Search

The ventral hippocampus (VH) has a high distribution of cannabinoid CB1 receptors which are important in modulating stress responses. Stress exposure activates the hypothalamic-pituitary-adrenal axis (HPA) which can impact hippocampal formation to change hippocampus-based memories. The purpose of the present study was to determine the possible role of the VH cannabinoid CB1 receptors in stress-induced amnesia using a step-through passive avoidance procedure in male Wistar rats. In order to induce acute stress, the animals were placed on an elevated platform for different time periods (10, 20 and 30min). Our results indicated that post-training 20 and 30min exposure to stress, but not 10min, induced amnesia. Post-training microinjection of a cannabinoid CB1 receptor agonist, arachydonilcyclopropylamide (ACPA; 2.5-7.5ng/rat) into the VH (intra-VH) induced amnesia. Interestingly, post-training intra-VH microinjection of the same doses of ACPA improved stress-induced amnesia. On the other hand, post-training intra-VH microinjection of a selective CB1 receptor antagonist, AM-251 (20-50ng/rat) with exposure to an ineffective stress (10min) potentiated the effect of stress on memory consolidation and induced amnesia. It should be noted that post-training intra-VH microinjection of the same doses of AM-251 alone had no effect on memory consolidation. Our results revealed that post-training intra-VH microinjection of AM-251, prior to ACPA microinjection, inhibited the reversal effect of ACPA on acute elevated platform stress. Taken together, it can be concluded that exposure to post-training inescapable stress impaired memory consolidation. The impairing effects of stress on memory retrieval may be mediated by the VH cannabinoid CB1 receptors.

Phoenixin (PNX) is a recently discovered neuropeptide shown to be involved in regulating the reproductive system, anxiety-related behaviors and pain though its receptor is still unknown. PNX-14, one of the endogenous active isoforms, is reported to regulate gonadotropin releasing hormone (GnRH) receptor expression and GnRH secretion. Because GnRH system is thought to be involved in the regulation of learning and memory processes, we hypothesized that PNX-14 might be mediate learning and memory. Here, we investigated the effects of PNX-14 in memory processes, using novel object recognition (NOR) and object location recognition (OLR) tasks. Our results revealed that intracerebroventricular (i.c.v.) injection of PNX-14 (25nmol) immediately after training not only facilitated memory formation, but also prolonged memory retention in both tasks. The memory-enhancing effects of PNX-14 were also seen when it was infused into the hippocampus. Moreover, these memory-improving effects of PNX-14 could be blocked by a GnRH receptor antagonist (Cetrorelix). The memory-improving effects of PNX-14 were not related to any effects on locomotor activity. Additionally, the results suggested that i.c.v. injection of PNX-14 mitigate the memory impairment induced by the amyloid-β1-42 (Aβ1-42) peptide and scopolamine. The present results indicate that PNX-14 facilitates memory formation and prolongs memory retention through activation of the GnRH receptor, and mitigates the memory-impairing effects of Aβ1-42 and scopolamine, suggesting that PNX-14 may be effective as a drug for enhancing memory and treating Alzheimer׳s disease.

Stress is a potent modulator of hippocampal-dependent memory formation. The aim of the present study was to assess the role of hippocampal signaling pathways in stress-induced memory impairment in male Wistar rats. The animals were exposed to acute elevated platform (EP) stress and memory formation was measured by a step-through type passive avoidance task. The results indicated that post-training or pre-test exposure to EP stress impaired memory consolidation or retrieval respectively. Using western blot analysis, it was found that memory retrieval was associated with the increase in the levels of phosphorylated cAMP-responsive element binding protein (P-CREB), peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) and its downstream targets in the hippocampus. In contrast, the stress exposure decreased the hippocampal levels of these proteins. In addition, stress-induced impairment of memory consolidation or retrieval was associated with the decrease in the P-CREB/CREB ratio and the PGC-1α level in the hippocampus. On the other hand, the hippocampal level of nuclear factor E2-related factor 2 (Nrf2) and gamma-glutamylcysteine synthetase (γ-GCS) which are the master regulators of defense system were decreased by the stress exposure. The increased hippocampal levels of Nrf2 and it׳s downstream was observed during memory retrieval, while stress-induced impairment of memory consolidation or retrieval inhibited this hippocampal signaling pathway. Overall, these findings suggest that down-regulation of CREB/PGC-1α signaling cascade and Nrf2 antioxidant pathways in the hippocampus may be associated with memory impairment induced by stress.

