M Phale, D Korgaonkar
brain, learning, memory, neurotransmitters
M Phale, D Korgaonkar. Pharmacology Of Learning And Memory. The Internet Journal of Pharmacology. 2008 Volume 7 Number 1.
For years, learning and memory were considered to be electrical activities processed in the nervous system. The memory appeared to be stored in certain circuits in the brain, such as the limbic system. The knowledge embedded with a transactive memory system helps groups apply prior learning to new tasks and develop an abstract understanding of a problem domain, leading to sustained performance.The memory and learning process have their own chemical bases. Many chemical factors including neurotransmitters influences learning and memory through actions on different brain regions. This review is prepared with the view that an increased understanding of mechanism associated with memory and learning will opened up the possibility to explore drugs acting on cognitive functions. A central claim of this wonderful assemblage of articles is that memory is a hyphenated phenomenon, a material-semiotic one. It is a conceptual site where phenomenology meets ontology meets materiality.
In psychology, memory is an organism’s ability to store, retain and subsequently retrieve information.
‘Memory’ is the ability of an individual to record sensory stimuli; events, information etc retain them over short or long periods of time and recall the same at a later date when needed. In today’s stressful and competitive world, problems like poor memory, lower retention and slow recall are very common. Age, stress, emotions are conditions that may lead to memory loss, amnesia, anxiety, high blood pressure, dementia or schizophrenia and Alzheimer’s disease (AD) 1
‘Learning’ is defined as a relatively permanent change in behavior that results from experience.
Memory is the natural counterpart of learning; it is a necessary condition for the behavior change to be permanent. 2
Processes involved with memory
From the information processing point of view there are three main stages in the formation and retrieval of memory:
Encoding or registration (processing and combining of received information)
Storage (creation of a permanent record of the encoded information)
Retrieval or recall (calling back the stored information in response to some cue for use in a process or activity)
Brain Regions Associated With Learning And Memory
The hippocampus is located deep inside the temporal lobe, and it receives inputs from virtually all association areas in the neocortex, including those in the parietal, temporal and frontal lobes, via the adjacent parahippocampal gyrus and entorhinal cortex. Therefore, the hippocampus has available highly elaborated multimodal information, which has already been processed extensively along different, and partially interconnected sensory pathways. Additional inputs come from the amygdale and via a separate pathway, from the cholinergic and other regulatory systems. Its extensively divergent system of output projections enables to feedback into most of the areas from which it receives inputs. Lesion studies indicate that the hippocampus is important in the encoding of various types of memory such as declarative, episodic or working memory. Neurophysiological evidence also directly indicates that many of the synapses within the hippocampus can become modified as a result of experience. 3
The hippocampal forms part of three related but different circuits: one at the time of acquisition, another at the time of memory formation and another at the time of retrieval.
During acquisition it must receive information from the working memory manager regions of the prefrontal cortex, which is related by the entorhinal cortex and the dentate gyrus.
At the time of retrieval, in the first few amygdala integrate a network with the entorhinal and parietal cortex, which are needed for retrieval.
The sequence of Biochemical Events in Hippocampus
Initially the sequence involves the activation of NMDA, AMPA and metabotropic glutamate receptors followed by changes in second messengers and biochemical cascade led by enhanced activity of protein kinase A,C and G and Calcium-calmodulin protein kinase II, followed by changes in glutamate receptor subunits and binding properties and increased expression of constitute and inducible transcription factors.
20-120% increased in the activity of enzymes such as NO syntase, heme oxygenase, PKG, PKA,PKC or Ca MkII, several- fold increased in cGMP and cAMP, 20-80% increased in AMPA binding or in the amount of measurable GluR1 or NMDA1 were seen after inhibitory avoidance learning.
