Post-training down-regulation of memory consolidation by a GABA-A mechanism in the amygdala modulated by endogenous benzodiazepines

In rats, amygdala benzodiazepine-like immunoreactivity decreases by 29% immediately after the animals step down from the platform of an inhibitory avoidance apparatus and decreases by a further 45% immediately after they receive a training footshock. The decrease is attributable to a release of diazepam or diazepam-like molecules. The immediate post-training intraamygdala injection of the central benzodiazepine antagonist flumazenil (10 nmole/amygdala) causes memory facilitation, and that of the GABA-A agonist muscimol (0.005 to 0.5 nmole) causes retrograde amnesia. Pretraining ip flumazenil administration (2.0 and 5.0 mg/kg) attenuates the effect of post-training muscimol by a factor of at least 100. The higher dose of pretraining flumazenil also causes memory facilitation. The data suggest that post-training consolidation is down-regulated by a GABA-A mechanism in the amygdala modulated by endogenous benzodiazepines released during training and at the time of consolidation.     

Post-acquisition release of glutamate and norepinephrine in the amygdala is involved in taste-aversion memory consolidation

Amygdala activity mediates the acquisition and consolidation of emotional experiences; we have recently shown that post-acquisition reactivation of this structure is necessary for the long-term storage of conditioned taste aversion (CTA). However, the specific neurotransmitters involved in such reactivation are not known. The aim of the present study was to investigate extracellular changes of glutamate, norepinephrine, and dopamine within the rat amygdala using in vivo microdialysis during the acquisition and 1-h post-acquisition of CTA paradigm. Microdialysis monitoring showed a significant norepinephrine increase related to novel taste exposure and a glutamate increase after gastric malaise induction by i.p. LiCl administration. Interestingly, we found a spontaneous concomitant increase of glutamate and norepinephrine, but not dopamine, 45 min after conditioning, suggesting the presence of aversive learning-dependent post-acquisition signals in the amygdala. These signals seem to be involved in CTA consolidation process, since post-trial blockade of N-methyl-D-aspartate or β-adrenergic receptors impaired long- but not short-term memory. These data suggest that CTA long-term storage involves post-acquisition release of glutamate and norepinephrine in the amygdala.     

Memory-enhancing corticosterone treatment increases amygdala norepinephrine and Arc protein expression in hippocampal synaptic fractions

Considerable evidence indicates that glucocorticoid hormones enhance the consolidation of memory for emotionally arousing events through interactions with the noradrenergic system of the basolateral complex of the amygdala (BLA). We previously reported that intra-BLA administration of a β-adrenoceptor agonist immediately after inhibitory avoidance training enhanced memory consolidation and increased hippocampal expression of the protein product of the immediate early gene activity-regulated cytoskeletal-associated protein (Arc). In the present experiments corticosterone (3 mg/kg, i.p.) was administered to male Sprague-Dawley rats immediately after inhibitory avoidance training to examine effects on long-term memory, amygdala norepinephrine levels, and hippocampal Arc expression. Corticosterone increased amygdala norepinephrine levels 15 min after inhibitory avoidance training, as assessed by in vivo microdialysis, and enhanced memory tested at 48 h. Corticosterone treatment also increased expression of Arc protein in hippocampal synaptic tissue. The elevation in BLA norepinephrine appears to participate in corticosterone-influenced modulation of hippocampal Arc expression as intra-BLA blockade of β-adrenoceptors with propranolol (0.5 μg/0.2 μL) attenuated the corticosterone-induced synaptic Arc expression in the hippocampus. These findings indicate that noradrenergic activity at BLA β-adrenoceptors is involved in corticosterone-induced enhancement of memory consolidation and expression of the synaptic-plasticity-related protein Arc in the hippocampus.     

