M-I Neurosciences Dr. Thomas M. Reeves Learning and Memory Objectives: 1. Describe the current understanding of the areas of the brain involved with memory storage and retrieval. 2. Describe the current understanding of the areas of the brain involved in the learning of motor and perceptual skills. 3. Describe selective neuropathologies affecting learning and memory. Introduction In recent decades, clinical and experimental observations have enabled considerable progress in our understanding of the nature of learning and memory. A large body of knowledge now exists which documents this evolving story, in both fact and theory, of how memories are established and retrieved, and how these processes may fail, for example with age, disease or injury. The material in this syllabus summarizes key aspects of the subject area of learning and memory, emphasizing the growing appreciation for distinct types of memory systems implemented in different anatomical regions of the brain. After a careful reading of this material, the student should possess a conceptual framework to better understand the methods and findings in this area. In a broad sense, learning is the process by which experience changes our nervous system and hence our behaviors. Thus, learning is one way in which the organism adapts to its environment, which itself may be in flux. These learning episodes may range from extremely simple to extraordinarily complex. Figure 1 shows that a basic distinction can be made between associative vs. nonassociative learning. As the name implies, associative learning is a process whereby new associations are established between experiences. In this way, stimuli are associated with responses, events with other events, ideas with other ideas, objects with other objects, and so on. In fact, the capacity and applications of associative learning are evidently infinite. At an intuitive level, when most people think of 'learning and memory' they are referring to the associative forms. However, the nervous system also reacts to certain environmental stimuli in nonassociative contexts. For example, through the process of habituation, we learn to ignore monotonous stimuli (e.g., we forget we are wearing the hat), and through sensitization a single stimulus can lead to a generalized augmented responsiveness (e.g., after hearing a gunshot, we are startled by a slamming door). While the study of nonassociative learning has lead to important mechanistic insights, particularly in cellular learning in simple invertebrate systems, the following material will focus on associative memory. Learning Memory Nonassociative Associative Short-Term Long-Term Habituation Sensitization Declarative Nondeclarative Figure 1. By definition, learning refers to a process of acquisition of information, and memory to the storage or retrieval of information. Figure 1 shows that memory is also divided into subtypes, namely short-term memory (STM) and long-term memory (LTM). This concept, of distinct memory systems with different time frames of operation, has proven quite useful in explaining experimental observations. It is now known that STM and LTM reflect the operation of different neural systems and processes. STM can be considered as having a limited storage capacity (seven, plus or minus two items) that "decay" and become inaccessible after a relatively brief interval (estimates range from 12 to 30 seconds). In addition to decay, loss of information from STM can occur by interference when new information displaces older information. Information can be maintained in STM for relatively long periods if ‘rehearsal’ is used, for example by mentally (subvocally) repeating the information to be maintained. In many cases, the reason one wishes to maintain information in STM is to allow time for it to be encoded into the LTM, and thus become more permanently available. LTM can store a vast quantity of information for very long periods of time. Figure 2. A description of memory as a two-part system (STM, LTM) is an oversimplification, because research in this area has verified the operation of multiple memory subsystems along the temporal dimension. Figure 2 illustrates the distinctions in these memory systems, beginning with memory registers that maintain sensory information for very brief intervals, which may be further processed in STM, where the information may, in turn, be consolidated into LTM. Storage and retrieval at each stage is subject to information loss (forgetting) due to the processes of interference (competing information) and decay (reflecting intrinsic limitations of neural systems). Mechanisms of the sensory registers are modality specific: the visual register is termed ‘iconic’ memory (sometimes called 'eidetic' memory), with visual traces persisting for ~ 250 milliseconds, and the auditory register is termed ‘echoic’ memory, and persists for about 3 seconds. Finally, modern cognitive neuroscientists are increasingly using the term ‘Working Memory,’ as a concept closely allied to STM, but expanded to include the contents of consciousness at any one time, and also described as an active memory store in which information can be manipulated. Declarative vs. Nondeclarative Memory Of vital importance, in contemporary concepts of learning and memory, is the distinction between declarative and nondeclarative forms of memory. Declarative memory is the type of memory usually referred to when the term ‘memory’ or ‘remembering’ is used. With experience, each person accumulates a vast store of facts, words, names (of people and things), memories of places, events, concepts, rules, laws and customs; the list Figure 3. is endless. These are all examples of declarative memory. A useful mnemonic is that we can declare the contents of declarative memory. In contrast, it is difficult, if not impossible, to specify the contents of nondeclarative memory, which is also referred to as "procedural" memory. The stored information that allows one to execute skilled motor acts, to play a musical instrument, or to perform the articulatory movements of speech, are all examples of procedural memory. In addition to motor activities, procedural memory also encompasses perceptual skills (e.g., learning to spot a motionless animal in the woods) and some cognitive skills (e.g., learning how to learn). Also subsumed under nondeclarative memory are forms of learning involving classical conditioning or learning with a strong emotional component, which is known to involve of the amygdala nucleus in the forebrain. Returning to our mnemonic, one cannot declare the contents of procedural memory. For example, it would be inadvisable to try to learn how to swim by reading a book about swimming. Only by engaging in the motor act (practicing the procedure) can this form of learning effectively occur. Learning theorists have further subdivided declarative memory into semantic and episodic memory (Figure 3). Semantic is memory for facts or meaning, while episodic refers to autobiographical memory for events or episodes that occur in a given place and time. There is clinical evidence that the semantic/episodic distinction is based on different processes implemented in different brain regions. For example, patients with frontal lobe lesions often exhibit "source amnesia," with selective inability to remember when and where events occurred. Also, patients with Alzheimer's Disease often show specific disabilities in episodic memory during the initial phases of the disease process. It is also notable that hippocampal damage, early in childhood, leads to more severe deficits affecting episodic memory than semantic memory (Vargha-Khadem et al, 2001). Neuroanatomy of Memory A major theme, of modern learning and memory theory, is that different memory modalities, declarative and nondeclarative, are more than merely descriptions of behaviors: they represent the operation of different anatomical brain regions (neurological substrates). Accordingly, they are differentially affected by ageing, disease, surgeries, or (in animal models) experimental manipulations. In fact, our knowledge of the anatomical segregation of memory function within the brain, has been provided in large measure by observing how the system fails when a portion of the brain is removed surgically (for example, to minimize intractable epilepsy), or is suppressed by natural causes (e.g., stroke). In addition, technical advances in research methods have permitted a greater understanding of CNS involvement in learning and memory. These include: 1. the development of primate models of human amnesia 2. the development of advanced brain imaging techniques (e.g., MRI, PET) -MRI (magnetic resonance imaging) has allowed the localization of anatomical lesions in humans which can be associated with memory deficits -PET (positron emission tomography) has identified areas of the brain activated during storage and retrieval of memories A failure of memory is called amnesia. In cases where the cause of amnesia is known (injury, surgery, disease, etc.), it is helpful to distinguish between anterograde amnesia and retrograde amnesia. Anterograde amnesia refers to an inability to form new memories after the trauma (event precipitating the amnesia). Retrograde amnesia refers to an inability to recall memories established prior to the trauma. As explained in the following sections, a systematic examination of the pattern of anterograde and retrograde amnesias resulting from various neurotraumatic events (planned experimental or naturally occurring in the clinic)