Chez l'humain, le vieillissement provoque des déficits auditifs centraux qui perturbent la localisation de sources sonores et la perception de la parole. Cette étude vise à déterminer si le vieillissement affecte les propriétés spectrales et directionnelles des neurones auditifs du collicule supérieur (CS), seule structure du système nerveux central à posséder une représentation topographique de l'espace auditif. Des enregistrements unitaires extracellulaires sont effectués dans les couches profondes du CS de rats Sprague-Dawley adultes (10-12 mois) et âgés (22-24 mois), anesthésiés. Les stimuli (sons purs et bruits gaussiens) sont présentés en champ libre à différentes positions en azimut de manière pseudo-aléatoire. Les résultats révèlent que, chez les rats âgés, les seuils d'intensité des fréquences caractéristiques et les seuils d'intensité aux bruits gaussiens des neurones auditifs du CS sont significativement plus élevés. De plus, l'étendue de la bande-passante spectrale des rats âgés, est aussi significativement plus large. Chez les deux groupes de rats, les champs récepteurs directionnels des neurones auditifs du CS sont tous situés dans l'hémi-espace controlatéral. Cependant, chez le rat âgé, l'organisation topographique de la carte directionnelle auditive est abolie et la sélectivité directionnelle est significativement plus vaste. Ces résultats montrent la présence de déficits centraux au niveau de la sélectivité spectral et directionnelle des neurones auditifs du CS dû au vieillissement. ______________________________________________________________________________ MOTS-CLÉS DE L’AUTEUR : Perte auditive, collicule supérieur, système auditif, audition spectrale et directionnelle, localisation sonore, vieillissement du système auditif.

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Rats that undergo hindlimb unloading (HU) as a simulation for space flight experience bone changes similar to astronauts in microgravity. The purpose of this research was to assess whether an exercise countermeasure would be effective in preventing or mitigating bone degradation during HU. Controlled electrical muscle stimulation was applied to the lower left hindlimb to simulate resistive exercise. Adult 6-mo. old male rats were assigned to 3 groups of 12 each: hindlimb unloaded (HU), aging cage control (CC), and baseline (BL). The CC group was pair-fed to match the nutritional intake of HU animals during the 28 days of the study. The left leg was exercised 3 days a week for the duration of the study, with the unexercised right leg serving as a contra-lateral control. Mechanical tests were conducted to assess the strength of cancellous bone in the proximal tibia metaphysis. Although isolated specimens of cancellous bone are not feasible, reduced platen compression (RPC) was employed to directly load only the cancellous core region of each specimen. There was no significant difference in ultimate stress or elastic modulus between BL, CC, and HU-Ex (exercised). However, HU-Ex results were dramatically and significantly higher than HU-No Ex (contra-lateral unexercised control) for both ultimate stress (68%) and elastic modulus (81%). It is also notable that ultimate stress was 32% higher (but not statistically significant) for HU-Ex compared to CC. The total bone mineral density in the tibial metaphysis was significantly larger, 11%, in the HUEx compared to the HU-No Ex group's values. The results clearly demonstrate the efficacy of the exercise protocol in preventing the substantial mechanical deterioration induced by HU.

Univ., Diss.--Heidelberg, 2005.

Freiburg (Breisgau), Universität, Thesis (doctoral), 2002.

