Module 7 How Do We Study the Brain's Structure and Functions? Flashcards
Functional Near-infrared Spectroscopy (fNIRS)
-Noninvasive technique that gathers light transmitted through cortical tissue to image oxygen consumption; form of optical tomography
-Gathers light transmitted through cortical tissue to image oxygen consumption in the brain
-Allows investigators to measure oxygen consumption as a surrogate maker of neuronal activity relatively select cortical regions, even in newborn infants
~When newborns listened to a familiar language, their brain showed a general increase in oxygenated hemoglobin; when they heard un unfamiliar language, oxygenated hemoglobin decrease overall
*But when the babies heard the same sentences played backward, there was no difference in brain response to either language
Brain-Behavior analyses combine the efforts
- Anatomists and genetics
- Psychologists and physiologists
- Chemists and physicists
- Endocrinologists and neurologists
- Pharmacologists and psychiatrists
- Computer scientists and programmers
- Engineers
- Biologists
Ernset Auburtim
-During a 1861 Anthropological Society of Paris meeting, argued that language functions are located in the brain’s frontal lobes
Paul Broca
- A fellow physician who attended the meeting noticed five days later observed a brain-injured patient who had lost his speech, but said “tan” and swear words.
- He examined the man’s brain and found the focus of the injury in the left frontal lobe
- By 1863, he colleceted eight other similar cases and concluded that speech production is located in the third frontal convolution of the left frontal lobe- a region now called ‘Broca’s area’
- His finding attracted others to study brain-behavior relationships in patients
Neuropsychology
- Study of the relationships between brain function and behavior, especially in humans
- Measuring brain and behavior increasingly includes noninvasive imaging, complex neuroanatomical measurement, and sophisticated behavioral analysis
Primary Tools of Neuroanatomy were Histological
- Brains were sectioned postmortem, and the tissue (histo- in Greek) was stained with various dyes
- There has been progression in microscopy toward greater resolution and specificity and a movement from visualizing dead tissue to living tissue
- Scientists can stain sections of brain tissue to identify cell bodies in the brain viewed with a light microscope, and they can selectively stain individual neurons to reveal their complete structure; an electron microscope makes it possible to view synapses in detail; multiphoton imaging can generate a three-dimensional image of living tissue
Korbinian Brodmann
-Divided the cerebral cortex into many distinct zones based on the characteristics of neurons in those zones
Early Twenty-first Century
-Dozen of techniques had developed for labeling neurons and their connections, as well as glial cells
Super-resolution Microscopy
-Is also being used to identify the locations of different receptors on the membranes of cells
Contemporary Techniques
- Allow researchers to identify molecular, neurochemical, and morphological (structural) differences among neuronal types and ultimately to relate these characteristics to behavior
- These techniques for visualizing neurons play a role in studying the connections between anatomy and behavior
Learning can be corelated with variety of neuroanatomical change
-Such as modification in the synaptic organization of cells in specific cortical regions or in the number of newly generated cells that survive in the dentate gyrus, a subregion of the hippocampus
Experimental Evidence
-Reveals that preventing the growth of new dentate gyrus neurons lead to certain kinds of memory deficits
~To test this idea that neurons of the dentate gyrus contribute to object memory formation within a context, researchers tested healthy rats and ADX rats-rats with adrenal glands removed, thus eliminating the hormone corticosterone
*Without corticosterone, neurons in the dentate gyrus die
Experimental context with rats
-Each context contained a different type of object
-Rats were placed in either context A or context B but with two different objects-one from that context and the second from the other context
-On the test day, the rate were placed in either context A or context b but with two different objects-one from that context and a second from the other context
~When healthy rats encounter objects in the correct context, they spend little time investigating because the objects are familiar; however, if they encountered an object in the wrong context, they are curious and spend about three-quarters of their time investigating, essentially treating the mismatched object as new
-The ADX rats with fewer cells in the dentate gyrus treated the mismatched and in-context object the same, spending about half of their investigation time with each object
-Another of ADX rate given treatment known to increase neuron generation in the dentate gyrus-enriched housing and exercise in running wheels- was unimpaired at the object-context mismatch task
~Concludes that cellular changes in the dentate gyrus and behavioral changes are closely linked: neurons of the dentate gyrus are necessary of contextual learning
Brainbow
- Not the discovery of stains that can highlight brain cell features, their complexity and connections would remain unknown
