Neurophysiologic Advance in Depressive Disorder.

Enormous efforts for near half-century have harvested a plenty of understanding on major depressive disorder (MDD), although the underlying mechanisms are still elusive. The available antidepressants are far from satisfaction due to long-delay action (LDA) of antidepressant efficacy and low response rates in MDD patients. Notably, discovery of a single low-dose ketamine-producing rapid-onset and sustained antidepressant efficacy has inspired new research direction. These new studies have revealed ketamine's NMDAR-dependent and NMDAR-independent mechanisms, most of which are well known to be the key bases of synaptic plasticity as well as learning and memory. In fact, animal models of MDD are all based on the principle of learning and memory, i.e., the change of a behavior, for which monoaminergic and glutamatergic systems are the major modulators and executors, respectively. Reconsidering MDD as an aberrant form of emotion-related learning and memory would endow us a clearer research direction for developing new techniques or ways to prevent, diagnose, and treat MDD.

The bidirectional effects of hypothyroidism and hyperthyroidism on anxiety- and depression-like behaviors in rats.

Thyroid hormone disorders have long been linked to depression, but the causal relationship between them remains controversial. To address this question, we established rat models of hypothyroidism using (131)iodine ((131)I) and hyperthyroidism using levothyroxine (LT4). Serum free thyroxine (FT4) and triiodothyronine (FT3) significantly decreased in the hypothyroid of rats with single injections of (131)I (5mCi/kg). These rats exhibited decreased depression-like behaviors in forced swimming test and sucrose preference tests, as well as decreased anxiety-like behaviors in an elevated plus maze. Diminished levels of brain serotonin (5-HT) and increased levels of hippocampal brain-derived neurotrophic factor (BDNF) were found in the hypothyroid rats compared to the control saline-vehicle administered rats. LT4 treatment reversed the decrease in thyroid hormones and depression-like behaviors. In contrast, hyperthyroidism induced by weekly injections of LT4 (15µg/kg) caused a greater than 10-fold increase in serum FT4 and FT3 levels. The hyperthyroid rats exhibited higher anxiety- and depression-like behaviors, higher brain 5-HT level, and lower hippocampal BDNF levels than the controls. Treatment with the antidepressant imipramine (15mg/kg) diminished serum FT4 levels as well as anxiety- and depression-like behaviors in the hyperthyroid rats but led to a further increase in brain 5-HT levels, compared with the controls or the hypothyroid rats. Together, our results suggest that hypothyroidism and hyperthyroidism have bidirectional effects on anxiety- and depression-like behaviors in rats, possibly by modulating hippocampal BDNF levels.

Nicotinic acid activates the capsaicin receptor TRPV1: Potential mechanism for cutaneous flushing.

OBJECTIVE: Nicotinic acid (also known as niacin or vitamin B3), widely used to treat dyslipidemias, represents an effective and safe means to reduce the risk of mortality from cardiovascular disease. Nonetheless, a substantial fraction of patients discontinue treatment because of a strong side effect of cutaneous vasodilation, commonly termed flushing. In the present study, we tested the hypothesis that nicotinic acid causes flushing partially by activating the capsaicin receptor TRPV1, a polymodal cellular sensor that mediates the flushing response on consumption of spicy food. APPROACH AND RESULTS: We observed that the nicotinic acid-induced increase in blood flow was substantially reduced in Trpv1(-/-) knockout mice, indicating involvement of the channel in flushing response. Using exogenously expressed TRPV1, we confirmed that nicotinic acid at submillimolar to millimolar concentrations directly and potently activates TRPV1 from the intracellular side. Binding of nicotinic acid to TRPV1 lowers its activation threshold for heat, causing channel opening at physiological temperatures. The activation of TRPV1 by voltage or ligands (capsaicin and 2-aminoethoxydiphenyl borate) is also potentiated by nicotinic acid. We further demonstrated that nicotinic acid does not compete directly with capsaicin but may activate TRPV1 through the 2-aminoethoxydiphenyl borate activation pathway. Using live-cell fluorescence imaging, we observed that nicotinic acid can quickly enter the cell through a transporter-mediated pathway to activate TRPV1. CONCLUSIONS: Direct activation of TRPV1 by nicotinic acid may lead to cutaneous vasodilation that contributes to flushing, suggesting a potential novel pathway to inhibit flushing and to improve compliance.

