The experiments reported in the present thesis examined the behavioural processes of Pavlovian fear extinction and latent inhibition. The first series of experiments studied the reacquisition of extinguished fear responses following different amounts of extinction training. Rapid reacquisition occurred when rats were reconditioned after moderate extinction, showing that the original learning remained intact across this extinction. In contrast, when reconditioning was given after massive extinction, reconditioned responding was first depressed but then spontaneously recovered over time. This suggests that massive extinction produces a relatively permanent loss of the originally learned responding, while additionally imposes on the extinguished CS a transient latent inhibitory process that prevented the immediate but not the delayed expression of reconditioning. The second series of experiments studied the impact of spontaneous recovery of extinguished fear responses on their additional extinction. These experiments demonstrated that a CS that had time to show spontaneous recovery underwent greater response loss across additional extinction than one lacking recovery. They also showed that an excitor extinguished in compound with a CS showing recovery suffered greater response loss than an excitor extinguished in compound with a CS lacking recovery. Further, extinction of a compound composed of two CSs, one showing recovery and a second lacking recovery, produced greater extinction to the CS that showed recovery. These results show that spontaneous recovery of extinguished responses deepens their extinction through an error-correction mechanism regulated by both common and individual error terms. The third series of experiments studied the spontaneous recovery of latently inhibited and extinguished fear responses in within-subject designs. Using a compound test procedure, a CS that had received extensive preexposure or extensive extinction was found to have undergone greater spontaneous recovery relative to a CS just moderately preexposed or moderately extinguished. A CS given a mixed history of preexposure and extinction also underwent greater recovery relative to a CS just preexposed or just extinguished. These results suggest that both latent inhibition and extinction share a transient depressive process, and that the resulting recovery of responding is proportional to the amount of this depression.

The experiments reported in the present thesis examined the behavioural processes of Pavlovian fear extinction and latent inhibition. The first series of experiments studied the reacquisition of extinguished fear responses following different amounts of extinction training. Rapid reacquisition occurred when rats were reconditioned after moderate extinction, showing that the original learning remained intact across this extinction. In contrast, when reconditioning was given after massive extinction, reconditioned responding was first depressed but then spontaneously recovered over time. This suggests that massive extinction produces a relatively permanent loss of the originally learned responding, while additionally imposes on the extinguished CS a transient latent inhibitory process that prevented the immediate but not the delayed expression of reconditioning. The second series of experiments studied the impact of spontaneous recovery of extinguished fear responses on their additional extinction. These experiments demonstrated that a CS that had time to show spontaneous recovery underwent greater response loss across additional extinction than one lacking recovery. They also showed that an excitor extinguished in compound with a CS showing recovery suffered greater response loss than an excitor extinguished in compound with a CS lacking recovery. Further, extinction of a compound composed of two CSs, one showing recovery and a second lacking recovery, produced greater extinction to the CS that showed recovery. These results show that spontaneous recovery of extinguished responses deepens their extinction through an error-correction mechanism regulated by both common and individual error terms. The third series of experiments studied the spontaneous recovery of latently inhibited and extinguished fear responses in within-subject designs. Using a compound test procedure, a CS that had received extensive preexposure or extensive extinction was found to have undergone greater spontaneous recovery relative to a CS just moderately preexposed or moderately extinguished. A CS given a mixed history of preexposure and extinction also underwent greater recovery relative to a CS just preexposed or just extinguished. These results suggest that both latent inhibition and extinction share a transient depressive process, and that the resulting recovery of responding is proportional to the amount of this depression.

The experiments reported in the present thesis examined the behavioural processes of Pavlovian fear extinction and latent inhibition. The first series of experiments studied the reacquisition of extinguished fear responses following different amounts of extinction training. Rapid reacquisition occurred when rats were reconditioned after moderate extinction, showing that the original learning remained intact across this extinction. In contrast, when reconditioning was given after massive extinction, reconditioned responding was first depressed but then spontaneously recovered over time. This suggests that massive extinction produces a relatively permanent loss of the originally learned responding, while additionally imposes on the extinguished CS a transient latent inhibitory process that prevented the immediate but not the delayed expression of reconditioning. The second series of experiments studied the impact of spontaneous recovery of extinguished fear responses on their additional extinction. These experiments demonstrated that a CS that had time to show spontaneous recovery underwent greater response loss across additional extinction than one lacking recovery. They also showed that an excitor extinguished in compound with a CS showing recovery suffered greater response loss than an excitor extinguished in compound with a CS lacking recovery. Further, extinction of a compound composed of two CSs, one showing recovery and a second lacking recovery, produced greater extinction to the CS that showed recovery. These results show that spontaneous recovery of extinguished responses deepens their extinction through an error-correction mechanism regulated by both common and individual error terms. The third series of experiments studied the spontaneous recovery of latently inhibited and extinguished fear responses in within-subject designs. Using a compound test procedure, a CS that had received extensive preexposure or extensive extinction was found to have undergone greater spontaneous recovery relative to a CS just moderately preexposed or moderately extinguished. A CS given a mixed history of preexposure and extinction also underwent greater recovery relative to a CS just preexposed or just extinguished. These results suggest that both latent inhibition and extinction share a transient depressive process, and that the resulting recovery of responding is proportional to the amount of this depression.