- Jean Livet and his colleagues at Harvard developed a transgenic technique that involves labeling different neurons by highlighting them with distinct colors; to mimic the wat an LCD or LED monitor produces the full range of colors that the human eye can see by mixing only red, green, and blue
- Scientists introduced genes that produced cyan (Blue), green, and red fluorescent proteins into mice cells
- Red genes is obtained from coral, and the blue and green genes are obtained from jellies
- The mice also received a bacterial gene called Cre, which activates the color genes inside the cells; due to change factors; however, the extent to which each gene is activator variable expression of the color-coding genes result in cells that fluoresce in at least 100 hues
- When viewed through a fluorescent microscope sensitive to these wavelengths, individual brain cells and their connections can be visualized because they have slightly different hues
- Individual cells can be visualized, Brainbow offers a way yo describe where each neuron sends its processes and how it interconnects with other neurons
- By visualizing living brain tissue in a dish, Brainbow provides a method for examining changes in neural circuits with the passage of time
- Will provide useful for examining populations of cells and this connects-such as which cells are implicated in specific brain diseases
- Could be turned on at specific times, as an individual ages or solves problems
- Even the simplest brain contains extraordinary numbers of neurons and fibers
- Modifications that restrict visualization to only a few cells and fibers at a time are necessary for their connections to be understood
behavioral Neuroscience
- Study of the biological bases of behavior in humans and other animals
- Seek to understand the brain-behavior relationship in humans and other animals
Major challenge for behavioral neuroscientists
- Is developing methods for studying both typical and atypical behavior
- Measuring behavior in humans and laboratory animals differs in large part because humans speak: investigators can ask them about their symptoms or give them paper-and-pencil and computer-based tests to identify specific symptoms
- Measuring behavior in laboratory animals are more complex; researches must learn the animals language, in short researchers must develop ways to enable the animals to reveal their symptoms
Ethology
- The development of the fields of animal learning
- The objective study of animal behavior, especially under natural conditions, provided the basis from modern behavioral neuroscience
Neuropsychological Testing of Humans
-The brain has exquisite control of functions ranging from movement control and sensory perception to memory, emotion, and language
-Any analysis of behavior must be tailored to the particular function(s) under investigation
~Consider the analysis of memory
-People with damage tot he temporal lobes often complain of memory disturbance
~Memory is not a single function; rather, multiple independent memory systems exist
*We have memory for events, colors, names, places, and motor skills, among other categories, and each must be measured separately
**It would be rare for someone to be impaired in all forms of memory
Neuropsychological Tests
-Three distinct forms of memory
~The Corsi block-tapping requires participants to observe an experimenter tap a sequence of blocks- blocks 4,6,1,8,3 for instance; the task is to repeat the sequence correctly
*Participant does not see number on the blocks but rather must remember the location of the tapped blocks
Block Span
-Provides a measure of short-term recall of spatial position
-the test can be made more difficult by determining the maximum block span of an individual participant and then adding one
-The participant will fail on the first presentation but, given the span + 1 repeatedly, will eventually learn it
-Span +1 identifies a different form of memory from block span
~Different types of neurological dysfunction interfere differentially with tasks that superficially appear quite similar
-Block span measures the short-term recall of information, where as the span +1 task reflects the learning and long-term memory storage of information
Mirror-drawing Task
-Requires a person to trace a pathway, such as a start, by looking in a mirror
-Motor task proves difficult because out movements appear backward in a mirror
-With practice, participants learn how to accomplish the task accurately, and they show considerable recall of the skill when retested days later
~Patients with certain types of memory problems have no recollection of learning the task on the previous day but neverless preform it flawlessly
Recent Memory Task
-Participants are shown a long series of cards, each bearing two stimulus items that are words or pictures
-On some trials, a question mark appears between items
~Their task is to indicate whether that have seen the items before and, if so, which item they saw most recently
*They might be able to recall that they have seen items before but may be unable to recall which was most recent
*Conversely, they might not be able to identify the items as being familiar, but when forced to choose the most recent one, they may be able to identify it correctly
Behavioral Repertories
-The rats display a long list of capabilities, some of which are categorized, that can be independently examined to understand the functional underpinning of those behaviors
Place Learning
- The rat must find the platform from a number of different starting locations in the pool.
