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Screening: Drugs Affecting Memory & Learning
- 1. SCREENING: Drugs Affecting Learning &Memory SHREYA GUPTA
- 2. INTRODUCTION Learning andmemory are closely related concepts. Learning is the acquisition of skill or knowledge, Memory is the expression of what you’ve acquired. Another difference is the speed with which the two things happen, If one acquires the new skill or knowledge slowly and laboriously, that’s learning If acquisition occurs instantly, that’s making a memory https://www.apa.org/topics/learning/
- 3. LEARNING Process ofacquiring new, or modifying existing knowledge, behaviours, skills, values, or preferences Relatively permanent change in behaviour as a result of experience Types: 1. Classical conditioning 2. Operant conditioning 3. Observational learning
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- 7. TYPES OF MEMORY LONGTERM MEMORY: 1. Explicit memory/ Declarative memory Consciously recalled, deals with facts/events Memories can be episodic, relate to experiences or 'episodes' in your life Or, they are semantic, relating to facts or general knowledge Affected by neurodegenerative diseases such as Alzheimer’s disease
- 8. TYPES OF MEMORY LONGTERM MEMORY: 2. Implicit memory/ Procedural memory- Unconscious memory, deals with skills/tasks May be procedural, involving learned motor skills—learning how to ride a bike Or, result from priming, which occurs when exposure to one stimulus influences your brain’s response to another. For example, in word-judging tasks, participants identify pairs of associated words such as bread–butter faster than non- associated pairs such as BREAD–DOCTOR.
- 9. TYPES OF MEMORY SHORTTERM MEMORY: Enables the brain to remember small amount of information for a short period of time Shortest type of memory is working memory, which can last just seconds, used to hold information in brain while we engage in other cognitive processes. A person’s working memory capability is one of the best predictors of general intelligence, as measured by standard psychological tests
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- 12. NEUROTRANSMITTERS ACETYLCHOLINE: increasesneuronal depolarization in cortex, increases memory formation GLUTAMATE: Enhance signal transduction & Synaptic plasticity DOPAMINE: Increase in Limbic region &hippocampus Increases memory GABA: may be involved in long-term object recognition memory and working memory. SEROTONIN: linked to emotional and motivational aspects of human behaviour
- 13. LEARNING DISABILITIES Dyslexia Dysgraphia Dyspraxia Dysphasia Central Auditory Processing Disorder Non-Verbal Learning Disorder
- 14. MEMORY DISORDERS DEMENTIA: Alzheimer'sdisease Dementia with Lewy Bodies (DLB) Frontotemporal Dementia (FTD) HIV Dementia Normal Pressure Hydrocephalus (NPH) Vascular Dementia AMNESIA Korsakoff's Syndrome Transient Global Amnesia (TGA)
- 15. DEMENTIA vs AMNESIA DEMENTIAAMNESIA Impairment of cognition, causing functional decline, severe impairment in memory, judgement, orientation, cognition Memory impairment with no other cognitive impairments Mostly irreversible May be reversible Aging is risk factor Aging not risk factor Slow and gradual Uncertain of beginning point Sudden onset of memory loss Causes: brain trauma Neurodegeneration Genetics Concussion Trauma PTSD Alcoholism
- 16. DRUGS DEHANCING MEMORY Benzodiazepines Statins Antiseizure drugs Opioids Nonbenzodiazepine sedative- hypnotics (Z- drugs) Anticholinergics Antihistamines (first generation) Antipsychotics Alcohol
- 17. DRUGS ENHANCING MEMORY Amphetamines Methylphenidate Modafinil, armodafinil Caffeine, nicotine Guanfacine Clonidine Atomoxetine Piracetam Rivastigmine Tacrine Donepezil Galantamine Memantine Pramipexole
- 18. NEED FOR SCREENING Although over 400 trials have been conducted in people for dementia (Alzheimer’s disease), almost no new drugs have been brought to the market One of major hurdle is the development of appropriate animal models for dementia Successful development of animal models may well depend upon our ability to accurately reproduce specific pathophysiological or etiologic factors https://www.nature.com/articles/d41586-018-05722-9
- 19. In Vitro Tests In Vitro Inhibition of Acetylcholine Esterase Activity in Rat Striatum. In Vitro Inhibition of Butyrylcholine-Esterase Activity in Human Serum Uncompetitive NMDA Receptor Antagonism Molecular Forms of Acetylcholinesterase from Rat Frontal Cortex and Striatum Release of ACh and Other Transmitters from Rat Brain Slices Oxotremorine Binding to Muscarinic Cholinergic Receptors in Rat Forebrain Inhibition of Respiratory Burst in Microglial Cells/Macrophages Stimulation of Phosphatidylinositol Turnover in Rat Brain Slices
- 20. In Vivo Tests Passive avoidance Active avoidance Discrimination testing Animals with memory deficits Upcoming tests
- 21. PASSIVE AVOIDANCE 1. Stepdown method 2. Step through method 3. Scopolamine-Induced Amnesia in Mice
- 22. IN-VIVO METHODS: Inhibitory/Passive Avoidance Evaluates inhibition to imitate activities or learned habits “Passive avoidance” describes experiments in which the animal learns to avoid a noxious event by suppressing a particular behavior.
