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The Physiology of Learning and Memory: Role of
Peptides and Stress
Article in Current Protein and Peptide Science · January 2005
DOI: 10.2174/1389203043379341 · Source: PubMed

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social memory. besides structural synaptic remodeling. oxytocin. cholecystokinin (CCK). E-mail: byegen@marmara. Throughout life. On the other hand. with a protective role during stress. dopamine. are widely distributed throughout the mammalian central nervous system. Arginine vasopressin (AVP). to meet the everchanging demands.00+. 2004. with the involvement of neurotransmitters and neuropeptides. contemporary theoretical formulations of learning and memory are based on two plausible principles: one is concerned with the activity (neuronal firing) and the other with the plasticity of the neurons (sprouting of new axons and dendrites. Both LTP and LTD occur prominently in the hippocampus (a structure implicated in memory storage and retrieval processes) and © 2004 Bentham Science Publishers Ltd. are also needed. PHYSIOLOGY OF LEARNING AND MEMORY For every living organism. the brain constantly “re-constructs” itself. 4. In addition to its duration (lasting for several hours in vitro. stress.00 molecular aspects of neuronal development. hypothalomo-pitiutary (HPA) axis. acquisition. along with these increases in synaptic efficacy in the form of LTP.A. and makes the appropriate adaptive responses in future-related settings [5]. Neuronal plasticity is a fundamental process by which the brain acquires sensory. termed as long-term depression (LTD). rather these specifications appear throughout experience. demonstrates specificity and associativity [4].tr 1389-2037/04 $45. bombesin and gastrin-releasing peptide (GRP). a huge number of studies with abundant knowledge regarding the cellular and *Address correspondence to this author at the Professor of Physiology. serotonin (5-HT). 5. the cognitive. ¸ Istanbul 34668. memory and learning has been carried out. diverse adhesion molecules. Istanbul. During learning and memory processes. Keywords: Alzheimer’s disease (AD). All these reconstructions associate with learning and memory. and new synapses) [1-4]. a number of structural and molecular developments take place. Among these peptides CCK. During this process. CRF is accepted as the main neuropeptide involved in both physical and emotional stress. Since the idea of “information storage by the modification of interneuronal connections” proposed by Cajal. social. 5-HT and CRF play strategic roles in the modulation of memory processes under stressful conditions. or combinations of this information. corticotropin releasing factor (CRF). emotional. Tel: +90-216-414-4736. as well as their respective receptors. and the “experience-dependent synaptic strengthening” postulated by Hebb. possibly through the activation of the hypothalamo-pitiuitary (HPA) axis. melanin concentrating hormone. LTP is rapidly induced. changes are observed at molecular and metabolic levels with the alterations in neurotransmitter and neuropeptide synthesis and release. However. it certainly cannot specify the pattern of neuronal connectivity [1]. suggesting that CCK may participate in the central control of stress response and stress-induced memory dysfunction. The physiological role and therapeutic efficacy of various neuropeptides and the impact of stress exposure in the acquisition and consolidation of memory will be reviewed thoroughly. serotonin (5HT). angiotensin II. Although genoma can encode for a variety of neuronal morphologies. 5-HT appears to play a role in behaviors that involve a high cognitive demand and stress exposure activates serotonergic systems in a variety of brain regions. The discovery of longlasting potentiated synapses provided a possible cellular mechanism for learning and memory. Departments of *Medical Education and Physiology. Yegen ˇ Marmara University School of Medicine. cholecystokinin (CCK). which are essential for the living organism. in order to cope with ongoing changes. all behaviors including learning and memory are modified by experience. strengthened by repetition. Turkey. as well as endocrine inputs. Turkey Abstract: The neuropeptides. cognitive. depending on both genetic and epigenetic information. Although there is no clear understanding of how experience gets into the brain. several weeks in vivo). 6]. 000-000 1 The Physiology of Learning and Memory: Role of Peptides and Stress M. . histamine. Gülpınar* and B. Marmara University School of Medicine. glucagon-like peptide-1 (GLP-1). decreases in synaptic efficacy. growth factors. corticotropin releasing factor (CRF) have modulatory effects on learning and memory.edu. By this lifelong selfadjustment and self-optimization processes. different neurotransmitters and neuropeptides. The peptide CCK has been proposed to facilitate memory processing and CCK-like immunoreactivity in the hypothalamus was observed upon stress exposure. etc. consolidation. The phenomenon of long-term potentiation (LTP) has been recently shown to be associated with the formation of new synapses and long-term depression are currently regarded as one of the best and universally accepted models of learning and memory formation [2. it is also well known that these functions are influenced by a tremendous number of neuropeptides and non-peptide molecules. how the brain organizes itself to get/remember/forget the knowledge. During learning and memory processes. Haydarpasa. Fax: +90-216-418-3327.. behavioural and emotional status of an organism is remodeled. LTP alone cannot provide enough explanation for the synaptic model of learning and memory.Ç. insulin.Current Protein and Peptide Science. While there is consensus that brain cholinergic neurotransmission plays a critical role in the processes related to learning and memory.

such as opioid dynorphin B and nitric oxide [29. For instance. parietal and temporal cortices. Both in the developing and mature brain. cholinergic cells within dorsolateral pontine regions contain co-existing messengers. Many cortical maps. in rodents (but not in higher primates) galanin is found in septohippocampal cholinergic and non-cholinergic neurons [27]. which are associated. There is also some integration between the cholinergic system and other neurotransmitter systems: thyrotropin releasing hormone (TRH) promotes cholinergic function and release of ACh. Recent studies in humans have also shown alterations in the regulation of NCAMs in several neuropsychiatric and neurodegenerative disorders. 30]. are not fixed. In other words. 6 appear to be mediated by mechanisms that are triggered by Ca2+ influx via activation of N-methyl-d-aspartate (NMDA) receptors. neocortical association areas and the cholinergic basal forebrain neurons). 12. The neural cell adhesion molecule (NCAM) is an important modulator of neuronal development and plasticity associated with learning and memory in rodents [14]. carrier proteins such as apolipoprotein E and several microtubule-associated proteins and other cytoskeletal proteins that undergo changes in the expression and subcellular distrubution [2]. early neonatal handling and “enriched environmental conditions” indicate that the structural changes are seen not only in the developmental stage. NCAM-binding peptide. impairs learning or memory processes [14. differentiate. As discussed in this review. Considering the synaptic plasticity. and intracranial injections of NCAM antibodies induce amnesia in rats and chicks. to some extent. which potentiate the synapse [4]. but show experience-dependent plasticity. . including sensory stimulus processing. but can also influence neurogenesis and neuronal survival by controlling activation and progression of the cell cycle in the process of neuronal differentiation. ciliary neurotrophic factor (CNTF). The experimental studies based on sensory deprivation. Early emotional experiences affect developing brain systems that subsequently mediate adult learning and memory in rodents [12]. changes in corticotropin releasing hormone (CRH) and somatostatin immunoreactivity in the cerebral cortex are correlated with a reduction in the choline acetlytransferase activity [31]. Among the neurotansmitters involved in learning and memory processes. NCAM knock-out mice exhibit deficient learning in the Morris water maze. that make connections with the cholinergic neurons [27]. Besides the organization of sensory cortical representations. During synaptic plasticity. Social deprivation or stress. the specification in the neuronal networks allows for the achievement of new epigenetic information [2]. 15-20]. by the “selective stabilization of synapses” (the strengthening of existing synapses. acetylcholine (ACh) is the well-known neurotransmitter of the basal forebrain cholinergic neurons that is associated with cognitive processes. such as the hippocampus. insulin-like growth factor (IGF)-1. besides the “developmental” one. is Gülpınar and Yegen ˇ associated with an increased rate of apoptosis in the hippocampus and a reduced rate of neurogenesis in adulthood [2]. olfactory bulb. the information in the brain is stored in a neural network. while low levels of intracellular Ca 2+ lead to the activation of phosphatases that depress the synapse. anterior cingulate cortex.2 Current Protein and Peptide Science.. Having the combination of these flexible and rigid connections. brain-derived neurotrophic factor (BDNF). the formation of new synapses and the destabilization of previously established synaptic contacts) proposed by JeanPierre Changeux. neuropeptides are often co-localized in the cholinergic neurons of the basal forebrain. In addition. It is also likely that some of the mechanisms used in information processing are also involved in the reactivation of the neural network during the retrieval of information [11]. So structural synaptic remodeling is not limited to the developmental stage. 