Post-training administration of corticosterone enhances consolidation of contextual fear memory and hippocampal long-term potentiation in rats

This study was designed to examine the effect of corticosterone on consolidation of contextual fear memory and hippocampal long-term potentiation (LTP) in rats. In Experiment 1, dose–response effects of corticosterone on consolidation of contextual fear memory were determined. Immediately after training in contextual fear conditioning task, rats received different doses of corticosterone. Testing 24 h later, it revealed that corticosterone enhanced memory consolidation in an inverted U shape as evidenced in increased freezing behavior of corticosterone-treated animals. The most effective dose was 3 mg/kg. In Experiment 2, LTP was examined in rats whose memory consolidation has been enhanced with corticosterone. The rats were trained as the above and received corticosterone (3 mg/kg) immediately after training. Immediately or up to one day after retention test, rats were anesthetized with urethane for LTP experiments. For LTP induction, three episodes of high frequency stimuli, 30 s apart, were delivered to the perforant path, each consisting of 10 stimuli at 250 Hz. LTP was assessed by measuring the increase in the initial slope of the population excitatory post-synaptic potentials and the amplitude of the population spikes. Data indicated that animals whose memory has been enhanced by corticosterone, also displayed enhanced hippocampal LTP. The above findings suggest that glucocorticoids may enhance contextual fear memory consolidation via enhancing hippocampal LTP.     

Biphasic ERK1/2 activation in both the hippocampus and amygdala may reveal a system consolidation of contextual fear memory

There is accumulating evidences to suggest that memory consolidation in some conditions involves two waves of neuronal plastic change. Using two fear conditioning procedures in male C57BL/6J mice, we have recently shown that consolidation of the foreground contextual fear memory required two waves of ERK1/2 activation in hippocampal CA1, while consolidation of cue conditioning was only associated with the early phase of activation. The present experiment further showed that this bi-phasic pattern of ERK1/2 activation was not restricted to hippocampal CA1, but could also be observed in other fear memory-related brain areas. The unpaired conditioning procedure (context in foreground) induced two waves of ERK1/2 activation in hippocampal CA1 and CA3, as well as in the LA and BLA nuclei of the amygdala. In contrast, the paired conditioning procedure (context in background) led to a transient early phase only in hippocampal CA1 and LA. In addition, ERK1/2 phosphorylation in the hippocampus was found to correlate with that in the amygdala nuclei specifically after the unpaired procedure. Taken together, our data suggest that the observed biphasic pattern of neuronal plastic events may reflect the interplay between hippocampal and amygdala activity-dependent plasticity critical for the system consolidation of contextual fear memory.     

Kindling-induced changes in plasticity of the rat amygdala and hippocampus

Temporal lobe epilepsy (TLE) is often accompanied by interictal behavioral abnormalities, such as fear and memory impairment. To identify possible underlying substrates, we analyzed long-term synaptic plasticity in two relevant brain regions, the lateral amygdala (LA) and the CA1 region of the hippocampus, in the kindling model of epilepsy. Wistar rats were kindled through daily administration of brief electrical stimulations to the left basolateral nucleus of the amygdala. Field potential recordings were performed in slices obtained from kindled rats 48 h after the last induced seizure, and in slices from sham-implanted and nonimplanted controls. Kindling resulted in a significant impairment of long-term potentiation (LTP) in both the LA and the CA1, the magnitude of which was dependent on the number of prior stage V seizures. Saturation of CA1-LTP, assessed through repeated spaced delivery of high-frequency stimulation, occurred at lower levels in kindled compared to sham-implanted animals, consistent with the hypothesis of reduced capacity of further synaptic strengthening. Furthermore, theta pulse stimulation elicited long-term depression in the amygdala in nonimplanted and sham-implanted controls, whereas the same stimulation protocol stimulation caused LTP in kindled rats. In conclusion, kindling differentially affects the magnitude, saturation, and polarity of LTP in the CA1 and LA, respectively, most likely indicating an activity-dependent mechanism in the context of synaptic metaplasticity.     

Post-training disruption of Arc protein expression in the anterior cingulate cortex impairs long-term memory for inhibitory avoidance training

The activity-regulated-cytoskeletal-associated protein (Arc) has a well established role in memory consolidation and synaptic plasticity in the hippocampus and amygdala. However the role of Arc within the anterior cingulate cortex (ACC), an area of the brain involved in processing memory for pain, has yet to be examined. Here we sought to determine if Arc protein within neurons of the rat ACC is necessary for the consolidation of a single-trial, contextual inhibitory avoidance (IA) task. Immunohistochemistry and western blotting revealed an increase in Arc protein within the ACC following IA training in a shock-specific manner, suggesting that ACC Arc expression may play a critical role in the consolidation of the aversive task. To directly test this hypothesis, male Sprague-Dawley rats were trained on the IA task and given post-training intra-ACC infusions of Arc antisense oligodeoxynucleotides (ODNs), designed to suppress Arc translation, or control scrambled ODNs that do not suppress Arc translation. Memory retention was tested 48h after training. Arc antisense-induced disruption of Arc protein expression in the ACC impaired long-term memory for the IA task as compared to rats given intra-ACC infusions of the scrambled control ODNS, suggesting that Arc expression in the ACC is important for the consolidation of emotional memory. Results further indicate that knock down of Arc 6h after training impairs IA memory. This is consistent with time course findings indicating elevated Arc expression at 3 and 6h after IA training but not 12 or 48h. Taken together, these findings support the hypothesis that Arc expression in the ACC participates in synaptic plasticity that underlies long-term memory.     

