Corticosterone effects on BDNF mRNA expression in the rat hippocampus during morris water maze training

Corticosterone and Brain-Derived Neurotrophic Factor (BDNF) have both been shown to be involved in spatial memory formation in rats. In the present study we have investigated the effect of corticosterone on hippocampal BDNF mRNA expression after training in the Morris water maze in young adult Wistar rats. Therefore, we first studied BDNF mRNA levels in the hippocampus in relation to corticosterone levels at several time points after 4 training trials in the Morris water maze. Corticosterone levels were significantly increased after this procedure, and hippocampal BDNF mRNA levels only displayed a minor change: an increase in CA1 at 1 hr after training. However, in a previous study we observed dramatically decreased hippocampal BDNF mRNA levels in dentate gyrus and CA1 at 3 hr after injection of corticosterone. In order to analyze this discrepancy, we subsequently investigated if hippocampal BDNF mRNA expression is affected by corticosterone at 3 hr after water maze training. Therefore, we incorporated ADX animals and ADX animals which were injected with corticosterone in our study. ADX animals which were subjected to water maze training displayed similar hippocampal BDNF mRNA levels 3 hr after training compared to control ADX animals. Furthermore, ADX animals which were injected with corticosterone showed decreased BDNF mRNA levels in all hippocampal regions compared to control ADX animals. Water maze training did not alter this effect. Thus, the increased corticosterone levels during water maze training do not affect hippocampal BDNF mRNA expression, although exogenous corticosterone is effective under these conditions. Hence, our results suggest that in this situation BDNF is resistant to regulation by endogenous corticosterone, which may be important for learning and memory processes.     

Activation and survival of immature neurons in the dentate gyrus with spatial memory is dependent on time of exposure to spatial learning and age of cells at examination

Neurogenesis continues to occur throughout life in the dentate gyrus of the hippocampus and may be related to hippocampus-dependent learning. We have recently reported that there is an enhancement of neurogenesis in the hippocampus only when BrdU is administered 6 days prior to starting spatial training but not when training started either 1 day or 11 days following BrdU administration. In that study, all rats were perfused on day 16 after BrdU injection in order to compare cells of the same age (i.e. 16 day old cells) and thus the survival time after learning was different between groups. This study was designed to address whether the amount of time that passed following training could also contribute to the effects of spatial learning on hippocampal neurogenesis and whether there was differential new neuron activation in response to spatial learning that depended on the age of new cells at the time of spatial learning. Here we tested whether a survival period of 5 days following spatial learning at either 1-5, 6-10 or 11-15 days following BrdU administration would alter cell survival and/or activation of new neurons. Our results indicate that 5 days after training in the Morris water task cell survival is unaltered by training on days 1-5, increased by training at days 6-10 and decreased when training occurs on days 11-15. Furthermore spatial learners trained on days 6-10 or 11-15 show greater activation of new neurons compared to cue-trained rats during a probe trial 5 days after training. In addition, rats trained on the spatial task on days 11-15 had a greater number of activated new neurons compared to rats trained on the spatial task on days 6-10. These results suggest there is a gradual removal of older BrdU-labeled new neurons following spatial learning perhaps due to a competitive interaction with a population of younger BrdU-labeled new neurons.     

Dietary restriction inhibits spatial learning ability and hippocampal cell proliferation in rats1

Abstract: We investigated the effect of dietary restriction on spatial learning ability and hippocampal cell proliferation in adult rats using two spatial learning tasks and immunohistochemical staining with 5‐bromo‐2′‐deoxyuridine (BrdU). Sixteen rats were divided into restricted or ad lib feeding groups at 70 days of age, and were trained in the delayed‐matching‐to‐place (DMTP) task (a working memory task) from 93 days of age, and then the Morris water maze task (a reference memory task). Dietary restriction had no effect on the DMTP task with 30 s delay and on the water maze task. However, in the DMTP task with 30 min delay, restricted rats performed significantly more poorly than ad lib rats. Quantitative analysis of hippocampal cell proliferation revealed that the density of newborn cells in restricted rats was significantly lower than that in ad lib rats. These results suggest that a loss of proliferating capacity in the hippocampus may be a candidate for an anatomical and biological basis for the cognitive decline caused by dietary restriction.     

