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Heat stress-induced memory impairment is associated with neuroinflammation in mice.

Lee W, Moon M, Kim HG, Lee TH, Oh MS - J Neuroinflammation (2015)

Bottom Line: It has been demonstrated that exposure to high temperature induces cognitive impairment in experimental animals and humans.We also observed that neuronal and synaptic densities were degenerated significantly in hippocampal regions after heat exposure, as determined by histological analysis of neuronal nuclei (NeuN), postsynaptic density protein 95 (PSD-95), and synaptophysin expression.Together, these findings suggest that heat stress can lead to activation of glial cells and induction of inflammatory molecules in the hippocampus, which may act as causative factors for memory loss, neuronal death, and impaired adult neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Life and Nanopharmaceutical Science, Graduate School and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea. wonil@khu.ac.kr.

ABSTRACT

Background: Heat stress induces many pathophysiological responses and has a profound impact on brain structure. It has been demonstrated that exposure to high temperature induces cognitive impairment in experimental animals and humans. Although the effects of heat stress have long been studied, the mechanisms by which heat stress affects brain structure and cognition not well understood.

Methods: In our longitudinal study of mice exposed to heat over 7, 14, or 42 days, we found that heat stress time dependently impaired cognitive function as determined by Y-maze, passive avoidance, and novel object recognition tests. To elucidate the histological mechanism by which thermal stress inhibited cognitive abilities, we examined heat stress-induced inflammation in the hippocampus.

Results: In mice subjected to heat exposure, we found: 1) an increased number of glial fibrillary acid protein (GFAP)- and macrophage-1 antigen (Mac-1)-positive cells, 2) up-regulated nuclear factor (NF)-κB, a master regulator of inflammation, and 3) marked increases in cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and cytokine interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the mouse hippocampus. We also observed that neuronal and synaptic densities were degenerated significantly in hippocampal regions after heat exposure, as determined by histological analysis of neuronal nuclei (NeuN), postsynaptic density protein 95 (PSD-95), and synaptophysin expression. Moreover, in heat-exposed mice, we found that the number of cells positive for doublecortin (DCX), a marker of neurogenesis, was significantly decreased compared with control mice. Finally, anti-inflammatory agent minocycline inhibited the heat stress-induced cognitive deficits and astogliosis in mice.

Conclusions: Together, these findings suggest that heat stress can lead to activation of glial cells and induction of inflammatory molecules in the hippocampus, which may act as causative factors for memory loss, neuronal death, and impaired adult neurogenesis.

No MeSH data available.


Related in: MedlinePlus

Effects of heat stress on neuronal loss in the hippocampus. (a) Representative Western blot showing the expression of neuronal nuclei (NeuN), a marker for neuronal cells, in the hippocampus. (b) Representative pictures of NeuN staining in the granule cell layer and the pyramidal cell layer of the hippocampus. NeuN-stained cells were markedly lower in the heat-treated groups than the control group. The number of cells was reduced significantly in both the CA3 (c) and CA1 (d) regions. Values are expressed as means ± S.E.M. *p < 0.05, **p < 0.01, and ***p < 0.001 as compared with the control group
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Fig8: Effects of heat stress on neuronal loss in the hippocampus. (a) Representative Western blot showing the expression of neuronal nuclei (NeuN), a marker for neuronal cells, in the hippocampus. (b) Representative pictures of NeuN staining in the granule cell layer and the pyramidal cell layer of the hippocampus. NeuN-stained cells were markedly lower in the heat-treated groups than the control group. The number of cells was reduced significantly in both the CA3 (c) and CA1 (d) regions. Values are expressed as means ± S.E.M. *p < 0.05, **p < 0.01, and ***p < 0.001 as compared with the control group

Mentions: Memory deficits strongly correlate with synaptic protein expression and hippocampal synaptic density; synaptic damage is associated directly with neuroinflammation [31–34]. Heat stress reportedly induces neuronal loss in rat hippocampus [35, 36]. However, no evidence exists suggesting that heat exposure might lead to synaptic loss in the hippocampus. First, we determined whether or not heat stress resulted in hippocampal neuronal loss using Nissl staining and NeuN immunostaining. Nissl- and NeuN-stained coronal brain sections showed that heat stress significantly reduced neuronal density in the CA1 and CA3 pyramidal cell layers (Figs. 7 and 8b-d). Some cells exhibited weak staining, suggesting that they were in the process of degenerating. Western blot analysis using an antibody recognizing the NeuN neuronal marker also revealed that heat stress for 7, 14, and 42 days induced neuronal loss in the hippocampus (Fig. 8a). Next, to investigate the effects of heat stress on synaptic density, we examined the expression of synaptic marker molecules, such as PSD-95 and synaptophysin, in the hippocampus. Optical densitometry data showed that both PSD-95 and synaptophysin immunoreactivity were time-dependently decreased in the CA3 subfields of the hippocampus in heat-exposed mice compared with control mice (Fig. 9). For the first time, we demonstrated that thermal stress might lead to synaptic damage in the hippocampus.Fig. 7


Heat stress-induced memory impairment is associated with neuroinflammation in mice.