Impaired contextual fear extinction and hippocampal synaptic plasticity in adult rats induced by prenatal morphine exposure.

Prenatal opiate exposure causes a series of neurobehavioral disturbances by affecting brain development. However, the question of whether prenatal opiate exposure increases vulnerability to memory-related neuropsychiatric disorders in adult offspring remains largely unknown. Here, we found that rats prenatally exposed to morphine (PM) showed impaired acquisition but enhanced maintenance of contextual fear memory compared with control animals that were prenatally exposed to saline (PS). The impairment of acquisition was rescued by increasing the intensity of footshocks (1.2 mA rather than 0.8 mA). Meanwhile, we also found that PM rats exhibited impaired extinction of contextual fear, which is associated with enhanced maintenance of fear memory. The impaired extinction lasted for 1 week following extinction training. Furthermore, PM rats exhibited reduced anxiety-like behavior in the elevated plus-maze and light/dark box test without differences in locomotor activity. These alterations in PM rats were mirrored by abnormalities in synaptic plasticity in the Schaffer collateral-CA1 synapses of the hippocampus in vivo. PS rats showed blocked long-term potentiation and enabled long-term depression in CA1 synapses following contextual fear conditioning, while prenatal morphine exposure restricted synaptic plasticity in CA1 synapses. The smaller long-term potentiation in PM rats was not further blocked by contextual fear conditioning, and the long-term depression enabled by contextual fear conditioning was abolished. Taken together, our results provide the first evidence suggesting that prenatal morphine exposure may increase vulnerability to fear memory-related neuropsychiatric disorders in adulthood.

The impairment of the hippocampal neuro-vascular unit precedes changes in spatial cognition in naturally aged rats.

Ageing is the major risk factor for the most neurodegenerative diseases, such as Alzheimer's disease (AD). Damage to neurovascular components (microvessels, glia, and neurons) occurs with ageing and is suspected to exacerbate or cause mild cognitive impairment (MCI), vascular dementia, and AD. However, whether vascular cells, glia, and neurons change synchronously or asynchronously during ageing is unclear, and the relationship between complex dynamic pathophysiological changes in the brain and cognitive ability needs to be further studied. We used male Sprague-Dawley (SD) rats of three different ages (2 months, 12 months, and 24 months) and explored changes in the neurovascular unit (cerebral vessels, microglia, astrocytes, and neurons) and spatial memory upon normal ageing by the Morris water maze (MWM) test and immunofluorescence staining. We found that the impairments of microvessels, glia, neurons, and spatial memory were age-dependent in the rat hippocampus. In middle-aged (12-month-old) rats, some neurovascular unit components have become abnormal: the density and length of microvessels, pyramidal neuron, and SST (Somatostatin) neuron number was decreased, the number of astrocytes was increased in the hippocampus. The diameter of microvessels and PV (Parvalbumin) neuron numbers were decreased, the microglial number was increased and spatial learning was deficit at 24 months of age. In conclusion, we found that the impairment of the hippocampal neuro-vascular unit precedes changes in spatial cognition in naturally aged rats.

Time of Day-Dependent Alteration of Hippocampal Rac1 Activation Regulates Contextual Fear Memory in Rats.

Fear memory in species varies according to the time of the day. Although the underlying molecular mechanisms have been extensively explored, they remain largely unknown. Here, we report that hippocampal Rac1 activity undergoes a time of day-dependent alteration both in nocturnal rats and diurnal tree shrews and that training at the lower hippocampal Rac1 activation period during the night leads to better contextual fear memory in rats. Furthermore, day and night reversion by 24 h darkness/24 h light housing inverses the external clock time of hippocampal Rac1 activation, but the better contextual fear memory still coincides with the lower Rac1 activation in rats during the night. Interestingly, exogenous melatonin treatment promotes hippocampal Rac1 activity and impairs better contextual fear memory acquired at the lower Rac1 activation period during the night, and Rac1-specific inhibitor NSC23766 compromises the effect of melatonin. These results suggest that the time of day-dependent alteration of hippocampal Rac1 activation regulates contextual fear memory in rats by forgetting.

Unveiling the chemotactic response and mechanism of Shewanella oneidensis MR-1 to nitrobenzene.

