Stress-induced Memory Deficits Research Articles

Neonatal Maternal Separation Induces Sexual Dimorphism in Brain Development: The Influence on Amino Acid Levels and Cognitive Disorders.

Repeated maternal separation (MS) is a useful experimental model in rodents for studying the long-term influence of early-life stress on brain neurophysiology. In our work, we assessed the effect of repeated MS (postnatal day (PND)1-21, 180 min/day) on the postnatal development of rat brain regions involved in memory using proton magnetic resonance spectroscopy (1HMRS) for tissue volume and the level of amino acids such as glutamate, aspartate, glutamine, glycine and gamma-aminobutyric acid (GABA) in the hippocampus. We assessed whether these effects are sex dependent. We also use novel object recognition (NOR) task to examine the effect of MS on memory and the effect of ethanol on it. Finally, we attempted to ameliorate postnatal stress-induced memory deficits by using VU-29, a positive allosteric modulator (PAM) of the metabotropic glutamate type 5 (mGlu5) receptor. In males, we noted deficits in the levels of glutamate, glycine and glutamine and increases in GABA in the hippocampus. In addition, the values of perirhinal cortex, prefrontal cortex and insular cortex and CA3 were decreased in these animals. MS females, in contrast, demonstrated significant increase in glutamate levels and decrease in GABA levels in the hippocampus. Here, the CA1 values alone were increased. VU-29 administration ameliorated these cognitive deficits. Thus, MS stress disturbs amino acids levels mainly in the hippocampus of adult male rats, and enhancement of glutamate neurotransmission reversed recognition memory deficits in these animals.

Sex-Dependent Effect of Chronic Piromelatine Treatment on Prenatal Stress-Induced Memory Deficits in Rats.

Prenatal stress impairs cognitive function in rats, while Piromelatine treatment corrects memory decline in male rats with chronic mild stress. In the present study, we aimed to evaluate the effect of chronic treatment with the melatonin analogue Piromelatine on the associative and spatial hippocampus-dependent memory of male and female offspring with a history of prenatal stress (PNS). We report that male and female young adult offspring with PNS treated with a vehicle had reduced memory responses in an object recognition test (ORT). However, the cognitive performance in the radial arm maze test (RAM) was worsened only in the male offspring. The 32-day treatment with Piromelatine (20 mg/kg, i.p.) of male and female offspring with PNS attenuated the impaired responses in the ORT task. Furthermore, the melatonin analogue corrected the disturbed spatial memory in the male offspring. While the ratio of phosphorylated and nonphosphorylated adenosine monophosphate response element binding protein (pCREB/CREB) was reduced in the two sexes with PNS and treated with a vehicle, the melatonin analogue elevated the ratio of these signaling molecules in the hippocampus of the male rats only. Our results suggest that Piromelatine exerts a beneficial effect on PNS-induced spatial memory impairment in a sex-dependent manner that might be mediated via the pCREB/CREB pathway.

Sex-dependent effects of multiple acute concurrent stresses on memory: a role for hippocampal estrogens.

Memory disruption commonly follows chronic stress, whereas acute stressors are generally benign. However, acute traumas such as mass shootings or natural disasters—lasting minutes to hours and consisting of simultaneous physical, social, and emotional stresses—are increasingly recognized as significant risk factors for memory problems and PTSD. Our prior work has revealed that these complex stresses (concurrent multiple acute stresses: MAS) disrupt hippocampus-dependent memory in male rodents. In females, the impacts of MAS are estrous cycle-dependent: MAS impairs memory during early proestrus (high estrogens phase), whereas the memory of female mice stressed during estrus (low estrogens phase) is protected. Female memory impairments limited to high estrogens phases suggest that higher levels of estrogens are necessary for MAS to disrupt memory, supported by evidence that males have higher hippocampal estradiol than estrous females. To test the role of estrogens in stress-induced memory deficits, we blocked estrogen production using aromatase inhibitors. A week of blockade protected male and female mice from MAS-induced memory disturbances, suggesting that high levels of estrogens are required for stress-provoked memory impairments in both males and females. To directly quantify 17β-estradiol in murine hippocampus we employed both ELISA and mass spectrometry and identified significant confounders in both procedures. Taken together, the cross-cycle and aromatase studies in males and females support the role for high hippocampal estrogens in mediating the effect of complex acute stress on memory. Future studies focus on the receptors involved, the longevity of these effects, and their relation to PTSD-like behaviors in experimental models.