Some of the biochemical changes are no doubt, structure-specific (they are not seen in other brain regions) and all appear to be learning- specific (they are not seen in animals exposed to the footshock alone or to the apparatus without the footshock). Some consequences of the biochemical changes may be synapse-specific, if they preferentially affect the synapses that are being activated at the time. 4
The dorsal striatum plays a vital role not only in learning new response strategies but also in the inhibition of pre-existing strategies when a shift in strategy is required. A dorsal striatum-dependent system may be necessary for the formation of reinforced S-R associations. In addition, a hippocampus –mediated system appears to be centre for acquiring multiple relationships among stimuli. This system is called as a declarative or relational memory system appears to be essential for processing information about and flexible utilization of the relationship between multiple external cues and events. The dorsal striatum is necessary for the mediation of stimulus response learning. 5
Parahippocampal Region (PHR)
The PHR receives inputs from widespread secondary or ‘association’ cortical regions and provides the major conduct for hippocampal outputs to the same cortical association areas. The anatomical evidence indicates that the PHR occupies a pivotal position for mediating memory functions of the hippocampal region.
Neurophysiological findings indicate that the PHR plays a critical role in recognition memory, independent of its role as an intermediary for cortical-hippocampal interactions. This evidence comes mainly from experiments examining the effects of damage to the hippocampal region on performance in a simple recognition memory test known as delayed nonmatching to sample (DNMS). PHR contains the necessary coding elements for identifying individual stimuli, for maintaining individual stimuli representations across long delays and for mediating specific match-nonmatch comparisons. 6
The cholinergic basal forebrain comprises cholinergic cell bodies in the medial septal nucleus, the diagonal band of Broca, and the nucleus basalis magnocellularis. Apparently regardless of training protocol Morris Water Maze (MWM) deficits were reported in rats with nucleus basalis lesions. Most severe hidden-platform acquisition and probe trial deficits were seen in rats with combined basal forebrain lesions of the medial septum/ diagonal bands and the nucleus basalis. 7
It has been shown that mice with cerebellar damage do display impaired MWM learning. The cerebellum receives input from brain areas involved in many aspects of MWM learning including visual cortex, superior colliculus and hippocampus, and, apart from motor control and acquisition/ retention of conditioned reflexes, its specific functions may include a variety of cognitive processes as well. Petrosini et al. suggested that the role of the cerebellum in spatial learning is primarily that of controlling the procedural aspects of the task. 7
Various Ions, Neurotransmitters And Messengers Associated With Memory
Memories are thought to be due to lasting synaptic modifications in the brain. Synaptic modifications within memory traces have been linked to a number of mechanisms that involve multiple and interacting afferent pathways, neurotransmitters, messenger molecules and gene products.
I) Ions and Ion channels
Ca [[[2+]]] plays an essential role in a variety of intracellular signaling cascade which underlie mechanisms for the dynamic control of cell functions. In cognition, Ca [[[2+]]] participates in control of not only the formation and development of neural structures that cognition depends on, but also signal processing and synaptic plasticity that define learning and memory.
Temporal and spatial control of Ca [[[2+]]] signaling through the neutral networks involved in learning and memory are fundamental for cognitive capacities. The Ca [[[2+]]] signals can not only spread through neurons as global Ca [[[2+]]] waves, but can also be highly localized within micro-domains of sub-cellular components such as at close oppositions of mitochondria and the endoplasmic reticulum (ER), dendritic spines or presynaptic terminals. Losing effective control of cytosolic free Ca [[[2+]]] concentrates ([Ca [[[2+]]] ] c) according to fundamental demands undoubtedly contributes to neurobiological and memory disorders and ageing. Blocking L- and N- type voltage- operated Ca [[[2+]]] channel (VOCC) or N-methyl- D- aspartate (NMDA) receptors has also been reported to cause degeneration of neurons.
Action potentials reliably evoke Ca [[[2+]]] transients in axons and boutions through VOCCs. The VOCCs are involved in providing the Ca [[[2+]]] for neural signals underlying learning and memory in neurals networks. Blocking the L-type VOCCs with ninodipine, has been reported to impair learning and memory. 8
Potassium-selective channels are constituents of plasma membranes. In neurons, both synaptic transmission and the onset and duration of excitations are governed to a large extent by K [[[+]]] channel kinetics. These properties of K [[[+]]] channels facilitate higher-order membrane phenomena such as signal integration, spike patterning and synaptic plasticity.
Modulations of the sAHP and A-type K [[[+]]] channel modification in hippocampal pyramidal neurons are thought to contribute to learning and memory.
