Impaired Hippocampus-dependent Memory Research Articles

Neuronal ACE1 knockout disrupts the hippocampal renin angiotensin system leading to memory impairment and vascular loss in normal aging

Angiotensin I converting enzyme (ACE1) maintains blood pressure homeostasis by converting angiotensin I into angiotensin II in the renin-angiotensin system (RAS). ACE1 is expressed in the brain, where an intrinsic RAS regulates complex cognitive functions including learning and memory. ACE1 has been implicated in neurodegenerative disorders including Alzheimer's disease and Parkinson's disease, but the mechanisms remain incompletely understood. Here, we performed single-nucleus RNA sequencing to characterize the expression of RAS genes in the hippocampus and discovered that Ace is mostly expressed in CA1 region excitatory neurons. To gain a deeper understanding of the function of neuronal ACE1, we generated ACE1 conditional knockout (cKO) mice lacking ACE1 expression specifically in hippocampal and cortical excitatory neurons. ACE1 cKO mice exhibited hippocampus-dependent memory impairment in the Morris water maze, y-maze, and fear conditioning tests. Total ACE1 level was significantly reduced in the cortex and hippocampus of ACE1 cKO mice showing that excitatory neurons are the predominant cell type expressing ACE1 in the forebrain. Despite similar reductions in total ACE1 level in both the hippocampus and cortex, the RAS pathway was dysregulated in the hippocampus only. Importantly, ACE1 cKO mice exhibited age-related capillary loss selectively in the hippocampus. Here, we show selective vulnerability of the hippocampal microvasculature and RAS pathway to neuronal ACE1 knockout. Our results provide important insights into the function of ACE1 in the brain and demonstrate a connection between neuronal ACE1 and cerebrovascular function in the hippocampus.

Distinct Disruptions in CA1 and CA3 Place Cell Function in Alzheimer's Disease Mice.

The hippocampus, a critical brain structure for spatial learning and memory, is susceptible to neurodegenerative disorders such as Alzheimer's disease (AD). The APPswe/PSEN1dE9 (APP/PS1) transgenic mouse model is widely used to study the pathology of AD. Although previous research has established AD-associated impairments in hippocampal-dependent learning and memory, the neurophysiological mechanisms underlying these cognitive dysfunctions remain less understood. To address this gap, we investigated the activities of place cells in both CA1 and CA3 hippocampal subregions, which have distinct yet complementary computational roles. Behaviorally, APP/PS1 mice demonstrated impaired spatial recognition memory compared to wild-type (WT) mice in the object location test. Physiologically, place cells in APP/PS1 mice showed deterioration in spatial representation compared to WT. Specifically, CA1 place cells exhibited significant reductions in coherence and spatial information, while CA3 place cells displayed a significant reduction in place field size. Both CA1 and CA3 place cells in APP/PS1 mice also showed significant disruptions in their ability to stably encode the same environment. Furthermore, the burst firing properties of these cells were altered to forms correlated with reduced cognition. Additionally, the theta rhythm was significantly attenuated in CA1 place cells of APP/PS1 mice compared to WT. Our results suggest that distinct alteration in the physiological properties of CA1 and CA3 place cells, coupled with disrupted hippocampal theta rhythm in CA1, may collectively contribute to impaired hippocampal-dependent spatial learning and memory in AD.

GAP43 Located on Corticostriatal Terminals Restrains Novelty-Induced Hyperactivity in Mice.

