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The neurotoxic effects of methamphetamine (METH) include not only neuronal apoptosis and autophagy, but also lead to substance use disorder and have become increasingly prominent. Studies suggest that synaptic plasticity may be the structural basis of METH-induced neurological impairment. Neuroligins are postsynaptic adhesion molecules involved in the regulation of synaptic organization and function. Animal studies have shown that neuroligin (NLG)− 1 is involved in memory formation; however, its role in METH-induced neurotoxicity is not clear. In the present study, we used 1 mM METH in vitro ; mice in the acute and subacute exposure groups received intraperitoneal injections of 30 mg/kg METH (1 injection) or 15 mg/kg METH (8 separate injections at 12-h intervals). We found that the expression of NLG-1, Synapsin-1, and postsynaptic density-95 were increased after METH exposure. We further observed that METH-induced inhibition of long-term potentiation and spatial memory loss could be alleviated when mice were pretreated with NLG-1 small interfering RNA. Therefore, our study provides evidence that NLG-1 is involved in METH-induced hippocampal synaptic plasticity and may be a potential target for the treatment of METH-induced neurotoxicity. • Methamphetamine (METH) increases neuroligin (NLG)− 1 expression in mouse hippocampus. • METH exposure inhibits long-term potentiation and affects spatial memory. • siRNA-mediated knockdown of NLG-1 rescues METH-induced neurotoxicity. • NLG-1 may be a potential therapeutic target in individuals with METH addiction. [ABSTRACT FROM AUTHOR]

The hippocampus is critical for rapid acquisition of many forms of memory, although the circuit-level mechanisms through which the hippocampus rapidly consolidates novel information are unknown. Here, the activity of large ensembles of hippocampal neurons in adult male Long-Evans rats was monitored across a period of rapid spatial learning to assess how the network changes during the initial phases of memory formation and retrieval. In contrast to several reports, the hippocampal network did not display enhanced representation of the goal location via accumulation of place fields or elevated firing rates at the goal. Rather, population activity rates increased globally as a function of experience. These alterations in activity were mirrored in the power of the theta oscillation and in the quality of theta sequences, without preferential encoding of paths to the learned goal location. In contrast, during brief "offline" pauses in movement, representation of a novel goal location emerged rapidly in ripples, preceding other changes in network activity. These data demonstrate that the hippocampal network can facilitate active navigation without enhanced goal representation during periods of active movement, and further indicate that goal representation in hippocampal ripples before movement onset supports subsequent navigation, possibly through activation of downstream cortical networks. [ABSTRACT FROM AUTHOR]

• Altered cage environment affects maternal behaviors and stresses offspring. • Young adult mice that experienced ELA have biased decision making and poor spatial memory. • PSD-95 synapses and dendritic spines are selectively altered in DLS and CA1 radiatum of ELA mice. • An increased number of synapses in DLS of ELA mice correlates with an enhanced habit memory. • Loss of small synapses in CA1 radiatum correlates with damaged spatial memory in ELA mice. The impacts of early-life adversity (ELA) on cognitive functions including striatal-dependent habit memory and hippocampal-dependent spatial memory were investigated in male mice. The ELA mouse model was generated via an altered cage environment with limited nesting and bedding materials during postnatal days 2–9 (P2–9). The altered cage environment affected the nesting behaviors of dams, creating a stressful condition for their offspring. The ELA mice had biased decision making and poor spatial memory when they grew into young adults (4-month-old). To explore the underlying synaptic basis of these effects, excitatory synapses represented by postsynaptic density protein-95 (PSD-95) were immunolabelled on a series of brain sections and stereologically quantified in the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), as well as in area CA1 of the dorsal hippocampus. Increased PSD-95-immunoreactive synapses were observed in DLS but not DMS, whereas selective loss of PSD-95 synapses was detected in the stratum radiatum of area CA1. The spine data supported the selective effects of ELA on PSD-95 synapses. Specifically, both thin and mushroom-type spines were increased in DLS, while loss of thin spines was apparent in CA1 radiatum in ELA mice versus controls. The correlation between PSD-95 synapses and memory performances was further analyzed, and the data suggested that increased small (<0.20 μm3) and large (>0.40 μm3) synapses in DLS might drive ELA mice to make decisions largely relying on habit memory, while loss of small synapses in hippocampal CA1 damage the spatial memory of ELA mice. [ABSTRACT FROM AUTHOR]

Background: Alumina nanoparticles (aluminaNPs), which are widely used in a range of daily and medical fields, have been shown to penetrate blood-brain barrier, and distribute and accumulate in different brain areas. Although oral treatment of aluminaNPs induces hippocampus-dependent learning and memory impairments, characteristic effects and exact mechanisms have not been fully elucidated. Here, male adult rats received a single bilateral infusion of aluminaNPs (10 or 20 µg/kg of body weight) into the hippocampal region, and their behavioral performance and neural function were assessed. Results: The results indicated that the intra-hippocampus infusions at both doses of aluminaNPs did not cause spatial learning inability but memory deficit in the water maze task. This impairment was attributed to the effects of aluminaNP on memory consolidation phase through activation of proBDNF/RhoA pathway. Inhibition of the increased proBDNF by hippocampal infusions of p75NTR antagonist could effectively rescue the memory impairment. Incubation of aluminaNPs exaggerated GluN2B-dependent LTD induction with no effects on LTD expression in hippocampal slices. AluminaNP could also depress the amplitude of NMDA-GluN2B EPSCs. Meanwhile, increased reactive oxygen specie production was reduced by blocking proBDNF-p75NTR pathway in the hippocampal homogenates. Furthermore, the neuronal correlate of memory behavior was drastically weakened in the aluminaNP-infused groups. The dysfunction of synaptic and neuronal could be obviously mitigated by blocking proBDNF receptor p75NTR, implying the involvement of proBDNF signaling in aluminaNP-impaired memory process. Conclusions: Taken together, our findings provide the first evidence that the accumulation of aluminaNPs in the hippocampus exaggeratedly activates proBDNF signaling, which leads to neural and memory impairments. [ABSTRACT FROM AUTHOR]

Introduction:In the present study, the effects of prenatal stress on spatial learning and memory deficit and its relationship with hippocampal insulin resistance were examined in male and female offspring. Methods: Female NMRI mice were mated with males overnight, and the 0-day of pregnancy was detected (Gestational day 0-GD0). The pregnant mice were then randomly divided into stress and control groups. The stress group received stress from the GD0 to GD10. On post natal day 30 (PND30), the offspring were divided into 4 subgroups, namely: male-control, female-control, male-stress, and female-stress. Barnes maze method was used for spatial learning evaluation. Plasma cortisol and insulin levels were measured at the beginning of the experiments. At the end of the experiments, the animals’ brains were removed, and their hippocampus was extracted. The hippocampus was homogenized, and its insulin and insulinreceptor contents were evaluated. Results: The stressed animals needed more time for reaching to target hole. In addition, they spend more distance to find the target hole, which was more pronounced in the male offspring. Both plasma and hippocampal insulin content were reduced in the stressed groups. Moreover, the hippocampal insulin receptors protein was reduced in the stressed animals. There was a positive relationship between plasma and hippocampal content and memory deficit in the stressed groups. Conclusion: These results indicated that prenatal stress could induce spatial learning and memory deficit in offspring, which is associated with plasma and hippocampal insulin and receptor content reduction (hippocampal insulin resistance) in these animals. [ABSTRACT FROM AUTHOR]

Serotonin (5-HT) is an essential neurotransmitter for the refined organization of the cerebral cortex. Studies have suggested that altered serotonin signaling contributes to cognitive impairment and psychiatric disorders. However, the exact role of this neurotransmitter on the development of hippocampal neurons is not recognized. Here we aimed to examine the effects of the para-chlorophenylalanine (PCPA; 100 mg/kg/daily, s.c. during the postnatal days 10-20), a reversible inhibitor of 5-HT synthesis, on the serotonin level of the hippocampal and prefrontal cortex. We also focused on the morphology of the neurons in the hippocampus and spatial learning and memory. Our results indicated that the administration of PCPA led to a decrease in serotonin levels in the hippocampus and prefrontal cortex. Postnatal serotonin depletion also induced subtle alterations in the neuronal populations of the hippocampus and impaired spatial memory in the adulthood period of life. We found that critical developmental periods of serotonin depletion caused degeneration and swelling of neurons as well as significant neuronal loss in the hippocampal CA1, CA3, and dentate gyrus (DG) areas. Thus, serotonin, a strikingly important neurotransmitter, can affect neuronal morphology, development, and hippocampal-dependent memory. [ABSTRACT FROM AUTHOR]