- Only cues available are outside the pool, so the rat’s must learn the relationship between several cues in the room and the platform’s location
Matching-to-place Learning
-The rat has already learned that a platform always lies somewhere in the pool, but the rat enters the pool from different starting location every day
-The rat is released and searches for the platform
~Once the rat finds the platform, the rat is removed from the pool and, after a brief delay (10 seconds), is released again
-The rat is to develop a strategy for finding the platform consistently: it is always in the same location on each trial each day, but each new day brings a new location for the rat.
Landmark
- The platform’s location is identified by a cue on the pool wall
- The platform moves on every trial, but the relationship to the cue is consistent
- The brain is learning that the distant cues outside the pool are irrelevant; only the local cues is relevant
Major problem facing people with stroke
- A deficit in controlling hand and limb movements
- Has prompted considerable interest in devising ways to analyze such motor behaviors for the purpose of testing new therapies for facilitating recovery
Manipulating Brain-behavior Interactions
- The precise manner depending on the specific research question being asked
- Research can manipulate the whole animal by exposing it to different diets, social interactions, exercise, sensory stimulation, and a host of other experiences
- The principal direct techniques are to inactivate the brain via lesions or with drugs or to activate it with electrical stimulation, drugs, or light
Brain Lesions
-Used for brain manipulation is to ablate (remove or destroy) tissue
Ablation
- Karl Lashley fried to find the site of memory in the brain
- Trained monkeys and rats on various mazes and motor tasks and then removed bits of cerebral cortex, with the goal of producing amnesia for specific memories
- Memory loss was related to the amount of tissue he removed
- Conclusion is that memory is distributed throughout the brain and not located in any single place
- Research strongly indicates that specific brain functions and associated memories are indicated localized to specific brain regions
Stereotaxic Apparatus
- Surgical instrument that permits a researcher or neurosurgeon to target a specific part of the brain
- The head is held in a fixated position, and because the location of brain structures is fixed in relationship to the junction of the skull bones, it is possible to visualize a three-dimensional brain map
- Rostral-caudal (front-to-back) measurements correspond to the y-axis
- Dorsal-ventral (top-to-bottom) measurements correspond to the z-axis, are made relative to the surface of the brain
- Medial-lateral measurements, x-axis, are made relative to the midline junction of the cranial boned
Parkinsonian Tremor
-Which the hands can shake so severely that the afflicted person cannot hold a glass of water
~The most widely use surgical treatment today is drill a hole in the skull and, using stereotaxic coordinates obtained for that patient with MRI, target the globus pallidus
-An electrode is then lowered into the globus pallidus, and currents is passed through it to destroy the structure and relieve the patient of the tremor
High-intensity Focused Ultrasound (HIFU)
-Now achieve the same result without the invasive surgery
-Uses many individual untrasonic beams that are all pointed at the same spot in the brain
~Each beam passes through tissue with little effect; at the convergent point where all the beams intersect, the energy heats the tissue
*Lightly heating the tissue temporarily prevents that part of the brain from working properly, thereby informing the surgeons that their targeting is correct
~The tissue heating can then continue until the target is permanently destroyed and the tremor is noninvasively eliminated
Compensation
- Following brain damage, the neuroplasticity ability to modify behavior from that used prior to the damage
- To avoid compensation following premiant lesions, researchers have also developed temporary and reversible lesion techniques such as regional cooling
Regional cooling
- Prevents synaptic transmission
- A hollow metal coil is placed next to a neural structure; then chilled fluid is passed through the coil, cooling the brain structure to about 18C
- When the chilled fluid is removed from the coil, the brain structure quickly warms, and synaptic transmission is restored
GABA local administration
- Which increases local inhibition and in turn, prevents the brain structure from communicating with other structures
- Degradation of GABA agonist reverses the local inhabitation and restores function
Brain Stimulation
-The brain operates on both electrical and chemical energy, so its possible to selectively turn the brain regions on and off by using electrical or chemical stimulation