The sAHP amplitude in hippocampal pyramidal neurons can be reduced by signaling pathways triggered by a variety of neurotransmitters, like Acetylcholine which have been implicated in learning and memory. 9
II) Principle Neurotransmitters
Glutamate is the major excitatory neurotransmitter in the brain. It mediates its functions through two types of receptors, ionotropic gluatamate (iGlu) receptors, such as the NMDA, AMPA and kainite receptors and metabotropic gluatamate (mGlu) receptors. mGlu1 receptors have also been suggested to play a role in the modulation of cognitive processes, based on results obtained with mouse mutants, or using either non-selective mGlu1/mGlu5 antagonists and/or compounds that were locally administered into the hippocampal area. 10 Hippocampal long-term potentiation (LTP) was impaired in knockout mice lacking the mGlu1 receptor and more recently it was demonstrated that pharmacological mGlu1 receptor blockade also impairs hippocampal LTP. All this suggests a prominent role of the mGlu1 receptor in learning and memory processes.
AMPA (α-amino- 3- hydroxyl-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors mediate fast excitatory transmission throughout the central nervous system. Positive modulation of these receptors can potentially enhance cognition by, firstly, offsetting losses of glutamatergic synapses; secondly promoting synapting plasticity; and thirdly increasing the production of tropic factors.
Induction of LTP, a presumed substrate of memory, requires intense depolarization of spine heads by AMPA receptors; increasing currents through the receptors is a plausible route for promoting the formation of LTP. Ampakines (AMPA receptor modulators) enhance the encoding of memory in a variety of animal models. 11
The central inhibitory neurotransmitter γ-aminobutyric acid (GABA) is found in all areas of the brain. It is well established that the GABA system is a target for a variety of central pharmacological agents including sedatives, analgesics and anticonvulsants.
The interaction between the cholinergic and GABAergic systems in learning and memory has been shown by several studies. The amygdala and hippocampus are some of the neuronal systems taking part in memory formation and are rich in cholinergic synapses that are under the inhibitory control of the GABAergic system. Findings suggest that
GABAergic drugs might impair memory formation through effects on cholinergic systems. However, other investigators have shown that the GABA receptor agonist’s muscimol and baclofen enhance memory. 12
Pharmacological data clearly indicate that muscarinic and nicotinic acetylcholine receptors have a role in the encoding of new memories. Localized lesions and antagonists infusions demonstrate the anatomical locus of these cholinergic effects, and computational modeling links the function of cholinergic modulation to specific cellular effects within these regions.
Computational models demonstrate that the cellular mechanisms of these effects could enhance the encoding of memories. These cellular mechanisms include: i) enhancement of the influence of afferent input to excitatory feedback; ii) regulation of inhibition and theta rhythm oscillations; iii) enhancement of persistence spiking for active maintenance and iv) enhancement of synaptic modification.
As shown in figure 1, acetylcholine might enhance the encoding of memory by enhancing the influence of feed forward afferent input to the cortex, making cortical circuits responds to features of sensory stimuli, while decreasing excitatory feedback activity mediating retrieval. This change in dynamics results from effects including nicotinic enhancement of excitatory afferent input and muscarinic presynaptic inhibition of excitatory feedback.
Acetylcholine might also enhance encoding via muscarinic presynaptic inhibition of excitatory feedback system within cortical circuits. High cholinergic levels during waking support feedback, providing dominant feedback effects appropriate for encoding, and reducing the influence of hippocampus on entorhinal cortex.
Acetylcholine might also enhance encoding through its role in increasing theta rhythm oscillations within the hippocampal formation. Learning is enhanced when stimuli are presented during periods of theta rhythmicity.
During the encoding phase, strong entorhinal input ensures accurate storage of new memories, whereas the reduction of CA3 input prevents retrieval of previously stored associations from causing interference. During the opposite phase, strong CA3 input ensures accurate retrieval of old memories.
Acetylcholine has been demonstrated to enhance persistent spiking of individual cortical neurons.
