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Psychopharmacology (2018) 235:909–933 https://doi.org/10.1007/s00213-018-4852-5

REVIEW

Alcohol, psychomotor-stimulants and behaviour: methodological considerations in preclinical models of early-life stress Kate McDonnell-Dowling 1 & Klaus A. Miczek 1 Received: 2 May 2017 / Accepted: 6 February 2018 / Published online: 6 March 2018 # Springer-Verlag GmbH Germany, part of Springer Nature 2018

Abstract Background In order to assess the risk associated with early-life stress, there has been an increase in the amount of preclinical studies investigating early-life stress. There are many challenges associated with investigating early-life stress in animal models and ensuring that such models are appropriate and clinically relevant. Objectives The purpose of this review is to highlight the methodological considerations in the design of preclinical studies investigating the effects of early-life stress on alcohol and psychomotor-stimulant intake and behaviour. Methods The protocols employed for exploring early-life stress were investigated and summarised. Experimental variables include animals, stress models, and endpoints employed. Results The findings in this paper suggest that there is little consistency among these studies and so the interpretation of these results may not be as clinically relevant as previously thought. Conclusion The standardisation of these simple stress procedures means that results will be more comparable between studies and that results generated will give us a more robust understanding of what can and may be happening in the human and veterinary clinic. Keywords Early-life stress . Animal models . Alcohol . Psychomotor stimulants . Behaviour

Abbreviations SD L-E L-H F-H Cont NS PND M F CPP AMP MA 2-BC MDMA CVS AA ANA

Sprague-Dawley Long-Evans Lister Hooded Fawn-Hooded Continuous Not specified Postnatal day Male Female Conditioned place preference Amphetamine Methamphetamine 2 Bottle-choice Methylenedioxymethamnphetamine Chronic variable stress Alko alcohol Alko non-alcohol

* Kate McDonnell-Dowling [email protected] 1

Department of Psychology, Tufts University, 530 Boston Avenue, Medford, MA 02155, USA

OSST SI EPM OFT FST LDB LA MWM cPRIDE AST ASR CMS TMT SUS RES NOR PCMS NSFT RHA RLA PPI SP FC RI Interm

Operant strategy-shifting task Social interaction Elevated plus maze Open field test Forced swim test Light/dark box Locomotor activity Morris water maze Consummatory partial reinforcement on incentive downshift effect Attention set-shifting task Acoustic startle response Chronic-mild-unpredictable stress Trimethylthiazoline Swim-test susceptible Swim-test resistant Novel object recognition Predictable chronic mild stress Novelty-suppressed feeding test Roman high avoidance Roman low avoidance Prepulse inhibition Sucrose/saccharin preference Fear conditioning Resident-intruder Intermittent

910 EE MS CORT F2

Psychopharmacology (2018) 235:909–933 Environmental enrichment Maternal separation Corticosterone Second generation

Early-life stress Sigmund Freud and Seymour Levine were of the first researchers to highlight the importance of ‘early experiences’ and current evidence provides support for these concepts including the link between stress in early-life and increases in incidents of depression, anxiety, and psychiatric illnesses as adults (Shetgiri 2013). Early-life stress in the form of bullying and violence is now recognised as a significant public health problem (National Institute of Child Health and Human Development 2006). Reports show that 10% of children are victims of serious bullying (Juvonen et al. 2003) whereas 50% of adolescents are involved in verbal or relational bullying (Wang et al. 2009). The brain is structurally developing during early-life (Paus 2005) and stress can significantly influence neural development and therefore impact later behavioural responses.

Types of clinical stress Early-life stress is most often divided into stressful life events (SLE) and childhood maltreatment although there is considerable overlap (Enoch 2011). With regards to SLE, 53% of adults report having experienced some form of stressor with the most frequent stressful events being parental divorce, family violence, economic adversity, mental illness, and parental death (Green et al. 2010). Schalinski et al. (2016) describes other adverse childhood experiences which include parental non-verbal emotional abuse, sexual abuse, witnessing physical violence, peer emotional and physical violence, and emotional and physical neglect. Of course, these children are often exposed to multiple stressors (Dong et al. 2004) meaning that the same child can experience stress through multiple adverse experiences. An important question to consider is to what extent the nature of the stressor (bullying, sexual abuse, neglect, etc.), frequency of the stressors (acute or chronic), severity of the stressors (mild or severe), and timing of the stressors (childhood or adolescence) determine the outcome or consequences in later life? The timing of early-life stress exposure may affect different brain regions undergoing growth spurts at that time so that brain regions rich in glucocorticoid receptors and undergoing postnatal development (e.g. hippocampus, amygdala, prefrontal cortex (PFC)) are particularly vulnerable to the long-term effects of stress (Teicher et al. 2003; Rincon-Cortes and Sullivan 2014). Schalinski et al. (2016) showed that psychiatric inpatients that

had adverse childhood experiences were more vulnerable to post-traumatic stress disorder (PTSD), dissociation, and depression if the experiences occurred during the pre-school age (4–6 years) or the pre-adolescent age (8–9 years). The same study showed that PTSD symptoms in these patients vary with the frequency of adverse experiences—which supports the dose-dependent model—meaning that increased frequency of adverse experiences leads to a greater severity in symptoms. Enoch (2006) discussed an important point in that not all children exposed to early-life stress develop a psychiatric disorder or mental illness. Therefore, resilience and mediating factors may play a role such as environment, good parenting, and good peer relationships.

Preclinical adolescent stress The last decade has seen a surge in the number of preclinical studies investigating the consequences of stress during adolescence on brain, physiology, and behaviour. Adolescence in both rodents and humans has been subdivided into early, mid, and late stages. The specific postnatal days (PND) which define adolescence in rodents can vary between studies but each stage is associated with specific hormonal, physical, and behavioural changes. In mice, rats, and humans, the early adolescent stage corresponds to PND 21–34 and 10–14 years, the mid-adolescent stage to PND 34–46 and 15–17 years, and the late adolescent stage to PND 46–59 and 18–21 years, respectively (Shriner et al. 2009; Daston et al. 2004; Burke and Miczek 2014). Puberty occurs at different times for males and females—namely between PND 45–48 (balanopreputial separation) and PND 32–34 (vaginal opening) (Lewis et al. 2002; McCormick and Mathews 2010)—and puberty in mice appears at an age similar to rats (Fig. 1) (Safranski et al. 1993). Adulthood is considered PND 60 onwards and the time of sexual maturity, but maturation may extend further into life for example dopamine receptor concentrations in the prefrontal cortex (Andersen et al. 2000).

Types of preclinical stress models The intensity between different types of stressors in rodent studies is quite variable, implying that not all stressors are equivalent. Habituation to a stressor can occur after repeated exposure and this is characterised by a reduction in the neuroendocrine response, protecting the animal from exposure to chronically high levels of glucocorticoids (Girotti et al. 2006). For example, repeated restraint stress (i.e. confining the animal in small spaces) undergoes habituation seen as reduced hypothalamic-pituitary-adrenal axis responses in later exposures (Girotti et al. 2006). Whereas social stress (i.e. exposure to an intermittent, short-lasting social stressor) does not result in habituation, seen as increased functional activation in the

Psychopharmacology (2018) 235:909–933

911

Fig. 1 Timeline of adolescent period between weaning and adulthood

Review methods The search terms ‘Adolescent, Rodent, Stress’, ‘Adolescent, Rodent, Aggression’, or ‘Adolescent, Rodent, ResidentIntruder’ were entered into PubMed search engine. Between 1964 and 2016 (July), 990 articles were published in this area (Fig. 2). Among these articles, 156 were relevant in that they involved stress exposure during adolescence.

Aims The purpose of this review is to illustrate the variation in methods employed when studying the effects of early-life stress in animal models. Although early-life is considered to be the first weeks of development after birth, for the purpose this review, the adolescent period has also been included for comparison. It is not possible to review all ages, models, and outcomes and therefore, for this review, we have focused on stress during the early-life period (PND 1–20) and the adolescent period (PND 21–59, Fig. 1). Due to the clinical relationship between chronic stress addiction and in the motivation to abuse addictive substances (Tomkins 1966; Wills and Vaughan 1989), this review has focused on the consequences of this stress on drug use (Table 1) and general behavioural outcomes (Table 2) in later life.

How does early-life stress exposure vary? Consistency with experimental variables is imperative to ensure that results seen are the result of the stress experience and nothing else. The protocols used for exploring the effects of early-life stress can vary in several areas. By looking separately at experimental variables, we can categorise these accordingly: (i) Animals, (ii) model of stress, and (iii) endpoints assessed (Fig. 3).