Neurotransmitter receptors involved in post-training memory processing by the amygdala, medial septum, and hippocampus of the rat.

Rats were trained and tested in habituation to a novel environment and step-down inhibitory avoidance. Immediately after training in each task the animals received intra-amygdala, intraseptal, or intrahippocampal micro-injections of agonists and antagonists of various neurotransmitter receptors. In the habitation task, intrahippocampal, but not intra-amygdala or intraseptal administration of the NMDA receptor antagonist aminophosphornopentanoic acid (AP5, 5.0 micrograms) or of the muscarinic receptor antagonist, scopolamine (2.0 micrograms) caused amnesia and the indirect antagonist of GABA-A receptors, picrotoxin (0.08 microgram), caused retrograde facilitation. Intrahippocampal administration of the respective agonists, glutamate, oxotremorine, and muscimol, had effects of their own opposite to those of the blockers, and norepinephrine (0.3 microgram) caused memory facilitation. In the avoidance task, results obtained with drug infusions given into the three structures were very similar: in all cases, AP5, scopolamine, and muscimol were amnestic, and glutamate, oxotremorine, norepinephrine, and picrotoxin caused memory facilitation. In addition, also in the three structures, picrotoxin counteracted the amnestic effect of AP5 and/or scopolamine and the beta-adrenoceptor blocker, timolol (0.3 microgram), while ineffective on its own, attenuated all the effects of picrotoxin. The results suggest that similar synaptic mechanisms in the amygdala, medial septum, and hippocampus are involved in memory consolidation: NMDA, muscarinic, and beta-noradrenergic receptors stimulate and GABA-A receptors inhibit this process, and beta-noradrenergic receptors modulate the GABAergic synapses. In the avoidance task these mechanisms operate in the three structures: in habituation only those in the hippocampus are operative. Possibly in each structure these mechanisms regulate, if not actually consolidate, a different aspect, component, or form of memory.     

Time-window for sensitivity to cooling distinguishes the effects of hypothermia and protein synthesis inhibition on the consolidation of long-term memory

The effects of hypothermia on memory formation have been examined extensively, and while it is clear that post-training cooling interferes with the process of consolidation, the nature of the temperature sensitive processes disrupted in this way remain poorly defined. Post-training manipulations that disrupt consolidation tend to be effective during specific time-windows of sensitivity, the timing and duration of which are directly related to the mechanism through which the treatment induces amnesia. As such, different treatments that target the same basic processes should be associated with similar time-windows of sensitivity. Using this rationale we have investigated the possibility that cooling induced blockade of long-term memory (LTM) stems from the disruption of protein synthesis. By varying the timing of post-training hypothermia we have determined the critical period during which cooling disrupts the consolidation of appetitive long-term memory in the pond snail Lymnaea. Post-training hypothermia was found to disrupt LTM only when applied immediately after conditioning, while delaying the treatment by 10 min left the 24 h memory trace intact. This brief (<10 min) window of sensitivity differs from the time-window we have previously described for the protein synthesis inhibitor anisomycin, which was effective during at least the first 30 min after conditioning [Fulton, D., Kemenes, I., Andrew, R. J., & Benjamin, P. R. (2005). A single time-window for protein synthesis-dependent long-term memory formation after one-trial appetitive conditioning. European Journal of Neuroscience, 21, 1347-1358]. We conclude that hypothermia and protein synthesis inhibition exhibit distinct time-windows of effectiveness in Lymnaea, a fact that is inconsistent with the hypothesis that cooling induced amnesia occurs through the direct disruption of macromolecular synthesis.     