2004. No. the basal forebrain cholinergic system contains many non-cholinergic neurons. given intracerebroventricularly (icv) prior to training in rats and mice. 13]. extend axons and express neuronal marker proteins. behavioural experience. while it has the opportunity to continously reoptimize and self-adjust throughout the life [2]. aurosal and memory function [27]. interleukin (IL)-1. The basal forebrain cholinergic neurons innervate the limbic and the cortical structures. Strengthening of certain synapses allows for the establishment of a neural network specific to that information [7-10].g. these networks tend to be relatively stable (rigid synaptic connections). with stress factors [21-26]. Neurons generated from progenitor cells then migrate into the granule cell layer. frontal. in some areas of the neuronal system. Vol. transforming growth factor (TGF)-beta. “adaptive” and “restorative” plasticity are also seen. on the contrary. such as γ−aminobutyric acid-releasing (GABA) interneurons. fibroblast growth factor (FGF). the structural synaptic remodeling of the brain continues throughout life as a mechanism of self-adaptation (flexible synaptic connections). substrate adhesion molecules (SAMs) and cell junctional molecules (JAMs) provide an essential link between genetic and epigenetic mechanisms by exerting critical interactions at both the cell surface and the cytoskeleton [2]. such as the representations of different sensory stimuli in the neocortex. nonhuman primates and humans. 5. not only promote synaptic modification and synaptogenesis. the brain ensures the stability of the principal characteristic functions on one hand. amygdala. Whereas in other areas. experience also influences the rate of neurogenesis derived from progenitor cells in the hippocampus and this capability of hippocampal cells is retained into adulthood in rodents. either during development or in adult animals. In these mechanisms. synaptic proteins such as synaptophysin and synapsin (SNAP). alertness. once neuronal connections are established during the brain development period. acquired both during development and in the adult brain. The involvement of the NMDA type of glutamate receptor in both learning and its modulation by experience is also well known [28]. but are also evident in adulthood [2. Moreover. hippocampus. Enriched environment in young or even senescent rodents results in persisting changes that dramatically reduce the rate of spontaneous apoptotic cell death later in life and protect against age-related decline of memory function. Other molecules that are required for the lifelong and high turnover of synapses are: nerve growth factor (NGF). morphoregulatory molecules such as cell adhesion molecules (CAMs). high levels lead to the activation of kinases. particularly the areas involved in the higher brain functions (e. growth-associated proteins (GAP). Also. According to the classical hypothesis.

Aged rats and mice show decrements in spatial memory performance [33-37]. abnormal sprouting or a regenerative failure are seen [2. stress can alter a cognition by modulating both norepinephrine (NE) and cortisol activity [61]. as can be seen in any other tissue. which are involved in the sympathetic-adrenomedullary and HPA stress response. 5. fear. end-products of the HPA axis. while administration of NE agonists improved memory performance [64-69]. Depending upon the physical (intensity. GSH has also been suggested to have neurotransmitter and neuromodulatory functions [44]. mediate more practiced responses. 31. 2004. According to the nature of stress. and release of glutamate and GABA. in particular the subject’s ability to predict and control its occurrence. different biological and psychological factors. 6 3 differences and several response patterns exist in coping with environmental challenges. (d) neuronal depolarization by acting at its own ionotropic receptor. the entorhinal cortex. and emotional processing. (b) as a substrate and an allosteric modulator of eicosanoid biosynthesis. in the hippocampus and frontal cortex. and the amygdala and is associated with many cognitive disturbances [27. These behavioral responses may be accompanied by different neuroendocrine responses ranging from high reactivity of the sympathetic response with increased plasma noradrenaline and high baseline levels of testosterone (seen with active coper) to lower plasma levels of testosterone. At the higherlevel cortical regions are involved and the cognitively demanding stimuli are managed [55].and intercellular signaling in the brain. LTD. With ageing. the other form of synaptic plasticity. including the brain. Furthermore. duration) and psychological (predictability and controllability) nature of stressors and individual differences -determined by the characteristics of organism. Several studies provided the evidences that ageing has a negative effect on LTP formation. which may be secondary to the structural and functional changes in the aged neurons. Psychological nature of stressors. 43].e. and dendritic reshaping in particular brain regions were observed [63]. affect learning and memory processes [3]. According to “free radical hypothesis of aging”. with a predominance in parasympathetic response and a more reactive HPA axis (seen with passive coper). affecting cognitive functions such as attention. freezing or crouching as a behavioural inhibition) behavioral strategy. NE depletion in rodents and monkeys was shown to cause increased distractibility and deficits in spatial working memory. such as: (a) uptake. i. escape or avoidance as a defense system) or a passive (immobility. Recent opinions on stress emphasize that individual Current Protein and Peptide Science. 41]. 42. (c) regulation of NMDA and non-NMDA glutamate receptor activity. A number of studies have shown that GSH protects catecholaminergic neurons against toxic species and free radicals formed during metabolic processes. the aberrant plasticity. the brain becomes more vulnerable to the deleterious effects of oxidative damage. according to Yerkes–Dodson law. the hippocampus is sensitive to antioxidant glutathione (GSH) depletion GSH deficiency. GSH depletion stimulates the expression of NGF gene transcription factor AP-1 [39. In general. various brain structures are involved and the neural circuits that underlie stress are organised at different levels. results in less protection against oxidative stress [39]. results in learning and memory disturbances [62] Glucocorticoids (GC). When glutathione (GSH) deficiency is observed in the brain. reflecting the varying demands for cognitive processing. Throughout life. Especially. the hippocampus. when observed in any tissue. an inverted U-shaped relationship exists between a state of stress or arousal and a cognitive task performance. the generation and accumulation of reactive oxygen species (such as superoxide and hydroxyl radicals) cause oxidative damage in the brain. 52. No. it results in reduced protection against oxidative stress.The Physiology of Learning and Memory neuropeptides also play a critical role in learning behaviors [32]. and (e) activation of transcription factors [44-50]. acute stress causes (a) . frequency. such as stress. The effects of stress on cognition are associated with catecholamines and glucocorticoids. due to significant reductions in antioxidants. It may serve for the intra. Low or moderate concentrations of circulating glucocorticoids and catecholamines can enhance learning and memory formation. the experimental and developmental variablesorganism may adapt an active (fight/flight. 39]. The altered HPA axis function with aging or in AD. Besides its antioxidant role. It was shown that the oxidative injury of the brain is ameliorated by the administration of dopamine (DA) [33]. In the normal aging process or in Alzheimer’s disease (AD) reductions are observed in the number of cholenergic neurons and in the brain cholinergic function accompanied with the degeneration of cholinergic neurons of the basal forebrain. associated with impaired feedback mechanisms originating from a damaged hippocampus and hyperactivation of the HPA axis. is more important than its physical nature [51. suppression of hippocampal activation. Simple automatic responses are mediated by the lower brain areas (periaqueductal grey matter and locus coeruleus). When certain pathological emotional states with the involvement of GC are present. which constitute the intermediate brain level. Considering cognitive functioning. 55]. In AD. enhancement of amygdala activity. In conducting the neuro-endocrine responses. In contrast. Stress and Learning-Memory Process Any physical or psychological stressor that threatens the homeostasis of an organism can initiate a set of behavioral and neuro-endocrinological responses. memory. hypothalomo-pitiutary (HPA) axis and sympatheto-adrenal axis are two major pathways mediating the major components of the stress response [5154]. have diverse effects on many neuropeptide/ neurotransmitter systems. while excessively high or prolonged elevations can lead to disruption [56-60]. In the other words. is increased during aging [38. 40]. It prominently affects brain areas such as the parietal and temporal cortices. which help the organism to adapt to the altered situation. anxiety and aging. arousal. A number of studies have reported that acute and choric stresses have different consequences. synthesis. while amygdala and septohippocampal systems. Individuals with normal HPA axis activity have a better ability to cope with stressful life events and have a better cognitive performance. perception. which results in diminished cognitive performance. Vol.