- 23. STEP-DOWN METHOD PURPOSE ANDRATIONALE An animal (mouse or rat) in an open field spends most of the time close to the walls and in the corners When placed on an elevated platform in the center of a rectangular compartment, it steps down almost immediately to the floor to explore the enclosure and to approach the wall
- 24. STEP-DOWN METHOD PROCEDURE Miceor rats of either sex are used A rectangular box (50 x 50 cm) with electrifiable grid floor Grid floor is connected to a shock device, which delivers scrambled foot shocks Wooden platform (10 × 7 × 1.7 c m) in the center of the grid floor
- 25. STEP-DOWN METHOD Paradigm consistsof three phases: Familiarization: animal is placed on platform, and latency to descend is measured. Returned to home cage after 10s of exploration Learning: Immediately after animal has descended from the platform an unavoidable foot shock is applied (50Hz;1.5mA; 1s) and animal is returned to the home cage Retention Test: 24 h after the learning trial the animal is again placed on the platform and the step down latency is measured. Test is finished when the animal steps down or remains on the platform (cut off time: 60 s).
- 26. STEP-DOWN METHOD EVALUATION Thetime of descent during the learning phase and the time during the retention test is measured Prolongation of the step-down latency is defined as learning.
- 27. STEP – THROUGHMETHOD PURPOSE AND RATIONALE This test uses normal behaviour of mice and rats. Animals avoid bright light and prefer dim illumination. When placed into a brightly illuminated space connected to a dark enclosure, they rapidly enter the dark compartment and remain there
- 28. STEP – THROUGHMETHOD PROCEDURE Mice and rats of either sex are used Apparatus: small illuminated (7W bulb) chamber connected to a larger dark chamber via a door The test animals are given an acquisition trial followed by a retention trial 24 h later Acquisition trial: animal is placed in the illuminated compartment at a maximal distance from door, latency to enter the dark compartment is measured Animals that do not step through the door within a cut-off time: 90 s (mice) or 180 s (rats) are not used
- 29. STEP – THROUGHMETHOD Immediately after the animal enters the dark compartment, door is shut automatically and an unavoidable foot shock (1mA; 1 s – mice; 1.5mA; 2 s – rat) delivered. Animal is then quickly removed (within 10 s) from the apparatus and put back into its home cage. Retention trial: Test procedure is repeated with or without drug, cut-off time on day 2 is 300 s (mice) or 600 s (rats), respectively
- 30. STEP – THROUGHMETHOD EVALUATION The time to step-through during the learning phase is measured and the time during the retention test is measured. An increase of the step-through latency is defined as learning.
- 31. STEP – THROUGHMETHOD Modifications of step through Unilateral ibotenic acid lesions in the right nucleus basalis as a rat model of Alzheimer disease L-DOPA caused memory deficits in mice, recommended this as a model for human dementia.
