Open Access Austin Journal of Clinical Neurology Review Article From Dark to Bright to Gray Sides of Memory: In Search of its Molecular Basis & Alzheimer’s Disease Carlos Velez-Pardo* and Marlene Jimenez-Del- Rio* Abstract Neuroscience Research Group, Medical Research Memory is one of the most fascinating functions of the brain. Without it, the Institute, University of Antioquia (UdeA), Colombia human being condition would be lost. Therefore, alterations of memory are at the center of research. In this review, the most prominent memory case disorders *Corresponding authors: Velez-Pardo C, are examined to identify basic differences and commonalities of the memory Neuroscience Research Group, Medical Research processes altered in the human brain. Then, relevant aspects of the molecular Institute, School of Medicine, University of Antioquia mechanism of memory between Aplysia, Drosophila, and mammals (mice) are (UdeA), Calle 70 No. 52-21, and Calle 62 # 52-59, highlighted in order to understand the biological aspect of memory in humans. Building 1, Room 412; SIU Medellin, Colombia, Tel: (574) The convergence of both topics provides a foundation for an integrative study of 219.64.57; Fax: (574) 219.64.44; Email: calberto.velez@ prevention and loss of memory in familial Alzheimer’s disease (FAD). Therefore, udea.edu.co we propose that highly superior autobiographical memory (HSAM) and familial Jimenez-Del-Rio M, Neuroscience Research Group, Alzheimer’s disease (FAD) are opposite extreme cases of “normal” memory and Medical Research Institute, School of Medicine, that their pathophysiology can be explained by changes in protein expression of University of Antioquia (UdeA), Calle 70 No. 52-21, and the PKA / CREB-1 / CPEB axis. We also propose that Aβ directly intermingles Calle 62 # 52-59, Building 1, Room 412; SIU Medellin, with the CPEB. As a result of “yin-yang” prion-like protein interactions, Aβ Colombia, Tel: (574) 219.64.57; Fax: (574) 219.64.44; is capable of interfering with the CPEB’s normal function. If validated, this Email: [email protected] hypothesis may help explain why anti-amyloid therapies have been negative or inconclusive so far. Therefore, therapies targeting intracellular Aβ oligomers are Received: March 26, 2015; Accepted: May 19, 2015; urgently needed. Molecular studies on HSAM individuals might be invaluable to Published: May 25, 2015 discover molecules to increase memory skills in FAD. Keywords: Alzheimer’s disease; CREB-1; CPEB; Explicit memory; Memory; HSAM; Implicit memory; Short-term memory Abbreviations –a theory of memory that influenced thinking for many centuries. AC: Adenylate Cyclase; AMPAR: α-amino-3-hydroxy-5-methyl- However, it was not until the mid-1880s that the young German 4-isoxazolepropionic Acid receptor; C/EBP: CCAAT-box-enhanced psychologist Herman Ebbinghaus (1850-1909) developed the first Binding Protein; CaMKII: Ca2+/Calmodulin Protein Kinase II; scientific approach to studying memory. Using himself as the research CaMAC: Ca2+/calmodulin-activated Adenylyl Cyclase; Ca-i-PKC: subject, Ebbinghaus was able to establish the shape of the learning Ca2+-independent PKC; CN: Calcineurin; CPEB: Cytoplasmic and forgetting curve where he discovered that early and late items in Polyadenylation Element Binding Protein; DAR: Dopamine a list are more likely to be recalled than middle items (i.e., primacy Receptor; PLC: Phospholipase C; PP1: Protein Phosphatase-1; PKA: and recency effects), and reported that even a small amount of initial Protein Kinase A; PKC: Protein Kinase C; NMDAR: N-methyl-D- practice, far below that required for retention, can potentially avoid aspartate Receptor; UH: Ubiquitin Hydroxylase; 5-HT-R: serotonin the need of re-learning. Ebbinghaus also classified memory into three receptor distinct types: sensory memory (SM, the ability to retain impressions of sensory information received through the five senses); short-term Introduction memory (STM, the capacity to hold a small amount of information in Memory is the ability of the brain to encode, store, retain, and the mind in an active, readily available state for a short period of time, recall information including facts, experiences, impressions, skills, in the order of 20-30 seconds up to 1 min); and long-term memory and habits. It gives living things the capability to learn (i.e., the process (LTM, the capacity to hold an indefinite amount of information for a of acquiring knowledge of the world and adapting from previous longer period of time, in the order of days, weeks, or years) [1]. This experiences to affect or influence current behavior). Etymologically, classification remains relevant to this day. the word “memory” derives from the Latin word memory and Furthermore, studies by George A. Miller (1920-2012) in the mid- memoir, or from the Greek word thymesis meaning “mindful” or 50s demonstrated that STM is limited to what he called “the magical “remembering.”Since memory is an important part of our most number seven, plus or minus two,” reflecting an STM capacity of 7 ± 2 intimate self-realization, philosophers, medical doctors, and lately, elements [2]. By 1972, the experimental psychologist Endel Tulving scientists have tried to understand what memory is, how it works, (1927-present) was the first to propose two distinct types of LTM: and why it goes wrong. Aristotle (384 a. C.