or social stress) concomitant with elevated levels of glucocorticoids indicated that stress results in behavioral and cognitive changes. we now have a basic understanding of the brain regions involved in stress responses and cognitive processes. (b) a hypoactivation in most of the central 5-HTergic system. a plastic and adaptable brain region where the physiological mechanisms (LTP and LTD) of memory storage take place. 86. 75-78]. in which a chronic psychosocial stress was applied. Electrophysiological studies. while during stressful situations with higher levels of corticosterone. both HPA and sympatho-adrenal axis with their hormones. 108. BDNF and neurotrophins) in the hippocampus and basal forebrain. chronic stress or chronic infusion of CRF causes (a) a reduction in CRF mRNA level in central amygdala and a slight elevation in PVN. prefrontal cortex and locus coeruleus also play crucial roles in both stress response and learning/memory processes [8. which plays a central role in the genesis of emotions as well as in the formation of emotional memory and neuroendocrine control of emotions. The excitatory amino acids are also involved in adaptive plasticity related to synapse formation. 21. which act through excitatory amino acids. Adults exposed to physical or sexual abuse at their childhood show reduced hippocampal volume and. which . By exposure to chronic stress. amygdala. The hippocampus. [82. especially in the hippocampus. in some instances. but also is an important center for integrating cognitive. Furthermore. 82. including impairment in learning performance. GC and NE. neocortex) and neuromessengers (eg. 81]. 95-102]. basal forebrain areas with cholinergic innervation. chronic restraint. including episodic.84]. The hippocampus. amygdala. showed that stress-induced Gülpınar and Yegen ˇ memory impairment might be related to impairment of the early form of LTP in the synapses [94]. 107]. glucocorticoids and serotonin. 109] such as reduction in mRNA levels for neurotrophins and their high affinity receptors in the brain. atrophy of the dendrites of hippocampal CA1. Besides the hippocampus. CA3 neurons. and decreases neurogenesis in the dentate gyrus and results in cognitive impairment [82. ranging from a reversible damage to a permanent neuronal loss [21. 88. plays a role in glucocorticoid negative feedback and this makes some hippocampal functioning particularly susceptible to stress. hippocampus. Basal levels of corticosterone increase the magnitude of LTP. Not surprisingly.4 Current Protein and Peptide Science. As indicated in several studies. participate in both of these processes [54. Among the CNS structures involved in cognitive function and stress response. 59. Although the whole picture cannot be demonstrated yet. immobilization. Cholinergic receptor activation enhances the responsiveness of NMDA glutamate receptors and facilitates the induction of LTP. locus ceruleus. stress and elevated stress hormone levels alter cognitive and emotional responses. 101. stabilization of neuronal populations long-term potentiation and memory [103-106]. which plays a role in the hippocampal structural remodelling [21]. Nicotinic and muscarinic ACh receptors in the hippocampus are required for the expression of LTP. these brain regions (eg. Several studies with exposure to different forms of stress (e. cholinergic. 101. and neurochemical responses to stress. resulting in structural and functional (transit disturbance of perception and memory) changes in the brain On the other hand. amgydala. 86. and nitric oxide are the two mediators [21. Since defects in hippocampal cholinergic neurotransmission lead to the deficits of learning and memory under stressful conditions. 5-HT and CCKergic systems) involved in learning and memory also play prominent roles in stress responses. is capable of considerable structural reorganization and it is also vulnerable to damage during aging and repeated stress. Whereas. 87. 61. and the prefrontal cortex. and the neocortex and lesions in these brain regions impair the learning process [79-81]. 5. medial septum. resulting in sympathetic nervous system activation [73. For example. No. 87. the hippocampus is the best-studied brain region. 90-93]. 97. 108. cognitive and morphological measures associated with the limbic system (particularly amygdala and septal regions) [46].or stress-related hippocampal damage. 2004. 58. stress also decreases neurotrophic factors (NGF. Findings of many studies indicate that the amygdala. alterations are also seen in behavioral. Chronic stress exposure in rats also reduced hippocampal neural cell adhesion molecule. neurohormonal. monoaminergic and glutamatergic systems and CRF. 102. 62.and cholecystokinin (CCK)-containing neurons [7074]. in conjunction with pathological changes in the hippocampal neurons. 80. 110-117]. It has been reported that the ageand stress-related alterations in hippocampal LTP and LTD correlate with impairments in hippocampal-dependent learning and memory tasks [38. Central Nervous System (CNS) Structures Involved in the Stress and Learning/Memory Processes Both stress and cognitive processes are managed with the involvement of more than one brain region at different levels.123-128]. In either age. present with impairments in memory [85-89]. and (d) CRF-hypersensitivity in locus coeruleus. Vol. amygdala.g. amygdaloid glutaminergic and GABAergic system. (b) stimulation in most of the central serotonin (5HT). those particularly found in paraventricular nuclei (PVN) of the hypothalamus and amygdala. enriched with receptors for corticosterone. 55. memory processes with long-lasting changes in synaptic efficiency takes place in the hippocampus. implantation of NGF-secreting fibroblasts into the nucleus basalis magnocellularis of aged and memory-impaired rats ameliorated memory impairment significantly [87]. 118. The hippocampus does not only play a crucial role in learning and memory process. For instance. declarative. contextual and spatial learning and memory. the neuronal death in the hippocampal CA3 and CA4 neurons [5. excessive glucocorticoid exposure through stress might be implicated as the cause of the associated hippocampal dysfunction [120-122]. their neuroanatomical and neurofunctional connections and the participation of neuromessengers. 6 hyperactivation in many central corticotropin releasing factor (CRF)-containing neurons. LTP is attenuated and the induction of LTD is enhanced [4. Because of this interaction. 119]. 95. chronic stress or glucocorticoid exposure can alter neuronal morphology in the hippocampus. (c) an increase in hippocampal cholinergic system.