- 32. CRITICAL ASSESSMENT OFBOTH METHODS High variability, it is necessary to test large groups of animals (minimum 10 animals per group) Tendency of the animal to escape contact with the human hand as it is placed on platform may shorten the step-down/ step through latencies Timing of the electric shock, it must not be applied at the first contact of the animal with the floor, since the light touch with the forelimbs does not cause the required shock intensity. The duration and intensity of the shock should be constant
- 33. SCOPOLAMINE-INDUCED AMNESIA IN MICE PURPOSEAND RATIONALE Scopolamine has been shown to impair memory retention when given to mice shortly before training in a dark avoidance task Based on ability of cholinergic agonist drugs to reverse the amnesic effects of scopolamine in animals and humans
- 34. SCOPOLAMINE-INDUCED AMNESIA IN MICE PROCEDURE Test is performed in groups of 10 male NMRI mice weighing 26–32 g in a one-trial 5min after i.p. administration of 3 mg/kg scopolamine hydrobromide, each mouse is individually placed in the bright part of 2 chambered apparatus for training. After a brief orientation period, mouse enters the second, darker chamber. Once inside the second chamber, the door is closed, a 1mA,1-s foot shock is applied through the grid floor, mouse is then returned to the home cage
- 35. SCOPOLAMINE-INDUCED AMNESIA IN MICE 24 hours later, testing is performed by placing the animal again in the bright chamber Latency in entering second darker chamber within a 5 min test session is measured Untreated control animals enter the darker chamber in the second trial with a latency of about 250 s, while treatment with scopolamine reduces the latency to 50s Test compounds are administered 90min before training. A prolonged latency indicates that the animal remembers that it has been punished and, therefore, does avoid the darker chamber.
- 36. SCOPOLAMINE-INDUCED AMNESIA IN MICE EVALUATION Using various doses, latencies after treatment with test compounds are expressed as percentage of latencies in mice treated with scopolamine Scopolamine amnesia test is widely used as primary screening test anti-Alzheimer drugs
- 37. DRUGS INDUCING AMNESIA N-methyl-d-aspartate antagonists phencyclidine, ketamine, and dizocilpine Chlordiazepoxide and dizocilpine combination in mice Pre-treatment with benzodiazepines Lipopolysaccharide-intoxicated mice as a model for Alzheimer’s disease. Induction of learning and memory impairment in mice by treatment with 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP). Trace amounts of copper in water induce β-amyloid plaques and learning deficits in a rabbit model of Alzheimer’s disease
- 38. ACTIVE AVOIDANCE 1. Runawayavoidance 2. Shuttle box avoidance (2-way shuttle box) 3. Jumping avoidance (1- way shuttle box)
- 39. IN-VIVO METHODS: Active Avoidance Active avoidance learning is a fundamental behavioural phenomenon Learning defined by appropriate reactions to the conditioned stimulus preceding the noxious stimulus It usually allows animal to escape which terminates the conditioned stimulus
- 40. 1. RUNAWAY AVOIDANCE PURPOSE& RATIONALE Straightforward avoidance situation features a fixed aversive gradient(shock) can be traversed by the animal The shock can be avoided when the safe area is reached within the time allocated
- 41. RUNAWAY AVOIDANCE PROCEDURE Miceor rats of either sex used Animal is placed in a box which is uniformly illuminated and has one small door to the safe area A loud speaker is mounted 50 cm above the start box, and provides acoustic conditioning stimulus (80db,2000Hz tone) 5min animal is allowed to explore the whole apparatus. Door is then closed and the animal is placed into the light starting area. After 10 s the acoustic CS is applied and the door is simultaneously opened. Shock is turned on after 5 s.