Growth-associated protein of 43 kDa (GAP43) is a key cytoskeleton-associated component of the presynaptic terminal that facilitates neuroplasticity. Downregulation of GAP43 expression has been associated to various psychiatric conditions in humans and evokes hippocampus-dependent memory impairments in mice. Despite the extensive studies conducted on hippocampal GAP43 in past decades, however, very little is known about its roles in modulating the excitatory versus inhibitory balance in other brain regions. We recently generated conditional knock-out mice in which the Gap43 gene was selectively inactivated in either telencephalic glutamatergic neurons (Gap43fl/fl ;Nex1Cre mice, hereafter Glu-GAP43-/- mice) or forebrain GABAergic neurons (Gap43fl/fl ;Dlx5/6Cre mice, hereafter GABA-GAP43-/- mice). Here, we show that Glu-GAP43-/- but not GABA-GAP43-/- mice of either sex show a striking hyperactive phenotype when exposed to a novel environment. This behavioral alteration of Glu-GAP43-/- mice was linked to a selective activation of dorsal-striatum neurons, as well as to an enhanced corticostriatal glutamatergic transmission and an abrogation of corticostriatal endocannabinoid-mediated long-term depression. In line with these observations, GAP43 was abundantly expressed in corticostriatal glutamatergic terminals of wild-type mice. The novelty-induced hyperactive phenotype of Glu-GAP43-/- mice was abrogated by chemogenetically inhibiting corticostriatal afferences with a Gi-coupled "designer receptor exclusively activated by designer drugs" (DREADDs), thus further supporting that novelty-induced activity is controlled by GAP43 at corticostriatal excitatory projections. Taken together, these findings show an unprecedented regulatory role of GAP43 in the corticostriatal circuitry and provide a new mouse model with a delimited neuronal-circuit alteration for studying novelty-induced hyperactivity, a phenotypic shortfall that occurs in diverse psychiatric diseases.

Sex differences in cholinergic signaling affect functional outcomes for theta-gamma coordination in hippocampal subcircuits following experimental febrile status epilepticus.

Sex determines cognitive outcome in animal models of early life seizure, where males exhibit impaired hippocampal-dependent learning and memory compared with females. The physiological underpinnings of this sex effect are unclear. Cholinergic signaling is essential for the generation of hippocampal oscillations, and supplementation of cholinergic precursors prior to status epilepticus in immature male rats prevents subsequent memory deficits. We hypothesized that there are sex differences in acetylcholine circuits and their response to experimental febrile status epilepticus (eFSE). eFSE was induced in male and female rat pups. We transversed the hippocampus of postnatal day >60 control (CTL) and eFSE rats with a 64-channel laminar silicon probe to assay cholinergic-dependent theta oscillations under urethane anesthesia. Local field potential properties were compared during (1) baseline sensory stimulation, (2) pharmacological stimulation via acetylcholine reuptake blockade, and (3) sensory stimulation after muscarinic acetylcholine receptor block (atropine). In all groups, a baseline tail pinch could elicit theta oscillations via corticohippocampal synaptic input. Following atropine, a tail pinch response could no longer be elicited in CTL male, CTL female, or eFSE female rats. In contrast, induced slow theta power in eFSE males after atropine was not decreased to spontaneous levels. Analysis of oscillation bandwidths revealed sex differences in acetylcholine modulation of theta frequency and slow gamma frequency and power. This study also identified significant effects of both sex and eFSE on baseline theta-gamma comodulation, indicating a loss of coupling in eFSE males and a potential gain of function in eFSE females. There are differences in cholinergic modulation of theta and gamma signal coordination between male and female rats. These differences may underlie worse cognitive outcomes in males following eFSE. Promoting the efficacy of muscarinic acetylcholine signaling prior to or following early life seizures could elucidate a mechanism for the temporal discoordination of neural signals within and between hippocampus and neocortex and provide a novel therapeutic approach for improving cognitive outcomes.

Environmental enrichment and the combined interventions of EE and metformin enhance hippocampal neuron survival and hippocampal-dependent memory in type 2 diabetic rats under stress through the BDNF-TrkB signaling pathways