arousal or vigilance. anxiety and fear. It detects and organizes the physiological responses to ``natural'' dangers. 5. 5 Some of the Well-Known Neurotransmitters and Neuropeptides[137] Classical Neurotransmitters acetylcholine dopamine gamma-aminobutyric acid glutamate/aspartate glycine histamine norepinephrine/epinephrine serotonin Neuropeptides adrenocorticotropic hormone angiotensin II α-melanocyte-stimulating hormone β-endorphin bombesin bradykinin cholecystokinin enkephalins gastrin glucagon gonadotropin-releasing hormone insulin motilin neurotensin oxytocin somatostatin substance P thyrotropin-releasing hormone vasoactive intestinal polypeptide vasopressin chemical messengers that bind to neuronal receptors at nonsynaptic sites. The prefrontal cortex is involved in the acquisition and transfer of a new information or skill [135]. Vol. 127-131]. In some of these cases. the neuropeptide is released along with the neurotransmitter in response to nerve stimulation [137]. usually a change in postsynaptic potential as a result of triggering of the opening of specific ion channels. Classical neurotransmitters are synthesized and packaged locally in synaptic vesicles in the cytosol of the axon terminal. Some neuropeptides released at synapse may function as true neurotransmitters but most are believed to function as neuromodulators. NEUROTRANSMITTERS ABD NEUROMODULATORS INVOLVED IN LEARNING AND MEMORY Recent researches have demonstrated that learning and memory functions are influenced by a tremendous number of neuropeptides and non-peptide molecules. 132. 2004. It is suggested that activation of glutamatergic neurotransmission in the prefrontal cortex represents a common mechanism by which stress influences normal and abnormal processes that sustain affection and cognition [134]. and norepinephrine levels in the CA3 region dopaminergic system [110]. Neuromodulators are Current Protein and Peptide Science. Therefore. In contrast to stress-induced neuronal pruning or remodeling reported in the hippocampus. modulates the consolidation of long-term explicit memories of emotionally arousing experiences by influencing other brain regions involved in memory consolidation. Memory and Peptide/Non-Peptide Molecules Although there is consensus that brain cholinergic neurotransmission plays the major role in learning. Prefrontal cortex with dopaminergic and glutaminergic system is another CNS structure that is involved in stress response and cognitive functioning. Neuropeptides differ from classical neurotransmitters in several important ways (Table 1). memory and attention. which in turn enhance memory consolidation [140]. . as well as their respective receptors. and conditioned or spontaneous emotional responses and cognitive processes. caudate nucleus. such as hippocampus. In several instances neuropeptides co-exist in the same nerve terminal with classical neurotransmitters (Table 2). Stress causes changes in the prefrontal cortex and amygdala dopaminergic system. Learning. frontal cortex has been identified as a part of the neural system mediating reward-related learning through complex interactions with the mesolimbic dopaminergic system [136]. it is also well known that these functions are influenced by a variety of neuropeptides [57] (Table 3). 132]. but acts also as a center to learn about novel threats (classical conditioning). The amygdaloid complex has been implicated in fear conditioning and aversive-emotional learning and memory [55. The neuropeptides. They do not cause the formation of postsynaptic potential but instead bring about long-term changes that subtly depress or enhance synaptic effectiveness often by activating second messenger systems. motivation. nucleus basalis and cortex [63. rapid-acting molecules that typically bring about a response in the postsynaptic neuron within a few milliseconds or less. Neuropeptides are larger molecules made up of anywhere from two to about forty amino acids. memory. Together with amygdaloid structures. No. dentate gyrus serotonergic system. Furthermore. 133]. are widely distributed throughout the mammalian central nervous system. chronic stress results in increased dendritic branching of pyramidal and stellate neurons in the amygdala [82. Classical neurotransmitters are small. They are synthesized in neuronal cell body in the endoplasmic reticulum and Golgi complex and are subsequently moved by axonal transport along the microtubular highway to the axon terminals. They are known to diffuse locally and act on the other adjacent neurons at much lower concentration than classical neurotransmitters and may bring about slower more prolonged response. These chemical messengers are primarily amino acids or closely related compounds [137-139]. concentration. chronic restraint stress results in changes in limbic brain regions that mediate learning. Neuropeptides participate in learning and memory processes by affecting attention. 6 Table 1. several neuropeptides modulate the release of stress hormones.The Physiology of Learning and Memory is also involved in attention and reward.

and the establishment of dominance hierarchies in nature. In another study. 149. but little is known about their physiological function in normal brain [165]. Intracerebral injections of Aβ-related peptides to mice or rats impair the learning and memory retention. AVP and OT have been shown to influence a number of forms of social behavior. with the glutaminergic receptors [151. Apolipoprotein E (apoE) is one of the primary apolipoproteins found in the brain. especially Gülpınar and Yegen ˇ learned ones [135. impairments in cognitive performance have been observed. and neuronal cytoskeleton abnormalities were observed [162-164]. AVP was demonstrated to facilitate both acquisition and consolidation processes [144]. but it appears that Aβ may also modulate neurotransmission or the molecular cascades linked with learning and memory [167]. critical for reproduction. 148]. social recognition and behavior and appetite conditioning [135. rather than longterm memory [167]. but also by oxytocin receptors [157]. but improved avoidance performance when given before the retrieval process [160]. stimulations of the supraoptic and paraventricular nuclei. which resulted in AVP release within the hypothalamus. which are natural AVP-deficient mutants. 142]. carrying important roles in cholesterol metabolism and neural plasticity [161]. by suppressing choline . AVP in the ventral hippocampus is involved in information processing. although they appear to influence different cognitive processes and may modulate different neural systems [141]. 5. degeneration of forebrain cholinergic pathways is a critical factor in AD [9] and intracerebral Aβ has toxic effects on brain cholinergic systems [168. and retrieval [7]. In vitro experiments demonstrate that AVP can exert a neurotrophic effect upon cerebral cortical neurons. 167]. hyperlipidemia. AVP appears more important for consolidation. It has been known that AVP has central effects on learning and memory. AVP-deficient Brattleboro rats exhibit deficits in cerebral cortical development as assessed by decreases in the cortical weight. In the cortices and hippocampi of aged apoE-knockout animals. 147. including affiliation. 141. these peptides show unique cognitive and behavioral effects depending upon the species [141]. Peripheral administration of AVP or its analogs and selected AVP metabolites were shown to enhance social memory [146]. Intracerebroventricular injections of AVP also enhanced recognition responses in normal rats [147]. In aged and apoE-deficient mice. 6 Table 2. 152]. Social memory is a unique form of memory. AVP has been shown to improve memory consolidation in various mnemonic tasks. storage. It is believed that AVP interacts with NMDA. Systemic or central administration of AVP was demonstrated to affect several types of learned behaviors such as active or passive avoidance conditioning. In rats. the hippocampus [155]. Extensive research has demonstrated that AVP affects many behaviors. increased loss of synaptic terminals. Since the neuroanatomical distribution of receptors for both OT and AVP show differences among species. Experimental studies have shown that AVP and OT are essential for social memory. AII and its fragments were shown to facilitate acquisition and retrieval processes [159]. It is well documented that extrahypothalamic vasopressinergic pathways. Vol. also have serious memory impairments [141. by the activation of V1 receptors. Similarly. It was found that AVP or AVP fragments when injected subcutaneously facilitated the processes of memory consolidation and retrieval [151]. Considerable evidence indicates that a separate and distinct renin–angiotensin system is present within the central nervous system. Brattleboro rats. In rats Aβ induces impairments of spatial and non-spatial short-term memory. 150]. 145]. noradrenergic and β-adrenergic receptors. Aβ-induced amnesia does not only involve neurodegeneration in specific brain regions related to learning and memory processing. or microinjections of AVP into the olfactory bulbs were shown to improve recognition responses in rats [141. No. In another study. 2004.6 Current Protein and Peptide Science. as well as causing neurodegeneration in brain areas related to cognitive function [166. It was found that removal of the posterior pituitary impaired learning in rats and this deficit could be restored by treatment with exogenous AVP [142. such as the septum [154]. and reproduction. 169]. aggression. territorial defense. and the amygdala [156] are involved in the effects of vasopressin. but more interestingly. memory consolidation. The behavioral memory effect of vasopressin in all these structures is mediated not only by vasopressin V1 receptors. AVP also stimulates NGF secretion in the hippocampus and the cerebral cortex [153]. The mechanisms by which AVP and OT facilitate “social memory” remain unclear. Co-existence of Classical Neurotransmitters and Neuropeptides within the Same Neuronal Terminal [139] Neurotransmitter Neuropeptide Acetylcoline Vasoactive intestinal polypeptide Dopamine Cholecystokinin Enkephalin Epinephrine Enkephalin Norepinephrine Somatostatin Enkephalin Neurotensin Serotonin Substance P Thyrotropin-releasing hormone Arginine 8-vasopressin (AVP) and oxytocin (OT) are members of a large group of ancient neuropeptides that have profound effects on a variety of mnemonic and social processes. Amyloid-beta (Aβ) peptide is the main constituent of senile plaques found in the aging brain and β-Amyloid precursor proteins (β-APPs) play a crucial role in the pathogenesis of AD. whereas in mice OT is essential for acquisition. AII did not affect the acquisition of passive avoidance. in particular limbic structures. 143]. Aβ impairs cholinergic neurotransmission. It has been reported that angiotensin II (AII) is involved in learning and memory. cortical lipid content and DNA content of the cerebral cortex [158].