Number of articles published

central and medial amygdala (Covington 3rd and Miczek, 2001). Chronic variable stress (CVS) and chronic mild stress (CMS), a combination of stress procedures, also aim to overcome habituation and so multiple stressors are employed in a random and unpredictable fashion (Willner 1997). Popular and commonly employed stress procedures such as footshock or tailshock (electric pulses to the feet or tail), forced swim test, predator scent exposure, and elevated platform are all effective means of initiating a stress response; however, there is a lack of translatability of these stress models to the clinical scenario and the relevance of these models will be discussed below. Much like in the clinical scenario of stress, it is important to consider whether the nature of the stressor (social, variable, aversive, etc.), frequency of the stressors (acute or chronic), severity of the stressors (mild, moderate, or severe), and timing of the stressors (early, mid, or late adolescence) determine the outcome or consequences in later life. And again, like the clinical scenario, much evidence exists to support this hypothesis. Looking at the timing of stress (developmental age of the rodent)—which is most often the basis for experimental design—many studies have shown that in early adolescence it takes twice as long to regain pre-stress corticosterone (CORT) levels after acute restraint stress compared to adults (Romeo and McEwen 2006; Romeo et al. 2006). However, it is evident that there are several protocols in use for each stress procedure. Hence, the findings are not consistent and it becomes difficult to interpret if the effects found are due to the stress, the protocol employed, the laboratory environment, or a yet-to-be-determined variable. Therefore, comparing the various protocols employed in early-life stress studies may highlight discrepancies and inconsistencies between studies and laboratories.

600 500 400 300 200 100 0 1970

1975

1980

1985

1990

1995

Year

Fig. 2 Adolescent stress papers published

2000

2005

2010

2015

OF1

WT S-D F-H/ Wistar F-H

L-E Wistar

L-E L-E L-E

L-E AA and ANA C57BL/6J

Wistar

CFW

C57BL/6J

L-E AA and ANA L-E Wistar Kunming

Hs/Ibg S-D NS S-D OF1

L-E

L-H L-H

S-D NS Wistar

Mice

Mice Rats Rats

Rats Rats

Rats Rats Rats

Rats Rats Mice

Rats

Mice

Mice

Rats Rats Rats Rats Mice

Mice Rats Hamsters Rats Mice

Rats

Rats Rats

Rats Rats Rats

Rats

Strain

PND 14 PND 21, 45–55 g NS PND 1

PND 20/21

PND 1 PND 1 PND 22 PND 1 PND 21

PND 1 PND 1 PND 1 PND 1 PND 1

PND 1

PND 1

PND 1

PND 24, 40 g PND 43–50 PND 1

PND 21 PND 21 PND 21–25

PND 21 PND 1

PND 21

PND 1 PND 1 PND 21

PND 21

Age on arrival

M M M

M M

M

M+F M M M+F M

M+F M+F M+F M+F M+F

M+F

M

M

F M M+F

M M M

M M

M

M+F F M

M

Sex

Social isolation Maternal separation Yohimbine injection

Social isolation Social isolation

Social defeat

Footshock Footshock Footshock Restraint Social defeat

Maternal separation ± social isolation Maternal separation Maternal separation Maternal separation Maternal separation Footshock

Early weaning ± social isolation Maternal separation

Social isolation Social isolation Social isolation ± CVS

Social isolation Social isolation Social isolation

Social isolation Social isolation

Social isolation

Social isolation Social isolation Social isolation

Social defeat

Model

PND 22 PND 2 PND 54–55

PND 21 PND 21

PND 35

PND 36/37 PND 26/27 PND 31 PND 24/38 PND 29

5 weeks 3 h × 11 1

3 weeks 8 weeks

1×4

10 1/8 1 × 11 1×5 1×4

15 min × 7 6 h × 21 3 h × 12 24 h 1/10

3 h × 12

PND 2

PND 1 PND 1 PND 2 PND 9 PND 28

3 h × 14

6 weeks 16 weeks 6 weeks and 2 × 14 10 days

6 weeks 6 weeks 6 weeks

13 weeks 10 days

9 weeks

6 weeks 2 weeks 8 weeks

1×4

No. stresses

PND 1

PND 16

PND 31 PND 43–50 PND 21 and 35

PND 28 PND 28 PND 28–32

PND 21 PND 25

PND 21

PND 21 PND 21 PND 21

PND 27

Age at stress

Cocaine self-ad Cocaine self-ad Cocaine self-ad

Cocaine self-ad Cocaine self-ad

Cocaine self-ad

Ethanol 2-BC Ethanol 2-BC Ethanol 2-BC Ethanol injection Cocaine CPP

Ethanol 2-BC Ethanol 2-BC Ethanol 2-BC Ethanol 2-BC Ethanol CPP

Ethanol 3-BC/ ethanol self-ad Ethanol 2-BC

Ethanol 2-BC

Ethanol 2-BC Ethanol injection Ethanol 2-BC/ ethanol self-ad Ethanol 2-BC Ethanol 1-BC Ethanol 2-BC

Ethanol self-ad Ethanol 1 or 2-BC

Ethanol 2-BC

Ethanol 2-BC Ethanol 2-BC Ethanol 2-BC

Ethanol self-ad

Endpoints measured

Early-life stress studies and drug intake in adulthood. The range of parameters employed in early-life stress studies. n=38 papers.

Species

Table 1

Advani et al. (2007)

Lancaster (1998) Roman et al. (2005) Huot et al. (2001) Penasco et al. (2015) Song et al. (2007)

↑ EtOH ↑ EtOH ↑ EtOH ↑ EtOH ↑ EtOH ↑ EtOH-induced CPP ↑ EtOH ↓ EtOH ↑ EtOH ↓ Response ↑ Cocaine-induced CPP ↑ Cocaine self-ad

↑ Cocaine self-ad ↓ Cocaine self-ad ↑ Cocaine self-ad

↑ Cocaine self-ad ↑ Cocaine self-ad

Cruz et al. (2008b)

↑ EtOH

Ding et al. (2005) O’Connor et al. (2015) Anker and Carroll (2010)

Chester et al. (2008) Brunell and Spear (2005) Ferris and Brewer (1996) Varlinskaya et al. (2013) Montagud-Romero et al. (2015) Burke and Miczek (2015) Baarendse et al. (2014) Howes et al. (2000)

Fahlke et al. (1997)

↓ EtOH

↑ EtOH ↑ EtOH ↑ EtOH

↑ EtOH ↑ Response ↑ EtOH

↑ EtOH ↑ EtOH

↑ EtOH

Lodge and Lawrence (2003) Deehan et al. (2007) Juarez and Vazquez-Cortes (2003) Skelly et al. (2015) Karkhanis et al. (2015) McCool and Chappell (2009) Butler et al. (2014) Ehlers et al. (2007) Lopez et al. (2011)

Rodriguez-Arias et al. (2016) Moriya et al. (2015) Van Waes et al. (2011) Hall et al. (1998)

↑ EtOH – ↑ EtOH ↑ EtOH

Reference

Findings

912 Psychopharmacology (2018) 235:909–933

Brielmaier et al. (2012) M PND 21 S-D Rats

Footshock

PND 27

10 min

Nicotine CPP

↓ AMP-induced CPP ↑ Nicotine-induced CPP AMP CPP 16 PND 30 Social isolation PND 22 Rats

L-E

M+F

– MDMA CPP 24 h PND 9 Maternal separation M+F PND 1 Wistar Rats

PND 21 OF1 Mice

M

M M Wistar OF1

It is beneficial to have animals that are bred in-house to eradicate stress associated with transport but the main reason is so that one can control the rearing environment to which the

Rats Mice

PND 23, 70–90 g PND 1 PND 21/42

In early-life stress studies, rat models are more frequently used, with 70 and 86% of these studies using laboratory rats as the test subject when investigating the consequences on drug use and behaviour, respectively (Table 3). Both rat and mice models provide reliable results that can be translated to humans and, although no comparison between these two rodent species has been made for early-life stress studies, it has been suggested that rats are less susceptible to stress effects (Collins et al. 1999). Hamsters and voles have also been used in a few studies investigating the consequences of early-life social isolation or footshock on ethanol intake (Ferris and Brewer 1996). Generally, the choice of species is based on the outcome to be measured in later life with rats known to be more suitable for intravenous self-administration studies (Burke and Miczek 2015; Baarendse et al. 2014; Ding et al. 2005), while mice are more frequently chosen for ethanol drinking studies (Lopez et al. 2011; Cruz et al. 2008b; Song et al. 2007) (Table 1). Another factor to consider is the strain of animal used. The principal rat strains previously used in early-life stress studies are Long-Evans and Wistar and the main mouse strains previously used are OF1, C57BL/6J, and CD-1 (Table 3). This is very important as there is much evidence to show different stress effects between strains. The use of different rat strains is known to lead to disparities in stress-induced effects (Becker et al. 2011). For example, after maternal separation (MS), Lewis rats are more sensitive to thermal nociception in the tail withdrawal test and are less sensitive in the formalin inflammatory nociception test than Fischer rats (Lariviere et al. 2006). The effects of isolation-rearing during adolescence on sucrose and saccharin preferences (SP) tests appear to be exacerbated in Fawn Hooded rats compared to Wistar rats (Hall et al. 1998). These findings add another complication when trying to interpret studies between laboratories and comparing the results found with different stress procedures. Since straindependent stress effects are common then direct comparisons between these studies are not possible.

Sex

Social defeat

PND 29

1×4

MDMA CPP

Marquardt et al. (2004) Garcia-Pardo et al. (2015) Garcia-Pardo et al. (2014) Llorente-Berzal et al. (2013) Mathews et al. (2008a) ↑ Cocaine ↑ MDMA-induced CPP –

Species and strain

Age on arrival

Aversive stimulation Social defeat

PND 1/30 PND 29/47

1 × 10 1×4

Cocaine 2-BC MDMA CPP

Reference Endpoints measured No. stresses Age at stress

There are many subject characteristics to be taken into account when designing a rodent model of stress including species, strain, animal source, sex, and the number of animals to be used in the experiment as well as husbandry procedures such as housing and weaning.