Cholecystokinin-expressing interneurons (CCKIs) are hypothesized to shape pyramidal cell-firing patterns and regulate network oscillations and related network state transitions. To directly probe their role in the CA1 region, we silenced their activity using optogenetic and chemogenetic tools in mice. Opto-tagged CCKIs revealed a heterogeneous population, and their optogenetic silencing triggered wide disinhibitory network changes affecting both pyramidal cells and other interneurons. CCKI silencing enhanced pyramidal cell burst firing and altered the temporal coding of place cells: theta phase precession was disrupted, whereas sequence reactivation was enhanced. Chemogenetic CCKI silencing did not alter the acquisition of spatial reference memories on the Morris water maze but enhanced the recall of contextual fear memories and enabled selective recall when similar environments were tested. This work suggests the key involvement of CCKIs in the control of place-cell temporal coding and the formation of contextual memories. [Display omitted] • CCKI silencing triggers broad disinhibitory network effects and enhances burst firing • CCKIs are involved in theta phase precession-mediated temporal coding • Disruption of theta phase precession did not prevent subsequent sleep replay • CCKI activity regulates the magnitude of contextual fear-memory recall Rangel Guerrero et al. silenced the activity of CA1 Cholecystokinin-expressing interneurons. Optogenetic silencing disrupted the theta oscillation-related temporal coding of place cells during exploration while sleep replay was enhanced. Chemogenetic silencing enhanced the recall of contextual fear memories the next day and enabled the differentiation of similar environments. [ABSTRACT FROM AUTHOR]

• Prenatal BPA exposure at 5 mg/kg/day downregulates the expression of miR-19a and miR-539 which is responsible for regulating the NMDA receptor subunit proteins in the male rat hippocampus. • The downregulation of miR-19a and miR-539 reduces the expression of GRIN2A and GRIN2B genes in the male rat hippocampus. • This results in anxiety-related behavior with impairment in fear and spatial memory when the rats reach adolescence age. • The decrement of GluN2A and GluN2B in the male rat hippocampus unveils the significant impairments in fear and spatial memory. Maternal bisphenol A (BPA) exposure has been reported to cause learning and memory deficits in born offspring. However, little is known that this impairment is potentially caused by epigenetic modulation on the development of NMDA receptor subunits. This study investigates the effect of prenatal BPA exposure on the hippocampal miR-19a and miR-539, which are responsible for regulating NMDA receptor subunits as well as learning and memory functions. Pregnant Sprague Dawley rats were orally administered with 5 mg/kg/day of BPA from pregnancy day 1 (PD1) until gestation day 21 (GD21), while control mothers received no BPA. The mothers were observed daily until GD21 for either a cesarean section or spontaneous delivery. The male offspring were sacrificed when reaching GD21 (fetus), postnatal days 7, 14, 21 (PND7, 14, 21) and adolescent age 35 (AD35) where their hippocampi were dissected from the brain. The expression of targeted miR-19a, miR-539, GRIN2A, and GRIN2B were determined by qRT-PCR while the level of GluN2A and GluN2B were estimated by western blot. At AD35, the rats were assessed with neurobehavioral tests to evaluate their learning and memory function. The findings showed that prenatal BPA exposure at 5 mg/kg/day significantly reduces the expression of miR-19a, miR-539, GRIN2A, and GRIN2B genes in the male rat hippocampus at all ages. The level of GluN2A and GluN2B proteins is also significantly reduced when reaching adolescent age. Consequently, the rats showed spatial and fear memory impairments when reaching AD35. In conclusion, prenatal BPA exposure disrupts the role of miR-19a and miR-539 in regulating the NMDA receptor subunit in the hippocampus which may be one of the causes of memory and learning impairment in adolescent rats. [Display omitted] [ABSTRACT FROM AUTHOR]

This study was designed to investigate the role of growth arrest and DNA damage-inducible β (GADD45B) in modulating fear memory acquisition and elucidate its underlying mechanisms. Adeno-associated virus (AAV) that knockdown or overexpression GADD45B were injected into ventral hippocampal CA1 (vCA1) by stereotactic, and verified by fluorescence and Western blot. The contextual fear conditioning paradigm was employed to examine the involvement of GADD45B in modulating aversive memory acquisition. The Y-maze and novel location recognition (NLR) tests were used to examine non-aversive cognition. The synaptic plasticity and electrophysiological properties of neurons were measured by slice patch clamp. Knockdown of GADD45B in the vCA1 significantly enhanced fear memory acquisition, accompanied by an upregulation of long-term potentiation (LTP) expression and intrinsic excitability of vCA1 pyramidal neurons (PNs). Conversely, overexpression of GADD45B produced the opposite effects. Notably, silencing the activity of vCA1 neurons abolished the impact of GADD45B knockdown on fear memory development. Moreover, mice with vCA1 GADD45B overexpression exhibited impaired spatial cognition, whereas mice with GADD45B knockdown did not display such impairment. These results provided compelling evidence for the crucial involvement of GADD45B in the formation of aversive memory and spatial cognition. [Display omitted] [ABSTRACT FROM AUTHOR]

Studies in ovariectomized (OVX) female rodents suggest that G protein-coupled estrogen receptor (GPER) is a key regulator of memory, yet little is known about its importance to memory in males or the cellular mechanisms underlying its mnemonic effects in either sex. In OVX mice, bilateral infusion of the GPER agonist G-1 into the dorsal hippocampus (DH) enhances object recognition and spatial memory consolidation in a manner dependent on rapid activation of c-Jun N-terminal kinase (JNK) signaling, cofilin phosphorylation, and actin polymerization in the DH. However, the effects of GPER on memory consolidation and DH cell signaling in males are unknown. Thus, the present study first assessed effects of DH infusion of G-1 or the GPER antagonist G-15 on object recognition and spatial memory consolidation in gonadectomized (GDX) male mice. As in OVX mice, immediate post-training bilateral DH infusion of G-1 enhanced, whereas G-15 impaired, memory consolidation in the object recognition and object placement tasks. However, G-1 did not increase levels of phosphorylated JNK (p46, p54) or cofilin in the DH 5, 15, or 30 min after infusion, nor did it affect phosphorylation of ERK (p42, p44), PI3K, or Akt. Levels of phospho-cAMP-responsive element binding protein (CREB) were elevated in the DH 30 min following G-1 infusion, indicating that GPER in males activates a yet unknown signaling mechanism that triggers CREB-mediated gene transcription. Our findings show for the first time that GPER in the DH regulates memory consolidation in males and suggests sex differences in underlying signaling mechanisms. [Display omitted] • GPER agonism enhanced spatial and object recognition memory consolidation in males. • GPER antagonism impaired spatial and object recognition memory formation in males. • Dorsal hippocampal GPER promotes memory formation like in ovariectomized females. • GPER agonism did not activate dorsal hippocampal JNK, cofilin, ERK, PI3K, or Akt. • GPER agonism increased hippocampal CREB phosphorylation 30 min after infusion. [ABSTRACT FROM AUTHOR]

The hippocampal formation is critically involved in learning and memory and contains a large proportion of neurons encoding aspects of the organism's spatial surroundings. In the medial entorhinal cortex (MEC), this includes grid cells with their distinctive hexagonal firing fields as well as a host of other functionally defined cell types including head direction cells, speed cells, border cells, and object-vector cells. Such spatial coding emerges from the processing of external inputs by local microcircuits. However, it remains unclear exactly how local microcircuits and their dynamics within the MEC contribute to spatial discharge patterns. In this review we focus on recent investigations of intrinsic MEC connectivity, which have started to describe and quantify both excitatory and inhibitory wiring in the superficial layers of the MEC. Although the picture is far from complete, it appears that these layers contain robust recurrent connectivity that could sustain the attractor dynamics posited to underlie grid pattern formation. These findings pave the way to a deeper understanding of the mechanisms underlying spatial navigation and memory. [ABSTRACT FROM AUTHOR]