-322 a. C.) was the first (i) episodic, defined as the collection of past personal experiences– to compare memory to making impressions in wax, and suggested autobiographical events, such as time, places, associated emotions, the idea that memories are copies of reality that a person stores and and other contextual particulars that can be explicitly stated; and (ii) later retrieves, sometimes referred to as the “storehouse metaphor,” semantic, which refers to the memory of meanings, understandings, Austin J Clin Neurol - Volume 2 Issue 5 - 2015 Citation: Velez-Pardo C and Jimenez-Del-Rio M. From Dark to Bright to Gray Sides of Memory: In Search of its ISSN : 2381-9154 | www.austinpublishinggroup.com Molecular Basis & Alzheimer’s Disease. Austin J Clin Neurol 2015;2(5): 1045. Velez-Pardo et al. © All rights are reserved Carlos Velez-Pardo and Marlene Jimenez-Del-Rio Austin Publishing Group of dementia and cognitive dysfunction [7], several studies indicate that memory is a highly complex function of the brain for which the exact (neural and molecular) mechanisms of action remain elusive. Therefore, except for the possibility of significantly reducing aversive memory by pharmacological treatment [8], therapies or over-the- counter medicines which maintain, improve, or avoid/stop loss of memory are not currently available. We will examine the most prominent memory disorders, (e.g., cases of ultra-superior memory, savant syndrome, clinical cases of severe amnesia and dementia (e.g., Alzheimer’s disease), to determine basic differences and commonalities of the memory processes altered in the human brain. The dark side of memory “What have you done to my memory?” H.M. Figure 1A: A schematic representation of the types of memory and region localization in the human brain. On September 1, 1953, the neurosurgeon William B. Scoville performed a bilateral resection of the medial temporal lobes (MTL) on Henry Molaison (1926 – 2008), known as patient H.M. in scientific literature, as an experimental approach to alleviate a pharmacological intractable epilepsy [9]. The resection extended posteriorly for a distance of 54.5 mm and 44.0 mm in the left and right hemispheres, respectively [10]. Although the surgery reduced the frequency of his pre-operatively severe epileptic attacks and enabled their control with drugs(e.g., phenytoin or Delantin®), H.M. thereafter showed severe antero grade amnesia, (i.e., he no longer was able to form new memories despite the fact that his short-term memory (or attention span) was intact [9], and partial retrograde amnesia, (i.e., he lost his memory access to events that occurred or information that was learned up to three years before surgery). Recently, the exact anatomical areas removed by Scoville have been reported to include the medial temporopolar cortex (Brodmann Area #38), Piriform cortex, entorhinal cortex (BA#28), perirhinal cortex (BA#35) and Figure 1B: A schematic representation of the types of memory and region subiculum (BA#27), the amygdala, anterior half of the hippocampus localization in the human brain. (BA#28), and the dentate gyrus. The posterior parahippocampal gyrus (BA#20) and medial temporal stem were partially damaged [11]. and other concept-based knowledge [3]. Both semantic and episodic By 1962, Milner reported the first experimental demonstration memory constitutes the category of declarative memory. Declarative of the dissociation between the acquisition of declarative memory memory– sometimes referred to as explicit memory– refers to and other kinds of learning (e.g., motor learning). Indeed, H.M. memories that can be consciously recalled; whereas non-declarative learned to draw the outlines of a star while looking at the star and or procedural memory- also referred to as implicit memory- is the his hand in a mirror. Clearly, H.M.’s time and error scores decreased second category of memory in which previous experiences aid the within and across three days of training on a mirror-tracing task [12]. performance of a task without conscious awareness of these previous Later work has shown that H.M. preserved others kinds of learning experiences [4,5]. abilities [13,14]. Furthermore, H.M. displayed adequate social skills The most popular model for studying memory- the multi-store or (excessively polite), preserved normal verbal skills, and exhibited modal model of memory proposed by Atkinson-Shiffrin in 1968 [6] is other normal psychological features (Table 1). depicted in Figure 1A-B. This model proposes memory as a sequence The significance of the reported case of H.M.’s amnesia was of three stages, from SM to STM to LTM (blue filled arrows). The brain fivefold. First, it established the fundamental principle that memory is regions (marked in red bold) used to stack memory processes such as a distinct cerebral function.