Biological basis of memory

memory its definition, classification, anatomy related to its and its biological basis

1. BIOLOGICAL BASIS OF MEMORY Karrar husain Moderator : Dr. Piyush P. Singh

2. Memory is fundamental to the discipline of psychiatry. Memory connects the present moment to what came before and is the basis for the formation of one's life story. Personality is, in part, a set of acquired habits that have been learned, many early in life, that create dispositions and determine how people behave. Neuroses can be products of learning—anxieties, phobias, and maladaptive behaviors that result largely from experience. Psychotherapy itself is a process by which new habits and skills are acquired through the accumulation of new experiences. INTRODUCTION

3. Memory is also of clinical interest because disorders of memory and complaints about memory are common in psychiatric illness. Memory problems occur in association with certain treatments, notably electroconvulsive therapy (ECT).

4. Our memory stores: Our personal experiences Emotions Preferences/dislikes Motor skills World knowledge Language Fundamentally, we as a person are derived from experiences that have been stored in our nervous system .

5. Definition “Memory is the ability to store, retain and retrieve information ”. word “memory” comes to us from the Anglo-French memoire or memorie , and ultimately from the Latin memoria and memor , meaning "mindful" or "remembering“.

6. Learning vs memory Squire (1987) Learning - process of acquiring new information Memory - persistence of learning in a state that can be revealed at a later time. Learning has an outcome - memory - which itself has a further outcome - a change in future behaviour. Learning need not imply any conscious attempt to learn. Simple repeated exposure can, and indeed usually does, lead to learning, and this is evinced by memory.

7. Storage (Maintain in memory) Retrieval (Recover from memory) Encoding (Code and put into memory) Basic Memory Processes

8. Historical Foundations: The Golden Age About 30 years ago Paul Rozin described the last decade of the 19th Century as the “Golden Age of Memory” because during that era many of the basic phenomena and ideas that still occupy researchers emerged. Paul Rozin

9. Historical Foundations: The Golden Age Théodule Ribot proposed that during disease of the brain, memories disappear in an orderly fashion. The Dissolution of Memory First Last

10. Ribot’s Law: Ribot also proposed that old memories are more resistant to disease/disruption than new memories.

11. Historical Foundations: The Golden Age Serge Korsakoff Described the syndrome produced by alcohol now called Korsakoff’s Syndrome. The syndrome is characterized by what we would now call anterograde amnesia —the inability to acquire new memories. During the late stages there is also retrograde amnesia —the loss of memories acquired before the onset of the disease. He also proposed that amnesia could be due to either storage failure or retrieval failure.

12. Historical Foundations: The Golden Age William James proposed that memories emerge in stages. An after image is supported by a very short-lasting trace, then replaced by the primary trace that also decays. Secondary memory is viewed as the reservoir of enduring memory trace that with an appropriate retrieval cue can be recalled.

13. Historical Foundations: The Golden Age Santiago Ramón y Cajal The Neuron Doctrine : The idea that the brain is made up of discrete cells called nerve cells, each delimited by an external membrane. The Synaptic Plasticity hypothesis : The idea that the strength of a synaptic connection can be modified by experience.

14. Historical Foundations: The Golden Age In the Pavlovian conditioning method, two events called the CS and US are presented together. Subsequently, the CS evokes the response called the CR. Psychologists assume that the CS evokes the CR because the CS gets associated with the US. Psychologists and neurobiologists continue to use this method to study associative learning in animals. Ivan P. Pavlov Developed the fundamental methodology for studying associative learning in animals.