Strain

Model

Animals

Animal source

Species

Table 1 (continued)

913

Findings

Psychopharmacology (2018) 235:909–933

PND 21/35 NS NS PND 29–31 PND 21 PND 21 PND 21 PND 21 PND 21 PND 21 PND 20/21 PND 24 PND 37, 184 g NS PND 1 PND 34 PND 1 NS

NS

OF1 OF1

C57BL/6 C57BL/6J C57BL/6J Wistar

S-D S-D S-D S-D S-D S-D S-D S-D S-D S-D L-E Wistar Wistar RHA & RLA L-E Wistar Groningen C57BL/6J

Kunming

C57/BL6 Swiss Albino

C57BL/6J Wistar S-D S-D S-D F-H/Wistar F-H S-D S-D L-E

Mice Mice

Mice Mice Mice Rats

Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats Mice

Mice

Mice Mice

Mice Rats Rats Rats Rats Rats Rats Rats Rats Rats

PND 20 PND 21–25, 10–14 g PND 1 NS PND 21 PND 1 PND 1 PND 21 PND 21 PND 1 PND 1 PND 21

NS PND 28 PND 35, 18–23 g PND 21–23

PND 21 PND 21/42

PND 21

OF1

Mice

Age on arrival

Strain

M+F M M M+F F M M M+F M M

NS M

M+F

M F M F M M M M M M M M M M M+F M M M

M M M M

M M

M

Sex

Social isolation Social isolation Social isolation Social isolation Social isolation Social isolation Social isolation Social isolation Social isolation Social isolation

Social isolation Social isolation

Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat Social defeat ± social instability Social isolation

Social defeat Social defeat Social defeat Social defeat

Social defeat Social defeat

Social defeat

Model

PND 30 PND 21 PND 21 PND 21 PND 21 PND 21 PND 21 PND 23 PND 28 PND 28

PND 21/22 PND 21–25

PND 21

PND 28/42 PND 28/42 PND 28/42 PND 29–31 PND 35 PND 35 PND 35 PND 35 PND 35 PND 35 PND 35 PND 45 PND 45 PND 45 PND 45 PND 45 PND 45 PND 28

PND 35 PND 35 PND 42 PND 28/35

PND 29 PND 29/47

PND 27

Age at stress

4 weeks 2 weeks 4 weeks 8 days 2 weeks 8 weeks 9 weeks 10 days 1.5/3 h 6 weeks

8 weeks 6 weeks

4/8/12/16 weeks

1×7 1×5 1×5 1×7 1×5 1×5 1×5 1×5 1×5 1×5 1×4 1×5 1×5 1×5 1 × 10 1×2 1×5 2 weeks

1 × 10 1 × 10 1 × 10 1 × 3 or 1 × 10

1×4 1×4

1×4

No. stresses EPM, passive avoidance, SI, Hebb–Williams maze OFT, EPM Passive avoidance, EPM, Hebb–Williams maze, SI SI, FST, EPM, SP SI SI, LA, FST, LDB, NOR Play behaviour, EPM, defensive Burying, SI OFT, defensive, burying, FST OSST OSST FST AMP LA Win-shift task, T-Maze FC EPM AMP LA, stereotypy behaviour LA OFT, cocaine LA SI SI RI, operant conditioning EPM, T-Maze Water conflict test RI, operant behaviour OFT, partition test, EPM, SI, FST LA, EPM, LDB, FST, induced-sleep ASR, OFT OFT, FST, splash test, hole-board test SI EPM, CPRIDE OFT, SI, hot plate SP FST SP EPM NOR Ethanol LA EPM, OFT, FC

Endpoints measured

Early-life stress studies and behaviour in adulthood. The range of parameters employed in early-life stress studies. n = 133 papers

Species

Table 2

Kercmar et al. (2011) Cuenya et al. (2015) Meng et al. (2010) Anderson et al. (2010) Van Waes et al. (2011) Hall et al. (1998) Lodge and Lawrence (2003) Douglas et al. (2003) Acevedo et al. (2013) Skelly et al. (2015)

Gan et al. (2014) Amiri et al. (2015)

Guo et al. (2004)

Bingham et al. (2011) Snyder et al. (2015a) Snyder et al. (2015b) Ver Hoeve et al. (2013) Burke et al. (2013) Novick et al. (2013) Novick et al. (2016) Watt et al. (2009) Burke et al. (2010) Burke et al. (2011) Burke and Miczek (2015) Vidal et al. (2007) Vidal et al. (2011b) Coppens et al. (2012) Furuta et al. (2015) Vidal et al. (2011a) Coppens et al. (2014) Kovalenko et al. (2014)

Iniguez et al. (2014) Warren et al. (2014) Huang et al. (2013) Buwalda et al. (2013)

Garcia-Pardo et al. (2014) Garcia-Pardo et al. (2015)

Rodriguez-Arias et al. (2016)

Reference

914 Psychopharmacology (2018) 235:909–933

Strain

L-E L-E S-D S-D L-E S-D L-E S-D CD-1 CD-1 L-E L-E

L-E

L-E

L-E

L-E

L-E

L-E

L-E

L-E

Wistar

Wistar/ Fischer C57BL/6

L-E

L-E S-D S-D

Wistar S-D C57Bl/6J L-E

Species

Rats Rats Rats Rats Rats Rats Rats Rats Mice Mice Rats Rats

Rats

Rats

Rats

Rats

Rats

Rats

Rats

Rats

Rats

Rats Mice

Rats

Rats Rats Rats

Rats Rats Mice Rats

Table 2 (continued)

PND 1 PND 21, 45–50 g PND 1 PND 1

PND 21 PND 21 PND 22

PND 21

PND 22 PND 1

PND 1

PND 25

PND 22

PND 22

PND 22

PND 22

PND 22

PND 21

PND 22

PND 21–25 PND 22 PND 21 PND 23 PND 22 PND 1 PND 24, 40 g PND 1 PND 26–28 PND 26–28 PND 22 PND 22

Age on arrival

M+F M M M+F

M M M

M+F

F M

M+F

M+F

F

M+F

M

M

M

M

F

M M+F M+F M+F M M+F F M+F M M M+F M+F

Sex

Variable stress PCMS CMS CMS/CVS

Variable stress Variable stress Variable stress

Variable stress

Social isolation Social isolation Social isolation Social isolation Social isolation Social isolation Social isolation Social isolation Social instability Social instability Social instability Social instability ± isolation Social instability and isolation Social instability and isolation Social instability and isolation Social instability and isolation Social instability and isolation Social instability and isolation Social instability and isolation Social instability, isolation and white noise Social isolation ± early weaning Play deprivation Variable stress

Model

PND 27/44 PND 28 PND 28 PND 23

PND 26 PND 27 PND 27/33

PND 22/35

PND 22/30 PND 25

PND 16

PND 33

PND 35

PND 30/45

PND 30

PND 30

PND 30

PND 30

PND 30

PND 28–32 PND 30 PND 30 PND 30 PND 30 PND 30–32 PND 31 PND 35 PND 31–33 PND 31–33 PND 30 PND 30

Age at stress

1×3 4 weeks 8–10 weeks 4 weeks

2 × 10 1×3 1×3

1×6

1/4 weeks 1×5

10 days

1 × 16

1 × 16

1 × 16/1

1 × 16

1 × 16

1 × 16

1 × 16

1 × 16

6 weeks 16 3 weeks 3 weeks 1/1 × 16 1×5 6 weeks 1 7 weeks 7 weeks 16 days 1 × 16

No. stresses

Hot plate, EPM, LA SI, ASR EPM, OFT, FC, MWM, AMP LA, active avoidance learning EPM, FST, shock probe burying test FC FC Shuttle avoidance and learning test, OF OFT, FST, SP SP, LA, NSFT, EPM, FST EPM, SI EPM, shock-probe burying, SP, food preference

LA

LA, nicotine LA

FC

NOR, spatial object location test Spatial object location test, MWM, alternation task EPM, OFT

FC

Food competition test

Spatial location test

EPM, LDB, SP, PPI LA, AMP LA Restraint stress, EPM FST, SP SI EPM, SI EPM, LDB, LA, NOR SI with ethanol LA SI, Y-Maze, NOR, MWM FST Nicotine LA

Endpoints measured

Zalsman et al. (2015) Suo et al. (2013) Conrad and Winder (2011) Pohl et al. (2007)

Wright et al. (2015) Yee et al. (2012) Tsoory and Richter-Levin (2006)

Schneider et al. (2014) Peleg-Raibstein and Feldon (2011) Wilkin et al. (2012)

Fahlke et al. (1997)

McCormick et al. (2004)

McCormick et al. (2013)

McCormick et al. (2008)

Green and McCormick (2013a)

McCormick et al. (2012)

Morrissey et al. (2011)

Cumming et al. (2014)

McCormick et al. (2010)