Our previous studies demonstrated that traumatic brain injury (TBI) and ventricular administration of thrombin caused hippocampal neuron loss and cognitive dysfunction via activation of Src family kinases (SFKs). Based on SFK localization in brain, we hypothesized SFK subtypes Fyn and c-Src, as well as SFK downstream molecule Rho-associated protein kinase (ROCK), contribute to cell death and cognitive dysfunction after TBI. We administered nanoparticle wrapped small interfering RNA (siRNA)-Fyn and siRNA-c-Src, or ROCK inhibitor Y-27632 to adult rats subjected to moderate lateral fluid percussion (LFP)–induced TBI. Spatial memory function was assessed from 12 to 16 days, and NeuN stained hippocampal neurons were assessed 16 days after TBI. The combination of siRNA-Fyn and siRNA-c-Src, but neither alone, prevented hippocampal neuron loss and spatial memory deficits after TBI. The ROCK inhibitor Y-27632 also prevented hippocampal neuronal loss and spatial memory deficits after TBI. The data suggest that the combined actions of three kinases (Fyn, c-Src, ROCK) mediate hippocampal neuronal cell death and spatial memory deficits produced by LFP-TBI, and that inhibiting this pathway prevents the TBI-induced cell death and memory deficits. [ABSTRACT FROM AUTHOR]

Background: Dendrobium nobile Lindl. alkaloids (DNLA) are effective in ameliorating cognitive deficit in SAMP8, AβPP/PS1, and LPS-induced AD animal models, and prevented Aβ-induced synaptic degeneration in cultured hippocampal neurons. However, the underlying mechanisms remain unexplored.Objective: This study investigated the protective effects of DNLA on synaptic damage in an Aβ25-35-induced rat AD model, in primary cortical neuron cultures, and in PC12 cells transfected with human AβPP695, focusing on the Wnt/β-catenin pathway.Methods: Sprague-Dawley rats received a single Aβ25-35 injection (10μg) into the bilateral hippocampi. DNLA (40 and 80 mg/kg/d) was intragastrically administrated 7 days prior to Aβ injection and continued for 28 days. The spatial learning and memory, synaptic morphology, synapse-related proteins, and Wnt signaling components GSK3β and β-catenin phosphorylation were evaluated. Rat primary cortical neuron cultures and AβPP695-PC12 cells were used to evaluate axonal mitochondria distribution, reactive oxygen species production, amyloidogenesis, and Wnt pathway in the protection.Results: DNLA ameliorated Aβ-induced cognitive impairment, increased the number of synapses, elevated the postsynaptic density thickness and expression of synapsin and PSD95 in the hippocampus, and suppressed Aβ-mediated GSK3β activity and the β-catenin phosphorylation. In primary neurons and AβPP695-PC12 cells, DNLA restored Aβ25-35 induced mitochondrial dysfunction and inhibited reactive oxygen species production and amyloidogenesis. Furthermore, the Wnt/β-catenin pathway inhibitor Dkk-1 blocked the effect of DNLA on the expression of Aβ1-42 and PSD95.Conclusion: DNLA rescued Aβ-mediated synaptic and mitochondrial injury and inhibited amyloidogenesis in vivo and in vitro, probably through the activation of Wnt/β-catenin signaling pathway to protect synaptic integrity. [ABSTRACT FROM AUTHOR]

A prediabetic population has an increased risk of cognitive decline and type 2 diabetes mellitus (T2DM). This study investigated whether the progression of memory dysfunction and dysregulated brain glycogen metabolism is prevented with 4 mo of exercise intervention from the presymptomatic stage in a T2DM rat model. Memory function and biochemical and molecular profiles were assessed in the presymptomatic stage of Otsuka-Long-Evans-Tokushima fatty (OLETF) rats, a T2DM model, with Long-Evans Tokushima (LETO) rats as genetic control. These rats were subjected to light- or moderate-intensity treadmill running for 4 mo with repetition of the same experiments. Significant hippocampal-dependent memory dysfunction was observed in the presymptomatic stage of OLETF rats, accompanied by downregulated levels of hippocampal monocarboxylate transporter 2 (MCT2), a neuronal lactate-transporter, without alteration in hippocampal glycogen levels. Four months of light or moderate exercise from the presymptomatic stage of T2DM normalized glycemic parameters and hippocampal molecular normalization through MCT2, glycogen, and brain-derived neurotrophic factor (BDNF) levels with the improvement of memory dysfunction in OLETF rats. A 4-mo exercise regimen from the presymptomatic stage of T2DM at a light and moderate intensities contributed to the prevention of the development of T2DM and the progression of cognitive decline with hippocampal lactate-transport and BDNF improvement. [ABSTRACT FROM AUTHOR]

Metabolic syndrome patients are commonly prone to major health problems as cardiovascular diseases, diabetes mellitus, chronic kidney disease, cancer and neuropsychological complications including dementia. This research investigates mechanisms linking metabolic syndrome to cognitive impairment and possible impact of vitamin D supplementation. Forty male Wistar rats were divided into 4 groups. Control, metabolic syndrome (20% fructose solution in drinking water for 12 weeks, vitamin D supplemented (500 IU/kg/day)) and metabolic syndrome supplemented with vitamin D. Animals were assessed for spatial memory, hippocampal expression of SNAP 25, VAMP and mGlut2 receptor and hippocampus histological examination. Animals with metabolic syndrome showed prolonged acquisition and retention latencies in morris water maze, decreased hippocampal expression of SNAP 25 and VAMP and increased mGlut2 expression. Histologically CA1, CA3 regions and dentate nucleus revealed increase in degenerated neurons and glia cells with decreased pyramidal cell layer thickness. Vitamin D supplementation mitigated alterations induced by metabolic syndrome. Metabolic syndrome decreased hippocampal synaptic proteins and altered glutamatergic transmission and increased hippocampal neuronal degeneration. Vitamin D supplementation offered neuroprotective effects. • Neuroprotective effects of vitamin D in metabolic syndrome rat model. • Vitamin D decline mGlut2 receptors in hippocampi of metabolic syndrome rats. • Vitamin D increased SNAP 25 and VAMP in hippocampi of metabolic syndrome rats. • Vitamin D partially corrected structural alterations in different hippocampal regions. • These mechanisms contribute to better cognition observed in metabolic syndrome rats. [ABSTRACT FROM AUTHOR]

David Sherry has been a pioneer in investigating the avian hippocampal formation (HF) and spatial memory. Following on his work and observations that HF is sensitive to the occurrence of reward (food), we were interested in carrying out an exploratory study to investigate possible HF involvement in the representation goal value and risk. Control sham-lesioned and hippocampal-lesioned pigeons were trained in an open field to locate one food bowl containing a constant two food pellets on all trials, and two variable bowls with one containing five pellets on 75% (High Variable) and another on 25% (Low Variable) of their respective trials (High-Variable and Low-Variable bowls were never presented together). One pairing of pigeons learned bowl locations (space); another bowl colors (feature). Trained to color, hippocampal-lesioned pigeons performed as rational agents in their bowl choices and were indistinguishable from the control pigeons, a result consistent with HF regarded as unimportant for non-spatial memory. By contrast, when trained to location, hippocampal-lesioned pigeons differed from the control pigeons. They made more first-choice errors to bowls that never contained food, consistent with a role of HF in spatial memory. Intriguingly, the hippocampal-lesioned pigeons also made fewer first choices to both variable bowls, suggesting that hippocampal lesions resulted in the pigeons becoming more risk averse. Acknowledging that the results are preliminary and further research is needed, the data nonetheless support the general hypothesis that HF-dependent memory representations of space capture properties of reward value and risk, properties that contribute to decision making when confronted with a choice. [ABSTRACT FROM AUTHOR]

