Animal Models

Human babies seem to have their own inborn temperament and personalities evidenced in the nature of their attention spans, reactivity to frustration, degree of activity and locomotion, developmental milestone timetable, food preferences and appetite, etc. Different animal species also present diversity of behaviors and corresponding neurobiological states that underlie behavior. For example, the obese Zucker fa/fa rat presents metabolic changes as early as 3-5 weeks of age (Beck, 2000). Increased concentrations of neuropeptide Y (NPY) are evidenced as early as post-natal day (pnd) 16, upon weaning on pnd 30, and into adulthood (Beck et al., 1992). In response to running stress (Richard et al., 1996) the obese Zucker rat generates increases in gene expression for the receptor of the stress neurohormone initiator, corticotropin releasing hormone receptor 1 (CRH-R1) in the paraventricular nucleus (PVN) of the hypothalamus. This is later accompanied by increases in corticosterone concentrations for later negative feedback to cool stress arousal as noted in section 1.41. This process is potentiated by concurrent decreases in the expression of the corticotropin releasing hormone receptor 2 (CRH-R2) and neurotensin receptors (Beck, 2000) in the ventromedial nucleus (VMN) of the hypothalamus. This strain has consistently higher basal plasma concentrations of corticosterone when compared to lean counterparts (Livingston et al., 2000), reflecting that this strain has difficulty in regulating the stress response even during resting states. This strain’s adrenocortical sensitivity (Livingston et al., 2000) may be due to the effects of (Tannenbaum et al., 1997) diet selection on the secretion of adrenocorticotropin hormone (ACTH), corticosterone, and glucose on sustained hypothalamic-pituitary-adrenal axis (HPA) activity.

Leptin signals for the leptin peptide itself are found defective in the obese ob/ob mouse (Beck, 2000). A mutation for the leptin gene prevents this peptide’s production. Leptin’s injection into the brain ventricles regulates the ob/ob mouse food intake. Urocortin also decreases food consumption and body weight by acting on the expression of the CRH-R2 (Beck, 2000; Bakashi & Kalin, 2001) in the paraventricular nucleus of the hypothalamus. Temporary disruption of either the arcuate (ARC) and paraventricular (PVN) nuclei of the hypothalamus (Choi & Dallman, 1999), along with dysregulated NPY activity (Beck, 2000), corresponds to noted alterations in leptin and insulin levels and increased weight gain in the Sprague-Dawley and Zucker strains, respectively. Temporary lesioning of the ventromedial hypothalamus did little to influence appetite and weight gain, but stimulation suppressed feeding for less than one hour (Ruffin & Nicolaidis, 1999). The literature seems to suggest that the dysregulated expression of neuropeptide receptors or increased concentrations of neuropeptides (e.g. NPY, leptin, galanin, neurotensin, CRH-R2, etc.) along with dysregulation of one or many hypothalamic nuclei seems to underlie hypersecretion of glucose and insulin associated with obesity. There is indeed a neural basis for increased food consumption and the development of obesity.

Certain rat strains, like the Lewis strain, are more susceptible for acquiring rheumatoid arthritis-induced streptococcal cell wall peptidoglycan polysaccharide (SCW) infection (Sternberg et al., 1989) when compared to the Fischer F344/N strain. The Lewis strain has lower corticosterone levels and higher immune-related thymus weights in response to infection. The Fischer F344/N rat on the other hand can mount higher plasma corticosterone levels in response to infection as well as to injection of the proinflammatory interleukin-1alpha (IL-1a). Both strains and their related counterpart, Sprague-Dawley, the maternal strain for inbred F344/N and Lewis strains (Dhabnar et al., 1993) also present different behavioral and neurobiological responses to stress. The Fischer F344/N strain presents low morning basal corticosterone levels and significant increases in stress-related morning corticosterone levels. The Fischer rat also presents higher evening basal corticosterone levels along with many other strains (Gomez et al., 1996) and increases in both morning and evening corticosterone levels during and with recovery from stress (Dhabner et al. 1993, 1995, 1997). In addition to increases in corticosterone, the Fisher F344/N rat also shows elevated ACTH levels in response to stress (Sternberg et al., 1992; Herman et al., 1999).

