Dehydration Impairs Physical Growth and Cognitive Development in Young Mice

Abstract

Infancy and childhood are periods of physical and cognitive development that are vulnerable to disruption by dehydration; however, the effects of dehydration on cognitive development during the periods have not yet been fully elucidated. Thus, the present study used a murine model to examine the effects of sustained dehydration on physical growth and cognitive development. Three-week-old C57BL/6J mice were provided either ad libitum (control group) or time-limited (15 min/day; dehydration group) access to water for 4 weeks. Physical growth was examined via a dual-energy X-ray absorptiometry whole-body scan, and cognitive development was assessed using the Barnes maze test. RNA-sequencing and qPCR analyses were carried out to assess the hippocampal transcriptome and the expression of key neurotrophic factors, respectively. These analyses showed that dehydrated mice exhibited a reduced body mass and tail length, and they spent four times longer completing the Barnes maze test than control mice. Moreover, dehydration significantly dysregulated long-term potentiation signaling and specifically decreased hippocampal brain-derived neurotrophic factor (Bdnf) expression. Collectively, these data confirm dehydration inhibits physical growth and suggest that it impairs cognitive development by altering the hippocampal transcriptional network in young mice; thus, they highlight the importance of water as a vital nutrient for optimal growth and development during infancy and childhood.

Keywords: brain transcriptome; brain-derived neurotrophic factor.; cognitive development; dehydration; hippocampus; physical growth.

Figure 1

Dehydration markedly alters spatial learning behavior in young mice. Spatial learning behavior was measured in control (CON) and dehydrated (DEH) mice by using the Barnes maze test to measure the (a) primary escape latency, (b) total distance moved, and (c) speed (calculated by dividing total distance moved by the primary latency) during the 4-day maze ‘training’ phase. (d) Representative heatmap images (i.e., heatmap indicates time spent at each position) tracking the path taken by mice through the maze on the final ‘test’ day. Arrow, target escape hole. (e) The average relative latency (%) required to identify the escape hole on the test day was calculated by dividing the escape latency (s) achieved on the test day by that achieved on the first day. Data are presented as the mean ± SEM. Statistical significance was evaluated using a Student’s t-test: * p < 0.05, ** p < 0.005, *** p < 0.001 versus day 1 in the DEH group; ## p < 0.01 versus day 1 in the CON group. NS, not statistically significant.

Figure 2

Dehydration alters hippocampal transcriptional networks. A hippocampal transcriptional network analysis was performed, comprising next-generation RNA sequencing and bioinformatic analyses. (a) Genes that were differentially regulated between the control (CON) and dehydrated (DEH) mice were classified into functional categories via an Ingenuity Pathway Analysis (IPA). Significantly changed biological functions are indicated by p-values calculated using a Fisher’s exact test, and the number of distinctively modulated molecules in each functional category is indicated. (b–d) Transcriptional networks related to altered glucose metabolism, synaptogenic cell-adhesion, and synaptic plasticity were differentially regulated in response to long-term dehydration. (e) Genes associated with long-term potentiation (LTP) signaling transduction were differentially up- (red) or downregulated (green) in the DEH compared to the CON mice.

Figure 3

Dehydration alters hippocampal brain-derived neurotrophic factor (Bdnf) expression levels in young mice. (a) Brain weight was measured after the dehydration experiment in the control (CON) and dehydration group (DEH). (b) The expression of neurotrophic factors in the hippocampus and (c) of Bdnf mRNA in other brain regions (excluding the hippocampus) were assessed via qPCR. (d) The relationship between hippocampal Bdnf transcript and plasma osmolality levels was evaluated via a Pearson’s correlation analysis. Data are presented as the mean ± SEM. * p < 0.05 versus CON group according to a Student’s t-test. R² and p-values were calculated via a Pearson’s correlation analysis. NS, not statistically significant.