Cognitive and neural correlates of depression-like behaviour in socially defeated mice: an animal model of depression with cognitive dysfunction

Abstract

Human depression is associated with cognitive deficits. It is critical to have valid animal models in order to investigate mechanisms and treatment strategies for these associated conditions. The goal of this study was to determine the association of cognitive dysfunction with depression-like behaviour in an animal model of depression and investigate the neural circuits underlying the behaviour. Mice that were exposed to social defeat for 14 d developed depression-like behaviour, i.e. anhedonia and social avoidance as indicated by reduced sucrose preference and decreased social interaction. The assessment of cognitive performance of defeated mice demonstrated impaired working memory in the T-maze continuous alternation task and enhanced fear memory in the contextual and cued fear-conditioning tests. In contrast, reference learning and memory in the Morris water maze test were intact in defeated mice. Neuronal activation following chronic social defeat was investigated by c-fosin-situ hybridization. Defeated mice exhibited preferential neural activity in the prefrontal cortex, cingulate cortex, hippocampal formation, septum, amygdala, and hypothalamic nuclei. Taken together, our results suggest that the chronic social defeat mouse model could serve as a valid animal model to study depression with cognitive impairments. The patterns of neuronal activation provide a neural basis for social defeat-induced changes in behaviour.

Fig. 1

Timeline of experimental procedures. (a) Behavioural tests. (b) c-fos mRNA study.

Fig. 2

Chronic social defeat induces depression-like behaviour. Mice were subjected to social defeat for 14 d. (a) Hedonic responses. Left panel: time-course of the effect of social defeat on sucrose preference. W/W (water/water), side preference for water before the sucrose preference test. Right panel: the averaged total sucrose preference over 7 d of testing. (b) Body-weight changes during social defeat. Data are expressed as mean ± s.e.m. (n = 8 for control group, n = 16 for defeated group). B, Baseline. * p < 0.05, ** p < 0.01 compared to non-defeated control mice.

Fig. 3

Chronic social defeat induces social withdraw. (a) Time spent in the interaction zone in the absence or presence of an aggressive CD1 social target. (b) Time spent in the corner zones in the absence or presence of an aggressive CD1 social target. Data are expressed as mean ± s.e.m. (n = 8 for control group, n = 16 for defeated group). *** p < 0.001 compared to non-defeated control mice.

Fig. 4

Effect of chronic social defeat on the performance of the T-maze continuous alternation task. The task consisted of one forced-choice trial and 14 free-choice trials. The percent of alternations was scored. Data are expressed as mean ± s.e.m. (n = 8 for control group, n = 16 for defeated group). * p < 0.05 compared to non-defeated control mice.

Fig. 5

Effect of chronic social defeat on contextual and auditory-cued fear conditioning. (a) Contextual fear conditioning. Time spent freezing in response to the familiar context was measured 24 h after training. (b) Cued fear conditioning. Time spent freezing was measured in a novel environment before and after an auditory cue (a tone) was given. (c) Hot-plate test. (d) Shock sensitivity test. Data are expressed as mean ± s.e.m. (n = 8 for control group, n = 16 for defeated group). * p < 0.05, *** p < 0.001.

Fig. 6

Effect of chronic social defeat on reference memory and behavioural flexibility. (a) The escape latencies in Morris water maze training during visible platform (days 1–2), hidden platform (days 3–12) and reversal (days 13–17) phases. (b) Probe test on day 12. Time spent in the initial training quadrant (target quadrant, TQ), the opposite quadrant (OQ), and average of two adjacent quadrants (AQ) during probe trials on day 12 of experiment shown in panel (a). (c) Probe test on day 17 of experiment as shown in panel (a). Data are expressed as mean ± s.e.m. (n = 8 for control group, n = 16 for defeated group).

Fig. 7

(a, b) Autoradiograms illustrating the distribution of c-fos mRNA expression within the selected brain regions in non-defeated control and defeated groups. Left panel, autoradiograms of coronal brain sections from non-defeated control ; middle panel, autoradiograms of coronal brain sections from defeated mice; right panel, the corresponding mouse brain atlas illustrating brain structures. 3V, 3rd ventricle ; NAc, nucleus accumbens; Arc, arcuate hypothalamic nucleus; BLA, basolateral amygdaloid nucleus; BNST, Bed nucleus of the stria terminalis ; CA1, field CA1 of hippocampus; CA2, field CA2 of hippocampus ; CA3, field CA3 of hippocampus ; CeA, central amygdaloid nucleus; CG, central grey; CM, central medial nucleus of the thalamus; CPu, caudate putamen; DG, dentate gyrus; DMH, dorsomedial nucleus of the hypothalamus; DR, dorsal raphe nucleus; LH, lateral habenula; LV, lateral ventricle ; M1, primary motor cortex ; M2, secondary motor cortex ; MeA, medial nucleus amygdala; MR, median raphe nucleus; PH, posterior hypothalamic area ; PVA, anterior periventricular nucleus of the thalamus; PVN, paraventricular nucleus; S1, primary somatosensory cortex ; Sfi, septofimbrial nucleus; SFO, subfornical organ; SO, substantia innominata; VMH, ventromedial hypothalamic nucleus; VTA, ventral tegmental area.

Fig. 7

(a, b) Autoradiograms illustrating the distribution of c-fos mRNA expression within the selected brain regions in non-defeated control and defeated groups. Left panel, autoradiograms of coronal brain sections from non-defeated control ; middle panel, autoradiograms of coronal brain sections from defeated mice; right panel, the corresponding mouse brain atlas illustrating brain structures. 3V, 3rd ventricle ; NAc, nucleus accumbens; Arc, arcuate hypothalamic nucleus; BLA, basolateral amygdaloid nucleus; BNST, Bed nucleus of the stria terminalis ; CA1, field CA1 of hippocampus; CA2, field CA2 of hippocampus ; CA3, field CA3 of hippocampus ; CeA, central amygdaloid nucleus; CG, central grey; CM, central medial nucleus of the thalamus; CPu, caudate putamen; DG, dentate gyrus; DMH, dorsomedial nucleus of the hypothalamus; DR, dorsal raphe nucleus; LH, lateral habenula; LV, lateral ventricle ; M1, primary motor cortex ; M2, secondary motor cortex ; MeA, medial nucleus amygdala; MR, median raphe nucleus; PH, posterior hypothalamic area ; PVA, anterior periventricular nucleus of the thalamus; PVN, paraventricular nucleus; S1, primary somatosensory cortex ; Sfi, septofimbrial nucleus; SFO, subfornical organ; SO, substantia innominata; VMH, ventromedial hypothalamic nucleus; VTA, ventral tegmental area.