Sex differences in sucrose reinforcement in Long-Evans rats

Background There are sex differences in addiction behaviors. To develop a pre-clinical animal model to investigate this, the present study examined sex differences in sucrose taking and seeking using Long-Evans rats. Methods Five experiments were conducted using separate groups of subjects. The first two examined sucrose or saccharin preference in two-bottle home cage choice tests. Experiment three assessed sucrose intake in a binge model with sucrose available in home cage bottles. Experiments four and five utilized operant-based procedures. In experiment four rats responded for sucrose on fixed and progressive ratio (FR, PR) schedules of reinforcement over a range of concentrations of sucrose. A final component of experiment four was measuring seeking in the absence of sucrose challenged with the dopamine D1 receptor antagonist SCH23390. Experiment five assessed responding for water on FR and PR schedules of reinforcement. Results When accounting for body weight, female rats consumed more sucrose than water; but there was no sex difference in saccharin preference over a range of saccharin concentrations. When accounting for body weight, females consumed more sucrose than males in the binge model, and only females increased binge intake over 14 days of the study. Females responded at higher rates for sucrose under both FR and PR schedules of reinforcement. Females responded at higher rates in extinction (seeking); SCH23390 reduced sucrose seeking of both females and males. Females responded at higher rates for water on FR and PR schedules than males, although rates of responding were low and decreased over sessions. Conclusions Across bottle-choice, binge intake, and operant procedures, female Long-Evans rats consumed more sucrose and responded at higher rates for sucrose. Although females also responded more for water, the vigor of responding did not explain the consistent sex difference in sucrose taking and seeking. The sex difference in sucrose taking was also not explained by sweet preference, as there was no sex difference in saccharin preference. These data provide a pre-clinical model to further evaluate sex differences in addiction behaviors and manipulations designed to reduce them.

Global Cerebral Ischemia in Male Long Evans Rats Impairs Dopaminergic/ΔFosB Signalling in the Mesocorticolimbic Pathway Without Altering Delay Discounting Rates

Global cerebral ischemia (GCI) in rats has been shown to promote exploration of anxiogenic zones of the Elevated-Plus Maze (EPM) and Open Field Test (OFT). This study investigated changes in impulsive choice and/or defensive responses as possible contributors of heightened anxiogenic exploration observed after ischemia. Impulsivity was assessed using delay discounting (DD) paradigms, while the Predator Odour Test (PO) served to assess changes in defensive responses towards a naturally aversive stimulus. Male Long Evans rats underwent 9 days of autoshaping training and 24 days of DD training prior to GCI or sham surgery (n = 9/group). Post-surgery, rats completed the OFT, EPM, and PO, followed by 6 days of DD sessions. Blood droplets served to evaluate corticosterone secretion associated with PO exposure. With impulsivity being regulated through mesocorticolimbic monoaminergic pathways, we also characterised post-ischemic changes in the expression of dopamine D2 receptors (DRD2), dopamine transporters (DAT), and 1FosB in the basolateral amygdala (BLA), nucleus accumbens core (NAcC) and shell (NAcS), and ventromedial prefrontal cortex (vmPFC) using immunohistofluorescence. Our findings revealed no impact of GCI on delay discounting rates, while PO approach behaviours were minimally affected. Nonetheless, GCI significantly reduced DRD2 and ΔFosB-ir in the NAcS and NAcC, respectively, while DAT-ir was diminished in both NAc subregions. Collectively, our findings refine the understanding of cognitive-behavioural and biochemical responses following stroke or cardiac arrest. They support significant alterations to the dopaminergic mesocorticolimbic pathway after ischemia, which are not associated with altered impulsive choice in a DD task but may influence locomotor exploration of the OFT and EPM.

Differential Effects of Lateral and Medial Entorhinal Cortex Lesions on Trace, Delay and Contextual Fear Memories

The entorhinal cortex (EC), with connections to the hippocampus, amygdala, and neocortex, is a critical, yet still underexplored, contributor to fear memory. Previous research suggests possible heterogeneity of function among its lateral (LEC) and medial (MEC) subregions. However, it is not well established what unique roles these subregions serve as the literature has shown mixed results depending on target of manipulation and type of conditioning used. Few studies have manipulated both the LEC and MEC within the same experiment. The present experiment systematically manipulated LEC and MEC function to examine their potential roles in fear memory expression. Long-Evans rats were trained using either trace or delay fear conditioning. The following day, rats received an N-methyl-D-aspartate (NMDA)-induced lesion to the LEC or MEC or received a sham surgery. Following recovery, rats were given an 8-min context test in the original context. The next day, rats were tested for tone freezing in a novel context with three discrete tone presentations. Further, rats were tested for hyperactivity in an open field under both dark and bright light gradient conditions. Results: Following either LEC or MEC lesion, freezing to context was significantly reduced in both trace and delay conditioned rats. LEC-lesioned rats consistently showed significantly less freezing following tone-offset (trace interval, or equivalent, and intertrial interval) in both trace and delay fear conditioned rats. Conclusions: These data suggest that the LEC may play a role in the expression of a conjunctive representation between the tone and context that mediates the maintenance of post-tone freezing.