BackgroundType 2 diabetes (T2D) with depression causes severe cognitive impairments. The devastating conditions will further compromise the overall quality of life. The overconsumption of high-fat and high-sucrose (HFS) diet is one of the modifiable risk factors for T2D, depression, and cognitive impairments. Thus, it is essential to identify effective therapeutic strategies to overcome the cognitive impairments in T2D with depression. We proposed environmental enrichment (EE) which encompasses social, cognitive, and physical components as the alternative treatment for such impairments. We also investigated the potential neuroprotective properties of the antidiabetic drug metformin. This study aimed to investigate the effects of EE and metformin interventions on hippocampal neuronal death, and hippocampal-dependent memory impairment in T2D rats under stress. MethodsThirty-two male rats (200–250 g) were divided into four groups: C group (standard diet + conventional cage), DS group [HFS-induced T2D + restraint stress (RS)], DSE group [HFS-induced T2D + RS + EE] and DSEM group [HFS + RS + EE + metformin]. Serum corticosterone (CORT) was measured to evaluate stress levels. The serum Free Oxygen Radicals Testing (FORT) and Free Oxygen Radicals Defence Test (FORD) were measured to evaluate the systemic oxidative status (OS). Serum brain-derived neurotrophic factor (BDNF) and T-maze tasks were performed to evaluate cognitive functions. Rats were humanely sacrificed to collect brains for histological, morphometric, and hippocampal gene expression studies. ResultsThe CORT and the serum FORT levels in the DSE and DSEM groups were lower than in the DS group. Meanwhile, the serum BDNF, T-maze scores, histological, and morphometric analysis were improved in the DSE and DSEM groups than in the DS group. These findings supported that EE and the combined interventions of EE and metformin had neuroprotective properties. The hippocampal gene expression analysis revealed that the DSE and DSEM groups showed improved regulation of BDNF-TrkB signalling pathways, including the BDNF/TrkB binding, PI3K – Akt pathway, Ras–MAPK pathway, PLCγ–Ca2+ pathway, and CREB transcription. ConclusionEE and the combined interventions of EE and metformin improved hippocampal neuron survival and hippocampal-dependent memory in T2D rats under stress by enhancing gene expression regulation of neurogenesis and synaptic plasticity.

Synergistic suppression of BDNF via epigenetic mechanism deteriorating learning and memory impairment caused by Mn and Pb co-exposure

Microglia, the resident immune cells of the central nervous system (CNS), play a dual role in neurotoxicity by releasing the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome and brain-derived neurotrophic factor (BDNF) in response to environmental stress. Suppression of BDNF is implicated in learning and memory impairment induced by exposure to manganese (Mn) or lead (Pb) individually. Methyl CpG Binding Protein 2 (MeCp2) and its phosphorylation status are related to BDNF suppression. Protein phosphatase2A (PP2A), a member of the serine/threonine phosphatases family, dephosphorylates substrates based on the methylation state of its catalytic C subunit (PP2Ac). However, the specific impairment patterns and molecular mechanisms resulting from co-exposure to Mn and Pb remain unclear. Therefore, the purpose of this study was to explore the effects of Mn and Pb exposure, alone and in combination, on inducing neurotoxicity in the hippocampus of mice and BV2 cells, and to determine whether simultaneous exposure to both metals exacerbate their toxicity. Our findings reveal that co-exposure to Mn and Pb leads to severe learning and memory impairment in mice, which correlates with the accumulation of metals in the hippocampus and synergistic suppression of BDNF. This suppression is accompanied by up-regulation of the epigenetic repressor MeCp2 and its phosphorylation status, as well as demethylation of PP2Ac. Furthermore, inhibition of PP2Ac demethylation using ABL127, an inhibitor for its protein phosphatase methylesterase1 (PME1), or knockdown of MeCp2 via siRNA transfection in vitro effectively increases BDNF expression and mitigates BV2 cell damage induced by Mn and Pb co-exposure. We also observe abnormal activation of microglia characterized by enhanced release of the NLRP3 inflammasome, Casepase-1 and pro-inflammatory cytokines IL-1β, in the hippocampus of mice and BV2 cells. In summary, our experiments demonstrate that simultaneous exposure to Mn and Pb results in more severe hippocampus-dependent learning and memory impairment, which is attributed to epigenetic suppression of BDNF mediated by PP2A regulation.

Insights into the structure and function of the hippocampus: implications for the pathophysiology and treatment of autism spectrum disorder.

The hippocampus is one of the brain areas affected by autism spectrum disorder (ASD). Individuals with ASD typically have impairments in hippocampus-dependent learning, memory, language ability, emotional regulation, and cognitive map creation. However, the pathological changes in the hippocampus that result in these cognitive deficits in ASD are not yet fully understood. In the present review, we will first summarize the hippocampal involvement in individuals with ASD. We will then provide an overview of hippocampal structural and functional abnormalities in genetic, environment-induced, and idiopathic animal models of ASD. Finally, we will discuss some pharmacological and non-pharmacological interventions that show positive impacts on the structure and function of the hippocampus in animal models of ASD. A further comprehension of hippocampal aberrations in ASD might elucidate their influence on the manifestation of this developmental disorder and provide clues for forthcoming diagnostic and therapeutic innovation.