Neurogenesis and the spacing effect: learning over time enhances memory and the survival of new neurons

Information that is spaced over time is better remembered than the same amount of information massed together. This phenomenon, known as the spacing effect, was explored with respect to its effect on learning and neurogenesis in the adult dentate gyrus of the hippocampal formation. Because the cells are generated over time and because learning enhances their survival, we hypothesized that training with spaced trials would rescue more new neurons from death than the same number of massed trials. In the first experiment, animals trained with spaced trials in the Morris water maze outperformed animals trained with massed trials, but there was not a direct effect of trial spacing on cell survival. Rather, animals that learned well retained more cells than animals that did not learn or learned poorly. Moreover, performance during acquisition correlated with the number of cells remaining in the dentate gyrus after training. In the second experiment, the time between blocks of trials was increased. Consequently, animals trained with spaced trials performed as well as those trained with massed, but remembered the location better two weeks later. The strength of that memory correlated with the number of new cells remaining in the hippocampus. Together, these data indicate that learning, and not mere exposure to training, enhances the survival of cells that are generated 1 wk before training. They also indicate that learning over an extended period of time induces a more persistent memory, which then relates to the number of cells that reside in the hippocampus.     

Hippocampus-dependent strategy choice predicts low levels of cell proliferation in the dentate gyrus

Neurogenesis continues to occur throughout life in the mammalian hippocampus. Previous research has suggested that the production of new neurons in the hippocampus during adulthood may be related to hippocampus-dependent learning and memory. However, the exact relationship between adult neurogenesis and learning and memory remains unclear. Here we investigated whether learning strategy selection is related to cell proliferation or to survival of new neurons in the hippocampus of adult male rats. We trained rats on alternating blocks of hippocampus-dependent (hidden platform) and hippocampus-independent (visible platform) versions of the Morris water task with the platform always in the same position. Following training, rats were given a probe session during which the platform was visible and in a novel location. Preferred strategy was determined by observing the initial swim path. Rats were classified as place strategy (hippocampus-dependent) users if they swam to the old platform location. Cue strategy (hippocampus-independent) users were classified as those rats that swam initially to the visible platform. Our results indicate that rats that preferentially used a place strategy had significantly lower cell proliferation than cue strategy users. However, there was no significant difference in cell survival or number of immature neurons between strategy user groups. These results suggest that low levels of cell proliferation in the dentate gyrus may be conducive or coincident with more efficient memory processing in the hippocampus.     

Rapid forgetting of social transmission of food preferences in aged rats: relationship to hippocampal CREB activation

A major characteristic of age-related changes in memory in rodents is an increase in the rate of forgetting of new information, even when tests given soon after training reveal intact memory. Interference with CREB functions similarly results in rapid decay of memory. Using quantitative immunocytochemistry, the present experiment examined the number of CREB- and pCREB-immunoreactive neurons in three regions of the dorsal and ventral hippocampus (dentate gyrus, CA3, and CA1) as a function of age and training. Rats were trained in a social transmission of food preference task. Using different food pairings, memory was tested in each rat immediately and 1, 2, 3, and 7 d later. Both young and old rats had intact and comparable memory scores at the immediate and 24-h tests, but old rats exhibited more rapid forgetting thereafter relative to that of young rats. The main findings were that training resulted in large increases in the number of pCREB-immunoreactive cells throughout the hippocampus in both young and aged rats. However, particularly in the ventral hippocampus, the training-elicited increase in pCREB-positive neurons was significantly lower in old than in young rats. Based on Western blot analyses in a separate set of rats, CREB levels were not responsive to training but were lower in the ventral hippocampus of old rats than of young rats. The present findings suggest that lower activation of CREB after training may contribute to the rapid forgetting seen in aged rats.     

Neurogenesis and learning: acquisition and asymptotic performance predict how many new cells survive in the hippocampus

Previous research has shown that some associative learning tasks prevent the death of new neurons in the adult hippocampus. However, it is unclear whether it is mere exposure to the training stimuli that rescues neurons or whether successful learning of the task is required for enhanced neuronal survival. If learning is the important variable, then animals that learn better given the same amount of training should retain more of the new cells after learning than animals that do not learn as well. Here, we examined the effects of training versus learning on cell survival in the adult hippocampus. Animals were injected with BrdU to label a population of cells and trained one week later on one of two trace conditioning tasks, one of which depends on the hippocampus and one that does not. Increases in cell number occurred only in animals that acquired the learned response, irrespective of the task. There were significant correlations between acquisition and cell number, as well as between asymptotic performance and cell number. These data support the idea that learning and not simply training increases the survival of the new cells in the hippocampus.     