Effects of the Bark Resin Extract of Garcinia nigrolineata on Chronic Stress-Induced Memory Deficit in Mice Model and the In Vitro Monoamine Oxidases and β-Amyloid Aggregation Inhibitory Activities of Its Prenylated Xanthone Constituents.

The present study describes investigation of the effects of the bark resin extract of Garcinia nigrolineata (Clusiaceae) on the cognitive function and the induction of oxidative stress in both frontal cortex and hippocampus by unpredictable chronic mild stress (UCMS). By using behavioral mouse models, i.e., the Y-maze test, the Novel Object Recognition Test (NORT), and the Morris Water Maze Test (MWMT), it was found that the negative impact of repeated mild stress-induced learning and memory deficit through brain oxidative stress in the UCMS mice was reversed by treatment with the bark resin extract G. nigrolineata. Moreover, the prenylated xanthones viz. cowagarcinone C, cowaxanthone, α-mangostin, cowaxanthone B, cowanin, fuscaxanthone A, fuscaxanthone B, xanthochymusxanthones A, 7-O-methylgarcinone E, and cowagarcinone A, isolated from the bark resin of G. nigrolineata, were assayed for their inhibitory activities against β-amyloid (Aβ) aggregation and monoamine oxidase enzymes (MAOs).

A single brief stressful event time-dependently affects object recognition memory and promotes familiarity preference in marmoset monkeys

A stressful experience can enhance information storage and impair memory retrieval in the rodent novel object recognition (NOR) task. However, recent conflicting results underscore the need for further investigation. Nonhuman primates may provide a unique, underexplored and more translational means to investigate stress-mediated changes in memory. Therefore, we assessed whether a single brief extrinsic stress event affects information encoding, storage and/or retrieval in adult marmoset monkeys submitted to the NOR task. This consisted of an initial 10 min familiarization period with two identical neutral objects. After a 6 h delay, a 10 min test trial was held where a new and familiar object could be explored. Stress was induced by a 15 min restraint event held before or after the encoding phase, or prior to retrieval. Pre-encoding stress had no effect on task performance, as this group displayed above-chance novelty preference similar to non-stressed controls. Post-encoding stress induced memory deficits, with both objects being explored equally. Interestingly, pre-retrieval stress induced an above-chance familiarity preference. A single brief stressful event thus affects recognition memory in a time-dependent manner. Also, negative discrimination ratios can be used as a measure of memory in the NOR task and a change in strategy may not mean memory failure in spontaneous learning paradigms.

Disrupted presynaptic nectin1-based neuronal adhesion in the entorhinal-hippocampal circuit contributes to early-life stress-induced memory deficits

The cell adhesion molecule nectin3 and its presynaptic partner nectin1 have been linked to early-life stress-related cognitive disorders, but how the nectin1-nectin3 system contributes to stress-induced neuronal, circuit, and cognitive abnormalities remains to be studied. Here we show that in neonatally stressed male mice, temporal order and spatial working memories, which require the medial entorhinal cortex (MEC)-CA1 pathway, as well as the structural integrity of CA1 pyramidal neurons were markedly impaired in adulthood. These cognitive and structural abnormalities in stressed mice were associated with decreased nectin levels in entorhinal and hippocampal subregions, especially reduced nectin1 level in the MEC and nectin3 level in the CA1. Postnatal suppression of nectin1 but not nectin3 level in the MEC impaired spatial memory, whereas conditional inactivation of nectin1 from MEC excitatory neurons reproduced the adverse effects of early-life stress on MEC-dependent memories and neuronal plasticity in CA1. Our data suggest that early-life stress disrupts presynaptic nectin1-mediated interneuronal adhesion in the MEC-CA1 pathway, which may in turn contribute to stress-induced synaptic and cognitive deficits.