Targeting Nociceptin/Orphanin FQ receptor to rescue cognitive symptoms in a mouse neuroendocrine model of chronic stress.

Chronic stress causes cognitive deficits, such as impairments in episodic-like hippocampus-dependent memory. Stress regulates an opioid-related neuropeptide named Nociceptin/Orphanin FQ (N/OFQ), the ligand of the G protein-coupled receptor NOP. Since this peptide has deleterious effects on memory, we hypothesized that the N/OFQ system could be a mediator of the negative effects of stress on memory. Chronic stress was mimicked by chronic exposure to corticosterone (CORT). The NOP receptor was either acutely blocked using selective antagonists, or knocked-down specifically in the hippocampus using genetic tools. Long-term memory was assessed in the object recognition (OR) and object location (OL) paradigms. Acute injection of NOP antagonists before learning had a negative impact on memory in naive mice whereas it restored memory performances in the chronic stress model. This rescue was associated with a normalization of neuronal cell activity in the CA3 part of the hippocampus. Chronic CORT induced an upregulation of the N/OFQ precursor in the hippocampus. Knock-down of the NOP receptor in the CA3/Dentate Gyrus region prevented memory deficits in the CORT model. These data demonstrate that blocking the N/OFQ system can be beneficial for long-term memory in a neuroendocrine model of chronic stress. We therefore suggest that NOP antagonists could be useful for the treatment of memory deficits in stress-related disorders.

Neuronal TIMP2 regulates hippocampus-dependent plasticity and extracellular matrix complexity

Functional output of the hippocampus, a brain region subserving memory function, depends on highly orchestrated cellular and molecular processes that regulate synaptic plasticity throughout life. The structural requirements of such plasticity and molecular events involved in this regulation are poorly understood. Specific molecules, including tissue inhibitor of metalloproteinases-2 (TIMP2) have been implicated in plasticity processes in the hippocampus, a role that decreases with brain aging as expression is lost. Here, we report that TIMP2 is highly expressed by neurons within the hippocampus and its loss drives changes in cellular programs related to adult neurogenesis and dendritic spine turnover with corresponding impairments in hippocampus-dependent memory. Consistent with the accumulation of extracellular matrix (ECM) in the hippocampus we observe with aging, we find that TIMP2 acts to reduce accumulation of ECM around synapses in the hippocampus. Moreover, its deletion results in hindrance of newborn neuron migration through a denser ECM network. A novel conditional TIMP2 knockout (KO) model reveals that neuronal TIMP2 regulates adult neurogenesis, accumulation of ECM, and ultimately hippocampus-dependent memory. Our results define a mechanism whereby hippocampus-dependent function is regulated by TIMP2 and its interactions with the ECM to regulate diverse processes associated with synaptic plasticity.

Enhancement of hippocampal-dependent spatial memory by Ashwagandha (Withania somnifera) characterized by activation of NMDA receptors against monosodium glutamate-induced neurotoxicity in rats

Background and Aim Monosodium glutamate (MSG) is used in food-additives, and the Food and Drug Administration has placed it under intense scrutiny following several reports that it causes glutamate neurotoxicity. Ashwagandha (ASH) roots are traditionally used for memory enhancement. This study aimed to evaluate the nootropic activity of ASH as well as its therapeutic anti-amnesic activity against MSG-induced hippocampal-dependent spatial memory impairment and hippocampal-NMDAR modulation. Method A total of 36 rats were divided equally into six groups (n = 6 in each group); the rats in the normal and negative groups were administered daily doses of normal saline and MSG (300 mg/kg), respectively, for 21 days. Two nootropic groups were administered ASH at 300 and 500 mg/kg o.p., respectively, for 21 days. Two other treatment groups were administered daily doses of MSG 300 mg/kg o.p. as well as 300 mg/kg and 500 mg/kg o.p. of ASH for 21 days. The rats’ spatial memory was assessed for five days using the MWM. Additionally, NMDAR were measured quantitatively by immunohistochemistry. Results We found that the rats in the nootropic groups showed significantly enhanced nootropic activity characterized by improved hippocampal-dependent spatial memory, as well as increases in the level of NMDAR in the Cornu Ammonis 1 region of their hippocampus. Moreover, we elucidated the therapeutic potential of ASH to protect against the depression of spatial memory caused by MSG-induced neurotoxicity. Conclusion Further, we elucidated a strong correlation between NMDAR-positive cells in the hippocampus and enhancement of spatial learning induced by long-term administration of ASH as well as a strong correlation between NMDAR positive cells in the hippocampus and depression of spatial learning induced by long-term administration of ASH and MSG.

