in episodic memory Cerebellar Contributions to Learning cerebellum (Cb) has clear role in learning motor skills complex and intricate structure of cerebellum allows integration of sensory inputs for precise timing and sequencing of motor functions organisation of cerebellum cell types o granule cells (input) o climbing ﬁbres (input) o purkinje cells (output from cerebellum) climbing ﬁbre smothers purkinje cell (1:1 connectivity) granule cells and purkinje cells (1: many and many:1) o thousands Cerebellar Learning Eyeblink conditioning in rabbits o noise (CS) followed by airpuW (US) o US normally causes eyeblink o eventually CS —> UR/CR o timing of eyeblink is very precise to milliseconds before airpuW § hard to do consciously o 30-40 trials to learn eyeblink (UR) mediated by trigeminal nucleus (sensory input) and cranial motor nucleus (motor output) eyeblink (CR) includes same nuclei as UR + o red nucleus in brainstem (output) § not involved in learning itself § rather lesion causes inability to demonstrate learning by blinking o pontine nuclei in brainstem (input info from CS and US) o inferior olive in brainstem (input info from CS and US) o cerebellum (output) damage to any of these structures eliminates CR but not UR Potine Nuclei receives input from auditory nucleus in brainstem o responds to noise sends signals to cerebellum electrical stimulation of pontine nuclei can serve as eWective CS (instead of CS) when paired with airpuW US pontine nuclei part of pathway conveying CS input Inferior Olive receives input from trigeminal nucleus o output to cerebellum o responds to airpuW (noxious stimuli) lesion prior to conditioning —> no conditioning lesion post conditioning —> eventual extinction of response to airpuW electrical stimulation elicits eye-blink an can serve as eWective US (instead of airpuW) if paired with noise inferior olive part of pathway conveying US input Cerebellum receives converging input from pontine nuclei and inferior olive o output to red nucleus can get conditioning with combination of pontine nuclei and olive lesion prior —> prevents learning lesion post —> blocks expression of previously learned CR CS and US converge in cerebellum mossy ﬁbres from pons synapse on granule cells (carrying CS info) parallel ﬁbres from granule cells form synapses with many purkinje cells o one receives synapses from 100,000+ parallel ﬁbres climbing ﬁbres from inferior olive (carrying US info) strong exclusive communication between climbing ﬁbres and purkinje cell: each receives 500+ synapses from one and only one climbing ﬁbre potential for many CSs (or many diWerent time signatures of CS) to be associated with US allows for precise timing mechanism What type of plastic changes occur in the cerebellar cortex? LTD between parallel ﬁbres and PC PC send inhibitory signals to interpositus nucleus in cerebellum o interpositus nucleus is what has output to red nucleus o interpositus nucleus are inhibited by PC, stopping it from sending a signal to the red nucleus o ie. LTD of purkinje cell releases interpositus nucleus from inhibition, allowing it to send excitatory signal to red nucleus How does the brain control our movements? Muscles skeletal (striate) muscles —> voluntary movement o myosin (thick protein) and actin (thin protein) (together called sarcomeres) —> myoﬁbril —> muscle ﬁbres —> fascicles o relaxed: myosin and actin separated o contracted: slide into each other to be interconnected § myosin cross-bridges “row” along actin ﬁlament to slide in o ~250,000 muscle ﬁbres in biceps and ~100,000 sarcomeres per ﬁbre Neuromuscular Junction motor neurons release acetylcholine into neuromuscular junction acetylcholine binds to nicotinic receptors on motor endplate (ie. muscle part of neuromuscular junction) triggers inﬂux of Ca++ that causes contraction motor unit = number of muscle ﬁbres receiving input from one motor axon o less —> more precise movement o eg. thigh muscle motor unit ~1000 ﬁbres o eg. extra-ocular muscle motor unit ~10 ﬁbres Myasthenia gravis: autoimmune attack on acetylcholine receptors o weakness o less able to active muscle ﬁbres Botox: o irreversible o binds to acetylcholine in axon terminal, prevents release into neuromuscular junction Motor Output motor signals via spinal cord or medulla, relaying from the brain spinal cord also controls spinal reﬂexes o eg. pain withdrawal response or stretch reﬂex breathing and walking driven by central pattern generators in spinal cord Spinal reﬂex: knee jerk aWerent input from muscle spindle (detects muscle stretch) monosynaptic connection in ventral horn to spinal motor neuron eWerent output to thigh muscles (to