McCool and Chappell (2009) Mathews et al. (2008a) Weintraub et al. (2010) Hong et al. (2012) Hodges and McCormick (2015) Doremus-Fitzwater et al. (2009) Butler et al. (2014) Varlinskaya and Spear (2012) Schmidt et al. (2009) Sterlemann et al. (2010) Mathews et al. (2008b) McCormick and Ibrahim (2007)

Reference

Psychopharmacology (2018) 235:909–933 915

Strain

S-D Wistar S-D Wistar S-D S-D S-D Wistar Fischer 344 S-D S-D

S-D L-E Dtg Hs/Ibg Wistar Wistar Wistar S-D Wistar L-E

S-D C57BL/6

CD-1 S-D S-D Wistar Wistar

Wistar

L-E S-D

Holtzman Wistar L-E

S-D L-E

Species

Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats

Rats Rats Mice Mice Rats Rats Rats Rats Rats Rats

Rats Mice

Mice Rats Rats Rats Rats

Rats

Rats Rats

Rats Rats Rats

Rats Rats

Table 2 (continued)

PND 1 PND 1

PND 1 PND 1 PND 1

PND 1 PND 1

PND 1

PND 1 PND 1 PND 1 PND 1 PND 1

NS PND 1

PND 1 PND 23 PND 1 PND 1 PND 1 PND 21 PND 21 PND 21 NS PND 1

PND 33–40 PND 1 PND 22 PND 21 PND 21 PND 21 PND 21 PND 1 NS PND 1 PND 1

Age on arrival

M+F M+F

M+F M+F M+F

M+F M

M+F

M+F M+F M+F M+F M+F

M M

F M M M+F M M M M M+F M

M M+F M M M M M M+F M+F M+F F

Sex

Maternal separation Maternal separation

Maternal separation Maternal separation Maternal separation

Maternal separation Maternal separation

Maternal separation

Maternal separation Maternal separation Maternal separation Maternal separation Maternal separation

CVS CVS Footshock Footshock Footshock Footshock Footshock Footshock Footshock Footshock ± scent exposure Tailshock Maternal separation

CMS CVS CVS CVS CVS CVS CVS CVS CVS CVS CVS F1

Model

PND 2 PND 2

PND 2 PND 2 PND 2

PND 2 PND 2

PND 1/2

PND 12 PND 1 PND 1 PND 1 PND 1

PND 35 PND 2

PND 45 PND 45 PND 25 PND 36/37 NS NS NS PND 35 PND 38 PND 8

PND 40–45 PND 25 PND 27 PND 28 PND 28 PND 28 PND 30 PND 36 PND 37 PND 37 PND 42–49

Age at stress

1 × 10 2 weeks

1 × 10 1×5 1×7

3 h × 12 2 weeks

1h

24 h 1 × 10 2 weeks 3 × 14 2 weeks

80 × 1 4 h × 18

2 weeks 1×7 1 10 3 weeks 2×6 2×6 1×5 1 1×5

1–3 × 3 weeks 2 × 10 1×3 1 × 10 1/2 × 28 4 weeks 6 weeks 1 × 12 1×8 1 × 12 1×7

No. stresses

OFT, LDB LA, cocaine LA NOR, LA, AMP LA, stereotypy behaviour OFT, LDB AMP LA, stereotypy behaviour

Social exploration OFT, EPM, FST, Y-Maze, MWM, SI, RI, tube dominance OFT, EPM, tail suspension EPM FST, SP LDB, SP Paw pressure test, tail flick test, flinch test, FC EPM, formalin test, FST, Morris labyrinth EPM, airpuff startle, SP FC

FST LDB, food preference FC, EPM, OF, MWM ASR OFT, FST OFT, EPM, Y-Maze EPM, MWM LA MWM LDB

FC Cocaine LA, LA OFT, NOR LA, restraint stress MWM LA, AMP LA Radial arm maze ASR, EPM, SP, FST EPM, FC FST, OF, SP OFT, EPM, FC in F2s

Endpoints measured

Spivey et al. (2009) Pritchard et al. (2012)

Huot et al. (2001) Callaghan and Richardson (2012) Spivey et al. (2008) Marin and Planeta (2004) Hensleigh et al. (2011)

Butkevich et al. (2015)

Martini and Valverde (2012) Koehnle and Rinaman (2010) Zhang et al. (2013) Chocyk et al. (2015) Chocyk et al. (2014)

Kubala et al. (2012) Shin et al. (2016)

Reich et al. (2013) Lepsch et al. (2005) Saul et al. (2012) Cruz et al. (2012) Isgor et al. (2004) Kabbaj et al. (2002) Chaby et al. (2015) Bourke and Neigh (2011) Taylor et al. (2013) Harrell et al. (2013) Zaidan and Gaisler-Salomon (2015) Wulsin et al. (2016) Handy et al. (2016) Joseph et al. (2013) Chester et al. (2008) Lyttle et al. (2015) Li et al. (2015) Li et al. (2016) Burke et al. (2011) Uysal et al. (2012) Sarro et al. (2014)

Reference

916 Psychopharmacology (2018) 235:909–933

Strain

S-D Wistar Wistar Wistar Wistar Wistar S-D Wistar Wistar

L-E

S-D

Wistar

CD-1

S-D S-D Wistar Wistar Wistar S-D Wistar S-D S-D S-D

S-D S-D S-D S-D Wistar S-D S-D Wistar

S-D

Wistar

Species

Rats Rats Rats Rats Rats Rats Rats Rats Rats

Rats

Rats

Rats

Mice

Rats Rats Rats Rats Rats Rats Rats Rats Rats Rats

Rats Rats Rats Rats Rats Rats Rats Rats

Rats

Rats

Table 2 (continued)

PND 21

PND 21

PND 25, 60–70 g PND 1 PND 1 PND 1 NS PND 1 PND 21, 80–100 g PND 22

NS PND 1 PND 1 PND 21 PND 1 PND 1 PND 21 PND 1 NS PND 21/35

PND 21

PND 1

PND 1

PND 1

PND 1 PND 1 PND 1 PND 1 PND 1 PND 1 PND 1 PND 1 PND 1

Age on arrival

M

M

M M M+F M+F M+F M+F M M

F M+F M+F M+F M M M M+F M+F M

M

F

M+F

F

M+F M M+F M+F M+F M+F M+F M+F M+F

Sex

Restraint Restraint Restraint Restraint Restraint Restraint Restraint Restraint, EPM and footshock Restraint and EtOH-withdrawal anxiety Scent exposure

Restraint Restraint Restraint Restraint Restraint Restraint Restraint Restraint Restraint Restraint

Maternal separation, food deprivation and footshock Maternal separation and saline injection Maternal separation using T-maze and social isolation Restraint

Maternal separation Maternal separation Maternal separation Maternal separation Maternal separation Maternal separation Maternal separation Maternal separation Maternal separation

Model

PND 33

PND 26

PND 29 PND 30 PND 30–32 PND 31 PND 31 PND 35 PND 42 PND 27

PND 25 PND 24/38 PND 25 PND 26 PND 28 PND 28 PND 28 PND 28 PND 28/35/28 PND 28/42

PND 28

PND 10 and 30

PND 2/9

PND 1 and 38

PND 2/14 PND 4/9/18 PND 9 PND 9 PND 9 PND 9 PND 9 PND 9 PND 9

Age at stress

12 × 2

3 weeks

1×7 1×5 1×5 1×5 1×7 1 1×7 1×4

1×7 1×5 1 h × 10 1×7 1×7 1 1 × 10 1×5 1 × 4/1/1 × 10 1×7

1/1 × 2 weeks

4 and 9

1×8

1 × 7 and 24 h

1×8 24 h 24 h 24 h 24 h 24 h 24 h 24 h 24 h

No. stresses

FC, SI, EPM, FST

SI

FC, LA, EPM, induced-sleep LDB, SP, FC SI, LA Cocaine LA, LA EPM Nicotine LA Ethanol LA LA, restraint stress SP SI OFT, defensive, burying, FST FC, EPM SI EPM, SI SI with ethanol, LA MWM SI with ethanol OFT, EPM, LDB, FC SP, OFT, EPM, AST

FST

Learned helplessness

MWM Swim stress Y-Maze, NOR, EPM ASR, AMP LA FST, EPM, hole-board test OFT NOR, SI, FST NOR, PPI PPI, EPM, hold-board test, maternal behaviour Binge eating

Endpoints measured

Kendig et al. (2011)

Wills et al. (2010)

Zhang and Rosenkranz (2013) Willey and Spear (2013) Doremus-Fitzwater et al. (2009) Varlinskaya et al. (2010) Dayi et al. (2015) Varlinskaya and Spear (2012) Negron-Oyarzo et al. (2014) Luo et al. (2014)

Lee and Noh (2015) Varlinskaya et al. (2013) Lepsch et al. (2005) Ariza Traslavina et al. (2014) Cruz et al. (2008a) Acevedo et al. (2013) Cruz et al. (2012) Anderson et al. (2010) Klein et al. (2010) Bingham et al. (2011)

Ota et al. (2015)

Raftogianni et al. (2012)

Freund et al. (2013)

Hancock et al. (2005)

Cao et al. (2014) Gruss et al. (2008) Marco et al. (2013) Choy and van den Buuse (2008) Llorente et al. (2007) Llorente-Berzal et al. (2013) Zamberletti et al. (2012) Llorente-Berzal et al. (2012) Llorente-Berzal et al. (2011)