[Display omitted] • IL-10 overproduction compromises NSC survival, leading to hippocampal neurogenesis reduction in adulthood. • IL-10 overproduction results in spatial learning and memory impairment. • IL-10 overproduction increases microglial CD200R expression and reduces microglial CX3CR1 expression in the hippocampus. • Effects by IL-10 overproduction resemble those produced by physiological aging. The subgranular zone of the dentate gyrus is an adult neurogenic niche where new neurons are continuously generated. A dramatic hippocampal neurogenesis decline occurs with increasing age, contributing to cognitive deficits. The process of neurogenesis is intimately regulated by the microenvironment, with inflammation being considered a strong negative factor for this process. Thus, we hypothesize that the reduction of new neurons in the aged brain could be attributed to the age-related microenvironmental changes towards a pro-inflammatory status. In this work, we evaluated whether an anti-inflammatory microenvironment could counteract the negative effect of age on promoting new hippocampal neurons. Surprisingly, our results show that transgenic animals chronically overexpressing IL-10 by astrocytes present a decreased hippocampal neurogenesis in adulthood. This results from an impairment in the survival of neural newborn cells without differences in cell proliferation. In parallel, hippocampal-dependent spatial learning and memory processes were affected by IL-10 overproduction as assessed by the Morris water maze test. Microglial cells, which are key players in the neurogenesis process, presented a different phenotype in transgenic animals characterized by high activation together with alterations in receptors involved in neuronal communication, such as CD200R and CX3CR1. Interestingly, the changes described in adult transgenic animals were similar to those observed by the effect of normal aging. Thus, our data suggest that chronic IL-10 overproduction mimics the physiological age-related disruption of the microglia-neuron dialogue, resulting in hippocampal neurogenesis decrease and spatial memory impairment. [ABSTRACT FROM AUTHOR]

The mammalian hippocampal formation contains several distinct populations of neurons involved in representing self-position and orientation. These neurons, which include place, grid, head direction, and boundary cells, are thought to collectively instantiate cognitive maps supporting flexible navigation. However, to flexibly navigate, it is necessary to also maintain internal representations of goal locations, such that goal-directed routes can be planned and executed. Although it has remained unclear how the mammalian brain represents goal locations, multiple neural candidates have recently been uncovered during different phases of navigation. For example, during planning, sequential activation of spatial cells may enable simulation of future routes toward the goal. During travel, modulation of spatial cells by the prospective route, or by distance and direction to the goal, may allow maintenance of route and goal-location information, supporting navigation on an ongoing basis. As the goal is approached, an increased activation of spatial cells may enable the goal location to become distinctly represented within cognitive maps, aiding goal localization. Lastly, after arrival at the goal, sequential activation of spatial cells may represent the just-taken route, enabling route learning and evaluation. Here, we review and synthesize these and other evidence for goal coding in mammalian brains, relate the experimental findings to predictions from computational models, and discuss outstanding questions and future challenges. To flexibly navigate, animals must have knowledge of both their self- and goal locations. Although neural correlates of self-location are well established, less is known about goal coding. Nyberg et al. comprehensively review both theoretical and empirical findings for such computations in the hippocampal formation. [ABSTRACT FROM AUTHOR]

Dopamine is a key factor in the enablement of cognition and hippocampal information processing. Its action in the hippocampus is mediated by D1/D5 and D2-like (D2, D3, D4) receptors. While D1/D5-receptors are well recognized as strong modulators of hippocampal synaptic plasticity and information storage, much less is known about the role of D2-like receptors (D2R) in these processes. Here, we explored to what extent D2R contribute to synaptic plasticity and cumulative spatial memory derived from semantic and episodic-like information storage. In freely behaving adult rats, we also assessed to what extent short and long-term forms of synaptic plasticity are influenced by pharmacological activation or blockade of D2R. Antagonism of D2R by means of intracerebral treatment with remoxipride, completely prevented the expression of both short-term (<1 h) and long-term potentiation (>4 h), as well as the expression of short-term depression (STD, <1 h) in the hippocampal CA1 region. Scrutiny of involvement of D2R in spatial learning revealed that D2R-antagonism prevented retention of a semantic spatial memory task, and also significantly impaired retention of recent spatiotemporal aspects of an episodic-like memory task. Taken together, these findings indicate that D2R are required for bidirectional synaptic plasticity in the hippocampal CA1 region. Furthermore, they are critically involved in enabling cumulative and episodic-like forms of spatial learning. [ABSTRACT FROM AUTHOR]

Following the initial consolidation process, memories can become reactivated by exposure to a reminder of the original learning event. This can lead to the memory becoming destabilized and vulnerable to disruption or other forms of modification. The memory must then undergo the protein‐synthesis dependent process of reconsolidation in order to be retained. However, older and/or stronger memories resist destabilization, but can become labile when reactivated in the presence of salient novelty. We have implicated the neurotransmitter acetylcholine, acting at M1 muscarinic cholinergic receptors (mAChRs) within perirhinal cortex (PRh), in novelty‐induced destabilization of remote object memories. It remains unclear, however, whether mAChRs are involved in destabilization of other forms of memory. We hypothesized that the role of M1 mAChRs previously demonstrated for PRh‐dependent object memory would extend to hippocampus‐dependent spatial memory. Using the object location (OL) task, which relies on the dorsal hippocampus (dHPC), we showed that (a) reactivation‐dependent reconsolidation of OL memories requires protein synthesis within the dHPC; (b) destabilization of relatively weak OL memories depends on M1 mAChR activation within the dHPC; (c) salient novelty during reactivation promotes destabilization of resistant strongly encoded OL memories; (d) novelty‐induced destabilization of strong OL memories requires activation of mAChRs within the dHPC; and (e) M1 mAChR activation within the dHPC in the absence of novelty during memory reactivation mimics the effect of novelty, destabilizing strongly encoded OL memories. These results implicate ACh acting at M1 mAChRs in the destabilization of dHPC‐dependent spatial memories, demonstrating generalizability of this cholinergic function beyond memory for object identity. These findings therefore enhance our understanding of the dynamics of long‐term memory storage and suggest implications for the treatment of human conditions such as Alzheimer's disease and aging, which are characterized by behavioral and mnemonic inflexibility. [ABSTRACT FROM AUTHOR]

[Display omitted] • Long-term postnatal whisker deprivation (WD) was induced in rats across PND3-59. • WD sex-dependently modified anxiety-like behaviors, fear-based and spatial memory. • Density of CA1 and CA3 pyramidal neurons was reduced by WD in young adult rats. • WD sex-dependently altered neuronal dendrite arbor and dendritic spine densities. • WD-induced hippocampal modifications may contribute to the behavioral outcomes. The role of normal sensory inputs in the development of sensory cortices is well known, however, their impacts on the hippocampus, an integrator of sensory modalities with important roles in cognitive functions, has received much less attention. Here, we applied a long-term sensory deprivation paradigm by trimming the rats' whiskers bilaterally, from postnatal day 3 to 59. Female sensory-deprived (SD) rats showed more on-wall rearing and visits to the center of the open-field box, shorter periods of grooming, less defecation and less anxiety-like behaviors in the elevated plus-maze compared to controls, who had their intact whiskers brushed. Passive avoidance memory retention was sex-dependently impaired in the female SD rats. In the radial arm maze, however, reference spatial memory was impaired only in the male SD rats. Nonetheless, working memory errors increased in both sexes of SD rats. Besides depletion of CA1 and CA3 pyramidal neurons in SD rats, Sholl analysis of Golgi-Cox stained neurons revealed that prolonged sensory deprivation has retracted the arborization of CA1 basal dendrites in SD group, while solely female SD rats had diminished CA1 apical dendrites. Sholl analysis of CA3 neurons in SD animals also disclosed significantly more branched apical dendrites in males and basal dendrites in females. Sensory deprivation also led to a considerable spine loss and variation of different spine types in a sex-dependent manner. Our findings suggest that experience-dependent structural plasticity is capable of spreading far beyond the manipulated sensory zones and the inevitable functional alterations can be expressed in a multifactorial sex-dependent manner. [ABSTRACT FROM AUTHOR]

A high-fat diet (HFD) during pregnancy influences the neurodevelopment of progeny, particularly in the hippocampus, a brain region involved in cognitive processes. The hippocampus has high levels of leptin receptors (Ob-R) that participate in synaptic plasticity. This study examined the effect of maternal HFD during gestation on Ob-R expression in the CA1 and CA3 hippocampal regions, and its relationship with spatial learning and memory in the offspring. We used 48 rat pups: 24 from dams fed a balanced diet (BD, 6.2% fat) and 24 from those fed an HFD (42% fat) during pregnancy. We recorded weight gain and food intake in each pup every day beginning on postnatal day 3 (PND 3). Memory acquisition was assessed on PND 28 and memory retention on PND 42 in the Morris water maze (MWM). Then, 12 pups per group were selected randomly and subjected to bioimpedance spectroscopy. The remaining offspring was perfused to determine Ob-R expression levels in the CA1 and CA3 hippocampal regions. Interestingly, HFD pups had significantly higher weight gain, food intake, and fat mass than BD offspring. Interestingly, the HFD group showed poor memory performance, which correlated with changes in the Ob-R expression in both hippocampal regions. These data indicate that maternal exposure to HFD impacts neurodevelopmental and cognitive functions of the offspring. [ABSTRACT FROM AUTHOR]