Inhibition of mTOR by rapamycin in the amygdala or hippocampus impairs formation and reconsolidation of inhibitory avoidance memory

Mammalian target of rapamycin (mTOR), a central regulator of protein synthesis in neurons, has been implicated in synaptic plasticity and memory. Here we show that mTOR inhibition by rapamycin in the basolateral amygdala (BLA) or dorsal hippocampus (DH) impairs both formation and reconsolidation of memory for inhibitory avoidance (IA) in rats. Male Wistar rats received bilateral infusions of vehicle or rapamycin into the BLA or DH before or after IA training or retrieval. Memory retention was tested at different time points after drug infusion. Rapamycin impaired long-term IA retention when given before or immediately after training or retrieval into the BLA. When infused into the DH, rapamycin produced memory impairment when given before training or immediately after retrieval. The impairing effects of post-retrieval rapamycin required memory retrieval and were not reversed by a reminder shock. The results provide the first evidence that mTOR in the BLA and DH might play a role in IA memory reconsolidation.     

The NO-cGMP-PKG signaling pathway regulates synaptic plasticity and fear memory consolidation in the lateral amygdala via activation of ERK/MAP kinase

Recent studies have shown that nitric oxide (NO) signaling plays a crucial role in memory consolidation of Pavlovian fear conditioning and in synaptic plasticity in the lateral amygdala (LA). In the present experiments, we examined the role of the cGMP-dependent protein kinase (PKG), a downstream effector of NO, in fear memory consolidation and long-term potentiation (LTP) at thalamic and cortical input pathways to the LA. In behavioral experiments, rats given intra-LA infusions of either the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibited dose-dependent impairments or enhancements of fear memory consolidation, respectively. In slice electrophysiology experiments, bath application of Rp-8-Br-PET-cGMPS or the guanylyl cyclase inhibitor LY83583 impaired LTP at thalamic, but not cortical inputs to the LA, while bath application of 8-Br-cGMP or the guanylyl cyclase activator YC-1 resulted in enhanced LTP at thalamic inputs to the LA. Interestingly, YC-1-induced enhancement of LTP in the LA was reversed by concurrent application of the MEK inhibitor U0126, suggesting that the NO-cGMP-PKG signaling pathway may promote synaptic plasticity and fear memory formation in the LA, in part by activating the ERK/MAPK signaling cascade. As a test of this hypothesis, we next showed that rats given intra-LA infusion of the PKG inhibitor Rp-8-Br-PET-cGMPS or the PKG activator 8-Br-cGMP exhibit impaired or enhanced activation, respectively, of ERK/MAPK in the LA after fear conditioning. Collectively, our findings suggest that an NO-cGMP-PKG-dependent form of synaptic plasticity at thalamic input synapses to the LA may underlie memory consolidation of Pavlovian fear conditioning, in part, via activation of the ERK/MAPK signaling cascade.     

On the role of hippocampal protein synthesis in the consolidation and reconsolidation of object recognition memory

Upon retrieval, consolidated memories are again rendered vulnerable to the action of metabolic blockers, notably protein synthesis inhibitors. This has led to the hypothesis that memories are reconsolidated at the time of retrieval, and that this depends on protein synthesis. Ample evidence indicates that the hippocampus plays a key role both in the consolidation and reconsolidation of different memories. Despite this fact, at present there are no studies about the consequences of hippocampal protein synthesis inhibition in the storage and post-retrieval persistence of object recognition memory. Here we report that infusion of the protein synthesis inhibitor anisomycin in the dorsal CA1 region immediately or 180 min but not 360 min after training impairs consolidation of long-term object recognition memory without affecting short-term memory, exploratory behavior, anxiety state, or hippocampal functionality. When given into CA1 after memory reactivation in the presence of familiar objects, ANI did not affect further retention. However, when administered into CA1 immediately after exposing animals to a novel and a familiar object, ANI impaired memory of both of them. The amnesic effect of ANI was long-lasting, did not happen after exposure to two novel objects, following exploration of the context alone, or in the absence of specific stimuli, suggesting that it was not reversible but was contingent on the reactivation of the consolidated trace in the presence of a salient, behaviorally relevant novel cue. Our results indicate that hippocampal protein synthesis is required during a limited post-training time window for consolidation of object recognition memory and show that the hippocampus is engaged during reconsolidation of this type of memory, maybe accruing new information into the original trace.     