- 42. RUNAWAY AVOIDANCE CScontinues until the animal reaches the safe area. It is left there for 50–70 s (intertrial interval, ITI) before returned to the same area again Training is continued until the animal attains the criterion of 9 avoidances in 10 consecutive trials
- 43. 2. SHUTTLE BOXAVOIDANCE (2-way shuttle box) PROCEDURE Rats of both sex are used Apparatus used consists of rectangular box 15 cm x 40 cm high metal walls and electrifiable grid floor It is divided into two 25x25 compartments by a wall and a small door Each compartment can be illuminated by a 20w bulb mounted in lid Fixed resistance shock source with an automatic switch (0.5 s on 1.5 s off) is used for automatic delivery of the conditioned stimulus (CS) and the unconditioned stimulus (US)
- 44. SHUTTLE BOX AVOIDANCE (2-wayshuttle box) Animal allowed to explore the apparatus for 5 min with the connecting door open and the compartment lights switched off Door is then closed After 20 s light is switched on in the compartment containing the animal, and the door is opened. A tone (CS, 80 dB, 2000Hz) is presented and 5 s later floor shock(US) is applied in the illuminated compartment and continued until the animal escapes to the dark side of the compartment The connecting door is closed and the shock discontinued
- 45. SHUTTLE BOX AVOIDANCE (2-wayshuttle box) After a variable intertrial interval (ITI; 30–90 s) light is switched on in the previous dark compartment, The door is opened and animal is required to cross to the other side The training is continued until the animal reaches the criterion of 9 avoidances in 10 consecutive trials.
- 46. 3. JUMPING AVOIDANCE (1-way shuttle box) PROCEDURE Apparatus is a rectangular box of 40x25 and a grid floor and one goal area (platform) with narrow walls Animal is allowed to explore goal area for 5 min. After that goal is blocked for 2s and acoustic conditional stimulus (100Hz; 85db) is applied, after 5 min shock (1mA; 50Hz;0.5s) applied Animal jumps on the platform. After 30 s the barrier pushes the animal off the platform onto the grid floor Sequence is repeated until the criterion of 10 consecutive avoidances is reached. Retention is tested on the second day
- 47. AVOIDANCE TESTING EVALUATION Thetime the animal needs to reach the safe area on 2 consecutive days measured Number of errors (not reaching the safe area) recorded. CRITICAL ASSESSMENT OF THE METHOD Automated method since no manual handling of animal between trials Early extinction of response may be seen if intertrial intervals are short
- 48. DISCRIMINATION LEARNING 1. Spatial habituallearning 2. Spatial learning in radial arm maze 3. Olfactory learning
- 49. 1. SPATIAL HABITUALLEARNING PURPOSE & RATIONALE Uses open-field test to utilize natural tendency of rodents to explore novel environments in order to open up new nutrition, reproduction and lodging resources Spatial habituation learning: Decrement in reactivity to a novel environment after repeated exposure to that now familiar environment This reduction in exploratory behaviour during re-exposures is interpreted in terms of remembering or recognition of the specific physical characteristics of the environment
- 50. SPATIAL HABITUAL LEARNING Testcan be used to examine: Short-term spatial memory (within-trial reductions in exploratory activity) Long-term spatial memory (between-trial reductions in exploratory activity after a retention interval of 24, 48 or 96 h after the initial exposure)
- 51. SPATIAL HABITUAL LEARNING PROCEDURE Open-field apparatus: rectangular chamber (rats: 60 x 60x40 cm, mice: 26x26x40 cm) made of painted wood or grey PVC 25W green or red light electric bulb is placed directly above the maze to achieve an illuminated density of 0.3lx at the centre Rodent is placed on the center or in a corner of the open-field for 5–10 minute sessions Animals are re-exposed to the open field 24 and 96 h after the initial trial
- 52. SPATIAL HABITUAL LEARNING EVALUATION Theexploratory behaviours registered are: Rearing or vertical activity: the number of times an animal was standing on its hind legs with forelegs in the air or against the wall Duration of each rearing Locomotion or horizontal activity: the distance in centimetres an animal moved
- 53. 2. SPATIAL LEARNINGIN THE RADIAL ARM MAZE PURPOSE & RATIONALE Allows the study of spatial reference and working memory processes in the rat Rat uses spatial information to efficiently locate the baited arms.
- 54. SPATIAL LEARNING INTHE RADIAL ARM MAZE Apparatus is wooden elevated eight-arm radial maze with arms extending from a central platform 26 cm in diameter Each arm is 56 cm long, 5 cm wide, 2 cm high rails along the length of the arm Maze is well illuminated Food pellets (reward) placed at the end of the arms
- 55. SPATIAL LEARNING INTHE RADIAL ARM MAZE During the test, rats are fed once a day and their body weights maintained at 85% of their free feeding weight to motivate the rat to run the maze. Animals are trained on a daily basis in the maze to collect the food pellets Session is terminated after 8 choices and the rat has to obtain the maximum number of rewards with a minimum number of errors Number of errors (entries to non-baited arms) are counted during the session.