Contextual learning induces an increase in the number of hippocampal CA1 neurons expressing high levels of BDNF

We examined behaviorally induced expression of brain-derived neurotrophic factor (BDNF) in area CA1 of the hippocampus. Sprague-Dawley rats were trained in a contextual fear conditioning (CFC) task, sacrificed 4h later, and their brains were processed for immunohistochemistry. We found distinctively high levels of BDNF immunoreactivity in a small number ( approximately 1%) of CA1 neurons in untrained animals. The number of these exceptional neurons, which are identified as BDNF(++) in this study, was increased by up to approximately 3% after CFC. This increase was blocked in the presence of a memory-impairing dose of a NMDA receptor antagonist (MK801 0.3 mg/kg, i.p.) given 30 min prior to training. The BDNF signal intensity in BDNF(++) neurons correlated with that of surrounding glutamic acid decarboxylase (GAD) 65. This correlation between GAD65 and BDNF signal intensities suggests that BDNF upregulation was associated with increased signaling via inhibitory GABAergic synapses that would lessen further intervening neuronal activity. Our observation that neurons which upregulate BDNF expression following a learning experience are rich in GAD65-enriched afferent synapses suggests that these neurons may have distinct roles in memory consolidation.     

Simultaneous training on two hippocampus-dependent tasks facilitates acquisition of trace eyeblink conditioning

A common cellular alteration, reduced post-burst afterhyperpolarization (AHP) in CA1 neurons, is associated with acquisition of the hippocampus-dependent tasks trace eyeblink conditioning and the Morris water maze. As a similar increase in excitability is correlated with these two learning paradigms, we sought to determine the interactive behavioral effects of training animals on both tasks by using either a consecutive or simultaneous training design. In the consecutive design, animals were trained first on either the trace eyeblink conditioning task for six sessions, followed by training on the water maze task for six sessions, or vice versa. The simultaneous design consisted of six or 11 training days; animals received one session/day of both trace eyeblink conditioning and water maze training. Separate groups were used for consecutive and simultaneous training. Animals trained on both tasks simultaneously were significantly facilitated in their ability to acquire the trace eyeblink conditioning task; no effect of simultaneous training was seen on the water maze task. No effect was seen on acquisition for either task when using the consecutive training design. Taken together, these findings provide insight into how the hippocampus processes information when animals learn multiple hippocampus-dependent tasks.     

Effect of neonatal handling on adult rat spatial learning and memory following acute stress

Brief neonatal handling permanently alters hypothalamic-pituitary-adrenal axis function resulting in increased ability to cope with stress. Since stress is known to affect cognitive abilities, in the present study we investigated the effect of brief (15 min) handling on learning and memory in the Morris water maze, following exposure to an acute restraint stress either before training or recall. Exposure of non-handled rats to the acute stress prior to training resulted in quicker learning of the task, than in the absence of the stressor. When acute stress preceded acquisition, male handled rats showed an overall better learning performance, and both sexes of handled animals were less impaired in the subsequent memory trial, compared to the respective non-handled. In addition, the number of neurons immunoreactive for GR was higher in all areas of Ammon's horn of the handled rats during the recall. In contrast, the number of neurons immunoreactive for MR was higher in the CA1 and CA2 areas of the non-handled males. When the acute restraint stress was applied prior to the memory test, neonatal handling was not effective in preventing mnemonic impairment, as all animal groups showed a similar deficit in recall. In this case, no difference between handled and non-handled rats was observed in the number of GR positive neurons in the CA2 and CA3 hippocampal areas during the memory test. These results indicate that early experience interacts with sex and acute stress exposure in adulthood to affect performance in the water maze. Hippocampal corticosterone receptors may play a role in determining the final outcome.     

Differential induction of c-Jun and Fos-like proteins in rat hippocampus and dorsal striatum after training in two water maze tasks