15. Figure 1.8 Pavlovian conditioning is widely used to study learning and memory in animals

16. TYPES OF MEMORY Sensory Memory Short-term (Secondary, Working) Long-term (Primary) Declarative (knowing what) Non declarative Episodic semantic

17. Time base of memory Memory model of Atkinson & Shiffrin (1986 ). Sensory memory is sub-second to seconds, as when we can recover what was said when we weren’t paying attention. Short term is seconds to minutes, as with retaining a phone number. Long-term is longer—days, weeks, going up to years, or even a lifetime. 17

18. Information-Processing Model of Memory (Atkinson- Shiffrin  model) Short-term memory Stimulus Sensory memory Long-term memory Attention Encoding Retrieval Forgetting Forgetting Forgetting

19. Ultrashort -term (sensory) memory Ability to retain impressions of sensory information after the original stimuli have ended. System via which perception enters memory system Iconic memory-200 milliseconds Echoic memory – 2000 milliseconds Memory of olfaction

20. S hort-term memory, L asts seconds to hours, during which processing in the hippocampus and elsewhere lays down long-term changes in synaptic strength Limited capacity system (7 + 2 chunks of information). Lost on distraction .

21. L ong-term memory which stores memories for years and sometimes for life. Capacity is unlimited. Depend upon change in neuronal structure. During short-term memory, the memory traces are subject to disruption by trauma and various drugs, whereas long-term memory traces are remarkably resistant to disruption

22. Working memory is a form of short-term memory that keeps information available, usually for very short periods, while the individual plans action based on it. It consists of a central executive located in the prefrontal cortex, and two "rehearsal systems," a verbal system for retaining verbal memories, and a parallel visuospatial system for retaining visual and spatial aspects of objects ( Baddeley , 2001) . The executive steers information into these rehearsal systems

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24. Working memory is modulated by dopamine. Working memory at bedside can be tested by digit span backwards.( harrison )

25. FROM SYNAPSES TO MEMORY Memory is a special case of the general biological phenomenon of neural plasticity. Neurons can show history-dependent behavior by responding differently as a function of prior input, and this plasticity of nerve cells and synapses is the basis of memory

26. Neuro -Plasticity Neurobiological evidence supports two basic conclusions. First, short-lasting plasticity, which may last for seconds or minutes, depends on specific synaptic events, including an increase in neurotransmitter release. Second, long-lasting memory depends on new protein synthesis, physical growth of neural processes, and an increase in the number of synaptic connections

27. Short- and long-lasting plasticity are based on enhanced transmitter release, although the long-lasting change uniquely requires the expression of genes and the synthesis of proteins. the long-term change is also accompanied by growth of neural processes of neurons within the reflex circuit

28. In vertebrates, behavioral manipulations can also result in measurable changes in the brain's architecture. For example, rats reared in enriched environments show an increase in the number of synapses, small increases in cortical thickness, inc. in the diameter of neuronal cell bodies, and inc. in the number and length of dendritic branches. Behavioral experience thus exerts powerful effects on the wiring of the brain.

29. Long-Term Potentiation LTP is observed when a postsynaptic neuron is persistently depolarized after a brief burst of high-frequency presynaptic stimulation. LTP has a number of properties that make it suitable as a physiological substrate of memory. First, it is established quickly and then lasts for a long time. Second, it is associative in that it depends on the cooccurrence of presynaptic activity and postsynaptic depolarization.

30. Third, it occurs only at the potentiated synapses, not at all the synapses terminating on the postsynaptic cell. Finally, LTP occurs prominently in the hippocampus, a structure with important memory functions The induction of LTP is mediated postsynaptically and involve activation of the N-methyl-D- aspartate (NMDA) receptor, which permits the influx of calcium into the postsynaptic cell.

31. Associative Learning Additional insights into memory have come from the study of the neural circuitry underlying the classical conditioning of the eye blink–nictitating membrane response in rabbits. Repeated pairings of a tone (conditioned stimulus) and an air puff to the eye (unconditioned stimulus) lead to a conditioned eye blink in response to the tone. Reversible lesions of the deep nuclei of the cerebellum eliminate the conditioned response without affecting the unconditioned response. These lesions also prevent initial learning from occurring, and, when the lesion is reversed, rabbits learn normally. Thus, the cerebellum contains essential circuitry for the learned association.

