Le système de l’immunité innée cérébrale module le fonctionnement du cerveau et les processus comportementaux tout au long de la vie d'un individu. Parmi les différents protagonistes de ce système de l'immunité innée cérébrale, les cellules gliales jouent un rôle majeur notamment en régulant la synthèse de facteurs inflammatoires tels que les cytokines. Ces dernières, outre leur rôle dans la coordination de l'action des différents partenaires cellulaires de ce système, modifient l'activité neuronale. Lors d'un épisode inflammatoire, le système de l'immunité innée s'active et l'ensemble des signaux mis en place par les processus immunitaires est regroupé sous le terme de neuroinflammation. Plus particulièrement, les cytokines proinflammatoires et l’ATP libérés dans ce cadre ont été décrits comme étant capables de moduler la plasticité synaptique d'une part et les capacités d’apprentissages et de mémorisation d'autre part. Cependant, la compréhension de l’impact d’un épisode inflammatoire sur le système nerveux central et les capacités d’apprentissage n’est pas totale. Une cible potentielle de ces facteurs est le système de neurotransmission glutamatergique. En effet, les facteurs proinflammatoires peuvent augmenter ou diminuer l’expression ou l’activité de certaines sous-unités des récepteurs glutamatergiques. Mon objectif a été de déterminer dans quelle mesure la transmission glutamatergique est altérée en condition neuroinflammatoire et comment cela pouvait induire des altérations des capacités d’apprentissage chez le rongeur. Pour cela nous avons choisi comme tâche comportementale l’aversion gustative conditionnée, dont les mécanismes moléculaires nécessaire à sa mise en place sont connus et reposent sur la transmission glutamatergique dans une structure corticale particulière chez les rongeurs: le cortex insulaire. Notre étude visait à déterminer les mécanismes cellulaires et moléculaires par lesquels une inflammation localisée à ce cortex peut induire des modifications comportementales et biochimiques. Nous avons pu montrer que l’infusion de lipopolysaccharide, un puissant agent inflammatoire, dans le cortex insulaire induisait une augmentation de l'aversion conditionnée. Ceci était corrélé à une augmentation d’expression des récepteurs AMPA au glutamate dans cette structure, plus particulièrement dans le compartiment synaptique. Nous avons également pu montrer que l’infusion de LPS dans le cortex insulaire induisait la synthèse et la libération de cytokines proinflammatoires localement, sans stimuler le système de l’immunité périphérique. Même si ces cytokines sont connues comme étant des agents modulateurs de la neurotransmission glutamatergique, leur infusion dans le cortex insulaire n’a pas reproduit dans notre cas les effets de l’infusion du LPS. Par contre, nous avons montré que l’ATP était impliqué dans les effets du LPS sur l’apprentissage aversif, puisque le blocage des récepteurs purinergiques dans le cortex insulaire a permis de reverser les effets du LPS sur l’acquisition de l’aversion gustative. En conclusion, nos résultats suggèrent qu'une inflammation localisée dans le cortex insulaire conduit à la libération et à l'action d’ATP sur les cellules gliales et/ou neuronales, aboutissant à une hausse de l’acquisition de l’aversion gustative conditionnée. / The cerebral innate immune system is activated under pathophysiological conditions and can consequently modulate brain functioning and cognitive processes. This modulation is exerted by signals produced by immune-like processes grouped under the term of neuroinflammation and involving neuro-glial communication within the brain. In particular, proinflammatory cytokines and ATP, all produced during this immune system activation have been directly linked to modulation of synaptic plasticity and/or learning and memory functions in animals models. However, the cellular mechanisms by which neuroinflammation modulates neural plasticity and cognitive processes are still unclear. One candidate is the glutamatergic system. Indeed, pro-inflammatory factors can increase or decrease glutamatergic receptors expression and/or activity. Our study was dedicated at deciphering to what extent glutamatergic transmission is altered under neuroinflammation and how this may lead to learning and memory alteration. To this aim, we used the conditioned taste aversion, a task highly dependent on glutamatergic transmission into the insular cortex. Indeed, blockade of NMDA or AMPA receptors in this cortical area before acquisition greatly impairs conditioned taste aversion. The aim of our study was thus to investigate the behavioral and cellular impact of an inflammation restricted to the insular cortex on glutamatergic receptors expression and CTA memory formation. Here we show that a cortical inflammation, induced by LPS infusion into the insular cortex, prior to CTA acquisition enhances the aversion strength presumably through LPS-induced increase of glutamatergic AMPA, but not NMDA, receptor expression/trafficking at the insular synapses. Moreover, we show that ATP release, but not pro-inflammatory cytokines, is responsible for LPS-induced CTA enhancement. In conclusion we propose that inflammation restricted to the insular cortex enhances CTA acquisition through an ATP-dependent mechanism presumably involving an increase of glutamatergic AMPA receptor expression at the neuronal synapses.