Objective: While stress reportedly impairs memory, saffron enhances it. This study investigated the therapeutic effects of saffron extract on different memory types, anxiety-like behavior, and expressions of BDNF and TNF-α genes in sub-chronically stressed rats. Methods: Rats were randomly assigned to control, restraint stress (6 h/day/7 days), two 7-days saffron treatments with 30 and 60 mg/kg, and two stress-saffron groups (30 and 60 mg/kg/7 post-stress days). Serum cortisol level and hippocampal BDNF and TNF-α gene expressions were measured. Open field, passive avoidance, novel object recognition, and object location tests were performed to assess anxiety-like behavior and avoidance as well as cognitive and spatial memories, respectively. Results: The low saffron dose in the sub-chronic stressed group led to a significant increase in passive avoidance latency from day 3 onward whereas this effect was observed after 7 days under the high-dose treatment that simultaneously led to a significant decline in serum cortisol level. While the low saffron dose led to a sharp drop in hippocampal TNF-α gene expression, the high dose significantly increased the hippocampal BDNF gene expression in the sub-chronic stress group. Finally, both saffron doses reduced anxiety in the stressed groups. Conclusion: Compared to the low saffron dose, the high dose had a latent but long-lasting impact. Cognitive and spatial memories remained unaffected by either stress or saffron treatment. In addition, only the high saffron dose reversed anxiety in the sub-chronically stressed group. These findings suggest that various doses of saffron act differently on different brain functions under sub-chronic stress conditions. Abbreviations: Brain derived neurotrophic factor (BDNF), tumor necrosis factor-α (TNF-α), hypothalamic–pituitary–adrenal axis (HPA), novel object recognition task (NORT), novel object location task (NOLT), open field test (OFT), passive avoidance (PA). [ABSTRACT FROM AUTHOR]

New neurons are continuously generated and functionally integrated into the dentate gyrus (DG) network during the adult lifespan of most mammals. The hippocampus is a crucial structure for spatial learning and memory, and the addition of new neurons into the DG circuitry of rodents seems to be a key element for these processes to occur. The Morris water maze (MWM) and contextual fear conditioning (CFC) are among the most commonly used hippocampus-dependent behavioral tasks to study episodic-like learning and memory in rodents. While the functional contribution of adult hippocampal neurogenesis (AHN) through these paradigms has been widely addressed, results have generated controversial findings. In this review, we analyze and discuss possible factors in the experimental methods that could explain the inconsistent results among AHN studies; moreover, we provide specific suggestions for the design of more sensitive protocols to assess AHN-mediated learning and memory functions. [ABSTRACT FROM AUTHOR]

Recent epidemiological and intervention studies have suggested that polyphenol-rich plant food consumption reduced the risk of cognitive decline. However, the findings were tentative and by no means definitive. In the present study, we examined the impact of short-term oral administration of cinnamtannin A2 (A2), an (−)-epicatechin tetramer, on adult hippocampal neurogenesis and cognitive function in mice. Mice received supplementation with vehicle (20% glycerol) or 100 μg/kg A2 for 10 days. Then, we conducted the open field test, the object location test, and the novel object test. In the open field test, the A2-treated group tended to spend more time in the center of the arena, compared to the vehicle-treated group. The A2-treated group spent significantly more time exploring objects placed in different locations, compared to the vehicle-treated group. There were no significant differences between groups in the object preference index or in the novel object test. In addition, A2 administration significantly increased the number of hippocampal bromodeoxyuridine-labeled cells in the dentate gyrus, but not in the CA1 or CA3 regions. These results suggested that short-term administration of A2 may impact spatial memory by enhancing neurogenesis in the dentate gyrus of adult mice. [Display omitted] • Ten daily gavage doses of cinnamtannin A2 (A2) increased exploration behavior in mice. • A2 enhanced mouse spatial memory detected with the object location test. • A2 increased BrdU-positive cells in hippocampal dentate gyrus, but not CA1 or CA3. [ABSTRACT FROM AUTHOR]

The hippocampal formation (HF) is well documented as having a feedforward, unidirectional circuit organization termed the trisynaptic pathway. This circuit organization exists along the septotemporal axis of the HF, but the circuit connectivity across septal to temporal regions is less well described. The emergence of viral genetic mapping techniques enhances our ability to determine the detailed complexity of HF circuitry. In earlier work, we mapped a subiculum (SUB) back projection to CA1 prompted by the discovery of theta wave back propagation from the SUB to CA1 and CA3. We reason that this circuitry may represent multiple extended noncanonical pathways involving the subicular complex and hippocampal subregions CA1 and CA3. In the present study, multiple retrograde viral tracing approaches produced robust mapping results, which supports this prediction. We find significant noncanonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1 (vCA1), perirhinal cortex (Prh), and the subicular complex. Thus, CA1 inputs to CA3 run opposite the trisynaptic pathway and in a temporal to septal direction. Our retrograde viral tracing results are confirmed by anterograde-directed viral mapping of projections from input mapped regions to hippocampal dorsal CA3 (dCA3). We find that genetic inactivation of the projection of vCA1 to dCA3 impairs object-related spatial learning and memory but does not modulate anxiety-related behaviors. Our data provide a circuit foundation to explore novel functional roles contributed by these noncanonical hippocampal circuit connections to hippocampal circuit dynamics and learning and memory behaviors. This study reveals extensive non-canonical synaptic inputs to dorsal hippocampal CA3 from ventral CA1, perirhinal cortex and subicular complex, and shows that genetic inactivation of projection from ventral CA1 to dorsal CA3 impairs object-related spatial learning and memory. [ABSTRACT FROM AUTHOR]

Several lines of evidence, including the discovery of place cells, have contributed to the notion that the hippocampus serves primarily to navigate the environment, as a repository of spatial memories, like a drawer full of charts; and that in some species it has exapted on this original one an episodic memory function. We argue that recent evidence questions the primacy of space, and points at memory load, whether spatial or not, as the challenge that mammalian hippocampal circuitry has evolved to meet. • Spatial correlates have been identified for neural activity in several places in the brain. • Hippocampal activity can be seen to be selective for many other variables, besides spatial ones. • Hippocampal involvement is typically needed when the memory load is massive. • The mammalian dentate gyrus appears to be specialized to set up new memories when there are many already. [ABSTRACT FROM AUTHOR]

Background and purpose: The anterior and posterior hippocampal networks represent verbal and spatial memory, respectively, and may play different roles in the pathological mechanism of amnestic mild cognitive impairment (aMCI) and non‐amnestic MCI (naMCI), which has not been explored. Methods: A total of 990 older adults with 791 normal controls (NCs) (65 ± 6 years, 502 women), 140 aMCI (66 ± 7 years, 84 women) and 59 naMCI (66 ± 7 years, 38 women) were included. A multivariate method, partial least squares, was used to assess the structural covariance networks of the anterior hippocampus (aHC) and posterior hippocampus (pHC), and their relationships with verbal memory and spatial memory in the three groups. Results: Three aHC and pHC structural covariance network patterns emerged: (1) the age pattern; (2) the specific aMCI pattern; and (3) the spatial memory pattern. Furthermore, aMCI patients had more extensive and severe damage in the three patterns, and correlated with greater decline in verbal memory, which was mainly characterized by the aHC network. Conclusions: The aMCI and naMCI showed different patterns and damage in the structural covariance networks, and functional segregation of the aHC and pHC networks still exists in the process of pathological aging. A potential neural explanation is provided for the conversion of aMCI and naMCI into different types of dementia in the future. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to investigate whether electroacupuncture (EA) promotes the survival and synaptic plasticity of hippocampal neurons by activating brain‐derived neurotrophic factor (BDNF)/tyrosine receptor kinase (TrkB)/extracellular signal‐regulated kinase (Erk) signaling, thereby improving spatial memory deficits in rats under SD. Methods: In vivo, Morris water maze (MWM) was used to detect the effect of EA on learning and memory, at the same time Western blotting (WB), immunofluorescence (IF), and transmission electron microscopy (TEM) were used to explore the plasticity of hippocampal neurons and synapses, and the expression of BDNF/TrkB/Erk signaling. In vitro, cultured hippocampal neurons were treated with exogenous BDNF and the TrkB inhibitor K252a to confirm the relationship between BDNF/TrkB/Erk signaling and synaptic plasticity. Results: Our results showed that EA mitigated the loss of hippocampal neurons and synapses, stimulated hippocampal neurogenesis, and improved learning and memory of rats under SD accompanied by upregulation of BDNF and increased phosphorylation of TrkB and Erk. In cultured hippocampal neurons, exogenous BDNF enhanced the expression of synaptic proteins, the frequency of the postsynaptic currents, and the phosphorylation of TrkB and Erk; these effects were reversed by treatment with K252a. Conclusions: Electroacupuncture alleviates SD‐induced spatial memory impairment by promoting hippocampal neurogenesis and synaptic plasticity via activation of BDNF/TrkB/Erk signaling, which provided evidence for EA as a therapeutic strategy for countering the adverse effects of SD on cognition. [ABSTRACT FROM AUTHOR]

