PHARMACOLOGICAL BASIS OF MEMORY

Md. Habibur Rahman, Asst. professor, Dept. of Pharmacology, Anurag Pharmacy College, Ananthagiri (V), Kodad(M), Nalgonda(dt), A.P-508206, www.anuragpharmacy.ac.in Email: habiburruh@gmail.com

2.1.1 Memory Memory is the storage and retrieval of information. Memories are essential for learning and incorporating our experiences into behavior and are part and parcel of our consciousness. 2.1.2 Stages of Memory 8 Memory storage involves two distinct stages shown in Fig-2.1 y y short-term memory and long-term memory

Short-term memory (STM), also called working memory, is the preliminary step like, the power that lets us to look up a telephone number to dial and then never think of it again. The capacity of STM is limited to seven or eight chunks of information, such as the digits of a telephone number or the sequence of words in an elaborate sentence. Long-term memory (LTM) has a limitless capacity. Although our STM devices cannot recall numbers much longer than a telephone number, we can remember scores of telephone numbers by committing them to LTM. However, our ability to store and to retrieve information declines with aging. Thus, long-term memories too can be forgotten, and our memory bank continually changes with time. The sensory information inputs into the cerebral cortex, they are processed, and some 5% of this information is selected for transfer to STM. STM serves as a sort of temporary holding for data that may or may not want to retain. The transfer of information from STM to LTM is affected by many factors, including y Emotional state: One can learn more when they are alert, motivated, surprised, and aroused. Norepinephrine, a neurotransmitter involved in memory processing of

emotionally charged events, is released when we are excited or stressed out, which helps to store longer period of time. 9 y y Rehearsal: Rehearsal or repetition of the material enhances memory. Association. Tying new information to old information already stored in LTM

appears to be important in remembering facts. y Automatic memory. Not all impressions that become part of LTM are consciously

formed. Concentrating on a certain things record as automatic memory for longer time.

Memories transferred to LTM take time to become permanent. The process of memory consolidation apparently involves fitting new facts into the various categories of knowledge already stored in the cerebral cortex.

Fig-2.1: Memory storage process from STM to LTM

2.1.3. Categories of Memory 8, 10 The brain distinguishes between factual knowledge and skills, and we process and store these different kinds of information in different ways. Declarative (fact) memory entails learning explicit information, such as names, faces, words, and dates. It is related to the conscious thoughts and ability to manipulate symbols and language. When fact memories are committed to LTM, they are usually filed along with the context in which they were learned. Non declarative memory is less conscious or even unconscious learning. Categories of non declarative memory are procedural (skills) memory (piano playing), motor memory (riding a

bike), and emotional memory. These kinds of memory are acquired through experience and usually repetition. They do not preserve the circumstances of learning; in fact, they are best remembered in the doing. 2.1.4. Brain Structures Involved in Memory 11, 12, 13 The involvement of different brain structure in memory process in shown in Fig: 2.2-(a, b).

Fig-2.2: (a) Essential structures of declarative memory circuits.(b) Essentialstructures of procedural (skills) memory

Scientific studies have revealed that different brain structures are involved in the memory process. It appears that specific pieces of each memory are stored in specific regions of the brain that need them so that new inputs can be quickly associated with the old. Accordingly, visual memories are stored in the occipital cortex, memories of music in the temporal cortex, and so on. When sensory input is processed in the association cortices, the cortical neurons dispatch impulses to the medial temporal lobe, which includes the hippocampus and surrounding temporal cortical areas. These temporal lobe areas play a major role in memory

consolidation and memory access by communicating with the thalamus and the prefrontal cortex. The prefrontal cortex and medial temporal lobe receive input from acetylcholine-releasing neurons in the basal forebrain. The sprinkling of acetylcholine onto these structures is thought to prime them to allow the formation of memories.14 The loss of this cholinergic input, for example in Alzheimers disease, seems to disrupt both the formation of new memories and the retrieval of old ones. Memories are retrieved when the same sets of neurons that were initially involved in memory formation are stimulated. Damage to the hippocampus and surrounding medial temporal lobe structures on either side results in only slight memory loss, but bilateral destruction causes widespread amnesia. Consolidated memories are not lost, but new sensory inputs cannot be associated with old, and the person lives in the here and now from that point on. This phenomenon is called anterograde amnesia in contrast to retrograde amnesia, which is the loss of memories formed in the distant past. One could carry on an animated conversation with a person with anterograde amnesia, five minutes later that person would not remember.15 Individuals suffering from anterograde amnesia can still learn skills such as drawing, which means a different learning circuit, must be used for procedural memory. Like the medial temporal lobe for declarative memory, the basal nuclei are the key players for procedural memory. Sensory and motor inputs passing through the cortex to the basal nuclei are then relayed via the thalamus back to the premotor cortex. The basal nuclei receive input from dopamine-releasing neurons in the substantia nigra of the midbrain. Just as acetylcholine is necessary for declarative memory, dopamine appears to be necessary for this procedural memory circuit to function. The loss of this dopamine input, as in Parkinsons disease, interferes with procedural memory.16 The two other kinds of nondeclarative memory involve yet other brain regions. The cerebellum is involved in motor memory, while the amygdala (Fig- 2.3) is crucial for emotional memory.

Fig 2.3: The brain structures of the limbic system (Lateral view) 2.1.5. Mechanisms of Memory Human memory is notoriously difficult to study. Animal experimental studies reveal that during learning (1) neuronal RNA content is altered and newly synthesized mRNAs are delivered to axons and dendrites,17 (2) dendritic spines change shape, (3) unique extracellular proteins are deposited at synapses involved in LTM, (4) the number and size of presynaptic terminals may increase, and (5) more neurotransmitter is released by the presynaptic neurons Each one of these changes is an aspect of long-term potentiation (LTP), which has been shown to be crucial for memory formation. LTP refers to a persistent increase in synaptic strength, first identified in hippocampal neurons that use the amino acid glutamate as a neurotransmitter. One kind of glutamate receptor, the NMDA receptor, can act as a calcium channel and initiate the cellular changes that bring about LTP. 18 Normally, NMDA receptors are blocked so that calcium entry is prevented. When the postsynaptic terminal is depolarized by binding of glutamate to different receptors, as would happen upon the rapid arrival of action potentials at the synapse, this NMDA block is removed

and calcium flows into the postsynaptic cell. Calcium influx triggers activation of enzymes that carry out two main tasks. First, they modify the proteins in the postsynaptic terminal, and also in the presynaptic terminal via retrograde messengers such as nitric oxide, which strengthens the response to subsequent stimuli. Second, they cause the activation of genes in the postsynaptic neurons nucleus, which leads to synthesis of synaptic proteins. The molecular messenger that brings the news to the nucleus that more protein is needed is a molecule called CREB (cAMP response-element binding protein).19 A neurotrophic factor called BDNF (brain-derived neurotrophic factor) is required for the protein synthesis phase of LTP. These changes create long-lasting increases in synaptic strength that are believed to underlie memory. The mechanisms underlying memory at a cellular level suggest several approaches to enhancing memory acquisition. Currently several drugs to improve memory are undergoing clinical trials. Among these are drugs that enhance CREB production the more CREB, the more protein synthesis and the stronger the synapse becomes.20