contract) regulates tension in muscle as a response to load Spinal reﬂex: golgi tendon reﬂex protects tendon from excess force aWerent input form golgi tendon organ (detects tendon stretch) o synapse on neuron which inhibits spinal motor neuron aWerent input from muscle spindle (detecting muscle stretch) o synapse on spinal motor neuron eWerent output to thigh muscle (to contract) Descending control brainstem o controls muscles of trunk, neck and proximal limbs o posture and correcting balance rubrospinal tract: red nucleus o controls arms and legs o limb movements independent of trunk (eg. reaching) corticospinal tract: motor cortex o controls muscles in arms, hands and ﬁngers o ﬁne manual movements (eg. writing, picking up an object) Internal capsule ﬁbres from cortex to thalamus, basal ganglia, brainstem and spinal cord stroke can cause hemiparesis and hemianesthesia o usually due to stroke eWecting internal capsule o eg. right motor cotex § weakness in left hand and face § but left side of face not paralysed § told joke —> able to smile § told to smile —> cant Neocortex Primary motor cortex (M1) o central sulcus o topographic map of body o electrical stimulation evokes movements in corresponding limb or muscle group o output to spinal cord via pyramidal tracts and red nucleus § ie. ﬁnal execution of movement Supplementary motor area (SMA) and Pre-motor area (PMA) o involved in planning of movements § anticipate direction and destination of movement § eg. monkey moving joy stick: neuron activity code for direction monkey will move § perform “mental rotation” o neurons active.. § before movement § before aborted movement § imagining movement o output to primary motor cortex Cerebellum 10% of brain weight but >50% of neurons Sensory input o vestibular o somatosensory o proprioceptive o visual and auditory § involved in eyeblink response o § cortex input via pons Output cerebellum —> thalamus —> red nucleus —> cortex Not direct control of motor output o rather ﬁne tuning of other motor centres Movement o smooth execution of sequences of coordinated movements o damage —> jerky, poorly controlled movements o short-term adaptation to visuomotor distortion § eg. glasses that turn everything upside down Cognition o connections with association cortex o damage —> deﬁcits in executive function o imaging studies § right cerebellum more active when generating a verb for a noun rather than just reading the noun § more active when attending to semantic rather than rhyming relationships between words § left cerebellum more active during lying than telling the truth Basal Gagnlia important for control of movement a group of structures o basal ganglia proper: Caudate, putamen and GP § work with cortex in loops (particularly motor cortex) and thalamus and substania nigra in midbrain History to determine Function of BG extrapyramidal diseases o eWects motor system but not motor tracts descending the spinal cord Huntington’s disease and Parkinson’s disease both characterised by motor dysfunction and BG degeneration o suggested BG involved in movement which led researchers to study it in this context Function of BG BG has no direct projection to motor output structures electrophysiology (electrical activity in brain) —> o neurons in BG active before and after movement o neural activity in BG does not code for particular movements § ie. cant predict movement animal is making based on neural activity in BG Connectivity of the BG BG form closed feedback loops with cortex and thalamus o ie. feedback to same point of origin/same neurons cortex —> striatum —> GP —> thalamus —> cortex o striatum = caudate and putamen inhibitory connections = GABA excitatory connections = glutamate convergence of inputs and divergence of outputs —> ampliﬁed excitation/inhibition Direct Path: excitatory feedback cortex —> striatum —> GPi —> thalamus —> cortex cortex excites striatum, striatum inhibits GPi which usually inhibits thalamus, thus thalamus can signal back to cortex Indirect Path 1: dampen feedback cortex —> striatum —> GPe —> GPi —> thalamus cortex excites striatum, striatum inhibits GPe which usually inhibits GPi from inhibiting thalamus, thus, GPi inhibits thalamus Indirect Path 2: dampen feedback cortex —> striatum —> GPe —> STN —> GPi —> thalamus cortex excites striatum, striatum inhibits GPe which usually inhibits STN from exciting GPi which inhibits thalamus, thus, GPi inhibits thalamus Models of BG function These models are not mutually exclusive and can co-occur Model 1: BG helps with initiation and termination of movement (aka scaling of movement) o PD: diWiculty in initiating movement Model 2: BG ﬁlters input, ampliﬁes/boosts