Curcumin alleviates restraint stress-induced learning and memory deficit and activity via modulation of biochemical, morphology changes, and apoptosis in the prefrontal cortex and hippocampus.

Restraint stress indicated induction of morphology, biochemistry, and behavioral impairments. Several investigations have reported that curcumin has a protective effect against stress disturbance. The present study is designed to investigate the effects of curcumin on learning and memory, activity, biochemical, morphology changes, and apoptosis in the hippocampus and prefrontal cortex of restraint stress rats. For chronic restraint stress, the rats were kept in the restrainers for 2.5 h per day for 21 consecutive days. The animals received the gavage of curcumin every other day for 21 days. After stress, the animals were subjected to behavioral tests. In restraint stress rats, locomotor activity and step-through latency were decreased using open field and shuttle box, respectively. Then, the rats were sacrificed to assess their serum and brains. A reduction was seen in the serum malonedialdehyde levels and number of neurons in the hippocampus and prefrontal cortex. The significantly decreased serum total antioxidant capacity levels and increased apoptotic cells were observed in the hippocampus and prefrontal cortex. Finally, curcumin inhibited and reversed the changes of stress induced in the prefrontal cortex and hippocampus of the rats. These findings provided evidence for the protective effect of curcumin therapy on biochemical, morphology, and behavioral changes induced by restraint stress. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

The protective effects of escitalopram on chronic restraint stress-induced memory deficits in adult rats

The protective effects of escitalopram on chronic restraint stress-induced memory deficits in adult rats

MST1-knockdown protects against impairment of working memory via regulating neural activity in depression-like mice.

We reported that over-expression of MST1 induced the impairment of spatial memory via disturbing neural oscillation patterns in mice. Meanwhile, the P-MST1 is increased in the hippocampus after chronic unpredictable mild stress (CUMS). However, it is unclear if MST1 knockdown protects against stress-induced memory deficits via modulating neural activities. In the study, a CUMS mouse model was established and an intrahippocampal injection of AAV-shMST1 was used to knockdown MST1 in the hippocampus. The data showed that there were memory deficits with over-expressed P-MST1 level in CUMS mice. However, MST1 knockdown can significantly prevent the damages of CUMS-induced working memory and synaptic plasticity via regulating neural oscillation patterns. It suggests that MST1 down-regulation effectively protected against stress-induced behavioral dysfunctions. Moreover, as a more convenient way, neural oscillation analysis could provide some assistance for the auxiliary diagnosis and treatment of depression.

Supplemental Material for Curcumin Alleviates Restraint Stress-Induced Learning and Memory Deficit and Activity via Modulation of Biochemical, Morphology Changes, and Apoptosis in the Prefrontal Cortex and Hippocampus

Supplemental Material for Curcumin Alleviates Restraint Stress-Induced Learning and Memory Deficit and Activity via Modulation of Biochemical, Morphology Changes, and Apoptosis in the Prefrontal Cortex and Hippocampus

The Effect of a Traditional Preparation Containing Piper nigrum L. and Bunium persicum (Boiss.) B.Fedtsch. on Immobility Stress-Induced Memory Loss in Mice.