-Mid-twentieth century, the first to use electrical stimulation directly on the human cerebral cortex during neurosurgery
-Later researchers used stereotaxic instruments to place an electrode or a cannula in specific brain locations
-The objective: enhancing or blocking neuronal activity and observing the behavioral effects
-Can also be used as a therapy
~The intact cortex adjacent to cortex injured by a stroke is stimulated electrically, for example, it leads to improvement in motor behaviors
Electrical self-stimulation
- The animal have the opportunity to press a bar that briefly turns on the current, they quickly learn to press the bar to obtain the current
- It appears that the stimulation is affecting a neural circuit that involves both eating and pleasurers
Deep-brain Stimulation (DBS)
-A neurological technique, electrodes implanted in the brain stimulate a targeted area with continuous pulse of low-voltage electrical current to facilitate behavior
-Subcortical structures, for example, DBS to the globue pallidus in the basal ganglia of Parkinson patients make movements smoother, often allowing patients to dramatically reduce their intake of medications
-Using several neural targets is an approved treatment for obsessives-compulsive disorder
~Experimental trials are under way to identify the brain regions optimal for DBS to be used as a treatment for intractable psychiatric disorders such as major depression, schizophrenia, and possibly for epilepsy
~May also be used as a treatment for stimulating recovery from traumatic brain injury (TBI)
Transcranial Magnetic Stimulation (TMS)
-Procedure in which a magnetic coil is placed over the skull to stimulate the underlying brain; used either to induce behavior or to disrupt ongoing behavior
-A high-voltage current pulsed through the coil produces a rapid increase and subsequent decrease in the magnetic field around the coil; the magnetic field easily passes through the skull and causes a population of neurons in the cerebral cortex to depolarize and fire
-If the motor cortex is stimulated, movement is evoked; or if a movement is in progress, it is distrupted
-Similarly, if the visual cortex is stimulated, the participant see dots of light (phosphenes)
~The effect of brief pulses of TMS do not outline the stimulation, but repetitive TMS (rTMS), or continuous stimulation for up to several minutes, produces more long-lasting effects, including changing function or temporarily inactivating tissue
-TMS and rTMS can be used to study brain-behavior relationships in healthy participants, and rTMS has been tested as a potential treatment for a variety of behavioral disorders.
Drug Manipulation
-Brain activity can also be stimulated by administration of drugs that pass either into the bloodstream and eventually enter the brain or through an indwelling cannula that allows direct application of the drugs to specific brain structures
-Drugs can influence the activity of specific neurons in specific brain regions
~Example
*Haloperidol, used to treat schizophrenia, reduces DA neuron function that makes healthy rats dopey and inactive (hypokinetics)
-In contrast, drugs that increase dopaminergic activity, such ass amthamines, produce hyperkinetic rats (hyperactive rats)
~The advantage of administering drugs is that their effects wear off in time as the drugs are metabolized
*Making it possible to study drugs effects on learned behaviors, such as skilled reaching and then to re-examine the behavior after the drug effect wears of
Claudia Gonzalez
-Administered nicotine to rats as they learned a skilled reaching task, then studied their later acquisition of a new skilled reaching task
~The researchers found that the earlier nicotine-enhanced motor learning impaired the later motor learning
-The findings surprised the investigators, but now appears that repeated exposure to psychomotors stimulants such as amphetamine, cocaine, and nicotine can produce long-term effects on the brain’s later plasticity (its ability to change in response to experience), including learning specific tasks
Synthetic Biology
-Design and construction of biological devices, systems, and machines not found in nature
-Has transformed how neuroscientist manipulate brain cells
-Techniques include inserting or deleting a genetic sequence into the genome of a living organism
~New technique called CRISPR-Cas9
CRISPR-Cas9
-Clustered Regularly interspaced Short Palindromic Repeats, one of many CRISPR techniques, was discovered in bacteria for fighting viruses; it serves as an all-purpose tool for cutting the DNA of any cell
-Simply provide the bacteria’s Cas9 protein with the RNA sequence corresponding to the length of DNA they would like to remove from the subject
-The CRISPR system can be used to silence one or many genes by cutting out those regions in the DNA