Cerebrovascular disease such as ischemic stroke develops cognitive impairment due to brain tissue damage including neural loss, demyelination and decrease in synaptic density. In the present study, we developed transient ischemia in the forebrain of the gerbil and found cognitive impairment using the Barnes maze test and passive avoidance test for spatial memory and learning memory, respectively. In addition, neuronal loss/death was detected in the Cornu Ammonis 1 (CA1) region of the gerbil hippocampus after the ischemia by cresyl violet histochemistry, immunohistochemistry for neuronal nuclei and histofluorescence with Fluoro-Jade B. Furthermore, in the CA1 region following ischemia, myelin and vesicular synaptic density were significantly decreased using immunohistochemistry for myelin basic protein and vesicular glutamate transporter 1. In the gerbils, treatment with COG-up® (a combined extract of Erigeron annuus (L.) Pers. and Brassica oleracea Var.), which was rich in scutellarin and sinapic acid, after the ischemia, significantly improved ischemia-induced decline in memory function when compared with that shown in gerbils treated with vehicle after the ischemia. In the CA1 region of these gerbils, COG-up® treatment significantly promoted the remyelination visualized using immunohistochemistry myelin basic protein, increased oligodendrocytes visualized using a receptor-interacting protein, and restored the density of glutamatergic synapses visualized using double immunofluorescence for vesicular glutamate transporter 1 and microtubule-associated protein, although COG-up® treatment did not protect pyramidal cells (principal neurons) located in the CA1 region form the ischemic insult. Considering the current findings, a gerbil model of ischemic stroke apparently showed cognitive impairment accompanied by ischemic injury in the hippocampus; also, COG-up® can be employed for improving cognitive decline following ischemia-reperfusion injury in brains. [ABSTRACT FROM AUTHOR]

Objective: Quercetin is one of the most popular flavonoid with protective effects against neural damages in Parkinson's disease (PD). We assessed the effect of quercetin administration on memory and motor function, hippocampal oxidative stress and brain-derived neurotrophic factor (BDNF) level in a 6-OHDA-induced Parkinson's rat model. Material and Methods: The animals were divided into the following five groups (n=8): control, sham-surgery (sham), lesion (PD), and lesion animals treated with quercetin at doses of 10 (Q10) and 25 (Q25) mg/kg. For induction of a model of PD, 6-OHDA was injected into the striatum of rats. The effects of quercetin were investigated on spatial memory, hippocampal BDNF and malondialdehyde (MDA) levels, and total antioxidant capacity (TAC). Spatial memory was assessed by Morris water maze test, and the neuronal firing frequency in hippocampal dentate gyrus (HDG) was evaluated by single-unit recordings. Results: Mean path length and latency time, rotational behavior and hippocampal MDA concentration were significantly increased, while time spent in the goal quadrant, swimming speed, spike rate, and hippocampal levels of TAC and BDNF were significantly decreased in the PD group compared to the sham group (p<0.01 to p<0.001). Quercetin treatment significantly enhanced time spent in goal quadrant (p<0.05), swimming speed (p<0.001) and spike rate (p<0.01), improved hippocampal TAC (p<0.05 to p<0.001) and BDNF (p<0.01 to p<0.001) level, and decreased mean path length (p<0.001), latency time (p<0.05 to p<0.001), rotational behavior and hippocampal MDA concentration (p<0.05). Conclusion: The cognitive-enhancing effect of quercetin might be due to its antioxidant effects in the hippocampus. [ABSTRACT FROM AUTHOR]

[Display omitted] • Acute administration of TCN impairs the spatial learning and memory of mouse. • The level of hippocampal neuronal loss increases following short term administration of TCN. • Short term administration of TCN exacerbates the level of glial activation in the hippocampus. During the last decades, graphitic carbon nitride (g-C3N4) has attracted increasing attention in several biomedical fields. In this study, the effects of sulfur-doped g-C3N4 (TCN) on cognitive function and histopathology of hippocampus were investigated in mice. The characteristics of synthetized sample were evaluated by X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FT-IR), Raman spectroscopy, transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), and energy dispersive X-ray (EDX). Twenty-four male NMRI mice received vehicle, TCN at doses of 50, 150, or 500 mg/kg via gavage for one week. Morris water maze test was done to assess the cognitive function at day 14 post TCN administration. Nissl staining was used to determine the number of dark cells in the hippocampus. Immunostaining against NeuN, GFAP, and Iba1 was done to evaluate the neuronal density and levels of glial activation, respectively. Behavioral tests indicated that TCN reduces the spatial learning and memory in a dose-dependent manner. Histological evaluations showed an increased level of neuronal loss and glial activation in the hippocampus of TCN treated mice at doses of 150 and 500 mg/kg. Overall, our data indicate that TCN induces the cognitive impairment that is partly mediated via its exacerbating impacts on neuronal loss and glial activation. [ABSTRACT FROM AUTHOR]

Evidence indicates that sharp-wave ripples (SWRs) are primary network events supporting memory processes. However, some studies demonstrate that even after disruption of awake SWRs the animal can still learn spatial task or that SWRs may be not necessary to establish a cognitive map of the environment. Moreover, we have found recently that despite a deficit of sleep SWRs the APP/PS1 mice, a model of Alzheimer's disease, show undisturbed spatial reference memory. Searching for a learning-related alteration of SWRs that could account for the efficiency of memory in these mice we use convolutional neural networks (CNN) to discriminate pre- and post-learning 256 ms samples of LFP signals, containing individual SWRs. We found that the fraction of samples that were correctly recognized by CNN in majority of discrimination sessions was equal to ~ 50% in the wild-type (WT) and only 14% in APP/PS1 mice. Moreover, removing signals generated in a close vicinity of SWRs significantly diminished the number of such highly recognizable samples in the WT but not in APP/PS1 group. These results indicate that in WT animals a large subset of SWRs and signals generated in their proximity may contain learning-related information whereas such information seem to be limited in the AD mice. [ABSTRACT FROM AUTHOR]

In humans and rodents, the entorhinal cortical (EC)‐hippocampal (HPC) circuit is crucial for the formation and recall of memory, preserving both spatial information and temporal information about the occurrence of past events. Both modeling and experimental studies have revealed circuits within this network that play crucial roles in encoding space and context. However, our understanding about the time‐related aspects of memory is just beginning to be understood. In this review, we first describe updates regarding recent anatomical discoveries for the EC‐HPC network, as several important neural circuits critical for memory formation have been discovered by newly developed neural tracing technologies. Second, we examine the complementary roles of multiple medial entorhinal cortical inputs, including newly discovered circuits, into the hippocampus for the temporal and spatial aspects of memory. Finally, we will discuss how temporal and contextual memory information is integrated in HPC cornu ammonis 1 cells. We provide new insights into the neural circuit mechanisms for anatomical and functional segregation and integration of the temporal and spatial aspects of memory encoding in the EC‐HPC networks. [ABSTRACT FROM AUTHOR]