Reference

Psychopharmacology (2018) 235:909–933 917

Marquardt et al. (2004) FST PND 1/30

1 × 10

Nishio et al. (2006) EPM PND 14/21

1×5

Moore et al. (2012) Ariza Traslavina et al. (2014) Ariza Traslavina et al. (2014) Tokumo et al. (2006) 1 1/1 × 7 1/1 × 7 1×5 PND 37 PND 26 PND 26 PND 14/21

M+F PND 1

M M+F M+F M+F PND 22–24 PND 21 PND 21 PND 1

M+F

M PND 22–24

PND 1

F PND 1

M+F PND 21

Underwater trauma Metabolic stress Immune stress Sound noise stress ± FST Sound noise stress ± FST Aversive stimulation

Moore et al. (2014)

Operant conditioning, FC, EPM, ASR EPM EPM EPM LA 1 PND 37

PND 28

1×7

RI, SI, maternal behaviour

Toledo-Rodriguez and Sandi (2007) Cordero et al. (2013) LA, NOR, EPM, FC PND 28

1×3

Wright et al. (2013) Wright et al. (2012) Wright et al. (2008) Post et al. (2014) OFT, observation test OFT, predator stress test OFT, scent exposure EPM, plantar test 1×5 1×5 1×5 1 × 5 and 1 PND 37–39 PND 38 PND 40 PND 23

Scent exposure Scent exposure Scent exposure Scent exposure and footshock Scent exposure and elevated platform Scent exposure and EPM Underwater trauma M+F M+F M+F M PND 1 PND 1 PND 1 PND 22

Model Age on arrival

Sex

Age at stress

No. stresses

Reference

Psychopharmacology (2018) 235:909–933

Endpoints measured

918

Fig. 3 Experimental variables that exist in early-life stress studies

animals are exposed. The environment for animals reared inhouse and in a breeding facility may vary greatly and many studies have shown that the presence or absence of environmental enrichment (EE) alone can greatly affect the development of young animals. EE during the time of MS prevented cognitive dysfunction and elevated circulating pro-inflammatory cytokines that was evident in MS pups (do Prado et al. 2016). In early-life stress studies, there is an equal divide between the number of studies using animal suppliers and breeding animals in-house (Table 4). Although differences may exist between animals sourced and animals bred in-house, literature exists to show that the supplier alone is a confounding factor to consider when choosing the animal model. A study looking at suppliers (i.e. Harlan Laboratories, Taconic Farms, and Charles River) revealed supplier-dependent differences among outbred Wistar rats with regard to alcohol intake in that the highest alcohol intake occurred in Harlan-sourced rats (Momeni et al. 2015). Many other comparative studies in the field of alcohol research have also exemplified supplier variances in their findings (Palm et al. 2011a; Palm et al. 2011b; Palm et al. 2012) Table 3 Most commonly used species and strains of animals for earlylife stress studies. Data expressed as percentage employing each strain. The % for each strain is given as a % of the total studies for the species

Strain

L-E L-E L-E S-D

Wistar

Wistar

S-D

S-D Wistar Wistar DDY

DDY

Wistar

Species

Rats Rats Rats Rats

Rats

Rats

Rats

Rats Rats Rats Mice

Mice

Rats

Table 2 (continued)

Drug use studies (n = 39)

Behavioural studies (n = 133)

Rats Sprague-Dawley Wistar Long-Evans Rats Fischer Long-Evans Wistar

70% 17% 28% 31% 86% 1% 22% 30%

Mice CFW C57BL/6J OF1 Mice DDY OF1 CD-1

25% 10% 20% 40% 14% 9% 14% 19%

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Table 4 Source of animals previously used for early-life stress studies. Data expressed as percentage employing each source Source

Drug use (n = 39) (%)

Behaviour (n = 133) (%)

NS

2

8

Bred in-house

48

45

Supplier

50

47

and these reports support the fact that the animal supplier is unfortunately a factor that can cause differences in experimental outcome. Although these studies are in adult rats, to the best of our knowledge there have been no similar studies performed for younger rats. These studies would be beneficial in determining if indeed animal source is related to supplierdependent differences but we can assume that this would hold true in even young animals. For these reasons, animals bred in-house or using the same supplier ensures consistency across studies in a single laboratory but this does not overcome the complexity of comparing findings across numerous laboratories.

Weaning If animals are bred in-house then the precise time of weaning is an important factor to consider but in early-life stress studies there appear to be disparities on when this occurs (Table 5). This raises an important question on when is the appropriate time to wean rodents? In general, at PND 16, pups will begin to eat solid foods and then separation from the mother takes place at PND 21. Numerous studies in rodents have demonstrated that the time point of weaning shapes the behavioural profile of the young. Fahlke et al. (1997) showed that early weaning (PND 16) in rats leads to higher activity levels, lower ethanol intake and preference, and slightly reduced levels of plasma CORT in adulthood compared to the 21-day weaned animals. Early weaning (PND 18) in rats also leads to higher neuropeptide-Y and astrogliosis in the hypothalamus of the adult offspring (Younes-Rapozo et al. 2015). Table 5 Age at weaning used in early-life stress studies. Data expressed as percentage employing each age

PND

NS 21 22 21–22 21–23 23 25 30

Drug use (n = 39) (%)

Behaviour (n = 133) (%)

10 50 30 – 5 – 5 –

22 55 13 1 2 2 3 2

Interestingly, late weaning (PND 28) in C57BL/6J mice triggered less anxious and more explorative behaviour than normally weaned mice in the open field test (OFT) and novel cage tests (Richter et al. 2016). In early-life stress studies, PND 21 is both the youngest age of weaning seen in the literature as well as the most commonly employed (over 50% of studies, Table 5). Other studies have employed later weaning ages such as PND 23 (Chester et al. 2008; Pohl et al. 2007), PND 25 (Wulsin et al. 2016), and PND 30 (Zaidan and Gaisler-Salomon 2015). However, as the aforementioned studies highlight, late weaning can have long-lasting effects on offspring and produce a different behavioural characteristics in these offspring.

Housing Regardless of whether animals are sourced or bred in-house, the housing conditions for the young animals are a key determinant to consider when designing an early-life stress study. This accounts not only for EE, as discussed earlier, but the social conditions for the animals, i.e. single vs. group housing. Social play during adolescence, including play fighting, is crucial for the development of adult social competence (Green and McCormick 2013b). Between the ages PND 28 and 35 in the rat, the adolescent animal demonstrates significant increases in social play and activity, exhibiting an inverted U-shaped ontogenetic pattern (Varlinskaya and Spear 2015; Himmler et al. 2013). By employing single housing during adolescence, which is quite common in early-life stress studies (Table 6), the animals are socially deprived, and it is thought that this deprivation may play an important role in the alteration of development of behaviour and brain relating to chronic social stress (Auger and Olesen 2009; Siviy et al. 2011). Social deprivation in adolescence is used in itself as a model of early-life stress called ‘social isolation’ and this will be discussed later. The use of single housing with other stress procedures stems from the fact that housing juvenile rats in an environmentally enriched or social environment following the stress protocol could attenuate many of the adult behavioural, physiological, and neurobiological stress responses. Single housing has been Table 6 Housing of animals in early-life stress studies. Data expressed as percentage employing each condition

PND

Drug use (n = 39) (%)

Behaviour (n = 133) (%)

NS Single Paired 3–5/cage 4/cage 4–6/cage 6+/cage

4 17 21 13 25 21 –

12 22 21 20 12 8 1

920

used with stress procedures such as social defeat (Iniguez et al. 2014; Warren et al. 2014; Vidal et al. 2007), variable stress (Wilkin et al. 2012; Wright et al. 2015; Conrad and Winder 2011), MS (Hancock et al. 2005; Lancaster 1998), and restraint (Bingham et al. 2011; Wills et al. 2010) to try and overcome this buffering effect of social housing. In these cases however, the control animals are also singly housed to control for the stress associated with this procedure. Some studies have used single housing for stressed animals and group housing for control animals and have included single housing as ‘part of the stress procedure’ (Coppens et al. 2014; Bourke and Neigh 2011; Harrell et al. 2013). When group housing is employed, pair-housing or three to five animals per cage are quite popular protocols (Table 6). Sex Most early-life stress studies include only male animals and so the possible sex differences in the outcome of stress has only been partially addressed. In humans, gender has shown to be an important determinant of the stress response with females showing higher peak levels than males (Romeo 2010). In rodents, there is also sex specificity seen in the effects of stress with male adolescents showing facilitation of the neuroendocrine response and facilitation of the feedback inhibition after stress cessation whereas females do not show this [reviewed by Romeo (2010)]. The mechanism behind this difference is the result of the regulation of the HPA-axis function by gonadal hormones which emerges in adolescence (Romeo 2010; McCormick and Mathews 2007). When examining early-life stress studies and their consequences on drug intake, only 32% of studies used female animals. Among the studies including males and females, many sex differences in early-life stress effects were reported. Social isolation has been shown to increase ethanol intake in male mice and decrease ethanol intake in female mice (Moriya et al. 2015; Advani et al. 2007) and the same effects have been found after MS (Roman et al. 2005). Lopez et al. (2011) also studied social isolation during adolescence and the consequences on ethanol intake in adulthood and found no sex differences. Although the social isolation occurred for similar lengths of time in these studies, the protocol for measuring ethanol consumption was continuous and intermittent access, respectively, which may explain the discrepancy in results. When examining early-life stress studies and their consequences on behavioural outcomes, only 36% of studies used female animals. Studies that used both sexes have shown that after social isolation, male mice have higher locomotor activity (LA) and anxiolytic-like behaviour compared to controls and this effect is not seen in females (Guo et al. 2004). Earlyadolescent social defeat impairs strategy-shifting in adulthood in males (Snyder et al. 2015b) but these deficits are not found in females (Snyder et al. 2015a). Although it appears that