~Then the DNA’s repair machinery can be harnessed to insert a new sequence that replaces the one that was removed
-As a therapeutic intervention, it could eventually lead to the elimination of many forms of inherited disease
~Could also counter antibiotic-resistant microbes, disable parasites, and improve food security
Optogenetics
-Transgenic technique that combines genetics and light to control targeted cells in living tissue
-A sequence that codes for a light-sensitive protein associated with an ion channel enables investigators to use light to change the shape (conformation) of the channel
-Based on the discovery that light can activate certain proteins that occur naturally and have been inserted into cells of model organisms
~Example
*Opsins
*Halorhodopsin
-Investigators can insert light-sensitive proteins into specific neuron types, such as pyramidal cells of the CA1 region of the hippocampus, and use light to selectively activate just that cell type
-Researchers hail optogenetic for its high spatial and temporal (time) resolution; ion channels can be placed into specific cell lines and turned on and off on millisecond time scales
-Find application in behavioral studies
~Example
*The amygdala is a key structure in generating fear in animals; if the target with opsins and then exposed to an inhibitory light, rats immediately show no fear and wander about in a novel open space; as soon as the light is turned off, they scamper back to safe hiding place
Opsins
-Proteins derived from microorganisms, combine a light sensitive domain whit ion channel
-Used for the optogenetic technique was channelrhodopsin-s (ChR2)
~When ChR2 is expressed in neurons and exposed to blue light, the ion channel opens and immediately depolarizes the neuron, causing excitation
Halorhodopsin (NpHR)
-Stimulation with a green-yellow light activates a chloride pump, hyperpolarizing the neuron and causing inhabitation
Chemogenetics
-Transgenic technique that combines genetic and synthetic drugs to activate targeted cells in living tissue
-The inserted synthetic genetic sequence codes for a G protein-coupled receptor engineered to respond exclusively to a synthetic small-molecule “designer drug”
-Better known by the acronym DREADD (Designer receptor exclusively activated by designer drugs)
~Principal advantage is that the drug activates only the genetically modified receptors, and the receptors are activated only by designer drugs, not by endogenous molecules
*Specificity is high, but temporal resolution is much lower that with optogenetic because receptors are activated by drugs rather than by light
Four Major Techniques for tracking the Brain’s Electrical Activity
-Single-cell recorder
-Electroencephalography (EEG)
-Event-related Potentials (ERPs)
-Magnetoencephalography (MEG)
~Used to record electrical activity from different parts of neurons; the electrical behavior of cell bodies and dendrites, which give rise to graded potential, tends to be much more varied and slower than the behavior of axons, which conduct action potential
Recording Action Potentials
-Early 1950s, became possible to record the activity of individual cells by measuring a single neuron’s action potentials with fine electrodes inserted into the brain
-These microelectrodes can be placed next to a cell (extracellular recording) or inside cells (intracellular recording)
~Extracellular recording techniques make it possible to distinguish the activity of as many as 40 neurons at once
~~Intracellular recording allows direct study and recording of a single neuron’s electrical activity
-The two disadvantages of inserting an electrode into a cell are that
~It can kill the cell
~It cannot be done in awake, free moving animals
-Single-cell recording is therefore confined to neurons grown in a dish or, for short periods (hours), to neurons in living brain slices
-From extracellular recordings that cells in the brain’s various sensory regions are highly sensitive to specific stimuli; some cells in the visual system fire vigorously to specific wavelengths of light (color) or to specific orientations of bars of light (vertical)
-Other cell in this region respond to more complex patterns, such as faces or hands
-Cells in the auditory system respond to specific sound frequencies (low or high pitch) or to more complex sound combinations, such a speech
Place Cells
- Neurons maximally responsive to specific locations in the world
- Code the spatial location of the animal and contribute to a spatial map of the world in the brain
John O’Keefe
-Discoveries of cells that constitute a positioning system in the brain
-Also demonstrated that, in mice with a genetically engineered mutation that produces deflicts in spatial memory, place cells lack specificity: the cell fire to a very broad region of their world; as a result, these mice have difficulty finding their way around, much as human patients with dementia tend to get lost.
