Chronic psychosocial stress causes apical dendritic atrophy of hippocampal CA3 pyramidal neurons in subordinate tree shrews

Abstract

We have shown previously that repeated laboratory restraint stress or daily corticosterone administration affects the structure of CA3 hippocampal neurons in rats. In the present study, we investigated the effect of repeated daily psychosocial stress on the structure of hippocampal CA3 pyramidal neurons in male tree shrews (Tupaia belangeri). Male tree shrews develop social hierarchies in which subordinates show characteristic changes in physiological and behavioral parameters when confronted with a dominant. In the present experiments, subordinate animals lost body weight soon after starting the daily social conflict, and urinary excretion of cortisol was elevated throughout the experiment as compared with the control period. Golgi-impregnated brain tissue from subordinates exposed to 28 d (1 hr/d) of social confrontations was compared with that from control nonstressed animals. The apical dendrites of the CA3 pyramidal cells from subordinates had a decreased number of branch points and total dendritic length as compared with controls. No differences were observed in apical dendritic spine density or in the basal dendritic tree morphology. The stress-induced CA3 apical dendritic atrophy in subordinates was prevented by administering daily oral doses of the antiepileptic drug phenytoin (Dilantin, Sigma, St. Louis, MO) (200 mg/kg), which interferes with excitatory amino acid (EAA) action. These results suggest that the naturalistic stressor psychosocial stress induces specific structural changes in hippocampal neurons of subordinate male tree shrews. These changes, like those in the rat after glucocorticoid treatment or restraint stress, probably are mediated by activation of the hypothalamo-pituitary-adrenal-axis acting in concert with endogenous EAAs from mossy fiber input.

Fig. 1.

Effect of 28 d of psychosocial stress on dendritic morphology of CA3 pyramidal neurons is shown for apical and basal dendrites. Note that psychosocial stress reduces the number of apical branch points in subordinates (SUB) as compared with controls (CON). Bars represent the mean ± SEM;double asterisk indicates p < 0.01, andasterisk indicates p < 0.05 as compared with controls (Student’s t test).

Fig. 2.

Camera lucida drawings of representative Golgi-impregnated CA3 pyramidal neurons from control (not subjected to stress) and subordinate tree shrews (after 28 d of psychosocial stress). Notice the decreased branching pattern in the subordinate apical dendritic tree as compared with the control.

Fig. 3.

Daily oral administration of phenytoin (DIL, 200 mg/kg) to subordinate animals (SUB) during the 28 d stress period prevented the occurrence of the CA3 apical dendritic atrophy. Control animals (CON) showed a number of apical dendritic branch points similar to that for subordinates treated with phenytoin. No statistical differences were found in apical dendritic length as well. Bars represent the mean ± SEM.

Fig. 4.

Effect of psychosocial stress on cortisol in morning urine and relative body weight during a control period (CO) and a subsequent period of psychosocial stress (PSS). Control animals were handled like subordinates and dominants, but were not subjected to psychosocial stress. Data are given as percentage of mean values during the control period (mean ± SEM).

Fig. 5.

Effect of phenytoin treatment on morning urine cortisol levels and body weight during a control period (CO) and a subsequent period of psychosocial stress (PSS). Control animals were handled and treated with phenytoin as subordinates, but were not subjected to psychosocial stress. Data are given as percentage of mean values during the control period (mean ± SEM).