The Lewis rat presents very low morning basal corticosterone levels and mounts delayed, but significant and brief (Dhabhar et al., 1997) corticosterone increases to stressful conditions (Dhabner et al., 1993, 1995, 1997; Windle et al., 1998). Evening basal corticosterone levels tend to be very low in the Lewis rat (Gomez et. Al., 1996). Although corticosterone levels are high during evening stress, unlike the Fischer F344/N strain the Lewis strain’s recovery levels of corticosterone are low. Lower corticosterone levels may be suggestive of strain-related involvement of other mechanisms to cool down from stress, e.g. anti-inflammatory cytokines. Furthermore, the Fischer F344/N strain is more likely to mount a higher corticosterone response to exogenous CRH at 10 and 30 minutes than the Lewis strain (Windle et al., 1998) and is not as efficient at suppressing ACTH response to dexamethasone (DEX) challenge (Zelazowski et al., 1992). The Lewis strain tends to exhibit 40% lower CRH, ACTH and POMC plasma levels (Calogero et al., 1992; Zelazowski et al., 1992) throughout the day and more efficiently suppresses ACTH in response to exogenous steroid. Both the Sprague-Dawley and Lewis strains tend to show renewed ACTH responses to novelty conditions even when novelty immediately followed previously experienced stress (Dhabhar et al., 1997). The Fischer F344/N rat does not demonstrate corresponding increases in this stress hormone in response to novelty. In response to swim, open-field, and restraint stressors the Lewis strain tends to present lower overall concentrations of ACTH and corticosterone when compared with Fischer F344/N (Sternberg et al., 1992). The former also tends to show signs of immobility after 5 minutes and an inability to remain afloat during the swim stress test when compared with the Fischer F344/N’s greater adaptability and ability to remain afloat (Sternberg et al., 1992) suggesting corticosterone’s role in negative feedback and mediating behavioral adapability during acute.

As far as the receptors to which corticosterone binds, the Lewis rat shows increases in corticosterone binding to the Type I receptor, the mineralocorticoid receptor, in the pituitary gland (Dhabhar et al., 1993), but significant decreases in hypothalamic Type I receptor binding. This strain also demonstrates significant increases in corticosterone binding to the Type II receptor, the glucocorticoid receptor, in the thymus-a structure that is known for synthesis, release, and secretion of proinflammatory cytokines. The Type II receptor decreases its expression and binding in the Fischer F344/N’s hippocampus, hypothalamus, pituitary, and cortex (Dhabhar et al., 1995). Handled Fisher F344/N rats (Herman et al., 1999) are significantly less aroused by stressful environments, as evidenced by lower concentrations of corticosterone. In response to sustained chronic stress unhandled Fischer F344/N rats present adrenal hypertrophy and thymic atrophy as evidenced in elevated adrenal weight and lower thymic weight respectively. This demonstrates this strain’s reliance on the HPA to potentiate and cool down from stress.

Many studies compare the stress responses of many different rat strains, i.e. the Fischer F344/N, Wistar, Wistar-Kyoto (WKY), Brown-Norway (BN), F1 hybrid, Lewis, spontaneously hypertensive rat (SHR), etc. The BN has the heaviest adrenal glands and releases less corticosterone to restraint stress (Sarrieau et al., 1998) when compared with the other strains. In a similar paradigm (Lahmame et al., 1997) BN and Wistar-Kyoto (WKY) rats demonstrate lower levels of struggling, longer periods of immobility, and greater passivity in response to stress. The BN strain also shows the greatest levels of the CRH receptor expression in the prefrontal cortex and hippocampus. The Fischer F344/N rat in response to restraint stress (Lahmame et al., 1997) tends to show the greatest activity and resistance to the impact of stress. The F344/N presents (Bakshi & Kalin, 2000) greater CRH receptor expression in the paraventricular nucleus of the hypothalamus than both the Wistar and Sprague-Dawley strains. Again, this is probably reflective of the F344/N’s tendency to stimulate the HPA in response to stress as noted above. The WKY strain responds with greater stress-related increases in arterial blood pressure (Singewald et al., 2000), presents greater passivity (Marti & Armario, 1996), prolonged immobility and higher levels of ACTH and corticosterone secretion well after cessation of stress (Rittenhouse et al., 2002). The WKY strain is most vulnerable to the influences of learned helplessness training (Wieland et al. 1986) which is a putative model for the development of depression (Garber et al., 1979). Lewis and spontaneously hypertensive (SHR) rats present intermediate levels of struggling and immobility in response to restraint stress (Lahmame et al., 1997). SHR, bred from progenitor WKY, behaviorally presents “a putative model for ADHD (due to)… sustained attentional problems and hyperactive behavior when reinforcers are sparse” (Sagvolden & Sergeant, 1998-page 4-my italics). The SHR reacts with increased behavioral activity in response to forced swimming stress (Marti & Armario, 1996). In summary, different rat strains’ responses to stress are shaped by their inborn neurobiological temperament.

References

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