~One reason may be that a change similar to engineered mutation in mice takes place in human brain cells
EEG
-Measures the summed graded potentials from many thousands of neurons
Electrocortcography (ECoG)
- Graded potentials recorded with electrodes places directly in the surface of the brain
- A method used during neurosurgery , electrodes are placed directly on the cerebral cortex
EEG Recordings
- EEG changes as behavior changes
- An EEG recorded from the cortex displays an array of patterns, some rhythmical
- The living brain’s electrical activity is never silent, even when a person is asleep or comatose
EEG Patterns
-When a person is arroused, excited, or even just alert has a low amplitude and a fast frequency
-This pattern is typical od an EEG taken from anywhere on the skull of an alert subject-not only humans but other animals too
-When a patient is calm and quietly relaxed, especially with eyes closed, the rhythmical brain waves often emerge
-Changes as a person moves from drowsiness to sleep and finally into deep state
~Rhythms become progressively slower and larger in amplitude; still slower waves appear during anesthesia, after brain trauma, or when a person is in a coma
-Only in brain death does the EEG permanently become a flat line
-A reliable tool for monitoring sleep stages, estimating the depth of anesthesia, evaluating the severity of head injury, and searching for brain abnormalities
-In epilepsy, brief periods of impaired awareness or unresponsiveness and involuntary movement associated with spiking patterns in the EEG characterize electrographic seizures
-Is an essential tool in diagnosis of epilepsy and in determining the kind of epilepsy and seizures the person had
Alpha Rhythms
- Regular wave pattern in an electroencephalogram; found in most people when they are relaxed with eyes closed
- Are extremely regular, with a frequency of approximately 11 cycles per second and amplitudes that wax and wane as the pattern is recorded
- In humans are generated in the region of the visual cortex at the back of the brain; if a relaxed person is disturbed, performs mental arithmetic, or opens their eyes, the alpha rhythms abruptly stops
Event-related potential (ERPs)
-Complex electroencephalographic waveform related in time to a specific sensory event
-Are largely the graded potentials of dendrites that a sensory stimulus triggers
-Are mixed in with so many other electrical signals in the brain that they are difficult to spot just by visully inspecting an EEG recording
-One way to detect is to produce the stimulus repeatedly and average the recording responsive
~Averaging tends to cancel out any irregular and unrelated electrical activity, leaving in the EEG record only the potentials the stimulus generated
-Caused by a sensory stimulus in hard to discern from all the other electrical activity around it
-Pattern consist of a number of negative (N) and positive (P) waves that occur within a few hundred milliseconds after the stimulus
-To spoke words even contain distinctive peaks and patterns that differences peaks and patterns that differentiate such similar-sounding words as cat and rat
-EEG technique is noninvasive, electrodes are placed on the scalp, not in the brain
-EEG and ERPs are inexpensive and can be recorded from many brain areas simultaneously by pasting an array of electrodes (sometimes more than 200) onto different parts of the scalp
~Can help with map brain functions
-Can not only detect which brain areas are processing particular stimuli but can also be used to study the order in which different regions participate
-These seconds are important because we want to know the route that information takes as it travels through the brain
-Can also be used to study how children learn and process information differently as they mature, as well as how a person with a brain injury compensates for the impairment by using undamaged brain regions
-Can even help reveal which brain areas are most sensitive to aging and are therefore more closely related to declining behavioral functions among the elderly