5. Vol. BNP. No.The Physiology of Learning and Memory Table 3. SP and NPY Colostrinin CRF CCK-related peptides improve learning and memory performance role for the CCK-B receptors in anxiety states lack of CCK-A receptors cause impaired learning and memory functions CCK-antiserum produces learning impairments CCK-8 potentiates amnesia CCK-4 interferes negatively with memory pretreatment with CCK-8S prevents experimental amnesia role in conditioned fear stress and anxiety enhance memory retention levels decreased in animals with hippocampal lesions SP improves functional recovery and increases the learning ability NPY can reverse drug-induced amnesi NPY either enhances memory or induces amnesia (depending on the site of injection) NPY antibodies induce amnesia facilitates the acquisition of spatial learning in aged rats improves memory retention and improves learning performance long-lasting enhancement of synaptic efficacy increased immunoreactivity in amyloid plaques of Alzheimer’s disease (AD) brains lower levels in the cerebrospinal fluid of AD pateints receptor antagonist given prior to training impairs fear conditioning lack of receptors impairs speed in learning Galanin impairs the learning and memory performances overexpression impairs cognition GLP-1 mediates or exacerbate β−amyloid protein-induced neurotoxicity. 2004. 6 Effects of Peptides and Non-peptide Molecules on Learning and Memory NEUROPEPTIDES AVP and OT AII facilitate “social memory”and learned behaviors facilitate both acquisition/ consolidation processes AVP-deficiency results in memory impairment facilitates retrieval processes when given before acquisition and impairs retention when given after training ANP. CNP facilitatory action on memory consolidation BN/GRP and NM improve memory performance CCK CGRP. Current Protein and Peptide Science. its antagonist prevents memory impairment HCNP abnormal accumulation and expression associated with memory and learning disorders Insulin improves short-term memory MCH modulates memory by acting on amygdala and hippocampus N/OFQ Orexin-A PACAP VIP impairs spatial learning receptor deficiency facilitates LTP and memory improves scopolamine-induced impairment of learning and memory inhibits LTP and retards spatial learning facilitates learning (consolidation and retrieval) ameliorates spatial cognitive deficits NON-PEPTIDE MOLECULES ApoE deficiency causes impairments in cognitive function Aβ intracerebral injections impair learning and memory retention (spatial and non-spatial short-term memory) PE abolishes the formation of amyloid beta peptide DA it has a beneficial impact on spatial working memory but excessive or insufficient levels lead to impairments 7 .

has been found to support the survival of neurons in vitro and in vivo . It has been postulated that NO takes a role in acquisition. Apamin was shown to improve the cognitive performance of mice and was suggested to be a cognition enhancer [180]. Since NOS is present in the HPA axis. Aβ: Amyloid-beta peptide. Apamin. 176]. is predominantly localized in the cortical and limbic structures. Increased NOS activity was shown to contribute to cognitive impairments in aged or apoE-knockout mice due to excess accumulation of oxidative damages in areas involved in learning and memory [164]. mediated by nitric oxide in the hippocampus. HCNP enhances the production of ChAT. CGRP: calcitonin-gene related peptide. Since glucocorticoids have been shown to modulate LTP and short-term potentiation in the hippocampus [151]. thereby modulating LTPrelated processes. which appears to depend on neutrotrophic factor-like activity [179]. which led to the purification of a novel undecapeptide (hippocampal cholinergic neurostimulating peptide. ciliary neurotrophic factor (CNTF). PACAP: pituitary adenylate cyclase activating polypeptide. DA: dopamine. BNP: brain-derived natriuretic peptide. NO has a number of neurological functions. CCK: cholecystokinin. Certain types of memory and learning disorders are found to be associated with abnormal accumulation and expression of HCNP analogue peptide and/or its precursor protein mRNA in the hippocampus [177]. but not of acetylcholine esterase (AChE). CNP: C-type natriuretic peptide. In the brain. acetyltransferase (ChAT) activity. of spatial memory [39. nNOS is expressed in diffused cortical areas and in the hippocampus [174]. 6 Gülpınar and Yegen ˇ (Table 3) contd… NON-PEPTIDE MOLECULES GLUTAMATE HISTAMINE NO OPIOIDS 5-HT malfunction is associated with the impairment of memory hypoactivation and hyperactivation cause impeded cognitive processing post-training administration attenuates memory retention depletion causes attenuation of acquisition inactivation of H1 receptors increases memory retention or memory recall promotes LTP higher synthesis in aged and cognitively impaired animals role in acquisition. and appears to be a retrograde messenger in promoting LTP [164. CRH: corticotropin releasing hormone. 175]. and induces glutamatergic dysfunction [170]. MCH: melanin-concentrating hormone. GLP-1: glucagon-like peptide. and the glial-cell-linederived neurotrophic factor (GDNF). SP: substance P.VIP: vasoactive intestinal peptide. Nitric oxide (NO) is a neurosignaling molecule with significant roles in cognition [171]. 5-HT: serootonin. Neuronal nitric oxide synthase (nNOS) messenger RNA expression in a variety of brain regions was significantly higher in aged and cognitively impaired animals than that in aged cognitively unimpaired animals [173].PE: Proline endopeptidase. Vol. [177]. ANP: atrial natriuretic peptide. HCNP). such as modulating glutamate-linked guanosine cyclic monophosphate (cGMP) production. AII: angiotensin II. No. it was suggested that glucocorticoids may have a direct impact on NOS. ApoE: apolipoprotein E. OT: oxytocin. Due to its oxidative properties. NPY: neuropeptide Y. BN/GRP and NM: bombesin/gastrin releasing peptide and neuromedin. interleukin-3 (IL-3). 2004. of spatial memory role in in memory acquisition administration impairs learning and memory chronic morphine treatment induces memory impairment lack of µ-opioid receptors causes spatial memory impairment dynorphin impairs spatial learning decreased levels block the effect of stress on memory stimulation of 5-HT1A receptors has detrimental effects on learning and working memory decrease in 5HT1A-binding causes memory impairment 5-HT4 agonists have potent cognitive enhancing activity AD patients display a reduction in 5-HT4 receptor binding sites AVP: angiotensin-vasopressin. the brain-derived peptidergic drug. Specific proteins play essential roles during the development and regeneration of specific neurons. HCNP: hippocampal cholinergic neurostimulating peptide. but not retention. NO has been implicated in several neurodegenerative diseases [172]. it appears that the stress axis. where NOS is described. is involved in the regulation of the synaptic plasticity process [85]. It was demonstrated that soluble extracts from the hippocampus of young rats enhance the development and growth of cholinergic neurons in rat medial septal nucleus. a highly selective and potent peptide that blocks the calcium-activated potassium channels. but also in learning and memory formation through neuronal plasticity [178]. The multimodal mechanism of cerebrolysin.8 Current Protein and Peptide Science. . NO: nitric oxide. but not retention. N/OFQ: nociceptin/orphanin FQ. 5. NGF and brainderived neurotrophic factor (BDNF) in the hippocampus play an important role not only in the development and regeneration of the system. fibroblast growth factors. which include NGF and related members of the neurotrophin family.