signal (boost) and reduced noise (indirect) to produce clear movement Model 3: 10% of striatal neurons respond to signals for reward o maybe allow motivation control of activity selection based on consequences Model 4: BG provides error correction o predicts feedback from movement allowing faster correction than permitted by slower peripheral feedback Multiple parallel loops multiple loops originating from diWerent cortical areas (not just M1) remain seregated through BG, returning to their origins diversity of function can contribute to variety of cogntive processes Dopamine input from SN dopaminergic projections into striatum o dopamine regulates balance of activity in direct and indirect pathways D1 receptors o excitatory o neurons part of direct pathway D2 receptors o inhibitory o neurons part of indirect pathway eWect of DA (dopamine) in BG explains psychomotor stimulant eWects of DA agonists o eg. drug enhances +ve feedback and reduce -ve feedback to cortex Huntington’s Disease genetic disease progressive loss of GABA neurons in striatum (especially caudate nucleus) initially twitches in face and hands o progressive tremors through body o tremors can resemble voluntary movements movement disorder accompanied by dementia o BG eWects other cognitive processes —> dementia loss of GABA neurons in striatum leads to decreased inhibition of GPe, resulting in increased inhibition of GPi, resulting in decreased inhibition of thalamus —> movement o indirect loops are failing to work o unable to ﬁlter out inappropriate movements Parkinson’s Disease age related disease greater diWiculty in initiating movement o abnormal gait (shuWling) and unable to swing arms o resting tremor degeneration of DA containing neurons in SN that project to caudate and putemen (nigro-striatal pathway) o lack of DA input —> loss of up regulation in direct pathway and loss of down regulation in indirect pathways —> net shift towards indirect pathways —> GPi massively suppresses thalamus —> diWiculty initiating movement Treatments of PD 1. dopamine agonist drugs (L-dopa) 1. but can result in similar symptoms to HD 2. cell transplant techniques currently being developed 3. brain lesions to GPi or STN 4. deep brain stimulation of STN All progressive deterioration of brain tissue and accompanying decline in functioning. Fatal. Creutzfeld-Jacob Disease progressive degenerative disease (months, sometime > 1 year) about 1 in 1 million post-mortem brain tissue full of small holes o sponge-like o spongiform encephalopathy caused by prions o causes are genetic, sporadic and also by infection § Kuru: consuming brains of diseased elders § iatrogenic cases: infection from other patient during surgery § not aWected by procedure that destroy nuclei acids § agent doesn't have DNA or RNA (ie. not a living pathogen) § only aWected by procedure that destroy proteins § prion = protein infection Prions = proteins infection Origin all animals carry genes that codes for prion protein (PrP) o slightly vary in diWerent species, thus, hard to transfer between species Two forms of PrP normal form (degraded by appropriate enzymes) aberrant form (resistant to usual enzymes) o form that causes disease o misfolded form of protein (ie. misfolded amino acid) diWerent genetic codes by same amino acid sequence infectiousness o misfolded shape is what makes it infectious o eg. healthy mice with PrP gene will develop disease if injected with misfolded protein § healthy mice without PrP gene will not develop the disease if injected o thus misfolded protein eWects normal protein making them misshapen Mad Cows and CJD in Britain due to change in dietary supplements for cows which may have had sheep products in it crossed species into humans o PrP diWer in 30 places cows to humans mostly absent in skeletal muscle, just brain tissue Huntingtons Disease HTT gene of chromosome-4 codes for Huntingtin protein expressed in all cells but particularly high in neurons HD patients have longer DNA sequence on HTT which creates mutant Huntingtin protein breakdown of mutant protein produces short fragments that get misfolded and form aggregates that are toxic Parkinson's Disease lewy bodies o contains aggregation of protein alpha-synuclein production of misfolded alpha-synuclein protein loss of function og parkin (which tags misfolded proteins for destruction) Alzheimers Disease about 50% of all dementia cases o risk increases with age widespread loss of brain tissue o entorhinal cortex and hippocampus o association cortex o speciﬁc subcortical nuclei: nucleus basalis (cholinergic), locus coeruleus (noradrenergic), raphe nuclei (serotonergic) Pharmacological