Cold is a common stressor that is likely to occur in everyday occupational or leisure time activities. Although there is substantial literature on the effects of stress on memory from behavioral and pharmacologic perspectives, the effects of cold stress on learning and memory were little addressed. The aims of the present work were to investigate the effects of acute cold exposure on Y-maze learning and the activation of cerebral MAPK cascades of rats. We found that the 2-hour cold exposure (-15 degrees C) and a subsequent 30-min rewarming significantly increased the performance of the rats in the Y-maze test. Serum corticosterone (CORT) level was increased after the cold exposure. After a transient reduction following the cold exposure, the P-ERK levels in the hippocampus and PFC drastically increased 30 min later. The levels of P-JNK increased gradually after the cold exposure in all the three brain regions we investigated, but the level of P-p38 only increased in the PFC. The levels of GABAA receptor alpha1 subunit remained unchanged after the cold exposure. Furthermore, the performance of rats treated with cold plus muscimol or bicuculline in the Y-maze test was similar to that of the rats treated with those GABAergic agents alone. These results demonstrated that acute cold exposure and the subsequent rewarming could result in enhanced performance of spatial learning and memory, and the activation of MAPKs in the brain. However, GABAA receptor may not be involved in the acute cold exposure-induced enhancement of memory.

We previously demonstrated that chronic stress impaired prefrontal cortex-sensitive working memory, but not reference memory. Since the hippocampal cholinergic system is also involved in these memories, we examined the effects of chronic stress on cholinergic transmission in the rat hippocampus. A microdialysis study revealed that the stress did not affect the basal acetylcholine release, but enhanced the KCl-evoked response. These results suggest that cholinergic transmission in the chronically stressed hippocampus does not contribute to working memory impairment, but it may be involved in maintenance of reference memory.

Several reports have indicated that various stress stimuli modulate learning and memory processes. In the present study, the effects of adrenocortical suppression with the 11beta-hydroxylase inhibitor metyrapone on the psychological stress-induced changes in memory storage in inhibitory avoidance training and in serotonin turnover in various brain regions were investigated in rats. Retention of one-trial inhibitory avoidance and the plasma corticosterone level were significantly enhanced by post-training exposure to psychological stress for 1 h. Pretreatment with metyrapone (12.5 or 25 mg/kg, s.c.) 90 min beforehand dose-dependently blocked the enhancement of memory storage and of the plasma corticosterone level produced by psychological stress. These results suggest that the adrenocortical system may contribute to the memory-enhancing effect of psychological stress. In a neurochemical study, a significant increase in serotonin turnover in the hippocampus and limbic forebrain, including the nucleus accumbens, were observed in rats that were exposed to psychological stress. In contrast to the behavioral experiments, these changes in serotonin turnover produced by exposure to psychological stress were not antagonized by pretreatment with metyrapone; instead, a further increase in serotonin turnover was observed only in the hippocampus. These results suggest that the serotonergic system in the hippocampus might be selectively regulated by adrenal steroids in response to stress, and imply the existence of negative feedback mechanisms via a hippocampal serotonergic system in the memory enhancement associated with corticosterone and psychological stress.

Consistent with a multiple systems approach to memory organization in the mammalian brain, numerous studies have differentiated the roles of the hippocampus and dorsal striatum in "cognitive" and "habit" learning and memory, respectively. Additional research indicates that activation of efferent projections of the basolateral amygdala (BLA), a brain region implicated in mammalian emotion, modulates memory processes occurring in other brain structures. The present brief review describes research designed to link these general concepts by examining the manner in which emotional state may influence the relative use of multiple memory systems. In a dual-solution plus-maze task that can be acquired using either hippocampus-dependent or dorsal striatal-dependent learning, acute pre-training or pre-retrieval emotional arousal (restraint stress/inescapable foot shock, exposure to the predator odor TMT, or peripheral injection of anixogenic drugs) biases rats towards the use of habit memory. Moreover, intra-BLA injection of anxiogenic drugs is sufficient to bias rats towards the use of dorsal striatal-dependent habit memory. In single-solution plus-maze tasks that require the use of either cognitive or habit learning, intra-BLA infusions of anxiogenic drugs result in a behavioral profile indicating an impairing effect on hippocampus-dependent memory that effectively produces enhanced habit learning by eliminating competitive interference between cognitive and habit memory systems. It is speculated that the predominant use of habit memory that can be produced by anxious and/or stressful emotional states may have implications for understanding the role of learning and memory processes in various human psychopathologies, including for example post-traumatic stress disorder and drug addiction.