L-Glutamate. The tachykinins are a family of peptides with putative neurotransmitter roles in the brain regions associated with emotion. suggesting that endogenous BN-like peptides have some role(s) for the modulation of learning and memory [181]. produced by deamidation of glutamine via glutaminase. was shown to facilitate the learning. including memory and mood regulation [216]. Moreover. 6 9 in rats [194] and long-term potentiation and memory are facilitated in mice lacking nociceptin receptors [195]. It has been shown that DA has a beneficial impact on spatial working memory [201]. while malfunction in glutamatergic activity is associated with the impairment of memory seen in Alzheimer patients. colostrinin administration facilitated the acquisition of spatial learning in aged rats. nociceptin injection improves scopolamineinduced impairment of learning and memory [199]. Colostrinin. Calcitonin gene-related peptide (CGRP). On the other hand. Neuromedin B (NMB) is a mammalian BN-like peptide that plays a role in regulating the stress response via the neural system. Insulin is reported to improve short-term memory. suggesting that galanin overexpression contributes to the memory deficits that characterize Alzheimer’s disease [205]. a serine endooligopeptidase involved in the degradation of various neuropeptides. 5. Isatin. Nociceptin. as well as ANP. Both the ORL1 receptor and N/OFQ are widely distributed in the central nervous system (CNS) [193]. have been detected in AD patients compared with healthy controls. Similarly. emotion. Dopamine (DA) has been implicated in learning and memory and its receptors are involved in the control of movement. SP and NPY levels were shown to be decreased in the hippocampus and a significant decrease of NPY in the cortex was observed in mice with lupus. was shown to inhibit LTP in the hippocampus and retard spatial learning [188. 189]. It has been shown that the facilitatory action of BNP and CNP. 203]. PE inhibitors are seen as potential pharmacological agents aimed at slowing down or abolishing the degenerating process taking place in AD [187]. substance P (SP) and neuropeptide Y (NPY) are postulated to play important roles in cognitive functions. Orexin-A. sensation. also known as orphanin FQ (N/OFQ). There is evidence that increased concentrations of corticosterone can elevate the basal level of glutamate in the hippocampus of rats [208. glutamatergic neurotransmission in neocortical regions and hippocampus is severely disrupted and corticocortical association fibers arising from glutamatergic pyramidal cells are disconnected [208. galanin is overexpressed in the basal forebrain of Alzheimer’s patients. N/OFQ inhibits the release of several neurotransmitters. is the most abundant free amino acid in brain and it plays an important role in neuronal differentiation. Conversely. Initial observations in humans indicated that colostrinin. and neuroendocrine secretion [200]. Higher fasting concentrations of insulin in plasma and lower concentrations of insulin in cerebrospinal fluid (CSF). on memory consolidation can be inhibited by isatin [212-214]. Thus. induced hyperglycemia does not increase the plasma concentration of insulin and does not improve cognitive function in patients with severe AD [192]. migration. 198]. Clinical studies provide compelling evidence for a beneficial effect of insulin in AD. No. galanin-overexpressing transgenic mice were shown to perform poorly on challenging cognitive tasks [206]. and resembles to some extent the endogenous opioid peptide dynorphin A. bringing it to the level observed in young subjects [191]. was speculated to facilitate the early postnatal development of the cerebral neurons and their plasticity. facilitates cognitive functioning in patients with Alzheimer’s disease [190]. infusion of GLP-1 antagonist was shown to prevent the memory impairment induced by β-amyloid alone [183]. is an endogenous ligand for the orphan opioid receptor-like receptor 1 (ORL1). Vasoactive intestinal peptide (VIP) appears to have an ameliorating effect on spatial cognitive deficits induced by scopolamine in the rat [184]. learning and memory [215]. CGRP. Endogenous glucagon-like peptide (GLP-1) has been demonstrated to mediate or exacerbate β−amyloid proteininduced neurotoxicity. which also controls learning and memory [182]. On the other hand. Furthermore. clinical observations show that induced hyperglycemia results in an increased plasma level of insulin and enhanced cognitive performance in patients with mild AD. which probably increases the vulnerability of the aging brain to neuronal damage. In rats. through its action on hippocampo-frontocortical circuitry. Vol. 2004. but excessive or insufficient levels of DA lead to impairments [110. has been shown to counteract the behavioural effects of atrial natriuretic peptide (ANP). SP treatment improved functional recovery . isolated first from the ovine hypothalamus. a complex of proline-rich polypeptides isolated from early milk. Central administration of the neuropeptide galanin to rodents was shown to impair the performances on learning and memory tasks [204]. which are indicative of insulin resistance. brain natriuretic peptide (BNP) and C-type natriuretic peptide (CNP) in vitro and in vivo. The pituitary adenylate cyclase activating polypeptide (PACAP). synaptic maintenance and plasticity. On the other hand. including serotonin [196] and dopamine [197.The Physiology of Learning and Memory Several studies reported that peripheral administration of bombesin (BN) and gastrin-releasing peptide (GRP) improved some forms of memory performance in rats and mice. 209]. has been reported to abolish the formation of amyloid beta (Aβ ) peptide and post mortem levels of human PE were affected in AD brains [186]. the consolidation of learning and the retrieval of the passive avoidance response [185]. Stress results in enhanced glutamate response. It contributes to learning and memory [207]. which is released from the axon terminals of the glucose-sensitive neurons in the lateral hypothalamus to act on its hippocampal receptors. It was shown that nociceptin microinjected into the hippocampus impairs spatial learning Current Protein and Peptide Science. 202. Both hypoactivation and hyperactivation of glutamatergic systems seem to cause impeded cognitive processing in animals. which is an endogenous indole with a highest concentration in the hippocampus [211]. cognition. 210]. Stress appears to have deleterious effects on cognition caused by glutamate neurotoxicity leading to attenuated synaptic activity [208]. Proline endopeptidase (PE). In Alzheimer’s disease.