In standard control conditions, entorhinal neurons will respond to an intracellular depolarizing current injection by generating spiking activity during the current injection, but will terminate spiking after the end of current injection. By contrast, during perfusion with the cholinergic agonist carbachol, neurons respond to the same magnitude and duration of depolarizing current injection with an increased number of spikes, and when the current injection ends, they persist in spiking for an extended period of many seconds or even minutes. 13
There are two robust effects of 5-HT in the hippocampus. First, 5-HT exerts a hyperpolarizing influence on principal cells; directly, via 5-HT1A receptors, and indirectly, via facilitation of GABA release from local interneurons through 5-HT3 receptors. Activation of 5-HT2A and 5-HT2C receptors has been suggested to induce depolarization in principal cells, but these effects appears to be dominated by the depolarizing effects of 5-HT, as both application of 5- HT will hyperpolarize principal cells in slice preparations of the dentate gyrus. In addition, through 5-HT2C, 5-HT4 and 5-HT7 receptors, after hyperpolarizing (AHP) currents are down regulated, leading to reduced adaptation in principal cells. The increased firing rate observed in slices after prolonged application of 5-HT has been linked to this mechanism.
Serotonin receptor subtypes that have been demonstrated to occur in brain regions capable of playing a role in learning and memory include the 5-HT1, 5-HT2, 5-HT3, 5-HT4, 5-HT6, and 5-HT7 class of receptors. 14
Serotonin receptor agonist Buspirone impaired the memory in rats in conditioned avoidance response by acting on 5-HT1A, Quipazine in rats shows enhanced effect by acting on 5-HT2A.
Thierry and colleagues described in 1973 that dopamine in the brain was not restricted in its occurrence to the rigrostriatal system and the tubero-infundibular systems, but also occurred in the cerebral cortex.
A few years later evidence was obtained that dopamine has a great impact on cognitive processes. Comparable findings in rats were obtained by Simon and Colleagues. Lesions of dopaminergic cells in the ventral segmented area impaired retention of previously learned delayed alteration responses.
In the field of memory and learning studies the mesolimbic dopaminergic and especially the mesolimbic system clearly have received most of the scientific attention. These areas are known to play a crucial role in various cognitive processes.
In studies of dopamine function in working memory have focused on the D1 and D2 receptors, with most evidence suggesting a dominant role for the D1 receptor. Since the dopamine D4 receptor is highly expressed in PFC, it may also contribute to working memory.
The data strongly suggest that both dopamine D2 and D3 receptors mediate the effects of dopamine on the integrative function of learning and memory. Dopamine D1 receptors in the prefrontal cortex selective modulate working memory processes responsible for the accurate recall of the location of food reward. In contrast, dopamine D1 receptors in the nucleus accumbens modulate memory-based search behavior, without prior knowledge of the location of food. 15
It was found that histamine produced a concentration-dependent increase in glutamate release in the hippocampus via H1 and H2 receptors. Therefore, the glutamate released from the hippocampus by histamine may be responsible for the spatial memory deficits. It has also been reported that postsynaptic H1 -receptors and presynaptic H3 -receptors are important for learning and memory in both active avoidance responses and radial maze performance in rats. 16
Cannabinoids presynaptically alter release of GABA and glutamate from hippocampal neurons, points to a potentially critical role for the cannabinoid receptor within this critical substrate for memory processing.
Recent observations have in fact shown that successful DNMS behavioral performance can be attributed to the intensity of encoding of trial-relevant information by hippocampal CA3 and CA1 neurons, and that cannabinoids disrupt this encoding phase. Thus, short-term memory likely represents a process involving not only the hippocampal cells, but also reciprocal projections between entorhinal cortex and hippocampus. 17
Endomorphins 1 and 2 have been shown to impair passive avoidance learning in mice. β-Funaltrexamine, a μ-opioid receptor antagonist, antagonizes the endomorphins-induced impairment of learning and memory. Furthermore, there is a possibility that endomorphins 1 and 2 markedly decrease acetylcholine release in the brain through the mediation of μ-opioid receptors, because opioid substances have been shown to decrease the output of acetylcholine in the brain area connected to learning and memory.
It was reported that κ-opiod receptor agonists, dynorphin A-(1-13) and U-50,488H, improved the scopolamine-induced impairement of spontaneous alteration performance in mice, carbon monoxide (CO)-induced delayed amnesia in mice and also the β-amyloid peptide and carbacol- induced impairement of learning and memory in mice and rats respectively.
