Rats as laboratory animals

The effects of prenatal ethanol exposure, via a liquid diet containing 35% ethanol derived calories, on spatial learning were assessed in the radial arm maze and Morris water maze at 30 and 60 days of age. No significant affects of ethanol exposure were found on either task at either age. The effects of postnatal ethanol exposure, via self administration of a 15% ethanol solution, on spatial learning were assessed in the radial arm maze and Morris water maze. No significant effects of ethanol exposure were found on either task at either 30 or 60 days of age. Subtle differences in performance in the radial arm maze were found at 30 days of age in both the prenatally and postnatally ethanol exposed groups. These differences suggest that the exposure to ethanol postnatally may be interfering with the rate of learning and the ability to learn.

This paradigm evaluated a novel chronic stressor paradigm that could be as effective as 24 hr of maternal deprivation (24-MD), yet be intrinsically capable of examination over numerous days in pre-weanling pups. It was hypothesized that a 19 hr chronic variable stressor paradigm (19-CVS) would be equally or more effective in eliciting a corticosterone (CORT) response than 24-MD and that 19-CVS would have elevated recovery CORT levels over 24-MD. The results indicated that (1) 19-CVS elicited a significantly greater CORT response than 24-MD immediately after stressor exposure and (2) 19-CVS had significantly elevated recovery CORT in comparison to 24-MD. These results demonstrate that 19-CVS early in development is capable of robustly activating the hypothalamic-pituitary-adrenal (HPA)-axis immediately after exposure and may prove useful as an early life stressor. However, additional work is necessary to clarify how these two distinct stressors differ in termination of their respective HPA response.

The midline thalamus of rats is anatomically and functionally part of the "limbic" thalamus. The midline thalamic rhomboid nucleus (RH) has not been well characterized. The rhomboid nucleus is located just dorsal to the reuniens nucleus (RE), and just ventral to the central medial nucleus (CeM) of the thalamus. Using the retrograde tracer fluorogold (FG) and anti-FG antibody, we examined afferent projections to RH in the rat. Control injections were also made in CeM and the submedial nucleus of thalamus (SMT). The main sources of input to RH were from the anterior cingulate, agranular insular, orbital, and somatosensory cortices; the claustrum; the reticular nucleus of the thalamus; the posterior hypothalamus; and various brainstem structures. Based on patterns of the afferent projections, the role of RH in arousal, attention, and mnemonic functions is discussed.

Experimentally naive rats show variance in their locomotor reactivity to novelty, some displaying higher (HR) while others displaying lower (LR) reactivity, associated with vulnerability to stress. LRHR phenotype is proposed as an antecedent to the development of stress hyper responsiveness. Results presented here show emergence of antidepressive-like behavior following peripubertal-juvenile exposure to chronic variable physical (CVP) and chronic variable social stress (CVS) in HR rats, and depressive-like behavior following CVP in the LRs. The antidepressive-like behavior in HR rats was accompanied by increased levels of acetylated Histone3 (acH3) and acetylated Histone4 (acH4) at the hippocampal brain-derived neurotrophic factor (BDNF) P2 and P4 promoters respectively. This effect may mediate increased mossy fibre (MF) terminal field size, particularly the suprapyramidal mossy fibre projection volume (SP-MF), in the HR animals following both stress regimens. These findings show that chronic variable stress during adolescence induces individual differences in molecular, neuromorphological and behavioral parameters between LRs and HRs, which provides further evidence that individual differences in stress responsiveness is an important factor in resistance or vulnerability to stress-induced depression and/or anxiety.

A rat model of novelty-seeking phenotype predicts vulnerability to nicotine relapse where locomotor reactivity to novelty is used to rank high (HR) versus low (LR) responders. This dissertation examines the neuropeptidergic and structural substrates of the expression of locomotor sensitization to a low dose nicotine challenge and associated social anxiety-like behavior following chronic intermittent nicotine exposure during adolescence in the LRHR phenotype. Data show the long-lasting nature of behavioral sensitization to nicotine and abstinence-related social anxiety-like behavior in nicotine pre-trained HRs compared to saline pre-trained controls. Moreover, this behavior is accompanied by an imbalance between the brain antistress/antianxiety, i.e., neuropeptide Y (NPY), and stress, i.e., corticotrophin releasing factor (CRF) systems in the amygdala. Moreover, a deficit in NPY signaling marked with decreased NPY and increased NPY Y2 receptor (Y2R) mRNA levels is observed in the hip pocampus, along with mossy fiber reorganization in nicotine pre-trained HRs. Furthermore, a Y2R antagonist administered 1 wk of abstinence reverses these behavioral, molecular and morphological effects in nicotine-exposed HRs. Additionally, the role of amygdalar synaptic plasticity in longlasting social withdrawal is also investigated by assessing brain-derived neurotrophic factor (BDNF) and spinophilin mRNA levels in HRs following a behaviorally-sensitizing nicotine regimen. A persistent increase in BDNF and spinophilin mRNA levels in the basolateral amygdala (BLA) is observed in nicotine pre-trained HRs even across a long (3-wk) abstinence spanning into young adulthood. This strongly suggests BDNFmediated long-lasting neuroplasticity within the BLA that may regulate abstinence-related negative affect in HRs.

Experimentally naive rats exhibit varying degrees of novelty exploration. Some rats display high rates of locomotor reactivity to novelty (high responders; HR), and others display low rates (low responders; LR). The novelty-seeking phenotype (LRHR) is introduced as a model of stress responsiveness. In this thesis I examined effects of chronic variable physical and social stress or control handling on the levels of various neurotrophins in the hippocampus, and changes in mossy fibre terminal fields in LRHR rats. A positive correlation is seen between histone deacetylase 2 and brain-derived neurotrophic factor (BDNF) levels both of which are oppositely regulated in LRHR CA3 fields in response to chronic social stress. Increase in BDNF levels in CA3 field accompanied increase in supra-pyramidal mossy fibre terminal field size (SP-MF) in HRs, and decrease in BDNF levels accompanied decrease in SP-MF volume in LRs. Epigenetic regulation of neurotrophic support underlying these structural changes is discussed.