as they occur during manipulation of the animal. have impaired learning and memory functions . 231]. It is well-known that acute opioid administration impairs learning and memory [223]. No. and regulates the `mood' of the animal. Moreover. has an influence on learning and memory. while its injection into the amygdaloid body and the caudal hippocampus induces amnesia. In the central nervous system. suggesting that CCK may participate in the central control of stress response and stressinduced memory dysfunction. 2004. Recent evidence has established that histamine plays an important role in the symptomatology of Alzheimer’s disease as a central neurotransmitter in the brain. amygdala. A. which modulates memory performance. which lack CCK-A receptor because of a genetic abnormality. implicating that histaminergic system may interact with the cholinergic system on memory retention [229]. CRF is accepted as the main neuropeptide involved in both physical and emotional stress. which is mainly located in the lateral hypothalamic area and projects to various other brain areas and modulates memory by acting on both the amygdala and hippocampus [230. while contradictory reports indicate that histamine H1 receptor activation may increase memory recall. acts as a neurohormone. Microinjection of dynorphin B into the dorsal hippocampus impairs spatial learning in rats. OA is involved in desensitization of sensory inputs. Octopamine (OA). and the locus coeruleus [241. The peptide CCK has been also proposed to facilitate memory processing and CCK-like immunoreactivity in the hypothalamus was observed upon stress exposure. Immunocytochemical studies have demonstrated that melanin-concentrating hormone (MCH). hippocampus. but are concentrated in the hippocampus. 244]. 235. The studies indicated that post-training administration of different doses of histamine attenuated memory retention. CCK or CCK receptors are found in brain areas involved with cognitive or emotional aspects of behavior. CHOLECYSTOKININ (CCK) Cholecystokinin. Neuronal CCK has been implicated in the control of feeding. implicating that CCK may be a modulator of emotional behavior and stress responsiveness [246]. cholecystokinin (CCK). Immunization with NPY antibodies also induces amnesia [221]. It was suggested that the behaviour deficits observed in these lupus mice are associated with an altered availability of NGF [216]. a biogenic monoamine structurally related to noradrenaline. The characteristic distribution of CCK and the presence of specific CCK receptive sites in the brain indicate the role of CCK-fragments in brain function. and NPY enhances memory retention in mice [219]. OLETF rats. NPY can reverse drug-induced amnesia [219] and its injection into the rostral hippocampus and the septal area enhances memory retention. Two CCK receptor subtypes (designated A and B) are found within the central nervous system (CNS). Considerable evidence indicates that NPY is involved in cognitive functions [218]. one of the most abundant neurotransmitter peptides in the mammalian cerebral cortex and hippocampus [237]. is involved in higher functions to act as a neurotransmitter and/or neuromodulator [238]. Major Strategic Molecules in the Modulation of Memory Processes in Stress Among all these peptides that are found to be associated with learning and memory. It has been shown that the inactivation of histamine H1 receptors by histamine receptor antagonists increases memory retention. pain perception and exploratory behaviors [239]. possibly through the activation of HPA axis [54. 236]. Vol. which is implicated in the modulation of cognition [220]. recently it was demonstrated that µ-opioid receptor knock-out mice exhibit a spatial memory impairment. and this opioid-induced impairment can be modulated by opioid antagonists [224]. amygdaloid and hippocampal areas and temporal cortex in AD brains [222]. The results of a number of studies have suggested that the central CRF. supporting a role for the CCK-B receptor in anxiety states and panic attacks [55. although CCK-B receptors are far more numerous and widely distributed [240]. cingulate. a Gülpınar and Yegen ˇ neuromodulator and a neurotransmitter only in invertebrates. Several studies have attempted to demonstrate the role of CCK in learning and mnemonic processes [247]. suggesting that these receptors play an important role in the modification of spatial learning and memory [226]. 242]. suggesting that the degenerative processes occurring in Alzheimer’s disease may involve changes in NPY-related innervation [220]. which is thought to be related to the the inhibition of the cholinergic system. On the other hand. 243. exerts a protective role during stress. 6 and increased the learning ability in animals with hippocampal lesions [217]. such as prefrontal cortex. 5-HT appears to play a role in behaviors that involve a high cognitive demand and stress exposure activates serotonergic systems in a variety of brain regions. Interest on the anxiogenic quality of CCK occurred when rats or healthy human volunteers were observed to have panic attacks when given CCK-4 intravenously. serotonin (5-HT) and corticotropin releasing factor (CRF) play a strategic role in the modulation of memory processes under stressful conditions.10 Current Protein and Peptide Science. to enable the animal to cope with stressors [232-234]. NPY-like immunoreactivity and NPY receptors have been shown to be present throughout the brain. NPY-like immunoreactivity was shown to decrease in cortical. 5. It is believed that OA is a stress hormone that is released in times of stress. It was also reported that chronic treatment with morphine induces memory impairment [225] . These findings suggest that the hippocampal dynorphin system plays a significant role in hippocampal learning processes and that dynorphin peptides have a regulatory function in memory acquisition and the early stages of memory formation [227]. while depletion of histamine by the administration of a selective inhibitor of the histamine-synthesizing enzyme caused an attenuation of acquisition in rats [228]. It was also indicated that the memory improvement induced by acetylcholine or nicotine can be impaired by histamine. There is also evidence that the CCKB receptors play a role in modulating activity within the hypothalamic–pituitary adrenal (HPA) axis [245].

In contrary. or it is due to impaired attention or arousal [66].The Physiology of Learning and Memory [248]. a correlation was found between the cognitive impairment in AD and lower levels of CRH in the cerebrospinal fluid. and behavioral deficits [283286]. other data suggest that glucocorticoid-independent mechanisms involving CRH mediate neuronal damage. behavioral and immune responses to stress in mammals and in modulating learning and memory performance. Furthermore. CORTICOTROPIN-RELEASING HORMONE AND GLUCOCORTICOIDS Corticotropin-releasing hormone (CRH. In Alzheimer’s disease. While most data suggest that increased glucocorticoid levels is the major component of the stress response that promotes detrimental effects in the brain. B. electrophysiological alterations. chronic stress causes a reduction in CRF mRNA level in central amygdala and a slight elevation in PVN and CRF-hypersensitivity in locus coeruleus resulting in sympathetic nervous system activation [25]. 250]. 256]. Localization of the CRH in the limbic system suggests that it plays an important role in activating the sympathetic nervous system for adaptive. 270]. particularly found in PVN of hypothalamus and amygdala. while hypothalamic CRH activity was enhanced following ACh administration. In accordance with these findings. whereas injection of a CCKantiserum was found to produce learning impairments [251]. CRH receptor knock-out mice showed an impaired speed in learning. while CCK-4 interfered negatively with memory [252-254]. However. decreased cholinergic function is well documented. which is observed as a reduction in neuron size. can lead to accelerated impairment and aging in the hippocampus [282]. and partially suppressed the increase obtained during the acquisition phase of memory. Thus. memory performance is physiologically improved when the CCK-B receptor in the rat hippocampus is stimulated with endogenous CCK8. CCK-like immunoreactivity and CCK-B receptor-mediated amygdaloid regulation of hypothalamus were observed upon stress exposure. panic. it is also evident that both endogenous and exogenous increases in Current Protein and Peptide Science. 74]. Intrinsic activation of brain CRH systems influences information processing [260262]. Intravenous administration of CCK-B receptor agonist. Based on several behavioral effects. It was found that stress resulted in a significant decrease in the extracellular levels of CCK-like immunoreactivity in the hippocampus. CCK-8 was found to potentiate the amnestic effects of scopolamine. On the contrary. however. the . abnormal and increased CRH immunoreactivity has been observed in the axons associated with amyloid plaques in the amygdala [269]. it was suggested that CRH enhances the anxiogenic nature of environmental stimuli and anxiety has profound effects on learning and memory processes. 2004. but it is not clear whether the acquisition deficit is a learning deficit. Neurochemical and anatomical evidence suggests that cholinergic and the CRH systems have important reciprocal interactions. produces dose-dependent release of adrenocorticotropin (ACTH) and cortisol. suggesting that the CCKergic system in the hippocampus is involved in stress-induced impairment of memory [56]. Systemic or icv pretreatment with CCK-8S prevents experimental amnesia. There is evidence that CRH may not be directly neurotoxic [268]. It was reported that acute stress causes hyperactivation in many central CRH-containing neurons. we recently demonstrated that acute stress activates HPA axis with the participation of central CCK receptors [54]. supporting the hypothesis that CCK-B agonists pharmacologically activate the HPA axis [257]. the induction of fear conditioning was impaired [272]. Earlier studies indicated that both in aging and after chronic glucocorticoid treatment. such as those seen during stress. stimulation of parts of the CRH system has been proposed as a potential treatment in Alzheimer’s disease [273-281]. suggesting that CCK may participate in the central control of neuro-endocrine response to stress [72. but more recent studies indicate the presence of hippocampal impairment. It was demonstrated that CCK-related peptides could improve learning [249. HPA axis function is altered with normal aging and the variability in HPA axis function between individuals may be the result of combined environmental and genetic factors including different CRH or stress responses [62. in AD brain. CRH was shown to induce a long-lasting enhancement of synaptic efficacy in the hippocampus [271]. 6 11 glucocorticoids are associated with deficits in both memory and attention [265] Since glucocorticoids can compromise the functioning of the hippocampus investigators have speculated that hippocampal-based cognitive functions may be at particular risk from the deleterious effects of glucorticoids [266]. which coincides with a decrease in cortical CRH and a reciprocal increase in cortical CRH receptors. CRF) is a peptide with both neuroendocrine and neurotransmitter properties [258]. It has been proposed that elevated concentrations of glucocorticoids. when a CRH receptor antagonist is injected prior to training. No. Moreover. neurons were killed. pentagastrin. CRH originates from clusters of peptidergic cells in the hypothalamic paraventricular nucleus (PVN) [259] as the key mediator of the stress response and also functions as a neuromodulator in a number of limbic and autonomic brain circuits. Similarly. 255. Furthermore. Exposure to acute stressful experience induces enhanced memory formation by the activity of glucocorticoids. Intra-amygdala injection improves memory retention and intra-hippocampal administration improves learning performance [263. It was concluded that cortisol can modulate cognitive processes and that the effects of corticosteroids on cognitive function are selective [267]. or corticotropin releasing factor.and stress-related behaviour. On the other hand. in primary embryonic hippocampal cultures CRH was found to protect the cells from degeneration caused by an amyloid-peptide and other insults related to the pathogenesis of AD. It was suggested that the CCK-B receptor might play an important role in conditioned fear stress and that it might be related to anxiety [247. 5. Extensive studies were carried out on the involvement of the CCKergic system in anxiety-. It was reported that frontoparietal cortical CRH release was inhibited by ACh. On the other hand. When exposed to such stressors as those that enhance learning. autonomic. 264]. Vol.