- 56. SPATIAL LEARNING INTHE RADIAL ARM MAZE EVALUATION Used to determine the neurobiological mechanisms underlying spatial learning in rodents and to evaluate the effect of drugs Deleterious effects: scopolamine, atropine, ethanol, benzodiazepines, haloperidol, ketamine, PCP Facilitatory effects: physostigmine, nicotine, picrotoxin, naloxone have been tested
- 57. 3. OLFACTORY LEARNING PURPOSEAND RATIONALE Odours provide rodents with important information on environment Odour reward associations exert more discriminative control over other sensory modalities like tones or light Animals have to learn to discriminate an arbitrary designated positive odour (i. e., banana) from a negative one (i. e., orange) to receive a reward
- 58. OLFACTORY LEARNING PROCEDURE Animalis deprived of water for 48h Apparatus is box 30x30x55cm with a photo sensitive cell on the top of water spout Rats are trained to approach the water spout and to break the light beam Responses to the positive order are awarded Session terminates when rat makes 90% correct choices.
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- 60. OLFACTORY LEARNING EVALUATION Animalis rewarded with 0.05 ml of water when it breaks the beam to the positive odor or when it does not respond to the negative odor Incorrect responses (“no go” to the positive odor or “go” to the negative odor are followed by a flash and a longer intertrial interval). Results are reported as the % correct responses or as a %correct/incorrect response ratio.
- 61. OLFACTORY LEARNING CRITICAL ASSESSMENTOF THE TEST Anatomical connections from olfactory bulbs to cortical and subcortical areas are known, and brain lesions that impair olfactory discrimination learning could be used as models of amnesia Systemic injections of scopolamine, PCP impair acquisition of odour discriminations
- 62. ANIMALS WITH MEMORY DEFICITS 1.Memory Deficits After Cerebral Lesions 2. Cognitive Deficits After Cerebral Ischemia 3. Naturally occurring models 4. Transgenic models
- 63. 1. MEMORY DEFICITSAFTER CEREBRAL LESIONS Cerebral lesions used as a method of determining involvement of a particular brain area in performing a particular function. By training an animal to perform a certain task, then lesioning a specific brain area, one can determine whether that area of the brain is necessary or sufficient to perform that function
- 64. MEMORY DEFICITS AFTER CEREBRALLESIONS ASPIRATIVE ELECTRICAL CHEMICAL • Sucking out the tissue of interest. • Lesions not selective with respect to tissue type. • Neurons, support cells, and fibers coursing through the area are all eliminated • Electrical lesions are also non-selective • They destroy all tissue types in the lesion area • studies in monkeys : 1. model of episodic memory impairment in with fornix transection 2. memory functions studied with lesions of the hippocampus and adjacent cortex • Injecting chemical agents into specific brain sites. • Induce more selective lesion, typically destroying cell bodies and dendrites while sparing axons
- 65. MEMORY DEFICITS AFTER CEREBRALLESIONS Chemically induced cerebral lesions: Most commonly used neurotoxins in memory research are glutamate, and glutamate analogs such as ibotenate, NMDA, kainate and AMPA Intracerebroventicular injection of streptozotocin,in a rats, causes prolonged impairment of brain glucose and energy metabolism Cyclooxygenase-2 inhibitor into the dorsal hippocampus attenuates memory acquisition in rats MPTP-treated rhesus monkeys.
- 66. 2. COGNITIVE DEFICITSAFTER CEREBRAL ISCHEMIA PURPOSE & RATIONALE Impairment of cerebral metabolism induced by reduced blood supply induces cognitive deficits In the brain of Mongolian gerbils, complete forebrain ischemia can be produced by occluding both common carotid arteries resulting in amnesia
- 67. COGNITIVE DEFICITS AFTER CEREBRALISCHEMIA PROCEDURE Male Mongolian gerbils (50–70 g)used, anesthetized by i.p. pentobarbital injection. Both common carotid arteries are exposed, occluded for 5 or 10min with miniature aneurysm clips In sham operated controls, carotids exposed, not occluded 24 h after occlusion, each animal is placed in the bright part of a light/dark chambered apparatus for training. After a brief orientation period, the gerbil enters the second, dark chamber.