Bioreduction by electroactive bacteria (EAB) is considered as a potential and cost-effective approach for the removal of nitroaromatic compounds (NACs). However, little is known about how the widespread EAB sense and respond to slightly soluble NACs in aquatic environments. Here, the chemotactic behaviors of Shewanella oneidensis MR-1, a model EAB, toward several NACs were examined and their underlying molecular mechanism was elucidated. S. oneidensis MR-1 was found to exhibit a strong chemotactic response to nitrobenzene (NB), but not to other selected NACs under aerobic conditions. To sense NB, this bacterium requires both the histidine kinase (CheA-3)-involved chemotactic signal transduction pathway and an inner-membrane c-type cytochrome CymA. Such a chemotactic response is mediated by an energy taxis mechanism. Additionally, external riboflavin was shown to greatly enhance the Shewanella taxis toward NB, implying a feasible way to increase the bioavailability of NACs. The present study deepens our understanding of the role of microbial chemotaxis in the removal of NACs and provides more options for the bioremediation of NAC-contaminated sites.

Developing of Focal Ischemia in the Hippocampus or the Amygdala Reveals a Regional Compensation Rule for Fear Memory Acquisition.

Circuit compensation is often observed in patients with acute ischemic stroke, suggesting the importance of the interaction between brain regions. Also, contextual fear memory is an association between multisensory contexts and fearful stimuli, for which the interaction between the hippocampus and the amygdala is believed to be critical. To understand how focal ischemia in one region could influence the other region, we used a modified photo-thrombosis to induce focal ischemia in the hippocampus or the amygdala or both in freely-moving rats. We found that the learning curve and short-term memory (STM) were not affected in the rats although focal ischemia was induced 5 h before learning in either the hippocampus or the amygdala; these were impaired by the induction of ischemia in both the regions. Furthermore, the learning curve and STM were impaired when ischemia was induced 24 h before learning in either the hippocampus or the amygdala when the synaptic transmission was altered in one region because of ischemia in the other region. These results suggest that the circuit compensation between the hippocampus and the amygdala is critical for fear memory acquisition.

A Temporal Activity of CA1 Neurons Underlying Short-Term Memory for Social Recognition Altered in PTEN Mouse Models of Autism Spectrum Disorder.

Memory-guided social recognition identifies someone from previous encounters or experiences, but the mechanisms of social memory remain unclear. Here, we find that a short-term memory from experiencing a stranger mouse lasting under 30 min interval is essential for subsequent social recognition in mice, but that interval prolonged to hours by replacing the stranger mouse with a familiar littermate. Optogenetic silencing of dorsal CA1 neuronal activity during trials or inter-trial intervals disrupted short-term memory-guided social recognition, without affecting the ability of being sociable or long-term memory-guided social recognition. Postnatal knockdown or knockout of autism spectrum disorder (ASD)-associated phosphatase and tensin homolog (PTEN) gene in dorsal hippocampal CA1 similarly impaired neuronal firing rate in vitro and altered firing pattern during social recognition. These PTEN mice showed deficits in social recognition with stranger mouse rather than littermate and exhibited impairment in T-maze spontaneous alternation task for testing short-term spatial memory. Thus, we suggest that a temporal activity of dorsal CA1 neurons may underlie formation of short-term memory to be critical for organizing subsequent social recognition but that is possibly disrupted in ASD.

Ferulic Acid Ameliorates Alzheimer's Disease-like Pathology and Repairs Cognitive Decline by Preventing Capillary Hypofunction in APP/PS1 Mice.

Brain capillaries are crucial for cognitive functions by supplying oxygen and other nutrients to and removing metabolic wastes from the brain. Recent studies have demonstrated that constriction of brain capillaries is triggered by beta-amyloid (Aß) oligomers via endothelin-1 (ET1)-mediated action on the ET1 receptor A (ETRA), potentially exacerbating Aß plaque deposition, the primary pathophysiology of Alzheimer's disease (AD). However, direct evidence is still lacking whether changes in brain capillaries are causally involved in the pathophysiology of AD. Using APP/PS1 mouse model of AD (AD mice) relative to age-matched negative littermates, we identified that reductions of density and diameter of hippocampal capillaries occurred from 4 to 7 months old while Aß plaque deposition and spatial memory deficit developed at 7 months old. Notably, the injection of ET1 into the hippocampus induced early Aß plaque deposition at 5 months old in AD mice. Conversely, treatment of ferulic acid against the ETRA to counteract the ET1-mediated vasoconstriction for 30 days prevented reductions of density and diameter of hippocampal capillaries as well as ameliorated Aß plaque deposition and spatial memory deficit at 7 months old in AD mice. Thus, these data suggest that reductions of density and diameter of hippocampal capillaries are crucial for initiating Aß plaque deposition and spatial memory deficit at the early stages, implicating the development of new therapies for halting or curing memory decline in AD.