Dopamine signaling in the prefrontal cortex is thought to play a role in ethanol abuse. However, little is known about how ethanol affects dopamine signaling in the region. There are a few rodent studies regarding the matter, but both the pharmacological effects of ethanol and the effects of self-administered ethanol on extracellular dopamine in the medial prefrontal cortex remain unclear. The goal of the studies conducted for this dissertation is to clarify these relationships. To accomplish this, we monitored both dialysate dopamine and ethanol concentrations in the medial prefrontal cortex of Long Evans rats while an experimenter administered or a rat operantly self-administered ethanol. In naïve rats, dopamine dose-dependently increased after the intravenous infusions of a 10% ethanol solution, while no changes were noted after saline infusions. In rats trained to orally self-administer drinking solutions, dopamine transiently increased at the initiation of consumption in both ethanol-plus-sucrose- and sucrose-solution-consuming rats. Dopamine concentrations remained significantly elevated for the entire 21-minute drinking period in the ethanol-plus-sucrose-consuming group and for the first seven minutes of the drink period in the sucrose-consuming group. Additionally, in the ethanol-plus-sucrose-consuming group, dialysate ethanol concentrations were lowest at the initiation of drinking and then slowly increased, peaking 35 minutes after drinking commenced. Taken together, these data suggest that the mesocortical dopamine system is responsive to acute, intravenous and repeatedly, orally, self-administered ethanol. It appears that direct pharmacological effects of ethanol were responsible for the dopamine increase after acute, ethanol administration. Furthermore, while is it possible that the direct pharmacological effects of ethanol also bolstered the dopamine response seen after ethanol self-administration, we cannot firmly conclude by what mechanism ethanol elicited the differences. Overall, our clarifying and novel results support a role for the mesocortical dopamine system in ethanol abuse, which deserves continued investigation. In addition to completing the two aforementioned data studies, we also published the methods we use to monitor dialysate ethanol concentrations, in a specific brain region, during ethanol self-administration in a video-methods journal. The methods are presented in both a detailed written protocol, as well as a video demonstrating how to perform the procedures. / text

Motor skill learning underlies much of what we do, be it hitting a tennis serve, playing the piano, or simply brushing our teeth. Yet despite its importance, little is known about the neural circuits that implement the learning process or how the motor program is represented in the brain. Here I explore the role of motor cortex through lesion studies in rats trained on a motor skill. First, I interrogate whether motor cortex is necessary for the production of a complex motor sequence by training animals to produce temporally precise self-initiated movement sequences on a lever-pressing task. The movement sequences that emerged over months of training were remarkably complex, yet very precise. This motor skill, once mastered, survives large bilateral motor cortex lesions, suggesting that motor cortex is not required for generating movement sequences after consolidation. Next, I explored the role of motor cortex in motor skills that require dexterous manipulations. Animals trained to make constrained spatially precise movements using a joystick were impaired after motor cortex lesions. The role of motor cortex thus depends on the nature of the movements involved but not on the sequencing of movements. Third, I explored the function of motor cortex in sensorimotor transformations by training animals on the same lever-pressing task but with external cues instead of self-initiated movement. Surprisingly, these animals were also not impaired after lesions, suggesting that the method of learning the motor sequence has no consequence once the motor sequences are consolidated. Lastly, I explored the role of motor cortex in learning motor skills. Animals that were lesioned after being exposed to the lever-pressing task could learn to adjust the timing of their movements, indicating that motor cortex is not required for adapting a previously-acquired motor sequence. Lesions of motor cortex prior to any training, however, severely disrupted learning. Even with extended training, animals were unable to fully master the task, demonstrating that motor cortex is necessary for the acquisition of new motor skills even when it is not required for their execution.