Objective Alzheimer's disease is a progressive, age-related, and neurodegenerative disease characterized by mental decline. The exact cause of Alzheimer's disease is unclear, but cholinergic dysfunction, protein accumulation, and oxidative stress are among the most important hypotheses. The main purpose of our study was to investigate the effects of aqueous and hydroalcoholic extract combination of these two medicinal plants, black pepper and cumin (as a related formulation in traditional Persian medicine), on memory and learning of an immobilized stress animal model. Methods In this study, hydroalcoholic and aqueous extracts of cumin and black pepper fruits were prepared. Six groups of mice were treated orally for 2 weeks: control group, immobility stress, and stress-induced immobility mice received different doses of the hydroalcoholic extract (100 and 200 mg/kg) and aqueous extract (100 and 200 mg/kg). The shuttle box, novel object detection, and rotarod test were used to evaluate memory and learning. The activities of acetylcholinesterase, catalase (CAT), and superoxide dismutase (SOD) and the level of reduced glutathione (GSH) and malondialdehyde (MDA) were measured in the brain tissue. Results Immobility stress significantly reduced learning and motor coordination. Furthermore, MDA levels and acetylcholinesterase activity were significantly increased, while CAT and SOD activities were significantly reduced in the brain of immobility-induced stress mice. Other findings indicated that hydroalcoholic and aqueous extracts (100 and 200 mg/kg) of cumin and black pepper fruits have an improving effect on animal motor coordination and learning ability, GSH content, and CAT, SOD, and acetylcholinesterase enzyme function in comparison with stress groups (p < 0.05). Conclusion The hydroalcoholic and aqueous extracts of cumin and black pepper fruits have protective effects against stress-induced memory deficit and oxidative stress and may have beneficial therapeutic effect in the treatment of neurodegenerative diseases.

Cognition enhancing effects of Clausena lansium (Lour.) peel extract attenuate chronic restraint stress-induced memory deficit in rats

Chronic stress exposure is now accepted as a problem that can produce deleterious effects on both brain structure and function. Numerous studies have proposed the potential of fruit peels as vital sources for acetylcholinesterase (AChE) inhibitors and antioxidants. Clausena lansium (Lour.) or wampee (WP) fruit peel is a rich source of antioxidants and flavonoids that could prove beneficial for human health. Currently, there has been no scientific evidence supporting the potency of WP peel extract to combat or reverse the memory impairment induced by chronic restraint stress (CRS). Therefore, we aimed to investigate the AChE-inhibiting and neuroprotective effects of WP peel extracts against CRS-mediated oxidative stress and cognitive dysfunction in rats. Initial assessment of the extract revealed antioxidant capacity and high concentrations of polyphenols. Further, Wistar rats were dosed orally with the WP peel extract (200, 400, and 600 mg/kg daily) and kept in a restrainer for 4 h a day for 28 consecutive days. The object recognition and Morris water maze tests were used to determine cognitive functions. After sacrifice, biomarkers of oxidative stress and AChE inhibitory activity in brain homogenates of rats were also investigated. CRS exposure produced oxidative stress and increased AChE activity, changes that led to learning and memory impairment in the cognition tests. Improved memory, reduced AChE activity, and a decreased oxidative stress status were seen in rats treated with WP peel extract. Overall, supplementation with WP peel extract may exert cognitive-enhancing effects through antioxidative neuroprotection and inhibition of AChE activity against CRS-induced oxidative stress.

Unexpected Role of Physiological Estrogen in Acute Stress-Induced Memory Deficits.

Stress may promote emotional and cognitive disturbances, which differ by sex. Adverse outcomes, including memory disturbances, are typically observed following chronic stress, but are now being recognized also after short events, including mass shootings, assault, or natural disasters, events that consist of concurrent multiple acute stresses (MAS). Prior work has established profound and enduring effects of MAS on memory in males. Here we examined the effects of MAS on female mice and probed the role of hormonal fluctuations during the estrous cycle on MAS-induced memory problems and the underlying brain network and cellular mechanisms. Female mice were impacted by MAS in an estrous cycle-dependent manner: MAS impaired hippocampus-dependent spatial memory in early-proestrous mice, characterized by high levels of estradiol, whereas memory of mice stressed during estrus (low estradiol) was spared. As spatial memory requires an intact dorsal hippocampal CA1, we examined synaptic integrity in mice stressed at different cycle phases and found a congruence of dendritic spine density and spatial memory deficits, with reduced spine density only in mice stressed during high estradiol cycle phases. Assessing MAS-induced activation of brain networks interconnected with hippocampus, we identified differential estrous cycle-dependent activation of memory- and stress-related regions, including the amygdala. Network analyses of the cross-correlation of fos expression among these regions uncovered functional connectivity that differentiated impaired mice from those not impaired by MAS. In conclusion, the estrous cycle modulates the impact of MAS on spatial memory, and fluctuating physiological levels of sex hormones may contribute to this effect.SIGNIFICANCE STATEMENT: Effects of stress on brain functions, including memory, are profound and sex-dependent. Acute stressors occurring simultaneously result in spatial memory impairments in males, but effects on females are unknown. Here we identified estrous cycle-dependent effects of such stresses on memory in females. Surprisingly, females with higher physiological estradiol experienced stress-induced memory impairment and a loss of underlying synapses. Memory- and stress-responsive brain regions interconnected with hippocampus were differentially activated across high and low estradiol mice, and predicted memory impairment. Thus, at functional, network, and cellular levels, physiological estradiol influences the effects of stress on memory in females, providing insight into mechanisms of prominent sex differences in stress-related memory disorders, such as post-traumatic stress disorder.