The purpose of the present research was to examine extinction of responding with regard to the rapidity and thoroughness of the process when conditioned reinforcement was available on one of five schedules during extinction. Forty-five mixed-breed pigeons served as subjects with 15 in each of three experiments. Reinforcement training schedules were as follows: Experiment 1, continuous; Experiment 2, fixed ratio 15; Experiment 3, variable-interval one-minute. After training, subjects experienced one of five extinction procedures (here called schedules of extinction) which were as follows: traditional schedule without keylight did not provide conditioned reinforcement; traditional with keylight had the keylight on continuously but withheld other conditioned reinforcement (no schedule, per se, was used); the remaining three schedules (i.e., continuous, fixed ratio 15, and variable-interval one-minute) provided the following four conditioned reinforcers: the sound of the food magazine, the hopper light, the sight of food, and the keylight. Predictions for responding were based on the discrimination hypothesis which states that the more alike training and extinction conditions are, the slower the process of extinction. In order to compare response rates among subjects, a percentage of baseline responding was computed. Four spontaneous recovery tests were conducted to measure the thoroughness of the extinction procedures. Results did not support predictions based on the discrimination hypothesis; that is, subject response rates did not appear to be affected by the similarity of the extinction condition to previous training history. The second finding was that the most rapid and thorough extinction was obtained when the extinction schedule was traditional without keylight. When conditioned reinforcement was available, the continuous extinction schedule produced the most rapid and thorough extinction. The third major finding was that the schedule of unconditioned reinforcement was more predictive of extinction responding than was the conditioned reinforcement schedule during extinction. The last finding was that a subject's pattern of responding was typical of the schedule whether it was on an unconditioned or a conditioned reinforcement schedule. It is suggested that extinction-of-a-human-intervention strategies might be more effective if conditioned reinforcement was identified and controlled.

Greater than 50% of all spinal cord injuries (SCIs) in humans occur at the cervical level and the biggest desire of quadriplegic patients is recovery of hand and digit function. Several weeks after spinal cord injury, re-organization and re-modeling of spared endogenous pathways occurs and plasticity of both supraspinal and interneuronal networks are believed to mediate functional recovery. Propriospinal interneurons (PNs) are neurons found entirely in the spinal cord with axons projecting to different spinal segments. PNs function by modulating locomotion, integrating supraspinal motor pathways and peripheral sensory afferents. Recent studies have postulated that if PNs are spared following SCI, these neurons can contribute to functional recovery by establishing synaptic connections onto motor neurons. However, to what extent cervical PNs are involved in recovery of reaching behavior is not known. In our first study, we generated a lentiviral vector that permits highly efficient retrograde transport (HiRet) upon uptake at synaptic terminals in order to map supraspinal and interneuronal populations terminating near forelimb motoneurons (MNs) innervating the limb. With this vector, we found neurons labeled within the C3-C4 spinal cord and in the red nucleus, two major populations which are known to modulate forelimb reaching behavior. We also proceeded to use a novel two-viral vector method to specifically label ipsilateral C3-C4 PNs with tetracycline-inducible GFP. Histological analysis showed detailed labeling of somas, dendrites along with axon terminals. Based on this data, we proceeded to determine the contribution of C3-C4 PNs and rubrospinal neurons on forelimb reaching and grasping before and after cervical SCI. In our second study, we have examined a double-infection technique for shutdown of PNs and rubrospinal neurons (RSNs) in adult rats. Adult rats were microinjected with a lentiviral vector expressing tetracycline-inducible inhibitory DREADDs into C6-T1 spinal levels. Adeno-associated viral vectors (AAV2) expressing TetON mixed with GIRK2 were injected into the red nucleus and C3-C4 spinal levels respectively. Rats were tested for deficits in reaching behaviors upon application of doxycycline and clozapine-n-oxide (CNO) administration. No behavioral deficits were observed pre-injury. Rats then received a C5 spinal cord lesion to sever cortical input to forelimb motoneurons and were allowed four weeks to spontaneously recover. Upon re-administration of CNO to activate inhibitory DREADDs, deficits were observed in forelimb reaching. Histological analysis of the C3-C4 spinal cord and red nucleus showed DREADD+ neurons co-expressing GIRK2 in somas and dendrites of PNs and RSNs. PN terminals expressing DREADD were observed near C6-T1 motoneurons and in the brainstem. Control animals did not show substantial deficits with CNO administration. These results indicate both rubro- and propriospinal pathways are necessary for recovery of forelimb reaching. In a separate study, we sought to determine if promoting severed CST sprouting rostral to a C5 lesion near C3-C4 PNs could improve behavioral recovery post SCI. Past studies have examined sprouting and regeneration of corticospinal tract (CST) fibers post-cervical SCI through viral upregulation of key components of the PI3K/Akt/mTOR cascade. We examined the regenerative growth potential of CST fibers that are transduced with AAV2 expressing constituively active Akt3 or STAT3 both separately and in combination (Akt3 + STAT3). We have observed significant increases in CST axonal sprouting and regeneration in Akt3 and Akt3 + STAT3 transduced samples. However, no recovery was observed as animals transduced with viral constitutively active Akt3 displayed an epileptic phenotype. Further, epileptic animals with constitutively active Akt3 were found to have significant cortical neuron cell hypertrophy, activatived astrogliosis, increased dendritic arbors and hemimegencephalitis (HME). These results indicate a new model for examining mechanisms of HME and mTOR hyperactivity-induced epilepsy in adult rodents. / Biomedical Sciences