Modulatory role of α-MSH in hippocampal-dependent memory impairment, synaptic plasticity changes, oxidative stress, and astrocyte reactivity induced by short-term high-fat diet intake

High-fat diet (HFD) consumption is associated with cognitive deficits and neurodegenerative diseases. Since the hippocampus is extremely sensitive to pathophysiological changes, neuroinflammation and the concomitant oxidative stress induced by HFD can significantly interfere with hippocampal-dependent functions related to learning and memory.The neuropeptide alpha-melanocyte stimulating hormone (α-MSH) mediates neuroprotective actions in the central nervous system and can reverse the effects of neuroinflammation in cognitive functions that depend on the hippocampus.In this study, we used male Wistar rats to evaluate the effect of short-term HFD intake (5 days) plus a mild immune challenge, Lipopolysaccharide (LPS 10 μg/kg) on contextual fear, changes in structural plasticity, oxidative stress, and astrocyte reactivation in the hippocampus. We also determined the possible modulatory role of α-MSH. HFD consumption was associated with an increase in markers of oxidative stress (Advanced oxidation protein products and Malondialdehyde) in the dorsal hippocampus (DH). We also found changes in hippocampal structural synaptic plasticity, observing a decrease in total spine in the DH after HFD plus LPS. We observed astrocyte proliferation and a significant increase in the percentage of the area occupied by GFAP. Treatment with α-MSH (0.1 μg/0.25 μl) in the DH reversed the effect of short-term HFD plus LPS on contextual fear memory, oxidative stress, and spine density. α-MSH also reduced astrocyte proliferation.Our present results indicate that HFD consumption for a short period sensitizes the central nervous system (CNS) to a subsequent immune challenge and impairs contextual fear memory and that α-MSH could have a modulatory protective effect.

The mRNA translation initiation factor eIF4G1 controls mitochondrial oxidative phosphorylation, axonal morphogenesis, and memory

mRNA translation initiation plays a critical role in learning and memory. The eIF4F complex, composed of the cap-binding protein eIF4E, ATP-dependent RNA helicase eIF4A, and scaffolding protein eIF4G, is a pivotal factor in the mRNA translation initiation process. eIF4G1, the major paralogue of the three eIF4G family members, is indispensable for development, but its function in learning and memory is unknown. To study the role of eIF4G1 in cognition, we used an eIF4G1 haploinsufficient (eIF4G1-1D) mouse model. The axonal arborization of eIF4G1-1D primary hippocampal neurons was significantly disrupted, and the mice displayed impairment in hippocampus-dependent learning and memory. Translatome analysis showed that the translation of mRNAs encoding proteins of the mitochondrial oxidative phosphorylation (OXPHOS) system was decreased in the eIF4G1-1D brain, and OXPHOS was decreased in eIF4G1-silenced cells. Thus, eIF4G1-mediated mRNA translation is crucial for optimal cognitive function, which is dependent on OXPHOS and neuronal morphogenesis.

Reciprocal interaction between mitochondrial fission and mitophagy in postoperative delayed neurocognitive recovery in aged rats.