Psychopharmacology (2018) 235:909–933

males may be more sensitive to early-life stress, many other studies have reported stress effects only seen in females but not males. Females exposed to chronic mild variable stress (CMVS) show reduced burying, decreased SP, and exaggerated CORT levels in response to cold-water immersion stress (Pohl et al. 2007). On the other hand, it is worth mentioning that no sex differences have also been reported after early-life stress. Outcomes such as social habituation and recognition are diminished by adolescent social isolation in rats and similar effects are seen in both males and females (Kercmar et al. 2011). While the stress effect on pain outcomes are also similar for males and females in that rats of both sexes exposed to short-term MS both exhibit enhanced pain sensitivity in the formalin test (Butkevich et al. 2015). This section highlights the sex differences that occur in response to early-life stress and how this variation in response is also related to the type of stress procedure, the severity of the procedure, and the outcome measured. Males seem to be more susceptible to anxiety-like and cognitive deficits in later life in response to stress procedures such as sporadic, variable stress, social defeat, and social isolation whereas females seem to be more susceptible to depressive-like effects in later life in response to stress procedures such as social isolation and CMVS.

Stress model Since different types of stress can elicit qualitatively different patterns of physiological stress responses and therefore, different patterns of behavioural responses, we reviewed each model of stress used in early-life studies with regard to protocols employed (timing, frequency, duration), severity of procedure, appropriate controls, and clinical relevance. Model type Many models of early-life stress exist and stressors include social defeat, social isolation, social instability, MS, restraint stress, yohimbine injection, aversive stimulation, underwater trauma, footshock/tailshock, and predatory scent exposure (Table 7). The most commonly employed model of stress when investigating drug intake is social isolation with 40% of studies using this procedure. When investigating behavioural outcomes, use of multiple stressors is most common with 16% of studies using this model, followed closely by MS and social defeat (15% each) (Table 7). Maternal separation Maternal separation is a lack or loss of parental stimulation and is a potent stressor during early-life (Fig. 4). As a stressor it produces immediate effects which can result in wide-spread dysregulation of physiological and behavioural responses suggesting that the quality of these first relationships program the infant to adapt to later-life environments (Rincon-Cortes and Sullivan 2014). Maternal

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Table 7 Models of stress used in early-life stress studies. Data expressed as percentage employing each model Drug use (n = 39) Model

Behaviour (n = 133) % Papers

Model

% Papers

Restraint

3

Metabolic/immune stress

1

Yohimbine injection

3

Underwater trauma

1

Aversive stimulation Multiple stressors

3 5

Social instability Scent exposure

2 3

Footshock Social defeat

13 13

Footshock/tailshock Restraint

5 12

Maternal separation

23

Social isolation

14

Social isolation

40

CVS/CMS Maternal separation

15 15

Social defeat Multiple stressors

15 16

separation is the only stress procedure in early-life studies that is employed before adolescence, i.e. between PND 1 and 21 (Tables 1 and 2). A recent in-depth review by Nylander and Roman (2013) investigating MS protocols stated that there are several models and protocols and each generates different outcomes. In the various protocols, the separations are done repeatedly, either daily or occasionally. Maternal separation can be short separations (5–15 min/day) used to simulate naturalistic conditions or repeated separations for longer periods of time (180–360 min/day) used to disrupt the mother–pup interactions that are vital for normal development and it is this latter model that is commonly used as a model of early-life stress. Maternal deprivation on the other hand is not used consistently and can refer to occasional 24 h separation or 180–360 min separations from the mother. In the mid-1950s, psychologist Seymour Levine studied the effects of early trauma on animal behaviour and interestingly found that brief separation from the dam proved protective as pups were ‘less fearful’ and resistant to a stress challenge in adulthood (Levine 1957; Levine and Lewis 1959). Opposing results were later found with prolonged MS in that separation resulted in an exaggerated stress response in adulthood (Plotsky and Meaney 1993; Francis and Meaney 1999; Kaffman and Meaney 2007).

Fig. 4 Maternal separation in rodents

Social defeat Social defeat is an intermittent, short-lasting social stressor that can have long-lasting effects on brain and behaviour (Buwalda et al. 2011). In social defeat stress, the intruder animal (experimental animal) experiences a large and sustained rise in heart rate, core temperature, and blood pressure and these elevations take hours to return to resting level (Covington 3rd and Miczek, 2001; Tornatzky and Miczek 1993). In stress research, social defeat is simulated in the resident–intruder paradigm. Here, experimental animals are placed into the territory of an aggressive resident animal after which the intruder is attacked and defeated by the resident (Fig. 5). In rats, the defeat stress is most commonly performed intermittently for 4 exposures (Burke and Miczek 2015) or for 10 exposures in mice (Furuta et al. 2015; Buwalda et al. 2013). In rats, the defeat posture is characterised by a supine posture with limp extremities and emission of loud and frequent ultrasonic 22 kHz vocalisations, whereas in mice, the defeat posture is characterised by a upright posture with limp forearms, head angled upward, and audible vocal signals (Miczek et al. 2008). To ensure the required outcome of the social confrontation, residents will usually be larger and will be familiarised with fighting prior to the experimental defeat (Buwalda et al. 2011). Social defeat can be used in both adult and juvenile animals (Burke and Miczek 2014). A single experience of social defeat stress can have persistent neurobiological and behavioural consequences and repeated episodes amplify and prolong these consequences. Social isolation Social isolation in rodents may model social exclusion from peer groups or peer victimisation behaviour in adolescence. In rodents, deprivation of social contact can affect the development of normal social behaviour. These effects are attributed to not only the deprivation of social contact but the deprivation of play fighting which normally peak in adolescence. Social play during adolescence is crucial for the development of adult social competence (Bell et al. 2009; Bell et al. 2010). Social isolation is a simple procedure and involves single housing of the animals, usually after weaning and for long periods of time (1 to 13 weeks, Fig. 6). Although this procedure is referred to as a social stressor, it differs from other chronic stress procedures in that its consequences do not

Fig. 5 Social defeat stress in rodents. (Adapted from Wood (2014))

922

Fig. 6 Social isolation stress in rodents

involve prolonged high elevations of glucocorticoids. Hence, there is an argument as to whether social isolation elevates HPA function (Lukkes et al. 2009; Weiss et al. 2001; Serra et al. 2005). Nevertheless, the effects of social deprivation are widely reported and result in long-lasting effects in these offspring. Social instability Social instability is most commonly employed with other stress procedures such as social defeat (Kovalenko et al. 2014) or social isolation (Morrissey et al. 2011; Green and McCormick 2013a; McCormick 2010; Cumming et al. 2014) as it is thought that rodents can habituate to novel partners. The hypothesis is that social instability will delay the recovery of CORT levels after defeat or isolation stress and therefore, inhibit habituation (McCormick 2010). However, social instability has been used alone in studies as a stress procedure (Schmidt et al. 2009; Sterlemann et al. 2010; Mathews et al. 2008b). The procedure involves daily 1 h isolation followed by pairing the experimental animal with an unfamiliar partner (exposed to the same protocol) and cage but it can also involve group compositions with the groups in each cage being changed twice per week for several weeks (Fig. 7) (Schmidt et al. 2009). Restraint stress Restraint stress is carried out by confining the animal in small spaces such as small containers or restrainers (Fig. 8). This procedure activates the HPA response causing an increase in glucocorticoid release; however, habituation to the endocrine response with this procedure is common after repeated exposure (Romeo 2010; Buwalda et al. 2011). Restraint stress can be used in both juvenile and adult studies and studies have shown that employing restraint stress during early-life creates a prolonged rise in plasma CORT compared to the HPA response after restraint stress in adults (Buwalda et al. 2011).