(-)-Pentazocine shows analgesic effects by acting on κ-receptors in mice and human, and (+)-Pentazocine improves learning and memory impairements in mice, acting on σ receptors.
When cholinergic neuronal transmission is impaired, κ-opioid and σ receptor agonists enhance this neuronal transmission, and as a result, the learning and memory impairement is improved. 18
Studies from two laboratories have demonstrated that chronic treatments with either corticosterone or restraint stress induce a remodeling of apical dendrites of layer II/III pyramidal neurons in the mPFC, such that there is greater proximal branching, whereas spine density is reduced. Although alterations of the corticosteroid milieu have also been reported to result in impaired spatial working memory, as measured in the T-maze. 19
Endogenous neuropeptides such as vasopressin (AVP), adrenocorticotropin and opioids have significant effects on learning and memory.
Researchers have demonstrated that either peripheral or central administration of AVP during the training process or after training significantly delays the extinction of the active avoidance response in intact rats. It appears that AVP and the C-terminal fragments may affect learning and memory processes through vasopressinergic receptors.
One study indicates that vasopressin modulates the noradrenergic system in some nuclei, such as the septum, hippocampus, and lateral nuclei of the thalamus which are related to memory formation. Peptides such as AVP,
DGAVP (desglycinamide arginine vasopressine) and PLG (L-prolyl-leucyl-glycinamide) have been found to increase or modulate the means and percentage of θ rhythms in the hippocampal EEG. One can assume that vasopressin can modulate hippocampal θ rhythm or hippocampal electrical activities to facilitate memory processes.
Subsequent to Murphy and Miller's demonstration in the 1950s that ACTH delayed the extinction of shuttle box avoidance behaviour in intact rats. Not only shock-motivated responses were influenced by ACTH and MSH, but also appetitively motivated tasks such as T-mazes with food or sex as the reward. They found that ACTH and MSH can enhance reversal learning in a two-choice visual discrimination paradigm in which rats were trained to avoid a shock by running to a white door.
The effects of endorphin and encephalin on learning and memory have been analyzed by observing the increasing of passive avoidance responses after injection (i.p.) of β-endorphin before learning. Both seem to have an effect on memory consolidation. Different endorphins or encephalins have different effects on memory retention.
The experimental results show that the major influences of endorphin and encephalin are memory consolidation and retention. β-endorphin, α-endorphin, and Met-encephalin facilitate memory consolidation; β-endorphin promotes memory retention as well. Retrograde-amnesia and impairment of memory consolidation are caused by γ-endorphin and Leu-encephalin.
Endorphin or encephalin could modulate other peptides related to learning and memory and thus influence the learned behavior. 20
Brain-derived neutrophic factor
During vertebrate development, neuronal survival depends on the supply of target-derived trophic factors such as nerve growth factor (NGF). Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family, including NGF, neurotrophin-3 (NT-3) and NT-4/5, which play important roles in the survival, maintenance, and growth of neurons in the central and peripheral nervous systems.
It has been demonstrated, using a nuclease protection assay and in situ hybridization that the level of BDNF mRNA is elevated in the rat hippocampus but not in the cerebellum, striatum, frontal, and mid- or caudal neocortex in learning groups compared with control groups after 3 and 6 days of training in a water maze.
Mitogen-associated protein kinase (MAPK), phospholipase C-γ (PLC-γ) and phosphatidylinositol-3 kinase (PI3-K) are the three major signaling molecules known to mediate neurotrophin signaling. 21
In molecular biology, ephrins and Eph receptors are components of cell signaling pathways involved in animal development, and implicated in some cancers.
The infusion of EphA5-Fc into hippocampus resulted in impaired performance in behavioral paradigms, whereas infusion of ephrinA5-Fc enhanced performance and improved anesthesia-induced memory loss. Then in 2001, two articles simultaneously reported changes in synaptic plasticity in EphB2 knockout mice. These mice show deficits in NMDA-dependent, hippocampal synaptic plasticity and minor defects in spatial memory. 22
Iv) Second Messenger And Enzymes
Different types of learning have been associated with changes in the activity of particular adenylyl cyclase (AC) subtypes in a mammalian brain. Current data support the idea that calcium- insensitive AC isoforms may subserve different forms of memory. For instance, decreased calcium-insensitive AC activity was observed in the hippocampus after spatial learning in a water-maze task, whereas, in contrast, an increase in this enzyme activity was found after acquisition in a procedural version of the task or in a bar-pressing task. 23
The tight regulation of PLA2 activity is necessary for maintaining basal levels of arachidonic acid, lysophospholipid, and PAF for performing normal brain function. Collective evidence from many recent studies suggests that increased PLA2 activity and PLA2-generated mediators play a central role not only in acute inflammatory responses in brain but also in oxidative stress associated with neurological disorders such as ischemia, Alzheimer's disease (AD), Parkinson's disease (PD), and multiple sclerosis (MS).