Emerging evidence suggests that mitochondrial dysfunction plays a crucial role in the pathogenesis of postoperative delayed neurocognitive recovery (dNCR). Mitochondria exist in a dynamic equilibrium that involves fission and fusion to regulate morphology and maintains normal cell function via the removal of damaged mitochondria through mitophagy. Nonetheless, the relationship between mitochondrial morphology and mitophagy, and how they influence mitochondrial function in the development of postoperative dNCR, remains poorly understood. Here, we observed morphological alterations of mitochondria and mitophagy activity in hippocampal neurons and assessed the involvement of their interaction in dNCR following general anesthesia and surgical stress in aged rats. Firstly, we evaluated the spatial learning and memory ability of the aged rats after anesthesia/surgery. Hippocampal mitochondrial function and mitochondrial morphology were detected. Afterwards, mitochondrial fission was inhibited by Mdivi-1 and siDrp1 in vivo and in vitro separately. We then detected mitophagy and mitochondrial function. Finally, we used rapamycin to activate mitophagy and observed mitochondrial morphology and mitochondrial function. Surgery impaired hippocampal-dependent spatial learning and memory ability and caused mitochondrial dysfunction. It also increased mitochondrial fission and inhibited mitophagy in hippocampal neurons. Mdivi-1 improved mitophagy and learning and memory ability of aged rats by inhibiting mitochondrial fission. Knocking down Drp1 by siDrp1 also improved mitophagy and mitochondrial function. Meanwhile, rapamycin inhibited excessive mitochondrial fission and improved mitochondrial function. Surgery simultaneously increases mitochondrial fission and inhibits mitophagy activity. Mechanistically, mitochondrial fission/fusion and mitophagy activity interact reciprocally with each other and are both involved in postoperative dNCR. These mitochondrial events after surgical stress may provide novel targets and modalities for therapeutic intervention in postoperative dNCR.

High-fat-sugar diet is associated with impaired hippocampus-dependent memory in humans

Overconsumption of high-fat and high-sugar (HFS) diet may affect the hippocampus, and consequently, memory functions. Yet, converging evidence is needed to demonstrate that the type of memory affected by HFS diet consumption is indeed hippocampus dependent. Moreover, the extent to which HFS diet can also affect executive functioning, and indirectly affect memory requires further examination. In this online study, we asked 349 young adults to report their HFS diet consumption and complete a word memory task, the Everyday Memory Questionnaire, and importantly two memory tasks that have been shown to robustly engage the hippocampus, i.e., the Pattern Separation and Associative Memory Tasks. Participants also completed two executive functioning tasks, the Trail Making Task (TMT) and the Stroop Task. These measures assess attention/cognitive flexibility and the ability to inhibit cognitive interference, respectively. After controlling for confounding variables, we found that participants who reported higher level consumption of a HFS diet performed worse on the Pattern Separation Task and that higher HFS intake was significantly associated with poorer TMT task performance and longer Stroop average reaction time (RT). TMT and Stroop RT scores indicative of reduced executive function also partially mediated the relationship between HFS diet and memory performance on the pattern separation task. Taken together, our results provide converging evidence that HFS diet may impair hippocampus-dependent memory. HFS diet may also affect executive functioning and indirectly impair memory function. The findings are consistent with human subject and animal studies and call for further investigations on the psychological and neural mechanisms underlying the dietary effects on cognitive processes.

Sexual Dimorphism in the Closure of the Hippocampal Postnatal Critical Period of Synaptic Plasticity after Intrauterine Growth Restriction: Link to Oligodendrocyte and Glial Dysregulation

Intrauterine growth restriction (IUGR) resulting from hypertensive disease of pregnancy (HDP) leads to sexually dimorphic hippocampal-dependent cognitive and memory impairment in humans. In our translationally relevant mouse model of IUGR incited by HDP, we have previously shown that the synaptic development in the dorsal hippocampus including GABAergic development, NPTX2⁺ excitatory synaptic formation, axonal myelination, and perineural net (PNN) formation were perturbed by IUGR at adolescent equivalence in humans (P40). The persistence of these disturbances through early adulthood and the potential upstream mechanisms are currently unknown. Thus, we hypothesized that NPTX2⁺ expression, PNN formation, axonal myelination, all events closing synaptic development in the hippocampus, will be persistently perturbed, particularly affecting IUGR female mice through P60 given the fact that they had worse short-term recognition memory in this model. We additionally hypothesized that such sexual dimorphism is linked to persistent glial dysregulation. We induced IUGR by a micro-osmotic pump infusion of a potent vasoconstrictor U-46619, a thromboxane A₂-analog, in the last week of the C57BL/6 mouse gestation to precipitate HDP. Sham-operated mice were used as controls. At P60, we assessed hippocampal and hemispheric volumes, NPTX2 expression, PNN formation, as well as myelin basic protein (MBP), Olig2, APC/CC1, and M-NF expression. We also evaluated P60 astrocytic (GFAP) reactivity and microglial (Iba1 and TMEM119) activation using immunofluorescent-immunohistochemistry and Imaris morphological analysis plus cytokine profiling using Meso Scale Discovery platform. IUGR offspring continued to have smaller hippocampal volumes at P60 not related to changes in hemisphere volume. NPTX2⁺ puncta counts and volumes were decreased in IUGR hippocampal CA subregions of female mice compared to sex-matched shams. Intriguingly, NPTX2⁺ counts and volumes were concurrently increased in the dentate gyrus (DG) subregion. PNN volumes were smaller in CA1 and CA3 of IUGR female mice along with PNN intensity in CA3 but they had larger volumes in the CA3 of IUGR male mice. The myelinated axon (MBP⁺) areas, volumes, and lengths were all decreased in the CA1 of IUGR female mice compared to sex-matched shams, which correlated with a decrease in Olig2 nuclear expression. No decrease in the number of APC/CC1⁺ mature oligodendrocytes was identified. We noted an increase in M-NF expression in the mossy fibers connecting DG to CA3 only in IUGR female mice. Reactive astrocytes denoted by GFAP areas, volumes, lengths, and numbers of branching were increased in IUGR female CA1 but not in IUGR male CA3 compared to sex-matched shams. Lastly, activated microglia were only detected in IUGR female CA1 and CA3 subregions. We detected no difference in the cytokine profile between sham and IUGR adult mice of either sex. Collectively, our data support a sexually dimorphic impaired closure of postnatal critical period of synaptic plasticity in the hippocampus of young adult IUGR mice with greater effects on females. A potential mechanism supporting such dimorphism may include oligodendrocyte dysfunction in IUGR females limiting myelination, allowing axonal overgrowth followed by a reactive glial-mediated synaptic pruning.