Fig. 7 Social instability stress in rodents

Psychopharmacology (2018) 235:909–933

Fig. 8 Restraint stress in rodents. (Chattarji et al. 2015)

Footshock/tailshock Shock stress can be applied in the form of electric pulses to the feet or tail of the animal (Fig. 9). It can be delivered as a low intensity or high intensity shock and can be employed as an acute procedure occurring only once or it can be used chronically over an extended period of time. Although these studies were regularly employed as a stress procedure in early preclinical studies, they are less commonly employed today with only 13% of early-life studies using this procedure when examining consequences on drug consumption outcomes and only 5% when examining behavioural outcomes (Joseph et al. 2013; Chaby et al. 2015; Lyttle et al. 2015; Li et al. 2015; Burke et al. 2011; Uysal et al. 2012; Kubala et al. 2012). Nonetheless, among alcohol studies in the literature, footshock stress was shown to be a most prominent procedure at enhancing alcohol intake (Noori et al. 2014). Scent exposure Scent exposure, as a model of stress, uses predator odour that results in the animal displaying behavioural responses associated with predation threat. 2,3,5-Trimethyl3-thiazoline (TMT) is one such predator odour which is a derivative of fox-faeces or cat odour in the form of hair and dander can also be used. TMT (10%) is generally placed onto a cotton ball/cloth below the metal grid floor of the animal’s cage or within close proximity to an arena/cage (Fig. 10) (Post et al. 2014; Toledo-Rodriguez and Sandi 2007; Cordero et al. 2013). Cat odour is acquired by using cat hair or dander, by rubbing cat dander and hair onto strips of cloth, or by using a piece of the cat collar (Wright et al. 2008; Wright et al. 2013; Kendig et al. 2011). It is thought that natural cat odour is more effective at eliciting defensive behaviours and activating the neural defence circuits compared to synthetic derivatives (Wright et al. 2013).

Fig. 9 Footshock stress in rodents

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923

(Charney et al. 1983) and animals (Davis et al. 1979). It is usually given as an i.p. injection at a dose of approximately 2.5 mg/kg just before outcomes are to be measured. As a stress model, it is rarely used in early-life stress studies with only one study in the literature to investigate how yohimbine injections in late adolescence affects later cocaine consumption (Anker and Carroll 2010). Fig. 10 Predator stress in rodents

Underwater trauma Underwater trauma is used as a stress model (traumatic stress experience) in experimental animals but may be more relatable to PTSD (Moore et al. 2012) than early-life stress. The underwater trauma is performed in a 60-s procedure. Animals are allowed to swim for 30 or 40 s in a large tank of saline and then are gently submerged for 30 or 20 s, respectively (Fig. 11). Afterwards, animals are removed and dried. Since forced swim is also used as a stress model and the water exposure and swim experience may alone have an aversive effect, the control animals for such a procedure are allowed to swim for the 60 s. Saline is generally used to minimise the effects of the submersion on the animal’s mucous membranes (Moore et al. 2014). This is quite a new animal stress model and so has only been employed in two early-life stress studies to date (Moore et al. 2014; Moore et al. 2012). Yohimbine injection Yohimbine is a pharmacological stressor used to initiate a stress response. Yohimbine, a norepinephrine α2 receptor antagonist, increases norepinephrine release in several brain areas implicated in stress, including the amygdala (Feltenstein and See 2006; Khoshbouei et al. 2002), and has been shown to produce anxiety-like behaviours in humans

Fig. 11 Underwater trauma in rodents. (Adapted from Abelaira et al. (2013))

Multiple stressors Multiple stressors models such as CVS and CMS use a combination of the above-mentioned stress procedures with additional procedures such as elevated platform, forced swim, wet or soiled bedding, cold exposure, food and water deprivation, vibration/shaker, tilted cages, overcrowding, light/dark cycle reversal, tail clamp, stroboscopic light, overnight illumination, white noise, novel environment, litter-shifting, ether exposure, loud noise, taxidermied bobcat, cat vocalisations, and hypoxia (Fig. 12). The hypothesis of this model is that the combination of procedures will reduce the risk of habituation as they are exposed in an unpredictable manner. Such stress models like CVS are the most extreme of all the models discussed with animals being exposed chronically (10 or more days) to 10 or more different stressors combining an array of different types of stressors. Although in the clinical scenario exposure to multiple stressors can be quite common in early-life (Dong et al. 2004), individually these stressors may not be clinically translatable but combined they create a severe and worst case scenario with regards to stress and the consequences are both intense and long-lasting. Timing of stress In early-life, CORT release is more long-lasting than in adulthood and this appears to be attributable to immature development of the negative feedback systems rather than due to differences in CORT clearance rates (Goldman et al. 1973; Vazquez and Akil 1993). Explorations of adolescent stress in preclinical studies involves a wide age range (PND 25–59) which results in many different ages used at the onset of stress exposure. As highlighted previously it is to be expected that outcomes of stress are stress-specific, with different stressors resulting in different outcomes, but the same stress procedure at one age in early-life is likely to yield different outcomes when exposed at a slightly different age given the rapidity of change (Green and McCormick 2013b). In early-life stress, the majority of studies investigating drug intake outcomes have focused on stress exposure during early-adolescence (PND 15–28) and studies investigating behavioural outcomes have focused on stress exposure during mid-adolescence (PND 29–42) (Table 8). Social isolation as a stressor in rats seems to consistently increase alcohol intake regardless of the age of animal at the start of isolation for example beginning in early adolescence between PND 21 and 31 (Deehan et al. 2007; Juarez and

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Fig. 12 Multiple stressors in rodents. (Adapted from Abelaira et al. (2013) and Chattarji et al. (2015)

Vazquez-Cortes 2003; Butler et al. 2014) or beginning in midadolescence between PND 43 and 50 (Ehlers et al. 2007). On the other hand, MS in rats beginning in the first few days of life (PND 1–2) results in increased alcohol intake in adulthood (Roman et al. 2005; Huot et al. 2001) but remains unchanged in adulthood if MS begins later on at PND 9 (Penasco et al. 2015). Social defeat stress on PND 28 in mice show increased social avoidance and decreased social interaction (Warren et al. 2014), and when exposed to this same stressor on PND 21, mice show similar outcomes with increased avoidance and submissive behaviours (Garcia-Pardo et al. 2015; RodriguezArias et al. 2016). Restraint stress does not alter depressivelike behaviour in rats after being exposed on PND 25 or 28 (Lee and Noh 2015; Anderson et al. 2010; Bingham et al. 2011), but when exposed on PND 42, depressive-like behaviour was increased in rats (Negron-Oyarzo et al. 2014). These results highlight the stress-specific outcomes and that the interaction between the stressor and the timing of the stressor ultimately determines the outcome. With most studies investigating the early adolescent period and the consequences of stress during this time, it appears that this developmental stage may be most vulnerable to stress compared to later adolescence. Frequency of stress exposures The frequency of stress exposures refers to the number of stressful experiences the offspring is exposed to and this can also influence behavioural outcomes in later life. Table 9 shows, for each stress procedure, the frequency of stress exposures most commonly used in early-life stress studies. Of course, as we can see the number of stress exposures varies between procedures and can vary between species but they can also vary between laboratories and studies, meaning that Table 8 Age of animals used across early-life stress studies. Data expressed as percentage employing each age PND

Drug use (n = 39) (%)

Behaviour (n = 133) (%)

PND 1–14 PND 15–28 PND 29–42 PND 43–56

23 43 27 7

20 35 39 6

many protocols exist for a single procedure. In early-life stress studies using social defeat as the stressor, most studies expose the animal to aggressive residents four or five times in both mice and rats (Montagud-Romero et al. 2015; Garcia-Pardo et al. 2014; Novick et al. 2013; Coppens et al. 2012). Yet, some protocols involve only 2 exposures (Vidal et al. 2011a), 7 exposures (Bingham et al. 2011; Ver Hoeve et al. 2013), or as many as 10 exposures (Iniguez et al. 2014; Huang et al. 2013; Furuta et al. 2015). MS is another stress procedure which can vary greatly in the number of experiences the offspring are exposed to. Generally between 12 and 14 separations are most commonly employed, however as many as 21 separations have previously been used with this stress model (Roman et al. 2005). Similar extreme protocols are seen when variable stress is used in that generally 3 or 14 exposures are used when investigating behavioural or drug use outcomes, respectively, but as many as 28 exposures have been employed previously (Isgor et al. 2004). Although this wide range of exposures in each of these stress procedures provides more information on the severity of the stress and how they translate to the severity of outcome, it makes it quite difficult to compare studies and to know which frequency of exposures translates to the clinical scenario. The question for future research should be what is occurring clinically and how can we translate this in our model, rather than how many exposures of this procedure do I need to use to find a significant effect?

Table 9 Number of stress exposures used across early-life stress studies. Data expressed as number of stress exposures employed for each model

Social defeat Social instability Maternal separation Footshock Restraint Variable stress Scent exposure

Drug use (n = 39)

Behaviour (n = 133)

×4 – × 12

×5 × 16 × 14

× 10 ×5 × 14 –

×5 ×7 ×3 ×5

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925

Duration of stress exposure

it is important to know what is the most common length of time that these stressors are experienced clinically?