Der Pavor nocturnus (nächtlicher Angstschreck) ist eine zwei bis drei Stunden nach dem Einschlafen auftretende Parasomnie (schlafbegleitende Störung) im Vorschulalter. Die Prognose der 5-15 Minuten dauernden Episoden ist auch ohne spezifische Therapie sehr gut. Nächtliches Erwachen mit Angst und vegetativer Begleitreaktion wird erstmals kasuistisch bei einem Cocker spaniel beschrieben und lässt sich von allgemeiner Ängstlichkeit und anderen Formen aggressiven Verhaltens gut abgrenzen. Wie beim humanen Pendant hat die Störung offensichtlich eine gute Prognose und bedarf keiner speziellen Therapie. / The pavor nocturnus (night terrors) is a parasomnia (sleep associated disorder) in pre-school age occurring two to three hours after falling asleep. The prognosis of the episodes lasting 5-15 minutes is excellent even without specific treatment. Nocturnal awakening with anxiety and autonomic symptoms is presented for first time in a Cocker Spaniel and can be well separated from trait anxiety or other forms of aggressive behavior. Like the human equivalent the disorder obviously has a good prognosis and does not need particular treatment.

Human sensorimotor control is remarkably adept at utilising contextual information to learn and recall systematic sensorimotor transformations. Here, we investigate the motor representations that underlie such learning, and examine how motor memories acquired based on different contextual information interact. Using a novel three-dimensional robotic manipulandum, the 3BOT, we examined the spatial transfer of learning across various movement directions in a 3D environment, while human subjects performed reaching movements under velocity-dependent force field. The obtained pattern of generalisation suggested that the representation of dynamic learning was most likely defined in a target-based, rather than an extrinsic, coordinate system. We further examined how motor memories interact when subjects adapt to force fields applied in orthogonal dimensions. We found that, unlike opposing fields, learning two spatially orthogonal force fields led to the formation of separate motor memories, which neither interfered with nor facilitated each other. Moreover, we demonstrated a novel, more general aspect of the spontaneous recovery phenomenon using a two-dimensional force field task: when subjects learned two orthogonal force fields consecutively, in the following phase of clamped error feedback, the expression of adaptation spontaneously rotated from the direction of the second force field, towards the direction of the first force field. Finally, we examined the interaction of sensorimotor memories formed based on separate contextual information. Subjects performed reciprocating reaching and object manipulation tasks under two alternating contexts (movement directions), while we manipulated the dynamics of the task in each context separately. The results suggested that separate motor memories were formed for the dynamics of the task in different contexts, and that these motor memories interacted by sharing error signals to enhance learning. Importantly, the extent of interaction was not fixed between the context-dependent motor memories, but adaptively changed according to the task dynamics to potentially improve overall performance. Together, our experimental and theoretical results add to the understanding of mechanisms that underlie sensorimotor learning, and the way these mechanisms interact under various tasks and different dynamics.

