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Severe Perinatal Hypoxic-Ischemic Brain Injury Induces Long-Term Sensorimotor Deficits, Anxiety-Like Behaviors and Cognitive Impairment in a Sex-, Age- and Task-Selective Manner in C57BL/6 Mice but Can Be Modulated by Neonatal Handling

Muntsant, Aida, Shrivastava, Kalpana, Recasens, Mireia, Giménez-Llort, Lydia·2019·Frontiers in Behavioral Neuroscience
DOI 10.3389/fnbeh.2019.00007PMC PMC6381068
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Figure 1 (A) Time line of the experimental schedule. (B) Behavioral and functional phenotype assessment: a three-stage protocol for behavioral and functional phenotype assessment evaluated the somatic development (primary screening), sensorimotor functions and motor activity (secondary screening) as well as non-cognitive and cognitive functions (tertiary screening). The tests used were the following: somatic development (weight), sensorimotor functions (visual and hind limb reflexes, rod test and hanger test), locomotor [activity test (ACT) and open-field (OF) test] as well as non-cognitive and cognitive functions-emotional and anxiety-like behaviors [corner, OF and dark-light box (DLB) tests]; learning and memory [T-maze test (TM) and Morris Water Maze (MWM)]. The behavioral assessment was performed at weaning and/or adulthood.
Figure 1 (A) Time line of the experimental schedule. (B) Behavioral and functional phenotype assessment: a three-stage protocol for behavioral and functional phenotype assessment evaluated the somatic development (primary screening), sensorimotor functions and motor activity (secondary screening) as well as non-cognitive and cognitive functions (tertiary screening). The tests used were the following: somatic development (weight), sensorimotor functions (visual and hind limb reflexes, rod test and hanger test), locomotor [activity test (ACT) and open-field (OF) test] as well as non-cognitive and cognitive functions-emotional and anxiety-like behaviors [corner, OF and dark-light box (DLB) tests]; learning and memory [T-maze test (TM) and Morris Water Maze (MWM)]. The behavioral assessment was performed at weaning and/or adulthood.CC BY · PubMed Central
Figure 2 Neuropathological analysis after hypoxic/ischemic (HI). (A) Drawing modified in Adobe Photoshop CS showing brain areas analyzed for quantification of brain damage in the ipsilateral side. CX, cortex; CC, corpus callosum; H, hippocampus. (B) Nissl staining showing HI effects on the cortex, hippocampus and CC of the contralateral (right side of the panel) and ipsilateral (left side of the panel) hemisphere 90 days after hypoxia. (C) Graphs show the changes in the total injury score along with the injury score in different regions analyzed. HI males and females presented higher injury scores than sham and HI + NH mice when we analyzed total injury score, the last ones were also different from sham. When we measured the injury scores in the different brain regions, we observed that HI + NH males were different from HI in most regions; however, in females, the significant differences only appeared when we measured the CC atrophy. Results are presented as mean ± SEM. Statistics: repeated measures analyses of variance (RMA), two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001. Student t-test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex.
Figure 2 Neuropathological analysis after hypoxic/ischemic (HI). (A) Drawing modified in Adobe Photoshop CS showing brain areas analyzed for quantification of brain damage in the ipsilateral side. CX, cortex; CC, corpus callosum; H, hippocampus. (B) Nissl staining showing HI effects on the cortex, hippocampus and CC of the contralateral (right side of the panel) and ipsilateral (left side of the panel) hemisphere 90 days after hypoxia. (C) Graphs show the changes in the total injury score along with the injury score in different regions analyzed. HI males and females presented higher injury scores than sham and HI + NH mice when we analyzed total injury score, the last ones were also different from sham. When we measured the injury scores in the different brain regions, we observed that HI + NH males were different from HI in most regions; however, in females, the significant differences only appeared when we measured the CC atrophy. Results are presented as mean ± SEM. Statistics: repeated measures analyses of variance (RMA), two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001. Student t-test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex.CC BY · PubMed Central
Figure 3 (A) Somatic development [postnatal day (PND)23–PND90] and (B) sensorimotor functions (PND23–PND70). Short- and long-effects of HI in males and females C57BL6 and effects of neonatal handling (NH). Results are presented as mean ± SEM. HI animals presented slower weight gain, with male being more sensitive than female; handling could not reverse the hypoxia’s effect. At sensorimotor level, HI impaired visual and hindlimb reflexes, which were first shown in females (PND23). Equilibrium, prehensility and coordination were also affected. Handling modulated the impaired reflex responses and an interaction with HI was also seen in other sensorimotor functions. Statistics: RMA, two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001, followed by Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment. Paired t-test comparison day 23 vs. day 70, aP < 0.05.