Stress within the postseizure time window inhibits seizure recurrence.

Recurrence is a key characteristic in the development of epilepsy. It remains unclear whether seizure recurrence is sensitive to postseizure stress. Here, tonic-clonic seizures were induced with a convulsive dose of pentylenetetrazole (PTZ), and acute seizure recurrence was evoked with a subconvulsive dose of the drug. We found that stress inhibited seizure recurrence when applied 30minutes or 2hours, but not 4hours, after the tonic-clonic seizure. The time-dependent anti-recurrence effect of stress was mimicked by the stress hormone corticosterone and blocked by co-administration of mineralocorticoid and glucocorticoid receptor antagonists. Furthermore, in a PTZ-induced epileptic kindling model, corticosterone administered 30minutes after each seizure decreased the extent of seizures both during the kindling establishment and in the following challenge test. These results provide novel insights into both the mechanisms of and therapeutic strategies for epilepsy.

Acute Administration of Methyleugenol Impairs Hippocampus-Dependent Contextual Fear Memory and Increases Anxiety-like Behavior in Mice.

Methyleugenol (ME) as a natural essential oil in many plant species is widely used in human food and beverage for its fragrance and possible beneficial health effects. Previous chronic or subacute studies in rodents show that ME mainly causes liver toxicity. However, whether and how acute ME affects the central nervous system still remain elusive. Here, we found that ME administrated into the hippocampus impaired the acquisition of hippocampus-dependent contextual fear memory in mice (ME vs control: repeated-measures two-way ANOVA, F(5,70) = 2.937, p < 0.05; Fisher test, p < 0.05, respectively, 53 ± 5.2% vs 73 ± 7.6% during trial 4 and 46.8 ± 6% vs 74.5 ± 9.3% during trial 5). Meanwhile, acute ME impaired hippocampal CA1 long-term potentiation (LTP; ME vs control: independent t-test, p < 0.01, 110.6 ± 1.8% vs 133.3 ± 5.6%) while facilitated long-term depression (LTD; p < 0.01, 75.7 ± 3.4% vs 88.6 ± 1.7%) in mice brain slices and inducing a decrease in learning-dependent phosphorylation of Ser831 (ME vs control: independent t-test, p < 0.001, 0.87 ± 0.03 vs 1.23 ± 0.03) and Ser845 (p < 0.01, 0.42 ± 0.07 vs 0.97 ± 0.14) sites of excitatory glutamate AMPA receptor subunit 1 (GluA1) in the hippocampus, which may be the underlying mechanisms of impairment of hippocampus-dependent learning. In addition, intrahippocampal infusion of ME also increased anxiety-like behaviors in mice. These results suggested that acute ME impaired the hippocampus function at behavioral, cellular, and molecular levels, indicating the potential risks of ME on the central nervous system.

Effects of pentylenetetrazol-induced brief convulsive seizures on spatial memory and fear memory.

Previous studies have demonstrated that in the pentylenetetrazol (PTZ) kindling model, recurrent seizures either impair or have no effect on learning and memory. However, the effects of brief seizures on learning and memory remain unknown. Here, we found that a single injection of a convulsive dose of PTZ (50 mg/kg, ip) induced brief seizures in Sprague-Dawley rats. Administration of PTZ before training impaired the acquisition of spatial memory in the Morris water maze (MWM) and fear memory in contextual fear conditioning. However, the administration of PTZ immediately after training did not affect memory consolidation in either task. These findings suggest that brief seizures have different effects on acquisition and consolidation of spatial and fear memory.

Spaced Training Enhances Contextual Fear Memory via Activating Hippocampal 5-HT2A Receptors.