Environ 30% des patients infectés par le virus de l’hépatite C guérissent spontanément. Le but de ce travailétait (i) d’examiner l’évolution des protéines d’enveloppe en cas de guérison spontanée (ii) de comparerl’infectivité des variants présents aux stades précoces (iii) d’explorer la capacité neutralisante des anticorps(Ac) vis-à-vis des variants majoritaires et minoritaires. Nous avons sélectionné 2 patients avec une hépatiteaigue C suivie d’une guérison très rapide. Pour explorer la capacité d’entrée de ces variants et leur aptitude àêtre neutralisés, nous avons produit des pseudo-particules rétrovirales portant les enveloppes de différentsvariants. Pour le 1er patient, une réponse neutralisante autologue était détectable précocement, avec unmaximum entre le 2ème et le 3èmemois suivant la cytolyse. Elle était encore détectable au 30ème mois. Pourle 2ème patient, des Ac vis-à-vis du variant majoritaire étaient détectés dans le sérum prélevé 4 jours après lacytolyse et dans les sérums plus tardifs. Le titre des Ac était maximum au 5ème mois. La réponse neutralisanteest d’apparition précoce et persiste même après l’élimination virale. Ces observations nous questionnent parrapport au rôle éventuel joué par ces Ac dans les cas de recontamination. / Only 30% of Hepatitis C virus infected individuals recover spontaneously. We investigated the mechanismsleading to early HCV clearance. The purpose of this work was: (i) to explore the diversity and the early geneticevolution of the HCV envelope glycoproteins, and the infectivity spectrum of isolated variants and (ii) toanalyze the ability of the autologous neutralizing response to control these variants. We selected two patientswho developed an acute HCV infection. To explore the impact of mutations on infectivity and neutralization,retroviral pseudoparticules were produced with representative E1 and E2 sequences. For the first case, themaximum neutralizing activity was observed in the serum collected between 2 and 3 months post ALT peak,the activity was still detectable after 30 months. For the second case, autologous neutralizing activity wasdetected in every serum collected between 4 days and 13 months after. A gradual increase of neutralizationactivity was observed over time with a maximum 5 to 6 months. We have shown that the neutralizing responsewas detectable at early stages of primoinfection and was sustained beyond the time at which the virus wascleared. These observations raise interesting questions about the role of such antibodies in case of re-exposure.

Der Pavor nocturnus (nächtlicher Angstschreck) ist eine zwei bis drei Stunden nach dem Einschlafen auftretende Parasomnie (schlafbegleitende Störung) im Vorschulalter. Die Prognose der 5-15 Minuten dauernden Episoden ist auch ohne spezifische Therapie sehr gut. Nächtliches Erwachen mit Angst und vegetativer Begleitreaktion wird erstmals kasuistisch bei einem Cocker spaniel beschrieben und lässt sich von allgemeiner Ängstlichkeit und anderen Formen aggressiven Verhaltens gut abgrenzen. Wie beim humanen Pendant hat die Störung offensichtlich eine gute Prognose und bedarf keiner speziellen Therapie. / The pavor nocturnus (night terrors) is a parasomnia (sleep associated disorder) in pre-school age occurring two to three hours after falling asleep. The prognosis of the episodes lasting 5-15 minutes is excellent even without specific treatment. Nocturnal awakening with anxiety and autonomic symptoms is presented for first time in a Cocker Spaniel and can be well separated from trait anxiety or other forms of aggressive behavior. Like the human equivalent the disorder obviously has a good prognosis and does not need particular treatment.

Following a stroke, normal usage of the impaired limb guides spontaneous recovery across many months or even years; however, recovery is rarely complete. Pre-clinical tools are needed to investigate stroke-induced cortical reorganization over long periods. This thesis aims to characterize stroke impairment and spontaneous recovery in parallel with a battery of behaviour tasks in a mouse model of focal stroke. Young adult Thy1-ChR2 mice were implanted with a transcranial window over the intact skull permitting cortex visualization and enabling longitudinal assessments with light-based motor mapping and intrinsic signal optical imaging. Furthermore, mice were tested on sensorimotor behavioural tasks in parallel to the mapping experiments. These experiments allowed for the quantification of impairments in the sensorimotor cortex and forelimb function while identifying regions within the sensorimotor cortex that show re-mapping associated with behavioural recovery. Following primary motor cortex-stroke induction, both sensory and motor map impairments occurred. Sensory map transient impairments recovered within the same atlas-defined regions two weeks after a primary motor cortex stroke as identified by intrinsic signal optical imaging. In contrast, motor forelimb recovery was observed four weeks after the stroke in the peri-infarct region, the supplemental motor cortex, and the contralesional motor cortex. This recovery was identified through a combination of analyses, including changes in the mapped area and the amplitude of evoked forelimb movements using light-based motor mapping. Behavioural recovery occurred four to six weeks post-stroke, depending on the sensitivity of the task in forelimb impairment. Additionally, the contralesional hemisphere and forelimb did not show impairment acutely but evoked forelimb amplitude was significantly increased by post-stroke week four for both forelimbs. As the first study to conduct within-animal longitudinal spontaneous recovery sensory and motor map experiments using bilateral forelimb and hemispheric representations, we show that 1) photothrombotic stroke impacts both forelimb representations pertained within the ipsilesional hemisphere in LBMM experiments, 2) recovery of the impaired forelimb occurs ipsilesionally and contralesionally and, 3) impairments from stroke observed through motor mapping are functionally relevant and precede behavioural recovery ranging from zero to two or more weeks depending on the motor cortex's involvement in the behavioural task.