Increasing evidence shows the close relationship between hippocampal glutamatergic and serotonergic systems through the modulation of behavioral responses. This study aimed to investigate the possible involvement of 5-HT4 receptors in the CA3 hippocampal region in anxiolytic-like effects induced by D-AP5 (a competitive antagonist of the glutamate NMDA [N-Methyl-D-aspartate] receptor). Male Wistar rats were placed in the elevated plus maze (EPM) apparatus that is used to assess anxiety-related behaviors, and the percentages of open arm time (%OAT) and open arm entries (%OAE) which are associated with anxiety-related behaviors were measured. The close arm entries (CAE) which is correlated with locomotor activity was also evaluated. The results showed that, intra-CA3 injection of D-AP5 (0.4 μg/rat), RS67333 (1.2 μg/rat; a 5-HT4 receptor agonist), and RS23597-190 (1.2 μg/rat; a 5-HT4 receptor antagonist) increased %OAT and %OAE, indicating the anxiolytic-like effect of these drugs. Also, only RS23597-190 (1.2 μg/rat) decreased CAE. Intra-CA3 injection of sub-threshold dose of RS67333 (0.012 μg/rat) or RS23597-190 (0.012 μg/rat), 5 min before the injection of D-AP5 (0.2 μg/rat) increased %OAT, indicating potentiating the anxiolytic-like effect of D-AP5. The isobolographic analyses also showed the additive or synergistic anxiolytic-like effect of intra-CA3 co-administration of D-AP5 with RS67333 or RS23597-190, respectively. In conclusion, CA3 5-HT4 receptors are involved in D-AP5-induced anxiolytic-like behaviors in rats.

Chronic traumatic encephalopathy (CTE) is a progressive neurodegenerative condition caused by repetitive mild traumatic brain injury (TBI) that leads to impaired executive functioning, emotional disturbances, and disordered memory, warranting both basic and translational research of potential therapeutic targets. One area of research concerns prophylactic zinc (Zn) supplementation; however, Zn supplementation remains poorly understood. This study explored the effects of Zn supplementation in a mouse model of repetitive mild TBI. Four-week-old male (n = 50) and female (n = 50) C57BL/6J mice consumed tap water or 10 parts per million Zn-supplemented water for eight weeks prior to injury. At 12 weeks of age, mice underwent either five sham procedures or five closed-head injuries spaced apart by 48 h after which they completed behavioral tests. Zinc-supplemented injured mice righted themselves and regained normal ambulatory function as fast as non-injured mice across four out of the five injury days. In contrast, non-supplemented injured mice exhibited impairment in normal ambulation by days 4 and 5. Injury also reduced free, ionic Zn in the dentate gyrus and CA3 region of the hippocampus and Zn supplementation partially remediated this reduction but not to the levels of non-injured mice. There were no structural differences in cortex, hippocampus, striatum, and corpus callosum, suggesting that Zn reduction was not due to macroscopic abnormalities. Overall, these results suggest that Zn may improve short-term and physical neurological recovery, but it may not be sufficient as a single pre-treatment for consequences of repetitive mild TBI such as cognitive impairment. These results further demonstrate the need for additional research documenting the underlying mechanisms of Zn in TBI-related neuropathology.

A unique feature of the space radiation environment is the presence of high-energy charged particles, including (56)Fe ions, which can present a significant hazard to space flight crews during and following a mission. (56)Fe irradiation-induced cognitive changes often involve alterations in hippocampal function. These alterations might involve changes in spine morphology and density. In addition to irradiation, performing a cognitive task can also affect spine morphology. Therefore, it is often hard to determine whether changes in spine morphology and density are due to an environmental challenge or group differences in performance on cognitive tests. In this study, we tested the hypothesis that the ability of exploratory behavior to increase specific measures of hippocampal spine morphology and density is affected by (56)Fe irradiation. In sham-irradiated mice, exploratory behavior increased basal spine density in the CA1 region of the hippocampus and the enclosed blade of the dentate gyrus. These effects were not seen in irradiated mice. In addition, following exploratory behavior, there was a trend toward a decrease in the percent stubby spines on apical dendrites in the CA3 region of the hippocampus in (56)Fe-irradiated, but not sham-irradiated, mice. Other hippocampal regions and spine measures affected by (56)Fe irradiation showed comparable radiation effects in behaviorally naïve and cognitively tested mice. Thus, the ability of exploratory behavior to alter spine density and morphology in specific hippocampal regions is affected by (56)Fe irradiation.