32. Molecular basis of memory LTP (long term potentiation ) induction of LTP requires an influx of Ca through NMDA into the postsynaptic cell. The Ca activates directly or indirectly at least three protein kinases: (1) calcium/calmodulin protein kinase II , (2) protein kinase C and (3) the tyrosine kinase

33. Ca2+/ calmodulin kinases , protein kinase c and tyrosine kinases promoting phosphorylation of neurotransmitter receptors LTP is associated with a selective increase in the AMPA-type receptor component of the EPSP the increase in response of the AMPA-type receptors is due to a rapid insertion of new clusters of receptors in the postsynaptic membrane from a pool of intracellular AMPA type receptors stored in recycling endosomes The activation of the molecules involved in these signalling pathways can last for minutes and thereby represent a sort of short-term “molecular memory ”

34. Short term to long term memory Consolidation of memory requires protein synthesis repeated exposure  PK-A recruits MAPK Both PKA and MAPK moves from the synapse to the nucleus of the cell where MAPK phosphorylates and inactivates the transcriptional repressor CREB2 PKA activates the transcription factor, CREB-1 (the cAMP response element-binding protein). CREB-1 acts on downstream genes to activate the synthesis of protein and the growth of new synaptic connections.

35. Structures involved in memory Hippocampal formation ( the dentate gyrus , the hippocampus, and the subicular complex) and linked regions of medial temporal lobe with prefrontal cortex play a critical role in encoding and retrieval of episodic memory. diencephalon structures : medial thalamus, mammilary body and fornix Interaction b/w HF and amygdala are important for emotional memories. Fear conditioning and extinction  interaction b/w amygdala and cingulate gyrus

36. basal ganglia and cerebellum is important for procedural memory Priming  neocortex DLPFC( dorsolateral prefrontal cortex)  working memory. Neocortex is the ultimate store of memory.

37. CORTICAL ORGANIZATION OF MEMORY In the 1920s, Karl Lashley carried out a series of experiments. Lashley recorded the number of trials that rats needed to relearn a preoperatively learned maze problem after removal of different amounts of cerebral cortex. The deficit was proportional to the amount of cortex removed, and, furthermore, it seemed to be qualitatively similar regardless of the region of cortex that was removed. Lashley concluded that memory for the maze habit was not localized in any one part of the brain but instead was distributed equivalently over the entire cortex.

38. Subsequent work has led to a revision of this idea. Maze learning in rats depends on many forms of information, including visual, tactual, spatial, and olfactory information. These various forms of information are processed and stored in different areas. Thus, the correlation between retention score and lesion size that Lashley observed reflected the progressive encroachment of the lesion on specialized cortical areas serving the many components of cognition important to maze learning.

39. Memory is distributed and localized in the nervous system. Memory is distributed in the sense that, as Lashley concluded, there is no single cortical center dedicated solely to the storage of memories. Yet, memory is localized in the sense that different aspects or dimensions of events are stored at specific cortical sites—the same regions that are specialized to analyze and process those particular aspects or dimensions of information.

40. Acetylcholine and Memory . Two sets of acetylcholine projections are , Arising from the brainstem neurotransmitter center . Arising from the basal forebrain. Basal nucleus, or nucleus basalis (of Meynert ), as well as the medial septal nucleus These cholinergic fibers  a prominent role in memory (S. Stahl textbook of psychoparmacology )

41. Both animal and human studies  Nucleus Basalis of Meynert in the basal forebrain is the major brain center for cholinergic neurons that project throughout the cortex . Have the principal role in mediating memory formation. Short-term memory disturbance of Alzheimer patients is due to degeneration of these cholinergic neurons. Other cholinergic neurons, such as those in the striatum and those projecting from the lateral tegmental area , are not involved in the memory disorder of Alzheimer’s disease. harrison’s principle of internal medicine.

42. “Cholinergic deficiency  degeneration limited to the nucleus basalis of the basal forebrain  mild cognitive impairment. Cholinergic deficiency may also be a part of vascular dementia or of alcoholic dementia. This may be why some patients with vascular dementia or alcohol-related dementias respond to cholinesterase inhibitors.