Conflicts between humans and black bears (Ursus americanus) jeopardize the safety of both humans and bears, especially when bears become food-conditioned to anthropogenic food sources in areas such as campgrounds. Interest in using non-lethal techniques, such as aversive conditioning, to manage such conflicts is growing. I conducted a captive experiment at The Wildlife Science Center in Minnesota and two field experiments in the La Sal Mountains, Utah, to investigate the effects of taste aversion conditioning using thiabendazole (TBZ) with a novel flavor cue and food removal on black bear food consumption and visitation to human food sources. In 2007, I conducted food trials with 6 captive black bears (3 control, 3 treatment). Controls received 1 kg baked goods scented with a peppermint-canola oil mixture and treatments received 1 kg baked goods also scented with a peppermint-canola oil mixture but mixed with 10-20 g TBZ. In the 2007 field experiment, I baited 24 field sites with 300 g of baked goods during a baseline phase for approximately 3 weeks. Half of these sites were then treated with 10 g of TBZ and camphor during a treatment phase for 4 weeks. In 2008, I baited 22 sites with 300 g of baked goods during a baseline phase for approximately 4 weeks. I then removed food and discontinued baiting at half of the sites for 4 weeks. Infrared cameras and barbed-wire hair snags were established at field sites to document bear visitation. I did not establish taste aversion in treated bears in captivity and bears fully consumed food in the majority of trials. Treating food supplies with 10 g TBZ and camphor flavor did not significantly reduce bear visitation (P = 0.615) or food consumption at field sites (P = 0.58). However, I observed a significant reduction in bear activity at sites where food was removed (P = 0.006). Potential reasons for my failure to reduce bear visitation using thiabendazole include insufficient conditioning, reluctance of bears to desist in investigating sites that previously contained untreated food, and masking of a treatment effect due to continued encounters of sites by new individuals.

No description available.

Long-term memories turn labile with reactivation and undergo a re-stabilization process, termed reconsolidation, involving molecular changes that allow updating of an existing memory trace. Such molecular changes may involve the activation of kinases and expression of proteins related to the increase of synaptic plasticity and memory formation. A kinase reported to have a role in a variety of memory tasks is the extracellular signal-regulated kinase 1/2 (ERK1/2). The downstream activation of ERK targets other regulatory enzymes, transcription factors and cytoskeletal proteins, which allow structural changes in the neuron due to protein synthesis up-regulation. Among the proteins up-regulated by ERK activity is the activity-regulated cytoskeleton-associated protein (ARC), an immediate early gene related to synaptic plasticity. The phase-dependent roles of ERK and ARC have not been examined as part of the molecular mechanisms triggered after a learning experience. In this study I used conditioned taste aversion (CTA) as the learning paradigm and investigated the expression of pERK and ARC in brain regions critical for taste information processing such as the insular cortex and the amygdala. A differential pattern of protein expression was observed in the insular cortex (IC) two hours after taste memory acquisition: pERK activity increased in the aversively conditioned group while ARC increased in the group that received only the novel taste. The central amygdala (CeA) showed a significant increase in pERK, but not ARC activity after CTA training. Immunoblotting experiments performed after memory retrieval in the appetitive group show that pERK continues to signal aversive taste to the IC with ARC exhibiting heightened expression an hour later. An increase in ARC expression 30 minutes after reactivation of the aversive taste was seen in the basolateral amygdala and the CeA exhibited a similar increase at 60 and 90 minutes. Local infusion of ARC antisense oligonucleotides within the IC interfered with the consolidation of safe taste memories, but not with their acquisition. Trace update experiments showed that ARC influences the memory switch from aversive to safe, but not the reverse. Our results indicate that ARC plays a critical role in consolidation and updating of safe taste memories, and the ARC signaling could possibly elicit ERK activation.