Reductions in Intestinal Taurine-Conjugated Bile Acids and Short-Chain Fatty Acid-Producing Bacteria Might be Novel Mechanisms of Type 2 Diabetes Mellitus in Otsuka Long-Evans Tokushima Fatty Rats

Background The pathogenesis of spontaneously diabetic Otsuka Long-Evans Tokushima Fatty (OLETF) rats, among the best models for human type 2 diabetes mellitus (T2DM), remains poorly defined. Therefore, we investigated the dynamic changes in taurine-conjugated bile acids (T-BAs) and intestinal microbiota during T2DM development in OLETF rats. Methods OLETF rats and corresponding diabetes-resistant Long Evans Tokushima Otsuka (LETO) rats were fed a normal baseline diet. The progress of T2DM was divided into four phases, including normal glycemia-normal insulinemia (baseline), normal glycemia-hyperinsulinemia, impaired glucose tolerance, and DM. Body weight, liver function, blood lipids, fasting plasma glucose, fasting plasma insulin, fasting plasma glucagon-like peptide (GLP)-1 and GLP-2, serum and fecal T-BAs, and gut microbiota were analyzed during the entire course of T2DM development. Results There were reductions in fecal T-BAs and short-chain fatty acids (SCFAs)-producing bacteria including Phascolarctobacterium and Lactobacillus in OLETF rats compared with those in LETO rats at baseline, and low levels of fecal T-BAs and SCFAs-producing bacteria were maintained throughout the whole course of the development of T2DM among OLETF rats compared with those in corresponding age-matched LETO rats. Fecal taurine-conjugated chenodeoxycholic acid correlated positively with Phascolarctobacterium. Fecal taurine-conjugated deoxycholic acid correlated positively with Lactobacillus and fasting plasma GLP-1 and inversely with fasting plasma glucose. Conclusion The fecal BAs profiles and microbiota structure among OLETF rats were different from those of LETO rats during the entire course of T2DM development, indicating that reductions in intestinal T-BAs and specific SCFA-producing bacteria may be potential mechanisms of T2DM in OLETF rats.

Strain Comparison in Rats Differentiates Strain-Specific from More General Correlates of Noise-Induced Hearing Loss and Tinnitus

Experiments in rodent animal models help to reveal the characteristics and underlying mechanisms of pathologies related to hearing loss such as tinnitus or hyperacusis. However, a reliable understanding is still lacking. Here, four different rat strains (Sprague Dawley, Wistar, Long Evans, and Lister Hooded) underwent comparative analysis of electrophysiological (auditory brainstem responses, ABRs) and behavioral measures after noise trauma induction to differentiate between strain-dependent trauma effects and more consistent changes across strains, such as frequency dependence or systematic temporal changes. Several hearing- and trauma-related characteristics were clearly strain-dependent. Lister Hooded rats had especially high hearing thresholds and were unable to detect a silent gap in continuous background noise but displayed the highest startle amplitudes. After noise exposure, ABR thresholds revealed a strain-dependent pattern of recovery. ABR waveforms varied in detail among rat strains, and the difference was most prominent at later peaks arising approximately 3.7 ms after stimulus onset. However, changes in ABR waveforms after trauma were small compared to consistent strain-dependent differences between individual waveform components. At the behavioral level, startle-based gap-prepulse inhibition (gap-PPI) was used to evaluate the occurrence and characteristics of tinnitus after noise exposure. A loss of gap-PPI was found in 33% of Wistar, 50% of Sprague Dawley, and 75% of Long Evans rats. Across strains, the most consistent characteristic was a frequency-specific pattern of the loss of gap-PPI, with the highest rates at approximately one octave above trauma. An additional range exhibiting loss of gap-PPI directly below trauma frequency was revealed in Sprague Dawley and Long Evans rats. Further research should focus on these frequency ranges when investigating the underlying mechanisms of tinnitus induction.

Impact of Exercise and Detraining during Childhood on Brown Adipose Tissue Whitening in Obesity

This study aimed to investigate the influence of childhood exercise and detraining on brown adipose tissue (BAT) whitening in obesity. Four-week-old male Long-Evans Tokushima Otsuka (LETO) rats (n = 9) and Otsuka Long-Evans Tokushima Fatty (OLETF) rats (n = 24) were used as non-obese and obese animals, respectively. OLETF rats were divided into non-exercise sedentary (n = 9) and exercise groups. OLETF rats in the exercise group were further divided into subgroups according to the exercise period—exercise from 10- to 12-weeks-old (n = 6); and exercise from 4- to 6-weeks-old, and detraining from 6- to 12-weeks-old (n = 9). At 12-weeks-old, immediately after exercise period, BAT whitening in OLETF rats was inhibited by exercise despite the fact that hypertrophy was not caused in the plantaris muscle. However, the effectiveness was attenuated during the detraining period. Histological BAT whitening and downregulation of uncoupling protein-1 (UCP-1) were found in non-exercise sedentary OLETF rats at 12-weeks-old. The downregulation was not inhibited, even though exercise histologically inhibited BAT whitening in OLETF rats. Childhood exercise decreased BAT whitening in obesity. Detraining attenuated the inhibition of BAT whitening. These results suggest that regular exercise is needed to improve BAT whitening and downregulation of UCP-1 in obesity.