Lycopene ameliorates atrazine-induced spatial learning and memory impairments by inhibiting ferroptosis in the hippocampus of mice.

Atrazine (ATR) is a commercially available herbicide that is used worldwide. The intensive use of ATR poses potential risks to animals' and humans' health. Lycopene (LYC) is an anti-oxidative phytochemical that normalizes health hazards triggered by environmental factors. In this study, we aimed to investigate the toxic effects of ATR on the hippocampus and its amelioration by LYC. Male mice were exposed to ATR (50mg/kg/day or 200mg/kg/d) and/or LYC (5mg/kg/d) for 21 days. The results showed that ATR exposure induced hippocampus-dependent learning and memory impairments. ATR-induced ferroptosis in hippocampal cells affects the homeostasis of lipid metabolism, whereas LYC ameliorates the neurotoxic effects of ATR in the hippocampus. LYC inhibited ATR-induced ferroptosis by increasing the expression of HO-1, Nrf2 and SLC7A11. Therefore, this study established that LYC ameliorates ATR-induced spatial learning and memory impairments by inhibiting ferroptosis in the hippocampus and also provides a novel approach for the treatment in contradiction of environmental pollutants.

Environmental Enrichment and Metformin Improve Metabolic Functions, Hippocampal Neuron Survival, and Hippocampal-Dependent Memory in High-Fat/High-Sucrose Diet-Induced Type 2 Diabetic Rats

Background: The Western-style diet-induced type 2 diabetes mellitus (T2D) may eventually trigger neurodegeneration and memory impairment. Thus, it is essential to identify effective therapeutic strategies to overcome T2D complications. This study aimed to investigate the effects of environmental enrichment (EE) and metformin interventions on metabolic dysfunctions, hippocampal neuronal death, and hippocampal-dependent memory impairments in high-fat/high-sucrose (HFS) diet-induced T2D rats. Methods: Thirty-two male rats (200-250 g) were divided into four groups: C group (standard diet + conventional cage); D group (HFS diet + conventional cage); DE group (HFS diet + EE cage/6hr daily); and DM group (HFS diet + metformin + conventional cage). Body weight was measured every week. T-maze tasks, anthropometric, biochemical, histological, and morphometric parameters were measured. The expression changes of hippocampal genes were also analyzed. Results: The anthropometric and biochemical parameters were improved in DE and DM groups compared with the D group. DE and DM groups had significantly higher T-maze percentages than the D group. These groups also had better histological and morphometric parameters than the D group. The interventions of EE and metformin enhanced the expression of hippocampal genes related to neurogenesis and synaptic plasticity (BDNF/TrkB binding, PI3K-Akt, Ras-MAPK, PLCγ-Ca2+, and LTP). Conclusion: Environmental enrichment (EE) and metformin improved metabolic functions, hippocampal neuron survival, and hippocampal-dependent memory in HFS diet-induced T2D rats. The underlying mechanisms of these interventions involved the expression of genes that regulate neurogenesis and synaptic plasticity.