treatment for loss of cholinergic —> mostly AChE inhibitors Causes o amyloid plaques § beta-amyloid § more short in healthy brain § more long in AD brain § —> misfolded and toxic § located mostly in temporal lobe and prefrontal areas o neuroﬁbrillary tangles § tau protein Distribution o amyloid-beta located mostly in temporal lobe and prefrontal areas o same areas active when doing nothing § thus, AD aWects areas of constant activity o Treatment for AD AChE inhibitors o inhibit loss of chloinergic activity o eg. donazepil o produces some improvements in cognitive function in early stages Memantine o NMDA antagonist § reduced activity of NMDA receptors o more cogntive function in early stages Monoclonal antibodies o eliminate β-amyloid and hyperphosphorylated tau, but evidence for cognitive/therapeutic beneﬁt unclear and side eWects Why is neuropharmacology relevant to the study and practice of psychology? approx. 20% of adults receiving psychotherapy also use a prescription medication for their MHC integrated pharmacological and psychosocial therapy leads to better outcomes complex comorbid cases often require treatment with one or more medications, inﬂuencing diagnosis and treatment decisions Most medications are old and limited emerging therapies on the horizon which may require specialist training and education to integrate with psychosocial therapies How can neuropharmacology help us understand the brain, behaviour and cognition? the majority of drugs have been developed without prior research o ie. right place, right time (serendipity) morphine —> helped us to identify and understand endorphins LSD —> helped us to understand psychosis and serotonin SSRIs —> heart medication but increased mood —> leading theory of depression now we have the techniques and ability to create drugs purposefully and selectively Pharmacological ‘modes of action’ common to psychiatric medications Pharmacodynamics and Pharmacokinetics Dynamics = what the drug does to the body (to achieve eWicacy or toxicity) Kinetics = what the body does to the drug (metabolism, transportation of brain, onset of action, duration of action, peak activity) What do drugs target in the brain to change function tri-partitite synapse o pre, post and astrocyte drugs manipulated these receptors eWecting the release and uptake of NTs mimicking endogenous NT release o binding to post-synaptic receptors o agonist inhibit enzymes which breakdown NTs or prevent reuptake o greater post-synaptic activity Receptors G-Protein coupled receptors (GPCRs) 40% of brain acting drugs target GPCRs role in signalling pathways of NTs (eg. serotonin, DA and norepinephrine) Gs and Gq are excitatory Gi is inhibitory DA1 receptor is excitatory (Gs) and DA2 is inhibitory (Gi) o related to basal ganglia complex signalling o may take longer than rapid onset for ligand-gated ion channels Ligand-gated ion channels 30% of brain acting drugs target these eg. benzodiapeines, nicotine, ethanol, ketamine, anaesthetics and some antipsychotics open in response to binding of NT o allows ion ﬂow across the membrane and alters electrical potential of the cell simple signalling (fast and potent, fast action) o rapid onset of action o however also have high risk of dependence, withdrawal, overdose and addiction Orthostery and Allostery Types of binding orthosteric = drug binds to receptor site where natural NT (ligand) would bind o mimic (agonist): dopamine to D2 o block (antagonist): anti-psychotic to D2 allosteric = drug binds to diWerent site on receptor than the natural NT (ligand)\ o potentially safer o does not block or activate o rather modiﬁes response to orthosteric binding § positive allosteric modulator (PAM): increases sensitivity in GABA receptor § negative allosteric modulator (NAM): more activity to turn on receptor Increasing receptor activity agonists o maximally increase activity of receptor partial agonists o sub-maximally increase activity of receptor o potentially safer o doesn't work for acute episodes positive allosteric modulations o increase activity of orthosteric ligand at the receptor biased agonists o functional selectivity Decreasing receptor activity antagonists o block binding (eg. caWeine blocks adenosine receptors) negative allosteric modulations o decrease activity of orthosteric ligand at the receptor o rarer low eWicacy partial agonists Enzymes Enzyme Inhibitors monoamine oxidase (MAO) o MAO-A: metabolises serotonin, noradrenaline, dopamine o MAO-B: metabolises dopamine MAO regulates synaptic NT levels MAO inhibitors prevent metabolisation resulting in higher NT levels risks: interact toxically with may other drugs, diets, and other