Research examining the neuroanatomical bases of memory in mammals suggests that the hippocampus and dorsal striatum are parts of independent memory systems that mediate "cognitive" and stimulus-response "habit" memory, respectively. At the molecular level, increasing evidence indicates a role for immediate early gene (IEG) expression in memory formation. The present experiment examined whether acquisition of cognitive and habit memory result in differential patterns of IEG protein product expression in these two brain structures. Adult male Long-Evans rats were trained in either a hippocampal-dependent spatial water maze task, or a dorsal striatal-dependent cued water maze task. Ninety minutes after task acquisition, brains were removed and processed for immunocytochemical procedures, and the number of cells expressing Fos-like immunoreactivity (Fos-like-IR) and c-Jun-IR in sections from the dorsal hippocampus and the dorsal striatum were counted. In the dorsal hippocampus of rats trained in the spatial task, there were significantly more c-Jun-IR pyramidal cells in the CA1 and CA3 regions, relative to rats that had acquired the cued task, yoked controls (free-swim), or na?ve (home cage) rats. Relative to rats receiving cued task training and control conditions, increases in Fos-like IR were also observed in the CA1 region of rats trained in the spatial task. In rats that had acquired the cued task, patches of c-Jun-IR were observed in the posteroventral striatum; no such patches were evident in rats trained in the spatial task, yoked-control rats, or na?ve rats. The results demonstrate that IEG protein product expression is up-regulated in a task-dependent and brain structure-specific manner shortly after acquisition of cognitive and habit memory tasks.     

Emotional and cognitive information processing: relations to behavioral performance and hippocampal long-term potentiation in vivo during a spatial water maze training in rats

Emotionality as well as cognitive abilities contribute to the acquisition and retrieval of memories as well as to the consolidation of long-term potentiation (LTP), a cellular model of memory formation. However, little is known about the timescale and relative contribution of these processes. Therefore, we tested the effects of weak water maze training, containing both emotional and cognitive demands, on LTP in the hippocampal dentate gyrus. The population spike amplitude (PSA)-LTP was prolonged in all rats irrespective of whether they memorized the platform position or not, whereas the field excitatory postsynaptic potential (fEPSP)-LTP was impaired in good learners and enhanced in poor learners. We then dissociated the behavioral performance of rats during the water maze task by principal component analysis and by means of stress hormone concentrations into underlying "emotional" and "cognitive" factors. PSA-LTP was associated with "emotional" and fEPSP-LTP with "cognitive" behavior. PSA-LTP was depotentiated after the blockade of corticosterone binding mineralocorticoid receptors (MRs) in trained animals, while fEPSP-LTP was unaffected. These results suggest that synaptic processing and encoding of emotional information in the hippocampal dentate gyrus is realized fast and further information transfer is detectable by the reinforcement of PSA-LTP, whereas that of cognitive memories is long lasting.     

Neurogenesis decreases with age in the canine hippocampus and correlates with cognitive function

New neurons are continually produced in the adult mammalian brain from progenitor cells located in specific brain regions, including the subgranular zone (SGZ) of the dentate gyrus of the hippocampus. We hypothesized that neurogenesis occurs in the canine brain and is reduced with age. We examined neurogenesis in the hippocampus of five young and five aged animals using doublecortin (DCX) and bromodeoxyuridine (BrdU) immunostaining. The total unilateral number of new neurons in the canine SGZ and granule cell layer (GCL) was estimated using stereological techniques based upon unbiased principles of systematic uniformly random sampling. Animals received 25mg/kg of BrdU once a day for 5 days and were euthanized 9 days after the last injection. We found evidence of neurogenesis in the canine brain and that cell genesis and neurogenesis are greatly reduced in the SGZ/GCL of aged animals compared to young. We further tested the hypothesis that an antioxidant fortified food or behavioral enrichment would improve neurogenesis in the aged canine brain and neurogenesis may correlate with cognitive function. Aged animals were treated for 2.8 years and tissue was available for six that received the antioxidant food, five that received the enrichment and six receiving both treatments. There were no significant differences in the absolute number of DCX or DCX-BrdU neurons or BrdU nuclei between the treatment groups compared to control animals. The number of DCX-positive neurons and double-labeled DCX-BrdU-positive neurons, but not BrdU-positive nuclei alone, significantly correlated with performance on several cognitive tasks including spatial memory and discrimination learning. These results suggest that new neurons in the aged canine dentate gyrus may participate in modulating cognitive functions.     