Spaced training is robustly superior to massed training, which is a well-documented phenomenon in humans and animals. However, the mechanisms underlying the spacing effect still remain unclear. We have reported previously that spacing training exerts memory-enhancing effects by inhibiting forgetting via decreasing hippocampal Rac1 activity. Here, using contextual fear conditioning in rat, we found that spaced but not massed training increased hippocampal 5-HT2A receptors' expression. Furthermore, hippocampal administration of 5-HT2A receptor antagonist MDL11939 before spaced training blocked the enhanced memory, while hippocampal administration of 5-HT2A receptor agonist TCB-2 before massed training promoted the memory. Moreover, MDL11939 activated hippocampal Rac1, while TCB-2 decreased hippocampal Rac1 activity in naïve rats. These results indicated the possibility of interaction between 5-HT2A receptors and Rac1, which was demonstrated by co-immunoprecipitation experiments. Our study first demonstrates that activation of hippocampal 5-HT2A is a mechanism underlying the spacing effect, and forgetting related molecular Rac1 is engaged in this process through interacting with 5-HT2A receptors, which suggest a promising strategy to modulate abnormal learning in cognitive disorders.

Morphine withdrawal affects both delayed-escape behaviour in Morris water maze and hippocampal NR2A/2B expression ratio.

Repeated low-dose morphine treatment facilitates delayed-escape behaviour of hippocampus-dependent Morris water maze and morphine withdrawal influences hippocampal NMDA receptor-dependent synaptic plasticity. Here, we examined whether and how morphine withdrawal influenced delayed-escape behaviour and NR2A/2B expression ratio of hippocampal synaptosomes. We found that both delayed-escape behaviour and NR2A/2B expression ratio showed an inverted-U curve and peaked on 4-day withdrawal during a 20-day withdrawal period. Furthermore, treatment of the glucocorticoid receptor antagonist RU38486 for 3 days reduced delayed-escape behaviour and NR2A/2B ratio on 4-day withdrawal to a level similar to those of 18-h withdrawal. In contrast, elevated-platform stress enabled delayed-escape behaviour of 18-h withdrawal to a higher level similar to that of 4-day withdrawal, but had no significant effect on the NR2A/2B ratio. Similar behavioural effects were also found after intrahippocampal infusions of the NMDAR antagonist AP-5 or NR2B-containing NMDAR antagonist Ro25-6981 for 3 days. These findings suggest that delayed-escape behaviour enabled by repeated low-dose morphine treatment may be a useful and simple rat model for studying addictive memories to be retrieved by stress exposure.

Protective efficacy of a single salvianolic acid A treatment on photothrombosis-induced sustained spatial memory impairments.

With respect to the high burden of ischemic stroke and the absence of pharmacological treatment for promoting rehabilitation, promising candidates with specific effects on long-term functional recovery are highly desired. Candidates need reasonable experimental paradigms to evaluate the long-term functional outcome focused on ischemia-induced sensorimotor and memory deficits. "Danshen", a traditional Chinese herb, has long been used to treat coronary and cerebral vascular diseases as well as dementia. Salvianolic acid A (SAA), one of the major active ingredients of Danshen, was demonstrated to be effective in protecting against cerebral ischemic injury. Here, employing an experimental stroke model induced by photothrombosis in the unilateral frontal cortex of rats, we investigated whether SAA has long-term protective effects on ischemia-induced sensorimotor and memory deficits in our behavioral tests. The results indicated that a single SAA treatment improved the cortical ischemia-induced sensorimotor deficits during 15 days' cylinder test period, and alleviated ischemia-induced sustained spatial memory impairments during the 2 months' dependent Morris Water Maze (MWM) tests. In addition, either ischemic injury or SAA treatment did not show any changes compared with sham group in other behavioral tests including rotarod tests, swimming speed in MWM tests, open field tests, elevated plus maze tests, treadmill tests and forced swimming tests. The results reveal that the cognitive deficits are not the results of animal's anxiety or confounding motor impairments. Overall, the present paradigm appears suitable for the preclinical evaluation of the long-term effects of pharmacological treatments on ischemic stroke. Meanwhile, SAA might have therapeutic potential for the treatment of memory deficits associated with ischemic stroke.

The effect of circulating miR-223 on surveillance of different cancers: a meta-analysis.