- 68. COGNITIVE DEFICITS AFTER CEREBRALISCHEMIA Once inside the second chamber, the door is closed, a 100V, 2- s foot shock is applied through the grid floor. The gerbil is then returned to the home cage. Testing is repeated 24 h later by placing the animal again in the bright chamber Latency in entering the dark chamber within a 5-min test session is measured Latency compared with sham operated controls is decreased depending on the duration of ischemia. After drug treatment, an increase of latency before entering the dark compartment indicates good acquisition.
- 69. 3. NATURALLY OCCURING MODELS Normal and aged rodents: Normal aging Senescence-accelerated mouse(SAM): signs of advanced senescence, such as reduced activity, hair loss, skin coarseness, peri-ophthalmic lesions, age-associated increase in hippocampal Aβ and behavioural impairment, and shortened life span
- 70. 4. TRANSGENIC MOUSEMODELS OF DEMENTIA Human Tau models Tg2576 model of AD PS1 FAD models APP23 model Secretase models APOE models Axonal transport models
- 71. UPCOMING MODELS OF ALZHEIMER'SDISEASE • Non human- Primate models • Mini Brains
- 72. 1. NON-HUMAN PRIMATE MODELS Marmoset model of Alzheimer’s disease: by using CRISPR to insert mutations into the gene PSEN1 in fertilized eggs, acquire amyloid plaques in 7 years https://www.nature.com/articles/d41586-018-05722-9 Macaques : injecting them with brain tissue from humans, which leads the animals to develop plaques and tau tangles, as well as cognitive impairment
- 73. 2. MINI BRAINS 3D tissue models of the brain Small organoids are grown from stem cells over period of a few weeks, Enable large numbers of drugs to be evaluated in a short amount of time HMS in Boston, Massachusetts (2014) grew human neural stem cells containing APP and PSEN1 mutations in a 3D culture system supported by a gel matrix
- 74. MINI BRAINS • Tissuecontained neurons that deposited amyloid-β into the gel, and plaques formed after 5 to 6 weeks. • A week or two later, the elusive tau tangles also appeared https://www.nature.com/articles/d41586-018-05722-9
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- 77. References Drug Discoveryand Evaluation Pharmacological Assays Co-Editors: Wolfgang H.Vogel Bernward A. Schölkens Jürgen Sandow Günter Müller Wolfgang F. Vogel Second Edition. Elder GA, Gama Sosa MA, De Gasperi R. Transgenic mouse models of Alzheimer's disease. Mt Sinai J Med. 2010 Jan-Feb;77(1):69-81. doi: 10.1002/msj.20159. PMID: 20101721; PMCID: PMC2925685. Meneses, A. (2014). Neurotransmitters and Memory. Identification of Neural Markers Accompanying Memory, 5–45.doi:10.1016/b978-0-12-408139- 0.00002-x https://www.nature.com/articles/d41586-018-05722-9 https://www.hopkinsmedicine.org/neurology_neurosurgery/centers_clinics/me mory_disorders/conditions/dementia.html https://www.sciencedirect.com/topics/medicine-and-dentistry/avoidance- response
Editor's Notes
- #8 Explicit memory- consciously recalled memories can be episodic, relate to experiences or 'episodes' in your life (e.g., a particular holiday or the first time you were stung by a bee); or, they are semantic, relating to facts or general knowledge
- #9 implicit, or unconscious memory. These unconscious memories may be procedural, involving learned motor skills—learning how to ride a bike or how to type using a keyboard, for example. Implicit memories can also result from priming, which occurs when exposure to one stimulus influences your brain’s response to another. For example, in word-judging tasks, participants identify pairs of associated words such as BREAD–BUTTER faster than non-associated pairs such as BREAD–DOCTOR.