43. Lewy bodies damage cholinergic neurons in DLB. Cholinergic deficiency may also become part of these dementias. May respond to cholinesterase inhibitors. When tau pathology affects the frontal and temporal lobe in frontotemporal dementia, the memory disturbance, personality changes, disinhibition , of this dementia are not generally improved by cholinesterase inhibitors, because the pathology and these symptoms do not arise from cholinergic neurons. S.Sthal textbook of psychopharmacology

44. Insights from AMNESIA “the ability to learn new information or the inability to recall previously learned information” The idea that the functional specialization of cortical regions determines the locus of information processing as well as the locus of information storage is important, but it does not provide a complete account of the organization of memory in the brain. If it did, then particular cortical injuries would disrupt only particular domains of learning and memory (i.e., visual memory or spatial memory). In other words, a global disruption of memory would never occur.

45. The hallmark of neurological memory impairment is a profound loss of new learning ability, or anterograde amnesia, that extends across all sensory modalities. Typically, this occurs together with retrograde amnesia, a memory loss of some knowledge acquired before the onset of amnesia. The retrograde deficit often has a temporal gradient, such that memory for recent events is impaired, but memory for remote events is intact. Other cognitive functions are preserved, including linguistic abilities, attention, immediate memory, personality, and social skills

46. This selectivity of the memory deficit in amnesia implies that the brain has, to some extent, separated its intellectual and perceptual functions from the capacity to lay down in memory the records that ordinarily result from intellectual and perceptual work. The fact that impaired new learning ( anterograde amnesia) can occur together with intact remote memory indicates that retrieval mechanisms are intact and that the brain structures damaged in amnesia are not the ultimate repositories of memory.

47. Common causes of amnesia Traumatic Brain Injury (TBI) Surgery Infarctions Alcohol and Illicit Drugs Vitamin Deficiencies Neurotoxins Anoxia and hypoxia Electroconvulsive Therapy Limbic Encephalitis

48. The temporal lobe and memory 1940s and 50s: neurosurgical treatments for epilepsy. Removal of medial temporal lobe, including the hippocampal formation  resulted in dramatic memory impairments, only if bilateral. Patient HM - Increasing frequency of his temporal lobe epilepsy led to bilateral surgery – 1953 when he was 27 years old. He remained of normal intelligence and had no psychological illness. However, the surgery resulted in intense anterograde amnesia 54

49. Patient HM Severe anterograde amnesia normal STM Normal LTM (for events prior to surgery) Problem : transfer from STM to LTM Could not consolidate new declarative knowledge Capable of acquiring implicit knowledge amygdala , uncus , hippocampal gyrus , and anterior two thirds of the hippocampus were removed.

50. hippocampus is not a permanent storage area for explicit knowledge. hippocampus is involved [with other cortical areas] in consolidation , a longer term process taking months to years (note retrograde amnesia in hippocampus lesion patients for up to 3 yrs). Consolidation is understood to involve biological changes taking place in those other areas of cortex, and involving strengthening of the associations between multiple stimulus inputs and previously stored information. Once this has fully taken place, the hippocampus is not required for retrieval. 56

51. Frontal lobe and Memory Although amnesia does not occur after limited frontal damage, the frontal lobes are fundamentally important for declarative memory. Patients with frontal lesions have poor memory for the context in which information was acquired, they have difficulty in free recall, and they may even have some mild difficulty on tests of item recognition.

52. Patient B. G . suffered an infarction restricted to the right frontal lobe, resulting in substantial false remembering. He had an abnormal tendency to claim that some stimuli were familiar, even though they had not been presented for study. His false responses probably arose because he relied on a general feeling of familiarity for the kind of stimuli that had been presented, rather than on specific memories for the stimuli.

53. Korsakoff's syndrome diencephalic amnesia Korsakoff's syndrome is characterized by a pronounced anterograde and retrograde amnesia and potential impairment in visuospatial , abstract, and other types of learning. result of a relatively severe deficiency in the vitamin B thiamine Degeneration of the mammillary bodies is the neuropathological hallmark of a Korsakoff's psychosis regions likely include the mammillary nuclei, the dorsomedial nucleus of the thalamus, the anterior nucleus, the internal medullary lamina, and the mammillothalamic tract

54. Patients with alcoholic Korsakoff's syndrome typically have frontal lobe pathology in addition to diencephalic damage Confabulation and personality change are more common in diencephalic amnesia (e.g., Korsakoff's syndrome) than in pure hippocampal amnesia, perhaps reflecting a concomitant involvement of frontal lobe structures or connections

55. MEMORY LOSS IN ALZHEIMERS DISEASE Degeneration of cholinergic neurons due to deposition of amyloid plaque may begin early within the nucleus basalis of the basal forebrain at the time of vague and undiagnosed memory symptoms. Spreading to projection areas such as hippocampus, amygdala , and entorrhinal cortex by the time of early diagnosis. Then diffusely throughout neocortex by the time of nursing home placement and loss of functional independence. Eventually involving the loss of a great many neurons and neurotransmitter systems by the time of death.