Hippocampal CA1 kindling but not long-term potentiation disrupts spatial memory performance

Long-term synaptic enhancement in the hippocampus has been suggested to cause deficits in spatial performance. Synaptic enhancement has been reported after hippocampal kindling that induced repeated electrographic seizures or afterdischarges (ADs) and after long-term potentiation (LTP) defined as synaptic enhancement without ADs. We studied whether repeated stimulations that gave LTP or ADs resulted in spatial performance deficits on the radial arm maze (RAM) and investigated the minimal number of ADs required for such deficits. Three experimental groups were run as follows: (1) 5 hippocampal ADs in 1 d (5-AD group), (2) 10 hippocampal ADs in 2 d (10-AD group), and (3) 12 -frequency primed-burst stimulations (PBSs) in 2 d in order to induce LTP without ADs (LTP group). Each experimental group was run together with a control group during the same time period. Rats were first trained in a spatial task on a radial arm maze with four of the eight arms baited, then given control or experimental treatment, and maze performance was tested in the first week (1-4 d) and fourth week (22-25 d) after treatment. Basal dendritic population excitatory postsynaptic potentials (pEPSPs) and medial perforant path (MPP)-evoked dentate gyrus population spike and polysynaptic CA1 excitation were recorded before and after experimental and control treatment. Spatial memory errors, in particular reference memory errors, were significantly higher in the 10-AD kindled group than any other group on the first and fourth week after treatment. Spatial memory errors were not significantly different in the 5-AD and LTP groups as compared with any control groups at any time. Basal dendritic pEPSP in CA1 was enhanced for about 1 wk after 12 PBSs, 10 ADs, or 5 ADs, while the dentate gyrus population spike and CA1 polysynaptic excitation evoked by MPP was increased for up to 4 wk after 10 ADs, but not 12 PBSs. Thus, distributed alteration of multiple synaptic transmission in the entorhinal-hippocampal circuit, but not LTP at the basal dendritic synapses in CA1, may disrupt spatial performance after 10 hippocampal ADs.     

Changing the rate and hippocampal dependence of trace eyeblink conditioning: slow learning enhances survival of new neurons

Trace eyeblink conditioning in which a conditioned stimulus and unconditioned stimulus are separated by a gap, is hippocampal dependent and can rescue new neurons in the adult dentate gyrus from death (e.g., Beylin et al., 2001; Gould et al., 1999). Tasks requiring more training trials for reliable expression of the conditioned response are most effective in enhancing survival of neurons (Waddell & Shors, 2008). To dissociate hippocampal dependence from acquisition rate, we facilitated hippocampal-dependent trace eyeblink conditioning in two ways: a shorter trace interval and signaling the intertrial interval with a post-US cue. Trace conditioning with a shorter trace interval (250ms) requires an intact hippocampus, and acquisition is faster relative to rats trained with a 500ms trace interval (e.g., Weiss et al., 1999). Using excitotoxic hippocampal lesions, we confirmed that eyeblink conditioning with the 250 or 500ms trace interval is hippocampal dependent. However, training with the post-US cue was not hippocampal dependent. The majority of lesion rats in this condition reached criterion of conditioned responding. To determine whether hippocampal dependence is sufficient to rescue adult-generated neurons in the dentate gyrus, rats were injected with BrdU and trained in one of the three trace eyeblink arrangements one week later. Of these training procedures, only the 500ms trace interval enhanced survival of new cells; acquisition of this task proceeded slowly relative to the 250ms and post-US cue conditions. These data demonstrate that rate of acquisition and not hippocampal dependence determines the impact of learning on adult neurogenesis.     

Hippocampal expression of the orphan nuclear receptor gene hzf-3/nurr1 during spatial discrimination learning

The immediate-early gene hzf-3, also known as nurr1, is a member of the inducible orphan nuclear receptor family and is one candidate in the search for genes associated with learning and memory processes. Here we report that acquisition of a spatial food search task is accompanied by elevated levels of hzf-3 mRNA in the hippocampus. Adult male Long-Evans rats were handled, food-restricted, and allowed to habituate to the maze prior to training. During acquisition, rats were given one training session per day for 5 days. Each training session consisted of five trials in which animals searched the maze for food located in 4 of 16 holes in the floor of the maze. Training resulted in spatial acquisition of the task. Northern blot analysis showed significant increases in hippocampal hzf-3 mRNA 3 h after training in the maze. Next, brains were obtained from Naive, Habituated, Day 1, Day 3, and Day 5 animals and processed for in situ hybridization. The results showed significant increases of hzf-3 mRNA in CA1 and CA3 subregions of the dorsal hippocampus during acquisition of the task. We conclude that expression of the hzf-3 gene in the brain is associated with long-term spatial memory processes. The present results are the first to implicate an orphan nuclear receptor in long-term information storage in the hippocampus.     