Two critical periods of protein and glycoprotein synthesis in memory consolidation for visual categorization learning in chicks

A protein synthesis inhibitor, anisomycin (ANI), and an inhibitor of glycoprotein synthesis, 2-deoxygalactose (2-D-gal), were used to investigate memory consolidation following visual categorization training in 2-day-old chicks. ANI (0.6 micromole/chick) and 2-D-gal (40 micromoles/chick) were injected intracerebrally at different time intervals from 1 hr before to 23 hr after the training. Retention was tested 24 hr post-training. Both ANI and 2-D-gal injections revealed two periods of memory sensitivity to pharmacological intervention. ANI impaired retention when injected from 5 min before to 30 min after the training or from 4 hr to 5 hr post-training, thus demonstrating that consolidation of long-term memory in this task requires two periods of protein synthesis. 2-D-Gal first produced an amnesia when it was injected in the interval from 5 min before to 5 min after the training. Injections made between 5 min and 5 hr post-training were without effect on the retention. The second period of memory impairment by 2-D-gal started at 5 hr post-training and lasted until 21 hr after the training. Administration of 2-D-gal made 23 hr after the training did not influence retention in the test at either 24 hr or 26 hr. These results are consistent with the hypothesis that two waves of protein and glycoprotein synthesis are necessary for the formation of long-term memory. The prolonged duration of performance impairment by 2-D-gal in the present task might reflect an extended memory consolidation period for a categorization form of learning.     

NMDA receptor blockade in the basolateral amygdala disrupts consolidation of stimulus-reward memory and extinction learning during reinstatement of cocaine-seeking in an animal model of relapse

Previous research from our laboratory has implicated the basolateral amygdala (BLA) complex in the acquisition and consolidation of cue-cocaine associations, as well as extinction learning, which may regulate the long-lasting control of conditioned stimuli (CS) over drug-seeking behavior. Given the well established role of NMDA glutamate receptor activation in other forms of amygdalar-based learning, we predicted that BLA-mediated drug-cue associative learning would be NMDA receptor dependent. To test this hypothesis, male Sprague-Dawley rats self-administered i.v. cocaine (0.6 mg/kg/infusion) in the absence of explicit CS pairings (2-h sessions, 5 days), followed by a single 1-h classical conditioning (CC) session, during which they received passive infusions of cocaine discretely paired with a light+tone stimulus complex. Following additional cocaine self-administration sessions in the absence of the CS (2-h sessions, 5 days) and extinction training sessions (no cocaine or CS presentation, 2-h sessions, 7 days), the ability of the CS to reinstate cocaine-seeking on three test days was assessed. Rats received bilateral intra-BLA infusions (0.5 microl/hemisphere) of vehicle or the selective NMDA receptor antagonist, 2-amino-5-phosphonovalerate (AP-5), immediately prior to the CC session (acquisition), immediately following the CC session (consolidation), or immediately following reinstatement testing (consolidation of conditioned-cued extinction learning). AP-5 administered before or after CC attenuated subsequent CS-induced reinstatement, whereas AP-5 administered immediately following the first two reinstatement tests impaired the extinction of cocaine-seeking behavior. These results suggest that NMDA receptor-mediated mechanisms within the BLA play a crucial role in the consolidation of drug-CS associations into long-term memories that, in turn, drive cocaine-seeking during relapse.     

Knockdown of Nurr1 in the rat hippocampus: implications to spatial discrimination learning and memory

Nurr1 expression is up-regulated in the brain following associative learning experiences, but its relevance to cognitive processes remains unclear. In these studies, rats initially received bilateral hippocampal infusions of control or antisense oligodeoxynucleotides (ODNs) 1 h prior to training in a holeboard spatial discrimination task. Such pre-training infusions of nurr1 antisense ODNs caused a moderate effect in learning the task and also impaired LTM tested 7 d later. In a second experiment, ODN infusions were given immediately after the animals had received two sessions of training, during which all animals showed normal learning. Although antisense treated rats were significantly impaired during the post-infusion stages of acquisition of the task, no group differences were observed during the LTM test given 7 d later. These animals were subjected 3 d later to reversal training in the same maze in the absence of any additional treatments. Remarkably, rats previously treated with antisense ODNs displayed perseveration: The animals were fixated with the previously learned pattern of baited holes, causing them to be significantly impaired in the extinction of acquired spatial preferences and future learning. We postulate that Nurr1 function in the hippocampus is important for normal cognitive processes.     