Aberrant survival of hippocampal Cajal-Retzius cells leads to memory deficits, gamma rhythmopathies and susceptibility to seizures in adult mice

Cajal-Retzius cells (CRs) are transient neurons, disappearing almost completely in the postnatal neocortex by programmed cell death (PCD), with a percentage surviving up to adulthood in the hippocampus. Here, we evaluate CR’s role in the establishment of adult neuronal and cognitive function using a mouse model preventing Bax-dependent PCD. CRs abnormal survival resulted in impairment of hippocampus-dependent memory, associated in vivo with attenuated theta oscillations and enhanced gamma activity in the dorsal CA1. At the cellular level, we observed transient changes in the number of NPY+ cells and altered CA1 pyramidal cell spine density. At the synaptic level, these changes translated into enhanced inhibitory currents in hippocampal pyramidal cells. Finally, adult mutants displayed an increased susceptibility to lethal tonic-clonic seizures in a kainate model of epilepsy. Our data reveal that aberrant survival of a small proportion of postnatal hippocampal CRs results in cognitive deficits and epilepsy-prone phenotypes in adulthood.

MiR-181a-5p promotes neural stem cell proliferation and enhances the learning and memory of aged mice.

Hippocampal neural stem cell (NSC) proliferation is known to decline with age, which is closely linked to learning and memory impairments. In the current study, we found that the expression level of miR-181a-5p was decreased in the hippocampal NSCs of aged mice and that exogenous overexpression of miR-181a-5p promoted NSC proliferation without affecting NSC differentiation into neurons and astrocytes. The mechanistic study revealed that phosphatase and tensin homolog (PTEN), a negative regulator of the AKT signaling pathway, was the target of miR-181a-5p and knockdown of PTEN could rescue the impairment of NSC proliferation caused by low miR-181a-5p levels. Moreover, overexpression of miR-181a-5p in the dentate gyrus enhanced the proliferation of NSCs and ameliorated learning and memory impairments in aged mice. Taken together, our findings indicated that miR-181a-5p played a functional role in NSC proliferation and aging-related, hippocampus-dependent learning and memory impairments.

Neonatal inflammation increases hippocampal KCC2 expression through methylation-mediated TGF-β1 downregulation leading to impaired hippocampal cognitive function and synaptic plasticity in adult mice

The mechanisms by which neonatal inflammation leads to cognitive deficits in adulthood remain poorly understood. Inhibitory GABAergic synaptic transmission plays a vital role in controlling learning, memory and synaptic plasticity. Since early-life inflammation has been reported to adversely affect the GABAergic synaptic transmission, the aim of this study was to investigate whether and how neonatal inflammation affects GABAergic synaptic transmission resulting in cognitive impairment. Neonatal mice received a daily subcutaneous injection of lipopolysaccharide (LPS, 50 μg/kg) or saline on postnatal days 3–5. It was found that blocking GABAergic synaptic transmission reversed the deficit in hippocampus-dependent memory or the induction failure of long-term potentiation in the dorsal CA1 in adult LPS mice. An increase of mIPSCs amplitude was further detected in adult LPS mice indicative of postsynaptic potentiation of GABAergic transmission. Additionally, neonatal LPS resulted in the increased expression and function of K+–Cl−-cotransporter 2 (KCC2) and the decreased expression of transforming growth factor-beta 1 (TGF-β1) in the dorsal CA1 during adulthood. The local TGF-β1 overexpression improved KCC2 expression and function, synaptic plasticity and memory of adult LPS mice. Adult LPS mice show hypermethylation of TGFb1 promoter and negatively correlate with reduced TGF-β1 transcripts. 5-Aza-deoxycytidine restored the changes in TGFb1 promoter methylation and TGF-β1 expression. Altogether, the results suggest that hypermethylation-induced reduction of TGF-β1 leads to enhanced GABAergic synaptic inhibition through increased KCC2 expression, which is a underlying mechanism of neonatal inflammation-induced hippocampus-dependent memory impairment in adult mice.