Figure 3 (A) Somatic development [postnatal day (PND)23–PND90] and (B) sensorimotor functions (PND23–PND70). Short- and long-effects of HI in males and females C57BL6 and effects of neonatal handling (NH). Results are presented as mean ± SEM. HI animals presented slower weight gain, with male being more sensitive than female; handling could not reverse the hypoxia’s effect. At sensorimotor level, HI impaired visual and hindlimb reflexes, which were first shown in females (PND23). Equilibrium, prehensility and coordination were also affected. Handling modulated the impaired reflex responses and an interaction with HI was also seen in other sensorimotor functions. Statistics: RMA, two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001, followed by Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment. Paired t-test comparison day 23 vs. day 70, aP < 0.05.CC BY · PubMed Central
Figure 4 Cylinder Test (CYT): short- and long-effects of HI in males and females C57BL6 and effects of NH. HI of both genders and HI + NH females presented higher paw preference scores (>50%) which indicate a greater reliance on the ipsilesional limb. Moreover, these groups presented a greater number of left rearings and H + NH female also presented more alternate left and right contacts. When we measured the total rearings performed, handling and HI + NH males presented the higher scores. Latency of first self-grooming behavior showed a clear sex-dependent effect, with females being faster in the expression of this emotivity-related behavior. All the other groups, showed fast elicitation of it, too. However, in the male sex, the total number of episodes made a difference between HI-animals and those with handling or HI+NH. Latency of pop-corn behavior was shorter in groups with handling, reaching statistical significance in handled males. Statistics: RMA, two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001, followed by Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #p < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment.
Figure 4 Cylinder Test (CYT): short- and long-effects of HI in males and females C57BL6 and effects of NH. HI of both genders and HI + NH females presented higher paw preference scores (>50%) which indicate a greater reliance on the ipsilesional limb. Moreover, these groups presented a greater number of left rearings and H + NH female also presented more alternate left and right contacts. When we measured the total rearings performed, handling and HI + NH males presented the higher scores. Latency of first self-grooming behavior showed a clear sex-dependent effect, with females being faster in the expression of this emotivity-related behavior. All the other groups, showed fast elicitation of it, too. However, in the male sex, the total number of episodes made a difference between HI-animals and those with handling or HI+NH. Latency of pop-corn behavior was shorter in groups with handling, reaching statistical significance in handled males. Statistics: RMA, two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001, followed by Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #p < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment.CC BY · PubMed Central
Figure 5 Spontaneous motor ACT: short- and long-effects of HI in males and females C57BL6 and effects of NH. Motor activity (PND23). Horizontal activity in ACT was increased in HI males and HI + NH females; however, the vertical activity was higher in handling males. Statistics: RMA, two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001, followed by Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment.