- #10 An example is remembering the numbers a new friend recites as you navigate your phone’s menu system to add a contact
- #11 First, the spinal cord receives and processes the sensory information that is collected from the outside world (your surroundings) and passes it to the brain stem. It then reaches the thalamus, which is known to be the "relay station" because it controls all of the flowing information in the brain and sends it to the appropriate region for further processing. The thalamus sends information to various cortices in the brain depending on the type of sensory input. For example, if you memorized something that you saw with your eyes then the thalamus would send the information to the occipital lobe (visual cortex). If you are a professional dancer, you are likely to memorize many dance routines and movements. Thus, if you were memorizing motor movement then the thalamus would send the information to the cerebellum, where it functions in body coordination and precision. Once information is sent to the appropriate cortices then it goes to the prefrontal cortex, where it analyzes and makes sense of the information. This is also where consciousness, planning, and logic is found in the brain. Finally, the last stop is the hippocampus. This region of the brain functions in storing both short and long term memory. When you recall or store information, this is where it comes from. Amazing right?
- #12 spatial memory is that part of the memory responsible for the recording of information about one's environment andspatial orientation.
- #33 be done by using a white noise generator (60–70dB).
- #34 Neuropathology of dementia of the Alzheimer type is not confined to the cholinergic system but NMRI outbred model was developed by Lynch et al. Poiley of the National Institutes of Health received stock from Lynch in 1937. The mice were inbred as NIH/P1. The Naval Medical Research Institute (NMRI) received stock from Lynch.
- #37 In spite of the fact that the pathogenesis of primary degenerative dementia (Alzheimer’s disease) in man has been only partially elucidated, the scopolamine amnesia test is widely used as primary screening test anti-Alzheimer drugs
- #46 After a variable intertrial interval (ITI; 30–90 s) the light is switched on in the previous dark compartment, the door is opened and the animal is required to cross to the other side. The training is continued until the animal reaches the criterion of 9 avoidances in 10 consecutive trials. Retention is tested at different intervals after the original training by retraining the animal to the same criterion again.
- #50 The rate of exploratory behaviour in an unfamiliar environment is limited through the inherent necessity to avoid potential dangers Therefore, observed behaviour is always a compromise between these conflicting interests
- #53 Rodents exposed to a big sized brightly lit open field tend to spent more time in the corners or close to the wall and avoid the central part of the apparatus. The emotional behaviors registered are: (1) Corner time: the time spent in the 4 corner squares (rats: 15 Å~ 15 cm; mice: 6.5 Å~ 6.5 cm). (2) Wall time: the time an animal spent close to the wall as a measure for thigmotaxis (scanning the walls of the apparatus with the vibrissae). (3) Center time: the time spent in the center of the open field (rats: 20 Å~ 20 cm; mice: 10 Å~ 10 cm). (4) Defecation: number of boli deposited. (5) Freezing: the time the animal stays completely immobile except for movements associated with respiratory activity (
- #57 One of the disadvantages of the test is that hypothalamic lesions or the anorectic effect of certain drugs (amphetamine) affect the appetitive nature of the maze and animals do not master the maze for this reason.
- #58 and the learning of successive olfactory discrimination problems in rats is closely related to the acquisition rules of higher primates.
- #68 . In shamoperated controls, the common carotid arteries are exposed but not occluded.
- #71 nictitating membrane is a transparent or translucent third eyelid present in some animals that can be drawn across the eye for protection and to moisten it while maintaining vision. The term comes from the Latin word nictare, meaning "to blink". It is often called a third eyelid or haw, and may be referred to in scientific terminology as the plica semilunaris, membrana nictitans, or palpebra tertia. Unlike the upper and lower eyelids, the nictitating membrane moves horizontally across the eyeball. APOE2Knock-InAPOE2 insertedwith expressionregulated byendogenousregulatoryelements and themouse APOEgene inactivated Transgenic modeling in mice is relatively inexpensive. Mice also have a relatively short life span, and the techniques for performing genetic modifications in them are well developed.
- #73 Non-human primates, which include rhesus macaques and marmosets, are not known to develop Alzheimer’s disease. However, like humans, they do accumulate deposits of amyloid-β in their brains. The brains of these animals also undergo structural and biochemical changes as they age that mirror those seen in people. However, most such primates do not develop tau tangles, and their use in research is accompanied by a host of practical challenges and ethical considerations.