Tactile modulation of memory and anxiety requires dentate granule cells along the dorsoventral axis

Touch can positively influence cognition and emotion, but the underlying mechanisms remain unclear. Here, we report that tactile experience enrichment improves memory and alleviates anxiety by remodeling neurons along the dorsoventral axis of the dentate gyrus (DG) in adult mice. Tactile enrichment induces differential activation and structural modification of neurons in the dorsal and ventral DG, and increases the presynaptic input from the lateral entorhinal cortex (LEC), which is reciprocally connected with the primary somatosensory cortex (S1), to tactile experience-activated DG neurons. Chemogenetic activation of tactile experience-tagged dorsal and ventral DG neurons enhances memory and reduces anxiety respectively, whereas inactivation of these neurons or S1-innervated LEC neurons abolishes the beneficial effects of tactile enrichment. Moreover, adulthood tactile enrichment attenuates early-life stress-induced memory deficits and anxiety-related behavior. Our findings demonstrate that enriched tactile experience retunes the pathway from S1 to DG and enhances DG neuronal plasticity to modulate cognition and emotion.

P-Coumaric acid ameliorates chronic restraint stress induced memory deficit through BDNF in mice

目的: 探索对香豆酸(p-CA)对慢性束缚应激(CRS)小鼠记忆障碍的作用及其可能机制。方法: 实验分两批进行,第一批小鼠随机分成对照组(Control)、慢性束缚应激＋溶媒组(CRS)和慢性束缚应激+ p-CA组(CRS+ p-CA), 每组8只,其中CRS小鼠每天接受4 h的束缚应激,连续束缚10 d,而对照组小鼠留在笼中不被打扰。第11日小鼠腹腔注射溶媒(10%吐温80)或p-CA(100 mg/kg),注射后2 h进行Y迷宫测试,注射后24 h进行新颖物体识别(NOR)采样,采样后2 h进行新颖物体识别测试。实验结束后断头取脑剥离海马并检测BDNF蛋白表达。第二批小鼠随机分成慢性束缚应激组(CRS) ,慢性束缚应激+ANA-12(原肌球蛋白激酶B拮抗剂)组(CRS+ANA-12),慢性束缚应激+p-CA组(CRS+ p-CA)和慢性束缚应激+p-CA +ANA-12组(CRS+ p-CA +ANA-12),每组8只,四组小鼠每天接受4 h的束缚应激,连续束缚10 d。第11日小鼠腹腔注射溶媒(10%吐温80)或p-CA(100 mg/kg),ANA-12在p-CA注射前30 min给药。注射后2 h进行Y迷宫测试,注射后24 h进行新颖物体识别采样,采样后2 h进行新颖物体识别测试。 结果: ①在实验一中,与Control组相比,CRS组小鼠Y迷宫和NOR测试的记忆显著性降低(P＜0.05),BDNF蛋白表达显著性降低(P＜0.01);而与CRS组相比,CRS+ p-CA组小鼠记忆显著性提高(P＜0.05),BDNF蛋白表达显著提高(P＜ 0.01)。②在实验二中,与CRS组相比,CRS+ p-CA组小鼠Y迷宫和NOR测试中记忆显著提高(P＜0.05);而与CRS+p-CA组相比,CRS+p-CA +ANA-12组小鼠 Y迷宫和NOR测试中记忆显著性降低(P＜0.05)。结论: P-CA可改善CRS诱导的小鼠记忆障碍,这种作用可能依赖于BDNF蛋白表达的上调。.

