Effects of early life trauma are dependent on genetic predisposition: a rat study

Abstract

Background: Trauma experienced early in life increases the risk of developing a number of psychological and/or behavioural disorders. It is unclear, however, how genetic predisposition to a behavioural disorder, such as attention-deficit/hyperactivity disorder (ADHD), modifies the long-term effects of early life trauma. There is substantial evidence from family and twin studies for susceptibility to ADHD being inherited, implying a strong genetic component to the disorder. In the present study we used an inbred animal model of ADHD, the spontaneously hypertensive rat (SHR), to investigate the long-term consequences of early life trauma on emotional behaviour in individuals predisposed to developing ADHD-like behaviour.

Methods: We applied a rodent model of early life trauma, maternal separation, to SHR and Wistar-Kyoto rats (WKY), the normotensive control strain from which SHR were originally derived. The effects of maternal separation (removal of pups from dam for 3 h/day during the first 2 weeks of life) on anxiety-like behaviour (elevated-plus maze) and depressive-like behaviour (forced swim test) were assessed in prepubescent rats (postnatal day 28 and 31). Basal levels of plasma corticosterone were measured using radioimmunoassay.

Results: The effect of maternal separation on SHR and WKY differed in a number of behavioural measures. Similar to its reported effect in other rat strains, maternal separation increased the anxiety-like behaviour of WKY (decreased open arm entries) but not SHR. Maternal separation increased the activity of SHR in the novel environment of the elevated plus-maze, while it decreased that of WKY. Overall, SHR showed a more active response in the elevated plus-maze and forced swim test than WKY, regardless of treatment, and were also found to have higher basal plasma corticosterone compared to WKY. Maternal separation increased basal levels of plasma corticosterone in SHR females only, possibly through adaptive mechanisms involved in maintaining their active response in behavioural tests. Basal plasma corticosterone was found to correlate positively with an active response to a novel environment and inescapable stress across all rats.

Conclusion: SHR are resilient to the anxiogenic effects of maternal separation, and develop a non-anxious, active response to a novel environment following chronic mild stress during the early stages of development. Our findings highlight the importance of genetic predisposition in determining the outcome of early life adversity. SHR may provide a model of early life trauma leading to the development of hyperactivity rather than anxiety and depression. Basal levels of corticosterone correlate with the behavioural response to early life trauma, and may therefore provide a useful marker for susceptibility to a certain behavioural temperament.

Figure 1

Elevated plus maze behaviour of SHR and WKY males (M) and females (F), maternally separated (MS) or non-maternally separated (nMS). Time spent in the open arms is expressed as a percentage of total time spent in the open and closed arms (a and b). Open arm entries are expressed as a fraction of the total arm entries (c and d). Distance travelled is the total distance travelled in the EPM for the total 5-minute period (e) or within each individual minute (f). For each parameter, data are shown for the total 5-minute period (a, c, and e) and for each individual minute (b, d and f). a. ^#SHR females spent more of the total 5-minute period in the open arms than SHR males (p < 0.05). b. ^#Females spent more time in the open arms than males (p < 0.05). c. *SHR entered the open arms more frequently than WKY (p < 0.05). d. *SHR entered the open arms more frequently than WKY (p < 0.05). ^#Females entered the open arms more frequently than males (p < 0.05). e. *SHR travelled greater distance than WKY (p < 0.05). f. *SHR travelled greater distance than WKY in every minute (p < 0.05). ^#Females travelled further than males from the 2^nd minute onwards (p < 0.01). ^@Maternal separation decreased distance travelled by WKY (p < 0.05). (SHR males: nMS, n = 9, MS, n = 9; SHR females: nMS, n = 5, MS, n = 14; WKY males: nMS, n = 9; MS, n = 9; WKY females, nMS, n = 10, MS, n = 8).

Figure 2

Forced swim test behaviour of SHR and WKY males (M) and females (F), maternally separated (MS) or non-maternally separated (nMS). Time spent immobile (a and b), climbing (c and d) or swimming (e and f) is expressed as a percentage of total time. For each parameter, data are shown for the total 5-minute period (a, c, and e) and for each individual minute (b, d and f). a. *WKY spent more of the total 5-minute period immobile than SHR (p < 0.01). Maternal separation did not increase time spent immobile in either strain. b. *WKY spent more time immobile than SHR (p < 0.01). ^#SHR males spent more time immobile than SHR females in the 1^st minute (p < 0.001). c. *SHR spent more of the total 5-minute period climbing than WKY (p < 0.05). d. *SHR spent more time climbing than WKY in the 1^st minute (p < 0.001). ^@Maternal separation increased climbing in SHR in the 4th minute (p < 0.01). e. *SHR spent more of the total 5-minute period swimming than WKY (p < 0.05). f. *SHR spent more time swimming than WKY (p < 0.05). ^#Females spent more time swimming during the 1^st minute than males (p < 0.01). (SHR males: nMS, n = 9, MS, n = 9; SHR females: nMS, n = 5, MS, n = 14; WKY males: nMS, n = 9; MS, n = 9; WKY females, nMS, n = 10, MS, n = 8).

Figure 3

Basal plasma corticosterone levels of SHR and WKY males (M) and females (F), maternally separated (MS) or non-maternally separated (nMS). *SHR had higher basal levels of corticosterone than WKY (p < 0.001). ^@Maternal separation increased basal levels of corticosterone in SHR females (p < 0.05). (SHR males: nMS, n = 5, MS, n = 9; SHR females: nMS, n = 4, MS, n = 14; WKY males: nMS, n = 7; MS, n = 9; WKY females, nMS, n = 10, MS, n = 6).