I tested the efficacy of aversive conditioning (AC) and conditioned taste aversion (CTA) on American black bears (Ursus americanus) in Whistler, British Columbia. Black bears subjected to 3-5 day AC programs responded by increasing their wariness toward humans, while control bears habituated. Bears were located closer to human developments during daylight hours after AC treatments. However, there was no difference in the proportion of utilization distribution that overlapped with developed areas in control or AC-treated bears. CTA may be effective for managing specific attractants that are difficult to secure from bears. Bears appeared to distinguish between baits treated with thiabendazole and baits that were not treated, but by using a protocol that caused severe illness and left the source of illness in doubt, I induced taste aversions to apples in 4 bears. Using both AC and CTA may help wildlife managers mitigate human-wildlife conflicts non-lethally more effectively. / Ecology

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may follow exposure to severe emotional trauma and presents with various symptoms of anxiety, hyperarousal and cognitive anomalies. Interestingly, only 10-30% of an exposed population will go on to develop full-blown PTSD. Cholinergic neurotransmission is implicated in anxiety as well as other typical manifestations of PTSD, particularly cognitive changes. The frontal cortex and hippocampus regulate and in turn are affected by stress, and have also been implicated in the underlying neuropathology of PTSD. These areas are densely innervated by cholinergic neurons originating from the basal forebrain. In this study, the time dependent sensitization (TDS) model was used to induce symptoms of PTSD in animals. The study was designed to determine the long-term effects of an intense, prolonged aversive procedure on central muscarinic acetylcholine receptor (mAChR) characteristics and the correlation if any of those findings to cognitive aspects and general arousal as characteristics associated with PTSD. In order to achieve this goal, male Sprague-Dawley rats were exposed to the TDS stress paradigm with behavioral/neuro-receptor assessments performed on day 7 post re-stress (duration of each experiment in whole is 14 days). Acoustic startle reflex (ASR) was used to determine emotional state (hyperarousal), while the conditioned taste aversion (CTA) paradigm was implemented in order to assess aversive memory. Muscarinic receptor binding studies were performed in the frontal cortex and hippocampus. Moreover, both the stress-exposed and control animals were pre-tested in the acoustic startle chamber in order to attempt to separate stress sensitive from stress-resilient animals based on predetermined ASR criteria. The ASR niodel was previously validated in our laboratory, while the CTA model was validated in this project before application. In the CTA model, an i.p. injection with lithium chloride (LiCl) (associated with digestive malaise), was used as unconditioned stimulus (US) and was paired with a saccharinlcyclamate drinking solution as conditioned stimulus (CS) to induce aversion to the novel taste (CS) when presented in the absence of the US. Population data of animals tested in the ASR experiment indicated no statistical significant difference between stressed and control animals. However, when each animal was assessed individually, 22.5 % of the exposed population displayed all increase above the predetermined criteria of 35 % in startle response, indicating a state of heightened arousal. In contrast, only 4.2 O h of control animals (no stress) displayed an increase in arousal based on the above mentioned criteria. Muscarinic receptor densities (Bm,) in the total population of animals exposed to stress showed a statistical significant increase in both the hippocampus and frontal cortex when compared to controls, with no changes in & values observed in either one of the areas. In the CTA experiment, TDS stress was implemented as US paired with a saccharinlcyclamate drinking solution as CS. An acute session of prolonged stress (as used in the TDS model) effectively induced aversion to a novel taste and a subsequent reminder of the stress (restress) paired with the CS sustained the acquire adversive memory. Furthermore, LiCl was reintroduced as US in order to assess the effect of prior exposure to two types of stress (acute and TDS) on subsequently acquired CTA memory. Prior exposure to acute stress had no significant effect on subsequently acquired aversive memory when measured either 3- or 7 days post-conditioning (CS-US). Stress-restress (TDS) exposure, however, indicated a significant decrease in aversive memory from 3- to 7 days post-conditioning (CS-US) as well as a significant decrease in aversive memory between the control- and the TDS group 7 days post-conditioning. The mAChR density (B,,) in the frontal cortex; but not in the hippocampus, was elevated at the same point in time (7 days post CS-US pairing) that CTA memory was impaired following TDS stress (stress-restress). Ultimately, these data support an association between altered cholinergic receptors and hyperarousallanxiety in an animal model of PTSD. The data also support the phenomenon of individual susceptibility to stress in animals that parallels that observed in humans exposed to severe trauma. Impaired aversive memory (CTA) is a consequence of prior exposure to TDS stress, but not acute stress, and is likewise mediated by an altered central cholinergic transmission displayed as an increase in mAChRs in the frontal cortex. The lack of studies regarding the influence of the cholinergic system in PTSD related behavior earns ,this project value as inimitable PTSD research. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.

Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.

Posttraumatic stress disorder (PTSD) is an anxiety disorder that may follow exposure to severe emotional trauma and presents with various symptoms of anxiety, hyperarousal and cognitive anomalies. Interestingly, only 10-30% of an exposed population will go on to develop full-blown PTSD. Cholinergic neurotransmission is implicated in anxiety as well as other typical manifestations of PTSD, particularly cognitive changes. The frontal cortex and hippocampus regulate and in turn are affected by stress, and have also been implicated in the underlying neuropathology of PTSD. These areas are densely innervated by cholinergic neurons originating from the basal forebrain. In this study, the time dependent sensitization (TDS) model was used to induce symptoms of PTSD in animals. The study was designed to determine the long-term effects of an intense, prolonged aversive procedure on central muscarinic acetylcholine receptor (mAChR) characteristics and the correlation if any of those findings to cognitive aspects and general arousal as characteristics associated with PTSD. In order to achieve this goal, male Sprague-Dawley rats were exposed to the TDS stress paradigm with behavioral/neuro-receptor assessments performed on day 7 post re-stress (duration of each experiment in whole is 14 days). Acoustic startle reflex (ASR) was used to determine emotional state (hyperarousal), while the conditioned taste aversion (CTA) paradigm was implemented in order to assess aversive memory. Muscarinic receptor binding studies were performed in the frontal cortex and hippocampus. Moreover, both the stress-exposed and control animals were pre-tested in the acoustic startle chamber in order to attempt to separate stress sensitive from stress-resilient animals based on predetermined ASR criteria. The ASR niodel was previously validated in our laboratory, while the CTA model was validated in this project before application. In the CTA model, an i.p. injection with lithium chloride (LiCl) (associated with digestive malaise), was used as unconditioned stimulus (US) and was paired with a saccharinlcyclamate drinking solution as conditioned stimulus (CS) to induce aversion to the novel taste (CS) when presented in the absence of the US. Population data of animals tested in the ASR experiment indicated no statistical significant difference between stressed and control animals. However, when each animal was assessed individually, 22.5 % of the exposed population displayed all increase above the predetermined criteria of 35 % in startle response, indicating a state of heightened arousal. In contrast, only 4.2 O h of control animals (no stress) displayed an increase in arousal based on the above mentioned criteria. Muscarinic receptor densities (Bm,) in the total population of animals exposed to stress showed a statistical significant increase in both the hippocampus and frontal cortex when compared to controls, with no changes in & values observed in either one of the areas. In the CTA experiment, TDS stress was implemented as US paired with a saccharinlcyclamate drinking solution as CS. An acute session of prolonged stress (as used in the TDS model) effectively induced aversion to a novel taste and a subsequent reminder of the stress (restress) paired with the CS sustained the acquire adversive memory. Furthermore, LiCl was reintroduced as US in order to assess the effect of prior exposure to two types of stress (acute and TDS) on subsequently acquired CTA memory. Prior exposure to acute stress had no significant effect on subsequently acquired aversive memory when measured either 3- or 7 days post-conditioning (CS-US). Stress-restress (TDS) exposure, however, indicated a significant decrease in aversive memory from 3- to 7 days post-conditioning (CS-US) as well as a significant decrease in aversive memory between the control- and the TDS group 7 days post-conditioning. The mAChR density (B,,) in the frontal cortex; but not in the hippocampus, was elevated at the same point in time (7 days post CS-US pairing) that CTA memory was impaired following TDS stress (stress-restress). Ultimately, these data support an association between altered cholinergic receptors and hyperarousallanxiety in an animal model of PTSD. The data also support the phenomenon of individual susceptibility to stress in animals that parallels that observed in humans exposed to severe trauma. Impaired aversive memory (CTA) is a consequence of prior exposure to TDS stress, but not acute stress, and is likewise mediated by an altered central cholinergic transmission displayed as an increase in mAChRs in the frontal cortex. The lack of studies regarding the influence of the cholinergic system in PTSD related behavior earns ,this project value as inimitable PTSD research. / Thesis (M.Sc. (Pharmacology))--North-West University, Potchefstroom Campus, 2007.