diseases Acetylcholinesterase inhibitors reduced in AD drugs prevents metabolism and increase synaptic acetylcholine levels can help improve cognitive function risks: can interfere with many other critical pathways and result in health risks Transporters Modulating reuptake transporter function to alter synaptic NT levels reuptake inhibitors (eg. SSRIs) block the transporting resulting in greater neurotransmitter levels in the synapse reversal transporters (eg. MDMA): some drugs with cause the transporter to eject intracellular NT stores into the synapse Case Studies Benzodiazepine Anxiolytics positive allosteric modulators (PAM) of inhibitory GABA-A receptors o bind to site diWerent from natural NT eg. Xanax, Valium, Ativan make other ligands (eg. alcohol) more potent and eWicacious increases eWects of GABA (inhibitory), increasing inhibitory activity throughout the brain, reducing anxiety o not selective produce tolerance, withdrawal, overdose and addiction accidental discovery, taught us about the function of GABA o phenotypic drug discovery process (ie. by describing the eWect of something) new and best anxiolytics are often discovered using animals models that naturally avoid light and open areas o good face validity (innate anxiety of rodents) o good predictive validity (from rodents to humans) o assists in development of construct validity cross-species neurobiological studies implicate amygdala is a key site of action for benzodiazepine anxiolytics o mechanistic knowledge often comes after discovery Methylphenidate for ADHD methylphenidate/ritalin dopamine activity in PFC and striatum may be under active in people with ADHD ritalin blocks function of dopamine reuptake transport (DAT) and noradrenaline reuptake transporter (NAT) o more dopamine to the cortex rather than the striatum function of drug depends on brain chemistry o stimulant make people with ADHD feel calm ritalin shares a mechanism with cocaine o have similar pharmacodynamics § both inhibit dopamine reuptake transporter o have distinct pharmacokinetics § cocaine has a rapid concentrated peak § ritalin has a slow peal concentration o given methylphenidate intravenously —> similar eWects to cocaine thus, mechanism (pharmacodynamics) isn’t everything, absorption (pharmacokinetics) matter hugely Drugs of Abuse dopamine is a common mechanism for drugs of abuse despite diverse pharmacodynamics (receptor/enzyme/transporter targets), all drugs of abuse have common eWects on dopamine pathways from VTA to NAc nicotine o agonist of excitatory nicotinic acetylcholine receptors in VTA causing dopamine release opioid o agonist of opioid receptors on GABA interneurons in VTA, reduced inhibition of VTA dopaminergic neurons causing dopamine release o disinhibition stimulants o enhanced release and reduced uptake o eg. amphetamine releases dopamine from transports o eg. cocaine: inhabitation of reuptake transporter Alcohol Alcohol’s dopamine-stimulating mechanism: taking the brakes oW dopamine’s tonic inhibition GAGA interneurons in VTA inhibit dopamine releasing cells alcohol binds to GABA receptors on these GABAergic interneurons and inhibits their activity o thus dopamine release to NAc o leading to reward and reinforcement with causes abuse Dopamine adaptations: a common mechanism for drugs of abuse chronic stimulation of VTA-NAc pathway changes the basal release of dopamine and glutamate systems reduction in normal release increase in how much can be released during conditioned stimuli o create pathways that should exist Anti-Depressants Anti-depressants and the monoamine theory of depression Monoamine theory of major depressive disorder o deﬁciency of monoamines (eg. serotonin, noradrenaline and dopamine) at synapse o boosting these NTs can treat depression SSRIs inhibit reuptake of NTs MAOs prevent metabolising of NTs Problems rapid pharmacological eWect (ie. elevated NTs rapidly) but delayed therapeutic eWect non-response in many patients (~30%) variability of monoamine levels some drugs that don’t target this system directly are eWective Emerging theories of depression neuroplasticity/neurotrophic theory o loss of neuroplasticity in people with MDD o some anti-depressant drugs promote activity in these systems neuroinﬂammation theory o inﬂammation is involved in MDD o lose neuroplasticity through neuroinﬂammation a new class of rapid acting anti-depressants supporting these theories o ketamine (NMDA antagonist) § increased neuroplasticity o Psilocybin (5HT2A agonist) § increased neuroplasticity and anti-inﬂammatory § cognitive ﬂexibility § really good evidence to support this Summary There are hundreds of potential mechanisms