Objective: Methadone is one of the widely used drug substances prescribed in treatment of opioid dependence and pain management; however, several studies have shown its neurotoxic effects on individuals and animal models. The purpose of this study was to assess neuroprotective effects of Coenzyme Q10 (CoQ10) on neurotoxicity induced by methadone in hippocampus of adult NMRI male mice. Materials and Methods: In this experimental study, 48 adult NMRI male mice were randomly divided into 4 groups (n=12 in each) including Methadone, Methadone with sesame oil, Methadone with CoQ10 and saline. The injections of methadone, saline and sesame oil were performed intraperitoneally for 20 days. 24 hours after last injection, half of the animals in each group (n=6) were randomly assessed for evaluating of spatial memory by radial maze. Following behavioral study, animals were sacrificed, and their brains were removed to evaluate pyknotic cells through histological assessment. The remaining were used to study the expression of Arc, Bax, Bcl-2 and Bdnf genes. Results: Results of the present study showed that daily administration of methadone increased the number of pyknotic neurons in the CA1 hippocampus and altered the expression of Bax, Bdnf, Arc and Bcl-2. However, it did not alter spatial memory comparing to saline group. CoQ10 treatment significantly reduced the number of pyknotic cells and expression of Bax, Bdnf, Arc when compared to the vehicle group treated by sesame oil. However, the expression of Bcl-2 significantly increased as a result of CoQ10 treatment. Conclusion: CoQ10 reduced the neuronal damage caused by methadone in the hippocampus CA1. [ABSTRACT FROM AUTHOR]

Increased physical activity has shown positive effects on various hippocampal memory functions through accumulating evidence that physical exercise and higher cardiorespiratory fitness can enhance human performance on nonspatial mnemonic discrimination tasks that rely on hippocampal pattern separation. However, there is less direct evidence of exercise effects on spatial pattern separation in humans, despite evidence for this association in rodent models. We examined the influence of strenuous exercise habits on spatial mnemonic discrimination among 176 young adults. We used a delayed match-/non-match-to-sample (same/different) task to assess pattern separation for spatial locations across varying degrees of similarity. Participants who reported regularly engaging in strenuous exercise three or more times per week performed significantly better than those who reported engaging in strenuous exercise fewer than three times per week, even when pattern separation tasks involved higher spatial similarity. These apparent exercise effects were observed for female, but not male, participants. These findings support likely benefits of strenuous exercise habits for human spatial pattern separation skills, and they suggest a need to explore potential interaction effects of exercise and gender. [ABSTRACT FROM AUTHOR]

• LCN2 is robustly upregulated in the central nervous system during acute and chronic inflammation. • Chronic, but not acute, central LCN2 treatment alters hippocampal cell composition. • Decreased mature neurons, but increased newborn neurons, Microgliosis, Immune cell invasion. • Cellular composition alterations in the hippocampus occur through MC4R-independent pathways. • Mice treated with chronic LCN2 display impaired spatial recognition memory. Lipocalin 2 (LCN2) is a pleiotropic molecule that is induced in the central nervous system (CNS) in several acute and chronic pathologies. The acute induction of LCN2 evolved as a beneficial process, aimed at combating bacterial infection through the sequestration of iron from pathogens, while the role of LCN2 during chronic, non-infectious disease remains unclear, and recent studies suggest that LCN2 is neurotoxic. However, whether LCN2 is sufficient to induce behavioral and cognitive alterations remains unclear. In this paper, we sought to address the role of cerebral LCN2 on cognition in both acute and chronic settings. We demonstrate that LCN2 is robustly induced in the CNS during both acute and chronic inflammatory conditions, including LPS-based sepsis and cancer cachexia. In vivo, LPS challenge results in a global induction of LCN2 in the central nervous system, while cancer cachexia results in a distribution specific to the vasculature. Similar to these in vivo observations, in vitro modeling demonstrated that both glia and cerebral endothelium produce and secrete LCN2 when challenged with LPS, while only cerebral endothelium secrete LCN2 when challenged with cancer-conditioned medium. Chronic, but not short-term, cerebral LCN2 exposure resulted in reduced hippocampal neuron staining intensity, an increase in newborn neurons, microglial activation, and increased CNS immune cell infiltration, while gene set analyses suggested these effects were mediated through melanocortin-4 receptor independent mechanisms. RNA sequencing analyses of primary hippocampal neurons revealed a distinct transcriptome associated with prolonged LCN2 exposure, and ontology analysis was suggestive of altered neurite growth and abnormal spatial learning. Indeed, LCN2-treated hippocampal neurons display blunted neurite processes, and mice exposed to prolonged cerebral LCN2 levels experienced a reduction in spatial reference memory as indicated by Y-maze assessment. These findings implicate LCN2 as a pathologic mediator of cognitive decline in the setting of chronic disease. [ABSTRACT FROM AUTHOR]

The receptive field of a neuron describes the regions of a stimulus space where the neuron is consistently active. Sparse spiking outside of the receptive field is often considered to be noise, rather than a reflection of information processing. Whether this characterization is accurate remains unclear. We therefore contrasted the sparse, temporally isolated spiking of hippocampal CA1 place cells to the consistent, temporally adjacent spiking seen within their spatial receptive fields ("place fields"). We found that isolated spikes, which occur during locomotion, are strongly phase coupled to hippocampal theta oscillations and transiently express coherent nonlocal spatial representations. Further, prefrontal cortical activity is coordinated with and can predict the occurrence of future isolated spiking events. Rather than local noise within the hippocampus, sparse, isolated place cell spiking reflects a coordinated cortical–hippocampal process consistent with the generation of nonlocal scenario representations during active navigation. This study of active navigation shows that, rather than being local noise within the hippocampus, sparse, isolated place cell spiking reflects a coordinated cortical-hippocampal process consistent with the generation of non-local scenario representations. [ABSTRACT FROM AUTHOR]

The hippocampus is known to be involved in source memory across a wide variety of stimuli and source types. Thus, source memory activity in the hippocampus is thought to be domain‐general such that different types of source information are similarly processed in the hippocampus. However, there is some evidence of domain‐specificity for spatial and temporal source information. The current fMRI study aimed to determine whether patterns of activity in the hippocampus differed for two types of visual source information: spatial location and background color. Participants completed three runs of a spatial memory task and three runs of a color memory task. During the study phase, 32 line drawings of common objects and animals were presented to either the left or right of fixation for the spatial memory task or on either a red or green background for the color memory task. During the test phase of both tasks, 48 object word labels were presented in the center of the screen and participants classified the corresponding item as old and previously on the "left"/on a "green" background, old and previously on the "right"/on a "red" background, or "new." Two analysis methods were employed to assess whether hippocampal activity differed between the two source types: a general linear model analysis and a classification‐based searchlight multivoxel pattern analysis (MVPA). The searchlight MVPA revealed that activity associated with spatial memory and color memory could be classified with above‐chance accuracy in a region of the right anterior hippocampus, and a follow‐up analysis revealed that there was a significant effect of memory accuracy. These results indicate that different types of source memory are represented by distinct patterns of activity in the hippocampus. [ABSTRACT FROM AUTHOR]

Previous studies have shown that testosterone attenuates stress-induced mood dysfunction and memory deterioration. However, the exact mechanism is still unknown. This study was conducted to investigate the role of long-term testosterone undecanoate on the behavioral responses in AD induced by AlCl3 + D-galactose administration and the possible alteration of the gene expression level of the Na/K ATPase pump. Adult male mice received AlCl3 in drinking water (10 mg/kg/day) and (D-gal 200 mg/kg/day), subcutaneously for 90 consecutive days, then received a single intramuscular (I.M) injection of castor oil (vehicle) on day 91, while treated groups received a single I.M injection of either low (100 mg/kg/45 days) or high dose (500 mg/kg/45 days) respectively of long-acting testosterone undecanoate on day 91. The time spent in the interaction zone during the open field test, preference index to novel objects in the novel object recognition test, spontaneous alternation percentage (SAP) in Y-maze test, and escape latency time in the Morris water maze test were used to measure the locomotor activity, long-term memory, and spatial memory in mice, respectively. The results showed that testosterone undecanoate treatment improved locomotor activity, improved preference to novel objects, improved spatial memory, and reversed anxiety and depression induced by AlCl3 + D-galactose administration in male mice, suggesting the enhancement of behavioral and memory functions brought by testosterone treatment. Moreover, testosterone undecanoate treatment did alter gene expression levels of Na/K ATPase isoforms in the brain hippocampus. In most cases, altered gene expression was significant and correlated with the observed behavioral changes. Taken together, our findings provide new insight into the effects of long-acting testosterone undecanoate administration on locomotor activity, long-term memory, anxiety, and spatial memory in male mice with Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The hippocampal spatial code's relevance for downstream neuronal populations—particularly its major subcortical output the lateral septum (LS)—is still poorly understood. Here, using calcium imaging combined with unbiased analytical methods, we functionally characterized and compared the spatial tuning of LS GABAergic cells to those of dorsal CA3 and CA1 cells. We identified a significant number of LS cells that are modulated by place, speed, acceleration, and direction, as well as conjunctions of these properties, directly comparable to hippocampal CA1 and CA3 spatially modulated cells. Interestingly, Bayesian decoding of position based on LS spatial cells reflected the animal's location as accurately as decoding using the activity of hippocampal pyramidal cells. A portion of LS cells showed stable spatial codes over the course of multiple days, potentially reflecting long-term episodic memory. The distributions of cells exhibiting these properties formed gradients along the anterior–posterior and dorsal–ventral axes of the LS, directly reflecting the topographical organization of hippocampal inputs to the LS. Finally, we show using transsynaptic tracing that LS neurons receiving CA3 and CA1 excitatory input send projections to the hypothalamus and medial septum, regions that are not targeted directly by principal cells of the dorsal hippocampus. Together, our findings demonstrate that the LS accurately and robustly represents spatial, directional as well as self-motion information and is uniquely positioned to relay this information from the hippocampus to its downstream regions, thus occupying a key position within a distributed spatial memory network. Calcium imaging of neurons in freely behaving mice reveals how the lateral septum, the main output of the hippocampal place cells, effectively represents information about not only location, but also head direction and self-movement, and may be pivotal in sending this information to downstream brain regions. [ABSTRACT FROM AUTHOR]