Reversible hippocampal lesions disrupt water maze performance during both recent and remote memory tests

Conventional lesion methods have shown that damage to the rodent hippocampus can impair previously acquired spatial memory in tasks such as the water maze. In contrast, work with reversible lesion methods using a different spatial task has found remote memory to be spared. To determine whether the finding of spared remote spatial memory depends on the lesion method, we reversibly inactivated the hippocampus with lidocaine either immediately (0-DAY) or 1 mo (30-DAY) after training in a water maze. For both the 0-DAY and 30-DAY retention tests, rats that received lidocaine infusions exhibited impaired performance. In addition, when the 0-DAY group was retested 2 d later, (when the drug was no longer active), the effect was reversed. That is, rats that had previously received lidocaine performed as well as control rats did. These findings indicate that the rodent hippocampus is important for both recent and remote spatial memory, as assessed in the water maze. What determines whether remote spatial memory is preserved or impaired following disruption of hippocampal function appears to be the type of task used to assess spatial memory, not the method used to disrupt the hippocampus.     

工作记忆训练诱发的神经可塑性——基于系列fMRI实验的脑区分布递减时空模型

工作记忆训练(Working Memory Training, WMT)诱发神经可塑性, 但其具体机制尚不明晰。为探索WMT改变正常人群大脑功能的时空特性, 以“扩展的智力顶额整合理论”和“神经效率假说”为依据, 采用逐层递进的5种方法, 分6个步骤来查究近20年来正常人群WMT的37篇fMRI文献。第一步, 用叙述性综述、频数分析和卡方检验法比较脑区激活模式和脑网络功能连接在WMT前后发生的改变, 发现WMT改变了大脑的5个联合区、7个宏观区和3个子区。其中, 额上回、顶下小叶和扣带回这3个子区各自激活减弱的报道文献数量多于其激活增强的, 且这种差异分别具有统计学意义。第二步, 采用激活似然估计法对其中26篇开展元分析, 发现大脑的3个子区激活减弱水平在WMT前后的差异具有统计学意义, 即额中回(BA6和8)、额上回(BA6)和前扣带回(BA24和32)。第三步, 综合定性和定量分析结果, 提出WMT脑区分布递减时空模型, 产生5个结果和讨论。第四步, 采用非参数检验进一步追踪WMT效应的调节因素, 发现训练的任务类型和时间分别对脑区激活的影响具有统计学意义。第五步, 针对正常人群WMT诱发神经可塑性的时空特性, 得出3个结论：第一, WMT改变了正常人群相应脑区的神经活动, 表现为减弱或增强, 但减弱更加突出, 且更新和较短时间的WMT倾向于诱发较多减弱; 第二, 这些神经活动变化主要发生在额顶叶联合区, 但也包括分别以颞叶、枕叶、扣带回及纹状体为主的联合区, 在一定范围内体现了整脑功能联合。这体现了WMT诱发神经可塑性的空间特性, 且符合“扩展的智力顶额整合理论”; 第三, 额中回、额上回、顶下小叶和扣带回(尤其前扣带回)这4个子区在激活减弱水平上重点展示了WMT神经可塑性的时间特性, 且符合“神经效率假说”, 恰好体现出“聪明的大脑更懒惰”。第六步, 指出WMT诱发神经可塑性的未来研究可能关注脑可塑性中的低活跃性、辨析额中回、额上回、顶下小叶和扣带回(尤其前扣带回)这4个子区在激活减弱水平上体现的时间特性、找寻训练减弱或增强大脑活动的综合性影响因素。     

催产素调控心理韧性:基于对海马的作用机制

心理韧性指个体面对逆境、挫折或重大威胁等应激情境下的有效且灵活适应的能力, 促进机体恢复正常的生理和心理功能。研究表明海马是调控心理韧性的重要脑区, 且催产素可能通过作用于海马增强心理韧性。海马内部环路内嗅皮层-齿状回-CA3可能调节恐惧记忆的泛化和消退以增强心理韧性; 海马外部环路齿状回-杏仁核-伏隔核及海马-伏隔核环路调节情绪, 可能分别通过促进奖赏和带来厌恶进而增强或降低心理韧性。催产素作用于海马增强心理韧性的可能途径有:催产素促进海马神经发生, 降低海马腹侧成熟神经元对应激的敏感性, 提高海马“模式分离”功能, 降低应激记忆泛化; 催产素恢复海马谢弗侧枝-CA1突触长时程增强, 促进机体适应应激; 催产素降低海马糖皮质激素受体水平, 重新建立机体稳态。