In addition to altering the frequency of exposures, stress protocols can be administered in a chronic pattern or as acute stress. This is more appropriate when discussing stress models such as social isolation, social instability, and MS. The stress may be applied once daily, numerous times a day, or every second day but the duration of the stress can be anywhere from 24 h to 16 weeks (Table 10). For example, social isolation and social instability are continuous stressors so that the animal is housed in these stressful conditions but the length of time these conditions are maintained differs between studies. Whereas, with MS the offspring can be exposed to any amount of separations but the separation itself may last 15 min, 90 min, or 24 h. Regardless of the procedure applied, the most popular duration of exposure to stress is between 1 and 10 days regardless of the outcome being measured (drug use or behaviour). Guo et al. (2004) compared the behavioural difference of mice isolated for 4, 8, 12, or 16 weeks. Male mice showed higher LA after 4, 8, or 12 weeks of isolation but this effect was not apparent after 16 weeks of isolation. Male mice showed anxious-like behavior at all time points except after 4 weeks of isolation. Social instability also shows varying results depending on the duration of stress exposure. Female mice have more depressive-like behaviour immediately after 16 days of social instability compared to controls but this effect is not seen after 2 weeks (Mathews et al. 2008b). However, if this social instability stress is applied for 7 weeks then the long-lasting effects can be seen up to 12 months after stress cessation as seen in cognitive impairments in the MWM (Sterlemann et al. 2010). MS is one of the most variable procedures which we previously mentioned and numerous protocols and durations of exposures are utilised. The duration of the separation replicates different environmental settings. For example, shorter separations from the dam (15 min) mimic naturalistic conditions. To replicate a risky environment and early-life stress, longer periods of separations are used (180–360 min) to disrupt the mother–pup interactions. Once more, the wide range of duration exposures in each of these procedures makes it difficult to compare studies and to know which exposure duration can be translated to the clinical scenario. For each stress procedure,

Appropriate controls The choice of control group in a stress study is vital for the evaluation of results. Common experimental groups that are used as controls include undisturbed, animal facility reared, handled, socially reared, saline treated, or exploration groups. The most commonly used control groups in early-life stress studies are undisturbed animals with 31–34% of studies (Table 11). Unfortunately, control groups which are undisturbed or animal facility reared (Bingham et al. 2011; Ver Hoeve et al. 2013; Mathews et al. 2008a) are left in understimulated surroundings that alone may generate effects in the offspring and so may not act as a suitable control. Therefore, control groups such as handled groups (Wilkin et al. 2012; Wright et al. 2015; Callaghan and Richardson 2012) may be better for early-life stress studies. With regard to HPA axis function, briefly handled animals have a low stress response compared to non-handled animals (Pryce and Feldon 2003; Meaney 2001). Although, if handled control groups are to be employed, it is of upmost importance that the handling by the experimenter and the general husbandry and housing conditions are kept consistent, especially in stress studies. Exploration groups are generally used in protocols where the experimental animal is introduced into a novel environment. For example, in the social defeat stress test, the experimental animal is placed into a resident’s cage for the duration of the stress exposure (Burke et al. 2013; Watt et al. 2009). Control animals can therefore be placed into a clean, novel cage for the same period of time to control for both the environment and the handling. This ensures that the effects found are due solely to the defeat stress rather than due to environmental stress. This type of control is preferable as the animals are being treated the exact same, except for the stressful experience. Socially reared control groups are used more often in social isolation or instability protocols (Schmidt et al. 2009; Meng et al. 2010). The animals are handled in the same way but the social environment that they are reared in is either isolated or social. Of particular concern, however, is the use of controls which are unrelated to the experimental groups. This is most notable when the experimental animal undergoes

Table 10 Duration of stress exposure across early-life stress studies. Drug use (n = 39) and behaviour (n = 133) studies. Data expressed as percentage employing each period Duration of exposure

Drug use Behaviour

24 h (%)

1–10 days (%)

2–3 weeks (%)

4–5 weeks (%)

5–6 weeks (%)

6–7 weeks (%)

8–9 weeks (%)

13–16 weeks (%)

16 weeks (%)

7 6

47 62

19 21

– 5

14 –

– 4

9 2

5 –

– 1

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Table 11 Controls previously used for early-life stress studies. Data expressed as percentage employing each control Drug use (n = 39)

Behaviour (n = 133)

Model

% Papers

Model

% Papers

EE

2

No control

1

Saline

2

Saline

1

Baseline Handled

2 5

NS Handled

6 15

No control Exploration group

5 12

Socially reared Exploration group

23 23

Undisturbed

34

Undisturbed

31

Socially reared

37

a stressful experience and is then singly housed whereas the control groups are group housed (Bourke and Neigh 2011; Harrell et al. 2013). Here the authors justify this protocol by portraying single housing a part of the ‘stress experience’ but if one is not controlling for this then we cannot know if the effects found are due to the stress or the single housing. Again, it is very important that the handling, general husbandry, and conditions are kept consistent for both experimental and control groups, especially in stress studies. Clinical relevance As with all animal models in preclinical research, each of these stress models must be reviewed in terms of clinical relevance and in particular in terms of construct, face, and predictive validity. This longstanding framework of three validators allows researchers to systematically review animal models in terms of validity and their strengths and weaknesses (McKinney 1989; Kornetsky 1989). Current animal models of stress have limitations such as weak validation and so generating convincing and meaningful animal models of stress is a major challenge. Construct validity can also be referred to as etiologic validity and it refers to the disease or disorder relevance of the methods by which a model is fashioned. This can be simplified further in that the methods causing the disease or disorder in humans should be the same methods employed in the preclinical setting. In the stress model, investigators would accomplish construct validity by exposing the animal to the etiologic processes that cause the stress in humans (Nestler and Hyman 2010). By doing this, one can then replicate the neural and behavioural features that are associated with stress in humans. Therefore, when comparing these above-mentioned models of stress used in early-life stress studies, it is clear that a lack of construct validity exists. We previously highlighted that the lead causes of early-life stress in humans are parental divorce, family violence, economic adversity, mental illness, parental death,

parental emotional abuse, sexual abuse, witnessing physical violence, peer emotional, peer physical abuse, and emotional and physical neglect (Green et al. 2010; Schalinski et al. 2016). Although it is not possible to model all of these experiences in animals, many of these experiences can be. MS shows high constructive validity as it models parental neglect, both emotional and physical. Social defeat models physical and emotional abuse as well as peer victimisation and bullying. Social isolation also models neglect relating to peers rather than parental. Unfortunately, other stress models such as restraint stress, yohimbine injection, shock stress, and scent exposure lack constructive validity and so may not be clinically relevant for modelling early-life stress. Face validity refers to the anatomical, biochemical, and behavioural features of the human condition that should be replicated in the animal model. Of course, the exact neurobiological processes that occur in humans for most diseases or disorders are unknown and so most preclinical studies rely on behavioural features to achieve face validity. Yet, Nestler and Hyman (2010) highlight that a given disease or disorder can be quite variable and therefore, judgments of face validity will often be challenged and researchers typically defend their choice of animal model and its validity. With regards to stress exposure, it results in activation of the HPA-axis which, in brief, involves increased hypothalamic CRF release and consequently increased glucocorticoid production (Rincon-Cortes and Sullivan 2014). Therefore, when comparing these above-mentioned models of stress used in early-life stress studies, it appears that endocrine face validity exists in most models as most have been shown to increase CORT release. Of course, the long-term consequences of stress in the brain are still under investigation both clinically and preclinically and so this makes the task of accomplishing face validity in animal stress models. The habituation to stress however, is not something that occurs clinically and so stress procedures such as restraint stress and shock stress, where habituation is common, may lack face validity. Predictive validity often involves pharmacological validity and relates to the response to treatments. In an ideal animal model, the effects of a pharmacological treatment would predict the response or effect of that treatment in humans. Again, as with face validity, many preclinical models rely on behaviour as its readout and will compare to existing reference drugs that act in a similar manner (Nestler and Hyman 2010). Although the purpose of this review is to examine the stress models, rather than pharmacological treatments for stress, it is worth noting that if the future goal of a preclinical study is to access a compound for treating the consequences of stress, then it is vital that the model has not only construct and face validity, but that it also has predictive validity for how these compounds will respond in humans. All in all, each stress model has its own strengths and weaknesses yet it appears that social stressors such as social defeat, social isolation, and MS may be the most

Psychopharmacology (2018) 235:909–933

appropriate models to employ in early-life stress studies in terms of construct and face validity and that relates most closely to the clinical scenario in terms of stress experiences and being clinically relevant, something that is becoming more and more important in preclinical research.

Conclusions The previous sections have focused on the range of experimental parameters that are important for an animal model of early-life stress. Overall, it is clear that there is a large diversity and little consistency among these studies and so the interpretation of these results and which ones are more clinically relevant are difficult. &

& &

&

&

&

For animals being used, it is important to choose the most appropriate species and strain relevant for each study; however, the literature would benefit from having a species and strain comparison study to look at the difference in outcomes across strains. Breeding animals in-house and weaning them at PND 2122 is desirable but if not feasible then the use of the same supplier ensures some consistency between studies. Regardless of animal source, all details regarding weight and age of the animals must be disclosed in order to allow comparison between studies and the use of both males and females is crucial for studies going forward. For early-life stress studies, the model of stress is pivotal to the study design should reflect salient features of the clinical situation. It is clear that regarding construct and face validity that the social stressors such as social defeat or MS are the most relevant to the clinical scenario. The early adolescent period seems to be the most vulnerable period for stress exposure and long-term consequences, but studies comparing different time points of stress exposure would be quite valuable in separating out this complex development period. Similarly to this, multiple frequencies and durations of stress exposure would help in mimicking each possible clinical pattern of exposure while also determining the developmental timeline and if the inverted U-shape exists with regard to outcomes based on severity of stressful experiences.

By keeping these parameters as clinically relevant as possible, it will also allow us to be more confident in the results obtained and confident that the human situation is being replicated as closely as possible. The standardisation of these simple stress procedures means that results will be more comparable between studies and that results generated will give us a more robust understanding of what can and may be happening in the human and veterinary clinic.

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