56.  Episodic memory  is impaired first; Then short-term memory  Then semantic memory  Finally procedural memory However, as the disease advances, parts of memory which were previously intact also become impaired, and eventually all reasoning, attention, and language abilities are disrupted.

57. Electroconvulsive Therapy ECT produces a transient amnesia, manifested by a diminished ability to form new memories during the period of treatment. The amnesia remits within days or, at most, a few weeks after completion of treatment. The patient is left with a retrograde amnesia for many events during the days or weeks of treatment.

58. Psychogenic amnesia Also k/a dissociative amnesia/ functional amnesia characterized by abnormal memory functioning in the absence of structural brain damage or a known neurobiological cause. It results from the effects of severe stress or psychological trauma on the brain, Psychogenic amnesias typically do not affect new learning capacity The main positive symptom in psychogenic amnesia is extensive and severe retrograde amnesia

59. Patients may be unable to recall their own name or to recollect pertinent information from childhood or from some part of their past By contrast, patients with neurological amnesia never forget their names, and their remote memories for the events of childhood and adolescence are typically normal Some patients with psychogenic amnesia have circumscribed retrograde memory loss that covers a particular time period or that covers only autobiographical memories

60. Assessment of memory A complete assessment of memory usually involves assesment of intellectual functions, new learning capacity, remote memory, and memory self-report.

61. New Learning Capacity two important principles First, tests are sensitive to memory impairment when more information is presented than can be held in immediate memory. e.g. paired-associate task Second, tests are sensitive to memory impairment when a delay, filled with distraction, is interposed between the learning phase and the test phase. Memory can be tested by unaided recall of previously studied material (free recall), by presenting a cue for the material to be remembered (cued recall), or by testing recognition memory (yes–no recognition tests, multiple-choice tests)

62. Remote Memory Autobiographical memory tests : word-probe task-patients are asked to recollect specific episodes from their past in response to single word cues (for example, bird and ticket) and to date the episodes. normal subjects  Most of the memories come from recent time periods (the past one or two months). Patients with amnesia  few episodic memories from the recent past, but producing as many remote autobiographical memories as normal subjects. Test about material in the public domain e.g. about former one-season television programs, news events, or photographs of famous persons.

63. Memory Self-Reports Patients can often supply descriptions of their memory problems Tests used are called tests of metamemory Depressed patients  rate their memory as poor in a rather undifferentiated way, endorsing equally all the items on a self-rating form. amnesic patients  endorse some items more than others; that is, there is a pattern to their memory complaints. Amnesic patients do not report difficulty in remembering very remote events or in following what is being said to them, but they do report having difficulty remembering an event a few minutes after it happens

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65. References Kaplan & Sadock's Comprehensive Textbook of Psychiatry, 9th Edition Review of Medical Physiology, William F. Ganong , Twenty- third Edition Biology of memory , Larry r. Squire, ph.D ., And kena . Paller , ph.D . Stahl essential psychopharmacology Harrison textbook of internal medicine,18 th edition. Cognitive Neuroscience and the Study of Memory Brenda Milner, March , 1998 Neuron, Vol. 20, 445–468.

66. The molecular biology of memory: cAMP , PKA, CRE, CREB-1, CREB-2, and CPEB, Eric R Kandel , Molecular Brain 2012, 5:14 The Biology of Memory: A Forty-Year Perspective, Eric R. Kandel , The Journal of Neuroscience, October 14, 2009 • 29(41):12748 –12756 New Oxford Textbook of Psychiatry (2 ed.)