Stress leads to an enhanced activity of the hypothalamus-pituitary adrenal (HPA) axis resulting in an increased release of glucocorticoids from the adrenal cortex. These hormones influence target systems in the periphery as well as in the brain. The present review paper describes the impact of the human stress hormone cortisol on episodic long-term memory. Starting out with our early observation that stress as well as cortisol treatment impaired declarative memory, experiments by the author are described, which result in an enhanced understanding of how cortisol influences memory. The main conclusions are that stress or cortisol treatment temporarily blocks memory retrieval. The effect is stronger for emotional arousing material independent of its valence. In addition cortisol only influences memory when a certain amount of testing induced arousal occurs. A functional magnetic resonance imaging (fMRI) study suggests that the neuronal correlate of the cortisol induced retrieval blockade is a reduced activity of the hippocampus. In contrast to the effects on retrieval cortisol enhances memory consolidation. Again this effect is often stronger for emotionally arousing material and sometimes occurs at the cost of memory for neutral material. A fMRI study revealed that higher cortisol levels were associated with a stronger amygdala response to emotional stimuli. Thus stimulatory effects of cortisol on this structure might underlie the cortisol induced enhancement of emotional memory consolidation. The findings presented are in line with models derived from experiments in rodents and are of relevance for our understanding of stress associated psychiatric disorders.

Despite cumulative evidence showing the detrimental effect of psychosocial stress on the learning/memory functions in dementia diseases, the precise neurobiological mechanisms behind such an effect remain unclear. Mice of the senescence-accelerated mice prone 10 (SAMP10) strain, a neurodegenerative dementia model, were chronically exposed to social isolation stress from the age of 5 weeks. At the age of 12 weeks, conditioning memory and spatial memory were evaluated by one-trial passive avoidance and Y-maze tests, respectively. Chronic social isolation stress significantly reduced conditioning memory but did not affect spatial memory. Although further behavioral tasks using an elevated plus maze and a pain threshold test exhibited stress-induced analgesia, an analysis of covariance excluded the possibility that such analgesia might contribute to the stress-induced impairment of conditioning memory. In addition, endocrinological and immunohistochemical analysis revealed that isolation stress elevated the serum corticosterone levels and inhibited the increase in c-Fos expression in the central amygdaloidal nucleus (CeA) that is required for conditioning memory during passive avoidance learning. In conclusion, chronic social isolation stress exacerbated conditioning memory in SAM mice, probably through a glucocorticoid-mediated decrease in neural activation in the CeA.

Post traumatic stress disorder (PTSD) is characterised by hyperarousal, anxiety and amnesic symptoms. Deficits in explicit memory recall have been causally related to volume reductions of the hippocampus and prefrontal cortex. While stress-related glucocorticoid secretion appears involved in this apparent atrophy, there is also evidence for low plasma cortisol in PTSD. Prior exposure to trauma is an important risk factor for PTSD, suggesting a role for sensitisation. Using Sprague-Dawley rats, we studied the effects of a time-dependent sensitisation (TDS) model of stress on spatial memory deficits, 1 week post-stress, using the Morris water maze. Basal and 7-day post-stress plasma corticosterone levels were also determined. Due to the putative role of serotonin in anxiety and stress, and in the treatment of PTSD, hippocampal 5HT(1A) and prefrontal cortex 5HT(2A) radioligand binding studies were performed. TDS stress evoked a marked deficit in spatial memory on day 7 post TDS stress, coupled with significantly depressed plasma corticosterone levels. Cognitive and endocrine changes at day 7 post stress were associated with a significant increase in receptor density (B(max)) and a significant decrease in receptor affinity (K(d)) for hippocampal 5HT(1A) receptors. The B(max) of prefrontal cortex 5HT(2A) receptors were unaffected, but K(d) was significantly increased. We conclude that TDS stress evokes cognitive and endocrine changes characteristic of PTSD. Moreover, TDS stress induces diverse adaptive 5HT receptor changes in critical brain areas involved in emotion and memory that may underlie the effect of stress on cognitive function.

Restraint stress, 6 h/day for 21 days, caused an impairment, during acquisition, of the performance of a spatial memory task, the eight-arm radial maze. The impairment was reversible, temporally limited and blocked by phenytoin, a blocker of excitatory amino acid action, or tianeptine, an antidepressant, which lowers extracellular serotonin. These effects on behavior parallel the reversible stress-induced atrophy of dendrites of hippocampal CA3 neurons that are also blocked by the drugs.