indicating that optimal concentrations of glucocorticoids are necessary for memory consolidation. or cortisol [299] resulted in impairments in verbal declarative memory function in healthy human subjects. which involves excessive release of cortisol for long periods. The 5HT1A receptor has a high concentration in the limbic system. which are believed to be important in anxiety. There are two major serotonergic systems in the brain. Accordingly.12 Current Protein and Peptide Science. which includes mnemonic as well as attentional components [311]. Similarly. and impaired concentration [307]. Glucocorticoids facilitate cognition and behavior associated with fear and anxiety responses. and are actively involved in the feedback regulation of the HPA axis [292293]. depression. 310]. The serotonergic system appears to play a role in behaviors that involve a high cognitive demand and in memory improvement or recovery from impaired cognitive performance. 6 organism responds by activating a complex series of physiological and behavioral responses that often involve the HPA axis and autonomic nervous system. also causes memory impairment [291]. the medial raphe nuclei (MRN) and the dorsal raphe nuclei (DRN). Stimulation of 5-HT1A receptors has detrimental effects on learning and working memory. due to chronic glucocorticoid elevation during repeated stress may result from neural atrophy in the hippocampus via facilitation of excitatory amino acid-mediated toxicity [296]. Both human and animal research suggests that the memory enhancing effects of glucocorticoids are especially relevant to emotional memory [289-291]. No. Experimental studies in rodents have shown that behavioral or pharmacological manipulations. Exogenous administration of glucocorticoids enhances some processes of learning [290]. dexamethasone [298]. but rather enhances learning. the hippocampus and frontal cortex. fear and in modulating cognitive processes [27]. with evidence of exacerbation of memory deficits with stress-induced cortisol elevations [299] and improvement in memory function with reduction in cortisol levels [48. the hippocampus. the consolidation of this task is enhanced by glucocorticoids secreted during the task [288] and if the learning is made more stressful. It is also evident that the complete absence of glucocorticoids as the result of adrenalectomy. Glucocorticoids may specifically influence the production of emotional and social behaviors such as attachment. 294]. Glucocorticoid administration or stress can enhance declarative memory performance and can lead to increased spontaneous cell firing in the amygdala and decreased glucose utilization in the hippocampus. also prevented memory impairments [56. the frontal cortex and the amygdala) are involved in the interaction between cognition and emotion. A large body of evidence supports that 5-HT4 receptor. has a major role in learning and memory [312]. temperament and mood [35]. Glucocorticoid receptors have been found in the hippocampus (declarative or spatial memory). Cortisol levels were Gülpınar and Yegen ˇ related to memory function. It was suggested that exposure to glucocorticoids does not just enhance performance of the response. patients receiving glucocorticoid treatment for a medical condition also show evidence of cognitive impairment [306]. post-mortem brains of AD patients display a reduction in the number of 5-HT4 receptor binding sites in the hippocampal region [313. whereas their inactivation selectively antagonizes these effects. These serotonin receptor subtypes are localized on ‘cognitive’ pathways. It has been hypothesized that the disruption of cognitive functions. amygdala (emotional memory) and prefrontal cotex (working memory). Administration of commonly used therapeutic doses of glucocorticoids [297]. 302] and can lead to increased HPA activity via the CRH system in the amygdala and the noradrenergic system in the brainstem [303. In addition. 5. C. AD is also characterized by HPA hyperactivity and hippocampal atrophy. 2004. Recently. have deficits in attention and memory that are correlated with hippocampal volume reduction [305]. Prolonged exposure to elevated cortisol concentrations can result in fatigue. The release of glucocorticoids from the adrenal cortex and epinephrine from the adrenal medulla constitute an important part of the stress response. 304]. Vol. which enhances the organism’s ability to deal with stress [287]. apathy. Chronic glucocorticoid administration can lead to deficits in verbal and declarative memory and spatial memory performance [295]. the role of 5-HT4 receptors in the neuronal mechanism of memory enhancement and the cognitive process was demonstrated using selective 5-HT4 . Increased levels of glucocorticoids during ageing are associated with a worsening of memory and hippocampal damage/atrophy in both animals and humans [309]. Different cerebral structures that are rich in 5-HT receptors (such as the lateral septum. Chronic stress influences several neurotransmitters in the forebrain as well as in the amygdala [301. Several studies have observed that patients with Cushing’s disease. which has a relatively high expression in the limbic system. It is believed that ageing is accompanied by increased basal cortisol levels and reduced feedback sensitivity of the HPA axis [308]. SEROTONIN (5-HT) 5-HT has been implicated in the neurochemistry of anxiety for a long time. the performance of the animal is further enhanced. where autoreceptors influence cognitive functions. which are relevant to cognition. by initiating changes in various functional brain systems that underlie cognitive mechanisms. If an animal learns a stressful task. which are targeted to prevent the ageinginduced HPA hyperactivity. Both low and high glucocorticoid levels are also associated with deficits in memory performance. the memory performance is impaired. Elevations in glucocorticoid may enhance focused attention toward an emotionally arousing stimulus by increasing the availability of norepinephrine [35. Endogenous glucocorticoids are necessary for transiently enhancing acquisition of new memories and also for the persistent enhancement of learning after stress [289]. If the animal is placed in a stressful environment during the time between the learning and the subsequent delayed recall. 300]. 314]. memory-enhancing effects can be obtained if glucocorticoids are given immediately after training [289].

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