by which drugs can act in the brain to change behaviour, cognition, and aWect. Serendipitously and phenotypically discovered drugs have taught the ﬁeld a lot about the brain and behaviour. Modern psychology practice is intertwined with neuropharmacology; understanding the mechanism of drugs is important! There is often a ﬁne line between therapeutics and drugs of abuse/toxicity. Experimental neuropharmacology enables us to test new theories of psychiatric disease. The next generation of psychologists will likely lead a new era of psychiatric medications. Predictions: using a cognitive map to make an assessment of what is likely to happen if you do something our ability to navigate our environment is made possible by the models we create through experience within these models there is a set of predictions which allow us to foresee what will happen next our predictions create our cognitive models if predictions are not accurate, our models will not be accurate main goal of learning is to make sure our predictions match reality Prediction error: when you are surprised by something, when something unexpected happens in the environment. used to act more appropriately in the environment Dopamine neurons: critical for prediction error Error we need to update our model by comparing what we were expecting to happen with what actually happened when prediction does not match reality prediction error = reality - expectations o prediction = λ - V o how much learning happens on the trial o after multiple exposures, reality with match expectations o increasing at a decreasing o if expectation is = 1, but reality = 0 or -1 § extinction Associative strength = capturing how likely you are to think about (predict an outcome) Learning episode = every time you experience the surprising outcome Prediction is the necessary catalyst for learning the blocking phenomenon (aka the Kamen Blocking eWect) dopamine neurons drive prediction error to drive learning blocking o you wont learn about the novel thing as the predictor is the same o no need to update cognitive model Example: learn about orange but not about multicoloured, even though shocked the same amount of time for both it about causality focus attention on purple and then on orange The blocking procedure shows that we only learn about associations when there is a prediction error where do we focus our attention? Revealing the neural correlates of blocking Example: orange would be expected to be more likely to lead to reward than the multicolour due to blocking measure prediction error in the brain during the compound conditioning Prediction errors in the midbrain (VTA) and NAc activation on a fMRI learned associations occurring in the orbitofrontal cortex o activity during test is correlated with eWective blocking contrast estimate = diWerence in activity between multicoloured and orange correlates positively with the degree of blocking Dopamine Prediction Error Dopamine neurons respond to behavioural triggers recording dopamine neurons SN and VTA o using single unit electro physiology dopamine neurons have a particular waveform which allow us to identify them o = wide-waveform o takes a while to return to baseline wide-wave form is best method to identify dopamine neurons 55% of dopamine neurons responded to trigger stimulus spike rate = how many times the neuron is ﬁring per second (ie. activity at particular points in time) dopamine neurons ﬁre/spike before a response is made o ie. responding to the door release rather than grabbing the food Experiment part 2: location indicator top row (medial vs lateral) trigger indicator bottom row (press the correct location) then reward a predicted about of time after results o dopamine neurons only respond to reward when it is unpredictable/unexpected o unpredictable gap between location and trigger in last one § so dopamine neurons respond to both negative prediction error when not given reward that is expected o decrease in dopamine neurons ﬁring Optogenetics virus into the brain that allows us to express channelrhodopsin and halorhodopsin o C = activation of ﬁring o H = inhibition of ﬁring light activates these can make this speciﬁc to dopamine neurons control neuronal activity with light at very speciﬁc timepoints considerations o driving wide changes in neurons (eg. all DA neurons ﬁre at the same time): how do these neurons usually ﬁre, try to make them ﬁre in that way Causal Link between Dopamine and Learning unblocked learning about the light by using cre-stimulation (ie. forced ﬁring using optogenetics)

Behaviour Notes PDF

Document Details

Tags

Related

Summary

Full Transcript

Upgrade to continue