Rat brain synaptosomes or differentiated PC12 cells release sPLA2 upon stimulation via acetylcholine and glutamate receptors or via voltage-dependent calcium channels through depolarization. Thus, sPLA2 may play an important role in neuronal metabolism. 24
PKC plays an important role in many types of learning and memory. Evidence has been provided that PKC activation and translocation are induced in associative learning tasks. PKC inhibition, on the other hand, impairs learning and memory, consistent with the observations that transgenic animal models with a particular PKC isoform deficit exhibit impaired capacity in cognition. The dramatic impact of PKC pharmacology on learning and memory is further emphasized by a regulatory role of PKC isozymes in amyloid production and accumulation. The study reveals that PKC activation greatly reduces neurotoxic amyloid production and accumulation. 25
General cellular mechanisms, enzymatic cascades including the cAMP-dependent protein kinase (protein kinase A, PKA) signaling pathway in CA1 region of the hippocampus have been demonstrated to be crucial to memory processing. The importance of the PKA pathway to memory formation is indicated by its unique profile of activation following learning experiences: PKA has two peaks of activity during long term memory consolidation period, the first within the first few minutes after training, and the second in a protracted way, beginning 2-3 h after the experience, after most enzymatic cascades have ceased their contribution.
Casein kinase II (CK2) is a multifunctional serine/threonine protein kinase that is associated with the development of neuritogenesis and synaptic plasticity. The phosphoinositide 3-kinase (PI-3K)/Akt pathway is implicated in long-term memory formation. In addition, serum- and glucocorticoid-inducible kinase 1 (SGK1) is another downstream target of PI-3K signaling that was shown to play an important role in spatial memory formation. CK2 impairs spatial memory formation through differential cross talk with PI-3 kinase signaling by activation of Akt and inactivation of SGK1 through protein phosphatase 2A. 26
Protein kinase C (PKC) is a serine/threonine kinase that has been widely reported to be involved in plasticity processes. It has been reported that this kinase is necessary for the establishment of memories and undergoes changes in its activity level after behavioral training or LTP induction. This kinase can lead to CREB activation inducing gene expression, which is an essential step in the formation of long-term memories. In the case of taste learning, it has been reported that PKC is necessary in the IC (Insular cortex), amygdale and parabrachial nucleus to form a taste aversive memory. In this regard, it is known that the injection of PKC inhibitors into the IC, amygdala or parabrachial nucleus (PBN) impairs CTA memory formation. 27
A-kianse anchoring proteins (AKAPs) form large macromolecular signaling complexes that specifically target cAMP-dependent protein kinase (PKA). Since strengthening or weakening of synaptic transmission is widely considered to be the cellular mechanism that underlies learning and memory, a role of AKAP/79150 in learning and memory can be expected. AKAP150 is widely distributed throughout the mouse brain. The highest AKAP150 expression levels were observed in striatum, cerebral cortex and several other forebrain regions. AKAP150 is strongly expressed in mouse brain regions involved in learning and memory. 28
Memory pharmacology that reverses memory decline has not yet been well characterized. The efficacy of memory therapeutics depends on our understanding of the basic mechanisms that characterize memory itself. Memories are thought to be due to lasting synaptic modifications in the brain.
Synaptic modifications within memory traces have linked to various mechanisms involving neurotransmitters, messenger molecules etc. Studies have correlated biophysical or biochemical modification with memory and learning behavior.
The paper attempts to bring together an extensive but parallel literature on memory. This will provide a unique opportunity to bring out to test novel drug acting on memory based on specific theory rather than trial and error.