Jobelyn Attenuates Oxidative Stress and Improves Memory Performance in Mice Exposed to Anoxic Stress.

Chronic stress impairs memory by damaging brain cells via induction of oxidative stress. Hence, the use of agents with antioxidant activity is being investigated as potential drugs against chronic stress-induced memory decline. This study evaluated the effect of Jobelyn® (JB), a potent antioxidant food supplement on memory deficit induced by anoxic stress in mice and on brain levels of biomarkers of oxidative stress. Male mice were distributed into 6 groups (n=6): group 1 (non-stress control) and group 2 (stress control) were a given saline, groups 3-5 received JB (5, 10, 25 and 50 mg/kg) while group 6 had donepezil-DP (1 mg/kg). Thirty minutes later, mice in groups 2-5 were exposed twice to anoxic condition for 15 min in acute anoxic stress. However, in sub-chronic anoxic stress, mice in groups 2-6 were subjected to the same anoxic condition for 15 min twice daily for 5 consecutive days. Thereafter, memory performance was assessed in each case using Y-maze paradigm. The concentrations of biomarkers of oxidative stress (glutathione and malondialdehyde) were only determined in the brains of mice exposed to sub-chronic anoxic stress. Mice exposed to sub-chronic anoxic stress had impaired memory function, which was significantly attenuated by JB. The increased oxidative stress as shown by elevated levels of malondialdehyde and decreased concentrations of glutathione was also reduced by JB. The results of this study suggest that the antioxidant activity of Jobelyn® might be contributing to its ability to attenuate sub-chronic anoxic stress-induced memory deficits in mice.

Protective Effects of Exercise and Insulin Against Stress-Induced Impairment of Spatial Learning

Background: Studies have shown that exercise and insulin can improve cognitive function. However, little is known about the combined effects of insulin and exercise on memory and learning under stress conditions. Objectives: This study was designed to investigate the effects of peripheral insulin injection and/or physical exercise on stress-induced memory deficit. Methods: Adult male Wistar rats (200 - 220 g) received immobilization stress (2 h/d × 7 d), mild-intensity exercise (30 min/d × 7 d), intraperitoneal (i.p.) injection of insulin (1, 6, 12 IU/kg) or saline, insulin-exercise treatment, or no intervention. The animals were assigned on a random basis to 21 experimental groups (N = 10). They were trained and tested in the Morris water maze. Results: Chronic restraint stress impaired spatial performance in the Morris water maze (P < 0.05) and elevated serum corticosterone levels (P < 0.001). Detrimental effects of stress were alleviated by exercise (P < 0.01). The lower dose (1 IU/kg) of insulin protected the animals against the deleterious effects of stress. The combined effects of exercise and insulin (low and moderate doses) prevented stress-induced learning and memory impairment. Conclusions: Insulin and/or exercise can prevent stress-induced memory deficits. The cognitive benefits of exercise continue to evolve after cessation of treatment. Insulin-exercise treatment is as effective as exercise alone and insulin alone for preventing the detrimental effects of stress.

Inhibiting RIP1 Improves Chronic Stress-Induced Cognitive Impairments in D-Galactose-Induced Aging Mice.