Little is known about the effects of protein-energy malnutrition (PEM) developing after stroke on brain recovery. The goal of this project was to develop two experimental models in the adult rat to allow evaluation of nutritional effects on post-stroke recovery: (1) a PEM model, and (2) a photothrombotic stroke model. Experiment 1 examined the hypothesis that a diet containing either 1% or 0.5% protein will produce an acute state of mild-moderate PEM in adult rats. Male, Sprague-Dawley rats (16 wk) were trained in the Montoya staircase before being randomized to diets containing 0.5% (n=8), 1% (n=8), or 12.5% protein (n=10 [CON]) for 31d. Both low protein diets increased liver lipid content (p< 0.001) and decreased food intake (p= 0.005) and body weight (p< 0.001) compared to the 12.5% protein diet. The 0.5% protein group best mimicked the stroke patient, as judged by decreased serum albumin (p= 0.018) and an acute decrease in mean (±SEM) body weight (g) by d7 (0.5%= 424±15; 1%= 428±14; CON= 477±10; p = 0.011). Increased concentrations of the positive acute phase proteins, alpha-2-macroglobulin and alpha-1-acid glycoprotein, were greatest in the 0.5% group (p< 0.001). No differences were observed in the Montoya test on d3, 15, or 30 (p= 0.26). Values on d30 were: 0.5%= 109.5±4.4% of pre-diet performance; 1%= 97.2±5.5%; CON= 98.5±10.2%. Experiment 2 tested the hypothesis that targeted laser irradiation and 30 mg/kg of rose Bengal injection will cause an infarct in the forepaw region of the cortex with accompanying functional deficits. Male adult rats trained in the Montoya staircase were randomized to ISCHEMIA (n=15) or SHAM (n=3) surgery. A cortical infarct occurred in 86% of rats, with some misplacement and variability in volume (5.7-12.8 mm3). Forepaw impairments were confirmed by decreased performance in the staircase at d3 (34.3±7.3 % of pre-stroke performance, p<0.001) and diminished use in the cylinder test (30.3±4.0% affected limb use versus 53.9±1.93% prestroke, p< 0.001). At d30, mean recovery was incomplete in the staircase (p< 0.001). These experimental models, with additional refinements, can be used to address the hypothesis that deteriorating nutritional status after a stroke interferes with brain recovery.

Psychopharmacological studies have implicated the mesolimbic dopamine (DA) system in the mediation of cost/benefit evaluations about effort-related costs associated with larger rewards. However, the role of DA in risk-based decision making remains relatively unexplored. The present study investigated how systemic manipulations of DA transmission affect risky choice assessed with a probabilistic discounting task. Over discrete trials, rats between two levers; a press on the “small/certain” lever always delivered one reward pellet, whereas a press on the other, “large/risky” lever delivered four pellets, but the probability of receiving reward decreased across the four trial blocks (100%, 50%, 25%, 12.5%). In separate groups of well-trained rats we assessed the effects of the DA releaser amphetamine, as well as receptor selective agonists and antagonists. Amphetamine consistently increased preference for the large/risky lever; an effect that was blocked or attenuated by co-administration of either D₁ (SCH23390) or D₂ (eticlopride) receptors antagonists. Blockade of either of these receptors alone induced risk aversion. Conversely, stimulation of D₁ (SKF81297) or D₂ (bromocriptine) receptors also increased risky choice. In contrast, activation of D₃ receptors with PD128,907 induced risk aversion. Likewise, D₃ antagonism with nafadotride potentiated the amphetamine-induced increase in risky choice. Blockade or stimulation of D₄ receptors did not reliably alter patterns of choice. These findings indicate that DA plays a critical role in mediating risk-based decision making, where increased activation of D₁ and D₂ receptors biases choice towards larger, probabilistic rewards, whereas D₃ receptors appear to exert opposing effects on this form of decision making.

Despite virtually identical genomes, inbred animals often vary in phenotype, including behaviour, but the molecular basis of this phenomenon is unknown. Our hypothesis is that differences in behaviour between inbred rats are correlated with differential cortical mRNA transcript levels. 40 Lewis rats were subjected to 5 behavioural tests: two were used to categorize 10 animals into either “high” or “low” phenotype groups. Microarray gene expression profiling was performed for 5 rats from each group. Three main analyses were performed to: (1) identify differential expression between the high and low groups, (2) identify correlations between transcript levels and individual behaviour scores, and (3) determine if the results of this replicate experiment overlapped with a previous pilot experiment. Some array results were confirmed by RT-PCR. We found that this experiment did not replicate the findings from the pilot, however several genes of interest were determined and were validated by RT-PCR.