Figure 5 Spontaneous motor ACT: short- and long-effects of HI in males and females C57BL6 and effects of NH. Motor activity (PND23). Horizontal activity in ACT was increased in HI males and HI + NH females; however, the vertical activity was higher in handling males. Statistics: RMA, two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001, followed by Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment.CC BY · PubMed Central
Figure 6 Corner test (CT). OF. DLB. TM: short- and long-effects of HI in males and females C57BL6 and effects of NH. Non-cognitive functions were evaluated during PND70–PND90. Results are presented as mean ± SEM. (A) The neophobia in the CT was increased in hypoxia males and in both handling and HI + NH males and females. HI induced anxiety-like behavior in the OF (B) that lead to reduced exploratory activity with males being mostly affected. The anxious profile could be also observed in several variables measured by DL (C) were HI males and HI + NH females performed fewer entrances into the lit area. Moreover, HI males presented also fewer number of stretch attendance. Finally, in the TM (D) the highest values in the first T-latency were spent by HI + NH female, although there’s no significant difference, HI male also spent more time to reach the intersection. Statistics: RMA, two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001, followed by Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment.
Figure 6 Corner test (CT). OF. DLB. TM: short- and long-effects of HI in males and females C57BL6 and effects of NH. Non-cognitive functions were evaluated during PND70–PND90. Results are presented as mean ± SEM. (A) The neophobia in the CT was increased in hypoxia males and in both handling and HI + NH males and females. HI induced anxiety-like behavior in the OF (B) that lead to reduced exploratory activity with males being mostly affected. The anxious profile could be also observed in several variables measured by DL (C) were HI males and HI + NH females performed fewer entrances into the lit area. Moreover, HI males presented also fewer number of stretch attendance. Finally, in the TM (D) the highest values in the first T-latency were spent by HI + NH female, although there’s no significant difference, HI male also spent more time to reach the intersection. Statistics: RMA, two-way ANOVA: “HI” Hypoxia effect; “NH” handling effect; “S” sex effect; “A” age effect *P < 0.05, **P < 0.01, and ***P < 0.001, followed by Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment.CC BY · PubMed Central
Figure 7 MWM: short- and long-effects of HI in males and females C57BL/6 and effects of NH. Cognitive functions were evaluated during PND70–PND90. Results are presented as mean ± SEM. Mean distance to reach the platform in the cue and place tasks for spatial learning. All days presented time effect. (A) Cognitive deficits were observed in the MWM in both sexes with reduced total learning capacities (acquisition of the task) and worse short and long-term learning. In HI mice a reduction of the mean distance covered to find the platform could be recorded in both “trial-by-trial” and “day-by-day”, especially in place tasks learning and were mainly important in HI males. Memory in HI males was more clearly affected than females in the MWM, however it was modulated by handling (B) In the probe trial for short-term memory, hypoxia males did not distinguish between the trained quadrant (P) and the adjacent (Ar, Al) or the opposed one (O) presenting a random swimming while handling (male and female) and HI + NH male presented a scanning swimming. Finally sham (male and female), HI and HI + NH female presented a focal searching swimming due they distinguish between the trained quadrant and the rest of the quadrants. The number of annulus crossings was also fewer in HI and HI + NH males. Statistics: Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment. Preference for the trained quadrant (P) as compared to adjacent right (Ar) and left (Al) or Opposite (O) quadrants in the probe trial. ANOVA, “Q” preference for trained quadrant. *P < 0.05, **P < 0.01, and ***P < 0.001; followed by Duncan’s post hoc test *P < 0.05 vs. P quadrant, oP < 0.05 vs. O quadrant. n.s. non-significant statistical differencs is found.