Lee W, Moon M, Kim HG, Lee TH, Oh MS - J Neuroinflammation (2015)

Effects of heat stress on neuronal loss in the hippocampus. (a) Representative Western blot showing the expression of neuronal nuclei (NeuN), a marker for neuronal cells, in the hippocampus. (b) Representative pictures of NeuN staining in the granule cell layer and the pyramidal cell layer of the hippocampus. NeuN-stained cells were markedly lower in the heat-treated groups than the control group. The number of cells was reduced significantly in both the CA3 (c) and CA1 (d) regions. Values are expressed as means ± S.E.M. *p < 0.05, **p < 0.01, and ***p < 0.001 as compared with the control group
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4465309&req=5

Fig8: Effects of heat stress on neuronal loss in the hippocampus. (a) Representative Western blot showing the expression of neuronal nuclei (NeuN), a marker for neuronal cells, in the hippocampus. (b) Representative pictures of NeuN staining in the granule cell layer and the pyramidal cell layer of the hippocampus. NeuN-stained cells were markedly lower in the heat-treated groups than the control group. The number of cells was reduced significantly in both the CA3 (c) and CA1 (d) regions. Values are expressed as means ± S.E.M. *p < 0.05, **p < 0.01, and ***p < 0.001 as compared with the control group
Mentions: Memory deficits strongly correlate with synaptic protein expression and hippocampal synaptic density; synaptic damage is associated directly with neuroinflammation [31–34]. Heat stress reportedly induces neuronal loss in rat hippocampus [35, 36]. However, no evidence exists suggesting that heat exposure might lead to synaptic loss in the hippocampus. First, we determined whether or not heat stress resulted in hippocampal neuronal loss using Nissl staining and NeuN immunostaining. Nissl- and NeuN-stained coronal brain sections showed that heat stress significantly reduced neuronal density in the CA1 and CA3 pyramidal cell layers (Figs. 7 and 8b-d). Some cells exhibited weak staining, suggesting that they were in the process of degenerating. Western blot analysis using an antibody recognizing the NeuN neuronal marker also revealed that heat stress for 7, 14, and 42 days induced neuronal loss in the hippocampus (Fig. 8a). Next, to investigate the effects of heat stress on synaptic density, we examined the expression of synaptic marker molecules, such as PSD-95 and synaptophysin, in the hippocampus. Optical densitometry data showed that both PSD-95 and synaptophysin immunoreactivity were time-dependently decreased in the CA3 subfields of the hippocampus in heat-exposed mice compared with control mice (Fig. 9). For the first time, we demonstrated that thermal stress might lead to synaptic damage in the hippocampus.Fig. 7

Bottom Line: It has been demonstrated that exposure to high temperature induces cognitive impairment in experimental animals and humans.We also observed that neuronal and synaptic densities were degenerated significantly in hippocampal regions after heat exposure, as determined by histological analysis of neuronal nuclei (NeuN), postsynaptic density protein 95 (PSD-95), and synaptophysin expression.Together, these findings suggest that heat stress can lead to activation of glial cells and induction of inflammatory molecules in the hippocampus, which may act as causative factors for memory loss, neuronal death, and impaired adult neurogenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Life and Nanopharmaceutical Science, Graduate School and Kyung Hee East-West Pharmaceutical Research Institute, Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 130-701, Republic of Korea. wonil@khu.ac.kr.

ABSTRACT

Background: Heat stress induces many pathophysiological responses and has a profound impact on brain structure. It has been demonstrated that exposure to high temperature induces cognitive impairment in experimental animals and humans. Although the effects of heat stress have long been studied, the mechanisms by which heat stress affects brain structure and cognition not well understood.

Methods: In our longitudinal study of mice exposed to heat over 7, 14, or 42 days, we found that heat stress time dependently impaired cognitive function as determined by Y-maze, passive avoidance, and novel object recognition tests. To elucidate the histological mechanism by which thermal stress inhibited cognitive abilities, we examined heat stress-induced inflammation in the hippocampus.

Results: In mice subjected to heat exposure, we found: 1) an increased number of glial fibrillary acid protein (GFAP)- and macrophage-1 antigen (Mac-1)-positive cells, 2) up-regulated nuclear factor (NF)-κB, a master regulator of inflammation, and 3) marked increases in cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), and cytokine interleukin (IL)-1β and tumor necrosis factor (TNF)-α in the mouse hippocampus. We also observed that neuronal and synaptic densities were degenerated significantly in hippocampal regions after heat exposure, as determined by histological analysis of neuronal nuclei (NeuN), postsynaptic density protein 95 (PSD-95), and synaptophysin expression. Moreover, in heat-exposed mice, we found that the number of cells positive for doublecortin (DCX), a marker of neurogenesis, was significantly decreased compared with control mice. Finally, anti-inflammatory agent minocycline inhibited the heat stress-induced cognitive deficits and astogliosis in mice.

Conclusions: Together, these findings suggest that heat stress can lead to activation of glial cells and induction of inflammatory molecules in the hippocampus, which may act as causative factors for memory loss, neuronal death, and impaired adult neurogenesis.

No MeSH data available.


Related in: MedlinePlus