PURPOSE: Abnormal expression of miR-223 in cancerous tissue has confirmed it as an important player in tumorigenesis of cancers, such as hepatocellular carcinoma, colorectal carcinoma, osteosarcoma, gastric cancer, and chronic lymphocytic leukemia. The present meta-analysis aimed to explore the association between circulating miR-223 and prognosis of cancers. METHODS: The studies were accessed by an electronic search of multiple databases. RevMan5.3 and STATA14.0 were used to estimate the heterogeneity among studies, pooled effects, and publication bias. RESULTS: Ten studies with data of 1,002 patients with cancer were included in this meta-analysis. The risk of metastasis from stages 3 to 4 of TNM did not decrease when high versus low circulating expression of miR-223 were compared (pooled odds ratio =0.50, 95% CI: 0.24-1.03). In case of prognosis, the overall survival time was not significantly longer with high circulating miR-223 expression (pooled hazard ratio [HR] =0.64, 95% CI: 0.38-1.11) in all cancer types. However, the overall survival time of chronic lymphocytic leukemia (pooled HR =0.19, 95% CI: 0.07-0.54) increased in subgroup analysis. Moreover, the treatment-free survival of chronic lymphocytic leukemia was significantly increased with high circulating miR-223 expression (pooled HR =0.38, 95% CI: 0.23-0.64). CONCLUSION: Circulating miR-223 was not an effective biomarker in prognosis surveillance in all cancers but in chronic lymphocytic leukemia.

Hippocampal Administration of Levothyroxine Impairs Contextual Fear Memory Consolidation in Rats.

Thyroid hormone (TH) receptors are highly distributed in the hippocampus, which plays a vital role in memory processes. However, how THs are involved in the different stages of memory process is little known. Herein, we used hippocampus dependent contextual fear conditioning to address the effects of hippocampal THs on the different stages of fear memory. First, we found that a single systemic levothyroxine (LT4) administration increased the level of free triiodothyronine (FT3) and free tetraiodothyroxine (FT4) not only in serum but also in hippocampus. In addition, a single systemic LT4 administration immediately after fear conditioning significantly impaired fear memory. These results indicated the important role of hippocampal THs in fear memory process. To further confirm the effects of hippocampal THs on the different stages of fear memory, LT4 (0.4 µg/µl, 1 µl/side) was injected bilaterally into hippocampus. Rats given LT4 into hippocampus before training or tests had no effect on the acquisition or retrieval of fear memory, however rats given LT4 into hippocampus either immediately or 2 h after training showed being significantly impaired fear memory, which demonstrated LT4 administration into hippocampus impairs the consolidation but has no effect on the acquisition and retrieval of fear memory. Furthermore, hippocampal injection of LT4 did not affect rats' locomotor activity, thigmotaxis and THs level in prefrontal cortex (PFC) and serum. These findings may have important implications for understanding mechanisms underlying contribution of THs to memory disorders.

The interhemispheric CA1 circuit governs rapid generalisation but not fear memory.

Encoding specificity theory predicts most effective recall by the original conditions at encoding, while generalization endows recall flexibly under circumstances which deviate from the originals. The CA1 regions have been implicated in memory and generalization but whether and which locally separated mechanisms are involved is not clear. We report here that fear memory is quickly formed, but generalization develops gradually over 24 h. Generalization but not fear memory is impaired by inhibiting ipsilateral (ips) or contralateral (con) CA1, and by optogenetic silencing of the ipsCA1 projections onto conCA1. By contrast, in vivo fEPSP recordings reveal that ipsCA1-conCA1 synaptic efficacy is increased with delay over 24 h when generalization is formed but it is unchanged if generalization is disrupted. Direct excitation of ipsCA1-conCA1 synapses using chemogenetic hM3Dq facilitates generalization formation. Thus, rapid generalization is an active process dependent on bilateral CA1 regions, and encoded by gradual synaptic learning in ipsCA1-conCA1 circuit.

Enriched environment experience overcomes the memory deficits and depressive-like behavior induced by early life stress.

Stress in early life is believed to cause cognitive and affective disorders, and to disrupt hippocampal synaptic plasticity in adolescence into adult, but it is unclear whether exposure to enriched environment (EE) can overcome these effects. Here, we reported that housing rats in cages with limited nesting/bedding materials on postnatal days 2-21 reduced body weight gain, and this type of early life stress impaired spatial learning and memory of the Morris water maze and increased depressive-like behavior of the forced swim test in young adult rats (postnatal days 53-57). Early life stress also impaired long-term potentiation in hippocampal CA1 area of slices of young adult rats. Remarkably, EE experience on postnatal days 22-52 had no effect on spatial learning/memory and depressive-like behavior, but it significantly facilitated LTP in control rats, and completely overcame the effects of early life stress on young adult rats. These findings suggest that EE experience may be useful for clinical intervention in preventing cognitive and affective disorders during development.