Remembrance of places lasts: Proactive inhibition and patterns of choice in rat spatial memory

A series of experiments was carried out to evaluate the notion that rats given a sequence of massed daily trials on the radial maze reset working memory at the end of each trial by deleting its contents. Although curves presented by D. S. Olton [Scientific American, 1977, 236, 82–98; In S. H. Hulse, H. Fowler, & W. K. Honig (Eds.), Cognitive processes in animal behavior, Hillsdale, N.J.: Erlbaum, 1978] show that rats return to errorless performance at the beginning of each trial after the first, the fact that accuracy falls less rapidly over choices on Trial 1 than on subsequent trials suggests a proactive inhibition (PI) effect. In Experiment 1, Olton's findings were replicated, and a PI effect was observed on Days 1–2 of testing. On Days 3–5, overall accuracy improved significantly and was associated with the development of a strong tendency for rats to enter adjacent alleys, which became particularly marked on the final trials of a day's testing. In order to prevent rats from achieving accurate performance by using an adjacent alleys pattern, a procedure was used in Experiment 2 which involved initial forced random choices followed by a retention test consisting of free choices. Repeated daily trials with this procedure yielded a significant PI effect, which was more marked at a 60-sec delay than at a 0-sec delay. Experiments 3 and 4 showed this PI effect to be robust and resistant to manipulations designed to produce release from PI. Both the PI effect and a strong tendency found in Experiment 1 for animals to avoid on the initial choices of Trial n those alleys most recently entered on Trial n?1 argue that rats do not reset working memory between trials.     

Phosphorylation of mitogen-activated protein kinase in the medial prefrontal cortex and the amygdala following memory retrieval or forgetting in developing rats

We examined neuronal correlates of forgetting in rats by detection of phosphorylated mitogen-activated protein kinase (pMAPK) in the medial prefrontal cortex (mPFC) and amygdala. In Experiment 1, postnatal day (P)23 and P16 rats received paired noise CS-shock US presentations. When tested immediately after conditioning, P23 and P16 rats exhibited similar levels of conditioned fear; when tested after 2 days, however, P16 rats showed poor CS-elicited freezing relative to P23 rats. In Experiment 2, P16 and P23 rats received either paired or unpaired CS-US presentations, and then were tested 48 h later. Consistent with Experiment 1, P16 rats showed forgetting whereas P23 rats exhibited good retention at test. Additionally, unpaired groups showed poor CS-elicited freezing at test. Immunohistochemistry showed that P23 and P16 rats given paired presentations exhibited significant elevation of pMAPK-immunoreactive (ir) neurons in the amygdala compared to rats given unpaired presentations. That is, MAPK phosphorylation in the amygdala tracked learning history rather than behavioral performance at test. In contrast, only the P23-paired group showed an elevated number of pMAPK-ir neurons in mPFC, indicating that MAPK phosphorylation in the mPFC tracks memory expression. Different test-perfusion intervals were employed in Experiment 3, which showed that the developmental dissociation in the pMAPK-ir neurons observed in the mPFC in Experiment 2 was not due to age differences in the rate of phosphorylation of MAPK. These findings provide initial evidence suggesting that while the mPFC is involved in memory retrieval, MAPK phosphorylation in the amygdala may be a persisting neural signature of fear memory.     

阻断内侧前额叶皮质TrkB受体对大鼠认知和海马BDNF表达的影响

脑源性神经营养因子(brain-derived neurotrophic factor, BDNF)广泛参与了个体学习和记忆等认知功能, 通过与其酪氨酸激酶受体(tyrosine kinase, TrkB)特异性结合, 实现其多种神经生化功能。本研究观察了TrkB受体阻断剂ANA-12的慢性内侧前额叶皮质(medial prefrontal cortex, mPFC)注射对大鼠旷场行为、Morris水迷宫空间学习和逆反学习的影响。研究结果表明, mPFC的慢性BDNF阻断显著降低了大鼠在逆反学习测试中的逃离潜伏期和运动距离即增强了大鼠的逆反学习能力, 但不影响其旷场行为和水迷宫空间学习能力。同时, 慢性阻断mPFC-TrkB受体也并未导致大鼠海马BDNF蛋白含量的显著改变。这些结果提示, 对于大鼠的Morris水迷宫空间学习和逆反学习, mPFC-BDNF主要在逆反学习调节中发挥重要作用。这对于进一步探索海马和mPFC在调节个体认知功能中各自的作用及其潜在的相互关系提供了有力的证据和支持。