Figure 7 MWM: short- and long-effects of HI in males and females C57BL/6 and effects of NH. Cognitive functions were evaluated during PND70–PND90. Results are presented as mean ± SEM. Mean distance to reach the platform in the cue and place tasks for spatial learning. All days presented time effect. (A) Cognitive deficits were observed in the MWM in both sexes with reduced total learning capacities (acquisition of the task) and worse short and long-term learning. In HI mice a reduction of the mean distance covered to find the platform could be recorded in both “trial-by-trial” and “day-by-day”, especially in place tasks learning and were mainly important in HI males. Memory in HI males was more clearly affected than females in the MWM, however it was modulated by handling (B) In the probe trial for short-term memory, hypoxia males did not distinguish between the trained quadrant (P) and the adjacent (Ar, Al) or the opposed one (O) presenting a random swimming while handling (male and female) and HI + NH male presented a scanning swimming. Finally sham (male and female), HI and HI + NH female presented a focal searching swimming due they distinguish between the trained quadrant and the rest of the quadrants. The number of annulus crossings was also fewer in HI and HI + NH males. Statistics: Duncan’s post hoc test. *P < 0.05 vs. sham of the same sex; #P < 0.05 vs. handling of the same sex; §P < 0.05 vs. hypoxia of the same sex; sP < 0.05 female vs. male of the same treatment. Preference for the trained quadrant (P) as compared to adjacent right (Ar) and left (Al) or Opposite (O) quadrants in the probe trial. ANOVA, “Q” preference for trained quadrant. *P < 0.05, **P < 0.01, and ***P < 0.001; followed by Duncan’s post hoc test *P < 0.05 vs. P quadrant, oP < 0.05 vs. O quadrant. n.s. non-significant statistical differencs is found.CC BY · PubMed Central
Figure 8 Neuroanatomical correlates of short- and long-term behavioral effects of HI in males and females C57BL/6 and those of NH. The graphical abstract summarizes the strongest neuroanatomical-behavioral correlations (P < 0.01) found in males (55 variables) and females (17 variables). This distribution, indicates that in spite of similar injury score, the NH was more effective restoring functions in males and that they were those related to the cognitive domains. In contrast, the domain of non-cognitive function was the more benefited in HI + NH females.
Figure 8 Neuroanatomical correlates of short- and long-term behavioral effects of HI in males and females C57BL/6 and those of NH. The graphical abstract summarizes the strongest neuroanatomical-behavioral correlations (P < 0.01) found in males (55 variables) and females (17 variables). This distribution, indicates that in spite of similar injury score, the NH was more effective restoring functions in males and that they were those related to the cognitive domains. In contrast, the domain of non-cognitive function was the more benefited in HI + NH females.CC BY · PubMed Central
Figure 9 Graphical abstract of sex- age- and task-dependent behavior impact of HI brain injury and its modulation by handling.
Figure 9 Graphical abstract of sex- age- and task-dependent behavior impact of HI brain injury and its modulation by handling.CC BY · PubMed Central

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Metadata

Authors
Muntsant, A., Shrivastava, K., Recasens, M., & Giménez-Llort, L.
Venue
Frontiers in Behavioral Neuroscience
Publisher
Frontiers Media SA
Published
2019-02-13
Volume
13
ISSN
1662-5153
DOI
10.3389/fnbeh.2019.00007
PMC
PMC6381068
Cited by
32
References
2
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • Fundació La Marató de TV3 (2011-110531)
  • Universitat Autònoma de Barcelona (EME-13-140335)

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CoChat. (2026). Citation check: Severe Perinatal Hypoxic-Ischemic Brain Injury Induces Long-Term Sensorimotor Deficits, Anxiety-Like Behaviors and Cognitive Impairment in a Sex-, Age- and Task-Selective Manner in C57BL/6 Mice but Can Be Modulated by Neonatal Handling. https://app.cochat.ai/papers/10.3389/fnbeh.2019.00007
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Muntsant, A., Shrivastava, K., Recasens, M., & Giménez-Llort, L. (2019). Severe Perinatal Hypoxic-Ischemic Brain Injury Induces Long-Term Sensorimotor Deficits, Anxiety-Like Behaviors and Cognitive Impairment in a Sex-, Age- and Task-Selective Manner in C57BL/6 Mice but Can Be Modulated by Neonatal Handling. Frontiers in Behavioral Neuroscience. https://doi.org/10.3389/fnbeh.2019.00007