Pyk2 is a Ca2+-activated non-receptor tyrosine kinase enriched in the forebrain, especially in pyramidal neurons of the hippocampus. Previous reports suggested its role in hippocampal synaptic plasticity and spatial memory but with contradictory findings possibly due to experimental conditions. Here we address this issue and show that novel object location, a simple test of spatial memory induced by a single training session, is altered in Pyk2 KO mice and that re-expression of Pyk2 in the dorsal hippocampus corrects this deficit. Bilateral targeted deletion of Pyk2 in dorsal hippocampus CA1 region also alters novel object location. Long term potentiation (LTP) in CA1 is impaired in Pyk2 KO mice using a high frequency stimulation induction protocol but not with a theta burst protocol, explaining differences between previous reports. The same selective LTP alteration is observed in mice with Pyk2 deletion in dorsal hippocampus CA1 region. Thus, our results establish the role of Pyk2 in specific aspects of spatial memory and synaptic plasticity and show the dependence of the phenotype on the type of experiments used to reveal it. In combination with other studies, we provide evidence for a selective role of non-receptor tyrosine kinases in specific aspects of hippocampal neurons synaptic plasticity. [ABSTRACT FROM AUTHOR]

Episodic memory requires information about objects to be integrated into a spatial framework. Place cells in the hippocampus encode spatial representations of objects that could be generated through signaling from the entorhinal cortex. Projections from lateral (LEC) and medial entorhinal cortex (MEC) to the hippocampus terminate in distal and proximal CA1, respectively. We recorded place cells in distal and proximal CA1 as rats explored an environment that contained objects. Place cells in distal CA1 demonstrated higher measures of spatial tuning, stability, and closer proximity of place fields to objects. Furthermore, remapping to object displacement was modulated by place field proximity to objects in distal, but not proximal CA1. Finally, representations of previous object locations were closer to those locations in distal CA1 than proximal CA1. Our data suggest that in cue‐rich environments, LEC inputs to the hippocampus support spatial representations with higher spatial tuning, closer proximity to objects, and greater stability than those receiving inputs from MEC. This is consistent with functional segregation in the entorhinal–hippocampal circuits underlying object‐place memory. [ABSTRACT FROM AUTHOR]

Cholestasis is a bile flow reduction that is induced following Bile Duct Ligation (BDL). Cholestasis impairs memory and induces apoptosis. Apoptosis consists of two pathways: intrinsic and extrinsic. The intrinsic pathway is modulated by BCL-2 (B cell lymphoma-2) family proteins. BCL-2 (a pro-survival BCL-2 protein) has anti-apoptotic effect, while BAD (BCL-2-associated death) and BAX (BCL-2-associated X), the other members of BCL-2 family have pro-apoptotic effect. Furthermore, TFAM (mitochondrial transcriptional factor A) is involved in transcription and maintenance of mitochondrial DNA and PGC-1α (peroxisome proliferator-activated receptor γ coactivator-1α) is a master regulator of mitochondrial biogenesis. On the other hand, NeuroAid is a Traditional Chinese Medicine with neuroprotective and anti-apoptosis effects. In this study, we evaluated the effect of cholestasis on spatial memory and expression of BCL-2, BAD, BAX, TFAM, and PGC-1α in the hippocampus of rats. Additionally, we assessed the effect of NeuroAid on cholestasis-induced cognitive and genetic alterations. Cholestasis was induced by BDL surgery and NeuroAid was injected intraperitoneal at the dose of 0.4 mg/kg. Furthermore, spatial memory was evaluated using Morris Water Maze (MWM) apparatus. The results showed cholestasis impaired spatial memory, increased the expression of BAD and BAX, decreased the expression of TFAM and PGC-1α, and did not alter the expression of BCL-2. Also, NeuroAid decreased the expression of BAD and BAX and increased the expression of TFAM, PGC-1α, and BCL-2. In conclusion, cholestasis impaired spatial memory and increased the expression of pro-apoptotic genes. Also, cholestasis decreased the expression of TFAM and PGC-1α. Interestingly, NeuroAid restored the effects of cholestasis. [ABSTRACT FROM AUTHOR]

Exposure to cyanuric acid (CA) causes multiple organ failure accompanied by the involvement in kinds of target proteins, which are detectable and play central roles in the CNS. The hippocampus has been identified as a brain area which was especially vulnerable in developmental condition associated with cognitive dysfunction. No studies have examined the effects of CA on hippocampal function after in vitro or in vivo treatment. Here, we aimed to examine hippocampal synaptic function and adverse behavioral effects using a rat model administered CA intraperitoneally or intrahippocampally. We found that infusion of CA induced a depression in the frequency but not the amplitude of spontaneous excitatory postsynaptic currents (sEPSCs), miniature excitatory postsynaptic currents (mEPSCs), or N-methyl-D-aspartate (NMDA)-mediated excitatory postsynaptic currents (EPSCs) of the CA1 neurons in dose-dependent pattern. Both intraperitoneal and intrahippocampal injections of CA suppressed hippocampal LTP from Schaffer collaterals to CA1 regions. Paired-pulse facilitation (PPF), a presynaptic phenomenon, was enhanced while the total and phosphorylated expression of NMDA-GluN1, NMDA-GluN2A, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-GluA1 subunits were comparable between CA-treated and control groups. In Morris water maze test, both groups could effectively learn and retain spatial memory. Our studies provide the first evidence for the neurotoxic effect of CA and the insight into its potential mechanisms. [ABSTRACT FROM AUTHOR]

Just as hippocampal lesions are principally responsible for “temporal lobe” amnesia, lesions affecting the anterior thalamic nuclei seem principally responsible for a similar loss of memory, “diencephalic” amnesia. Compared with the former, the causes of diencephalic amnesia have remained elusive. A potential clue comes from how the two sites are interconnected, as within the hippocampal formation, only the subiculum has direct, reciprocal connections with the anterior thalamic nuclei. We found that both permanent and reversible anterior thalamic nuclei lesions in male rats cause a cessation of subicular spatial signaling, reduce spatial memory performance to chance, but leave hippocampal CA1 place cells largely unaffected. We suggest that a core element of diencephalic amnesia stems from the information loss in hippocampal output regions following anterior thalamic pathology. [ABSTRACT FROM AUTHOR]

Spatial memory in vertebrates requires brain regions homologous to the mammalian hippocampus. Between vertebrate clades, however, these regions are anatomically distinct and appear to produce different spatial patterns of neural activity. We asked whether hippocampal activity is fundamentally different even between distant vertebrates that share a strong dependence on spatial memory. We studied tufted titmice, food-caching birds capable of remembering many concealed food locations. We found mammalian-like neural activity in the titmouse hippocampus, including sharp-wave ripples and anatomically organized place cells. In a nonÐfood-caching bird species, spatial firing was less informative and was exhibited by fewer neurons. These findings suggest that hippocampal circuit mechanisms are similar between birds and mammals, but that the resulting patterns of activity may vary quantitatively with species-specific ethological needs. [ABSTRACT FROM AUTHOR]