Mounting evidence shows that chronic stress can affect both the structure and function of the brain resulting in decreased synaptic plasticity and cognitive dysfunction. Although several studies have indicated that aged brains are more vulnerable to chronic stress, it remains unknown how to prevent stress-induced memory deficits in aged animals. Neuroinflammation plays an important role in the pathogenesis of chronic stress-related brain dysfunction. Receptor-interacting protein 1 (RIP1) is a key molecule that can modulate inflammation, apoptosis, and necroptosis. Here, we investigated whether inhibiting RIP1 using necrostatin-1 during chronic stress could improve chronic stress-related brain dysfunction in D-galactose-induced aging mice. The stressed mice underwent restraint stress for 14 days. Necrostatin-1 (6.25 mg/kg) or vehicle was administered intraperitoneally once every 3 days during the stress period. Locomotor activity was tested using the open field test and cognitive function was assessed using the novel object recognition and Barnes maze tests. The hippocampus was collected to assess neuroinflammation (Iba1, IL-1α, IL-1β, TNF-α, and C1q), necroptosis [RIP1, RIP3, mixed lineage kinase domain-like (MLKL), and NF-κB], neuroplasticity (doublecortin, NR1, NR2A, NR2B, GluA1, and GluA2), and the expression of glucocorticoid and mineralocorticoid receptors. Blood samples were collected to quantify the levels of corticosterone. We found that chronic stress induced obvious memory impairment and neuroinflammation, decreased neurogenesis and GluA2 expression, and increased the expression of RIP1 and NF-κB. Inhibiting RIP1 by necrostatin-1 during chronic stress rescued the memory impairment and alleviated the pathological changes induced by stress. These suggest that inhibiting RIP1 using necrostatin-1 improves chronic stress-related brain dysfunction in D-galactose-induced aging mice. The potential mechanisms include limitation of neuroinflammation and the rescue of neurogenesis and GluA2 expression.

Dorsal CA1 interneurons contribute to acute stress-induced spatial memory deficits

Exposure to severely stressful experiences disrupts the activity of neuronal circuits and impairs declarative memory. GABAergic interneurons coordinate neuronal network activity, but their involvement in stress-evoked memory loss remains to be elucidated. Here, we provide evidence that interneurons in area CA1 of the dorsal hippocampus partially modulate acute stress-induced memory deficits. In adult male mice, both acute forced swim stress and restraint stress impaired hippocampus-dependent spatial memory and increased the density of c-fos-positive interneurons in the dorsal CA1. Selective activation of dorsal CA1 interneurons by chemogenetics disrupted memory performance in the spatial object recognition task. In comparison, anxiety-related behavior, spatial working memory and novel object recognition memory remained intact when dorsal CA1 interneurons were overactivated. Moreover, chemogenetic activation of dorsal CA1 interneurons suppressed the activity of adjacent pyramidal neurons, whereas a single exposure to forced swim stress but not restraint stress increased the activity of CA1 pyramidal neurons. However, chemogenetic inhibition of dorsal CA1 interneurons led to spatial memory impairments and failed to attenuate acute stress-induced memory loss. These findings suggest that acute stress may overactivate interneurons in the dorsal CA1, which reduces the activity of pyramidal neurons and in turn disrupts long-term memory.

Suppressed Calbindin Levels in Hippocampal Excitatory Neurons Mediate Stress-Induced Memory Loss

Calbindin modulates intracellular Ca2+ dynamics andsynaptic plasticity. Reduction of hippocampal calbindin levels has been implicated in early-life stress-related cognitive disorders, but it remains unclear how calbindin in distinct populations of hippocampal neurons contributes to stress-induced memory loss. Here we report that early-life stress suppressed calbindin levels in CA1 and dentate gyrus (DG) neurons, and calbindin knockdown in adult CA1 or DG excitatory neurons mimicked early-life stress-induced memory loss. In contrast, calbindin knockdown in CA1 interneurons preserved long-term memory even after an acute stress challenge. These results indicate that the dysregulation of calbindin in hippocampal excitatory, but not inhibitory, neurons conveys susceptibility to stress-induced memory deficits. Moreover, calbindin levels were downregulated by early-life stress through the corticotropin-releasing hormone receptor 1-nectin3 pathway, which in turn reduced inositol monophosphatase levels. Our findings highlight calbindin as a molecular target of early-life stress and an essential substrate for memory.