Both epidemiologic and laboratory studies suggest that parents can shape their offspring's development. Recently, it has been shown that maternal exercise during pregnancy benefits the progeny's brain function. However, little is known regarding the influence of paternal exercise on their offspring's phenotype. In this study we attempt to determine the effects of 6 weeks paternal treadmill exercise on spatial learning and memory and the expression of brain-derived neurotrophic factor (BDNF) and reelin in their male offspring. Sibling males were divided into two groups: the control (C) and the exercise group (E). The mice in the E group were exercised on a motor-driven rodent treadmill for 5 days per week for 6 weeks. After 6 weeks of exercise, the male mouse was mated with its sibling female. After weaning, male pups underwent behavioral assessment (Open field and Morris water maze tests). Immunohistochemistry staining, real time-PCR and western blot were performed to determine hippocampal BDNF and reelin expression of the male pups after behavior tasks. Our results showed that paternal treadmill exercise improved the spatial learning and memory capability of male pups, which was accompanied by significantly increased expression of BDNF and reelin, as compared to those of C group. Our results provide novel evidence that paternal treadmill exercise can enhance the brain functions of their F1 male offspring.

The lateral mammillary nuclei are a central structure within the head direction system yet there is still relatively little known about how these nuclei contribute to spatial performance. In the present study, rats with selective neurotoxic lesions of the lateral mammillary nuclei were tested on a working memory task in a radial-arm maze. This task requires animals to distinguish between eight radially-oriented arms and remember which arms they have entered within a session. Even though it might have been predicted that this task would heavily tax the head direction system, the lesion rats performed equivalently to their surgical controls on this task; no deficit emerged even when the task was made more difficult by rotating the maze mid-way through testing in order to reduce reliance on intramaze cues. Rats were subsequently tested in the dark to increase the use of internally generated direction cues but the lesion rats remained unimpaired. In contrast, the lateral mammillary nuclei lesions were found to decrease retrosplenial c-Fos levels. These results would suggest that the head direction system is not required for the acquisition of the standard radial-arm maze task. It would also suggest that small decreases in retrosplenial c-Fos are not sufficient to produce behavioural impairments.

Chronic exposure to stressful conditions may affect spatial learning and memory abilities and the brain structure, and disruptions in oligodendrocyte function may cause cognitive dysfunction. Leucine-rich repeat and immunoglobulin-like domain-containing protein 1 (LINGO-1) is a potent negative regulator of oligodendrocytes and axon myelination. However, the questions we sought to answer in this study are whether hippocampal oligodendrocytes are involved in the pathological process of spatial learning and memory impairments induced by chronic stress (CS) and whether antibodies targeting LINGO-1 improve stress-induced spatial learning and memory impairments by protecting the hippocampal oligodendrocytes in stressed rats. After 4 weeks of CS, rats were randomly divided into either the CS standard group or anti-LINGO-1 group. The anti-LINGO-1 group was treated with an anti-LINGO-1 antibody (8 mg/kg) for 3 weeks; all rats were assessed in the Morris water maze. Immunohistochemical staining and modern stereological methods were used to precisely quantify the total number of 2',3'-cyclic nucleotide 3'-phosphodiesterase-positive (CNPase+) oligodendrocytes in each subregion of the hippocampus. At the behavioural level, after three weeks of treatment, the anti-LINGO-1 group displayed significantly more platform crossings in the Morris water maze test than the CS standard group. The total swimming distance and swimming speed were not significantly different. In the open field test, the percentage of distance travelled in the central region did not differ between the CS standard group and control group or between the anti-LINGO-1 group and the CS standard group. Unbiased stereological analyses revealed significantly greater total numbers of CNPase+ cells in the CA3 and dentate gyrus (DG) areas of the hippocampus in the anti-LINGO-1 group than in the CS standard group. A significant difference in the total number of CNPase+ cells was not observed in the hippocampal CA1 region between the anti-LINGO-1 and CS standard groups. Based on the results of the present study, the anti-LINGO-1 antibody alleviated spatial memory impairments and protected oligodendrocytes in the hippocampus of chronically stressed rats.

Numerous clinical and animal studies have found that antenatal chronic stress can lead to pathological changes the hippocampal development from embryos to adult, but the mechanisms are not well understood. Proteomic analyses provide a new insight to explore the potential mechanisms of this impairment. In this study, gestating rats were subjected to chronic unpredictable mild stress (CUMS) during pregnant days using nine different stimulations, and the changes of the learning and memory performance and the expression of proteins in the hippocampus of offspring were measured. It was found that prenatal chronic stress led to growth retardation, impaired spatial learning and memory ability in the offspring. Furthermore, prenatal stress caused various degrees of damage to neurons, Nissl body, mitochondria and synaptic structures in hippocampal CA3 region of offspring. In addition, 26 significantly different expressed proteins (DEPs) were found between the two groups by using isoquantitative tag-based relative and absolute quantification (iTRAQ) proteomics analysis. Further analyses of these DEPs showed that involved with different molecular functions and several biological processes, such as biological regulation and metabolic processes. Among these, the KEGG pathway enrichment showed that learning and memory impairment was mainly associated with the cyclic guanosine monophosphate protein kinase G (cGMP-PKG) pathway. At the same time, compared with OPC group, the NO, nNOS and cGMP level were significantly decreased, and the expression of PKG protein was also dropped. All of these results suggested that pregnant rats exposed to chronic psychological stress might impair spatial learning and memory ability of offspring, by disturbing the NO/cGMP/PKG signaling pathway.