Thesis advisor: Jon C. Horvitz / Previous research has yielded conflicting results regarding the involvement of mesolimbic dopamine in Pavlovian and operant tasks. While there is abundant evidence that an operant lever press requires intact dopamine (DA) D1 transmission in the nucleus accumbens (ACB) and in the basolateral amygdala (BLA), there is conflicting evidence regarding the specific brain sites at which DA mediates a Pavlovian approach response. The present study was designed to compare the effects of ACB and BLA D1 receptor-blockade on an operant and Pavlovian task, while minimizing differences in behavioral response topography. Animals were trained on either a Pavlovian cued approach task or an operant cued nosepoke task. In the Pavlovian approach task, a tone signaled a pellet delivery to which animals responded with a head entry into a food compartment. In the operant nosepoke task, animals were trained to emit a nosepoke in response to the same tone, in order to trigger a pellet delivery. Bilateral microinfusions of the D1 antagonist SCH 23390 (0, 1 or 2 microgram/side) into either the ACB or the BLA produced a dose-dependent disruption of the operant nosepoke. In contrast, the Pavlovian cued approach response was unaffected by D1 antagonist microinfusions into either the ACB or the BLA. In addition, infusion of SCH 23390 into either site suppressed general locomotion. The results suggest a dissociation of the anatomical substrates mediating an operant nosepoke and a Pavlovian approach, despite similar response topographies. These findings are consistent with the notion that D1 activity at the ACB and BLA plays a role in the expression of operant responses, but not in the expression of Pavlovian approach responses. / Thesis (PhD) — Boston College, 2010. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

Female mice exhibit a hardwired preference to investigate pheromones released by male conspecifics. The neural pathways that convey pheromonal inputs to brain regions controlling motivated behaviors remain largely unknown. One brain region known to process pheromonal information conveyed via main- and accessory olfactory bulb inputs is the Medial Amygdala (Me), a limbic structure comprised of anterior (MeA) and posterior (MeP) subdivisions. Electrolytic lesions of the MeP blocked the normal preference of estrous female mice to investigate urinary odors emitted from breeding as opposed to castrated males whereas lesions of either the MeA or MeP significantly reduced females' display of the receptive lordosis posture in response to male mounts. Quantitative analysis of synaptic puncta in the efferent projection targets of these two amygdaloid subregions, visualized using fluorescent anterograde tract tracing techniques, revealed that the MeA and MeP differentially innervate several forebrain regions. The medial olfactory tubercle (mOT; a component of the ventral striatum) receives dense monosynaptic input from the MeA and responds selectively to breeding male (but not female) soiled bedding volatiles, indexed by augmented FOS expression. Using injections of the retrograde tracer, cholera toxin B (CTb), neurons were identified in the MeA and ventral tegmental area (VTA) that projected to the mOT in female mice and which also co-expressed FOS after exposure to breeding male, but not female, soiled bedding/urinary volatiles. This suggests that the MeA and VTA convey opposite-sex (male) pheromonal information to the mOT. Bilateral dopaminergic lesions of the anteromedial VS (a region which includes the mOT) eliminated females' preference for breeding male vs. female urinary pheromones, suggesting that dopaminergic modulation in the VS is necessary for the display of these behaviors. Lastly, bilateral silencing of mOT neuronal firing by the activation of the inhibitory DREADD receptor, hM4Di, induced by intraperitoneal injection of its ligand (CNO), also disrupted females' preference to investigate urinary odors from breeding males; this deficit was reversed when saline was administered instead of CNO. The Me, VTA, and mOT are essential segments of a neural reward circuit that motivates estrous female mice to seek out male pheromones, thereby facilitating mate recognition and reproductive success.

Les comportements motivés tels que les comportements alimentaires ou sexuels sont émis de façon irrégulière sous l’impulsion du système nerveux central. Ils sont régulés par des informations sensorielles et des apprentissages. Dans un apprentissage associatif, le conditionnement opérant appétitif, l’animal apprend les conséquences de son action parl’association d’une action à l’obtention d’une récompense (un stimulus à forte valeur appétitive). Il est établi que cet apprentissage induit la transition d’une motricité initialement peu fréquente et irrégulière en une motricité rythmique, fréquente et régulière. Cependant, les mécanismes cellulaires du système nerveux central qui sont responsables de cettetransition, restent largement méconnus. Notre étude chez le mollusque aplysie nous a permis d’identifier ces mécanismes dans un réseau neuronal identifié et générateur des patterns moteurs du comportement alimentaire. Sur des préparations du système nerveux isolé, nous avons sélectivement contrôlé l’expression fréquente d’une part et régulièred’autre part de la motricité apprise grâce à la manipulation expérimentale de la plasticité fonctionnelle de neurones pacemakers identifiés. Ainsi, nous avons nouvellement établi un lien de causalité entre (1) des modifications membranaires et l’accélération motrice et (2) le renforcement de synapses électriques et la régularité motrice. Nous avons mis en évidence le rôle du transmetteur dopamine dans l’induction de ces plasticités fonctionnelles et l’expression de la motricité fréquente et régulière. Enfin, nous avons analysé les propriétés intrinsèques du neurone responsable de l’impulsion spontanée et irrégulière de la motricité des animaux naïfs. Pour conclure, l’ensemble de ces travaux de thèse offre une vue étendue des mécanismes cellulaires qui déterminent la variabilité d’un comportement motivé et sarégulation par apprentissage. / Motivated behaviors such as feeding or sexual behavior are irregularly expressed by impulsive drives from the central nervous system. However, such goal-directed acts are regulated by sensory inputs and learning. In a form of associative learning, appetitive operant conditioning, an animal learns the consequences of its own actions by making the contingentassociation between an emitted act and delivery of a rewarding (highly appetitive) stimulus. It is now established that this learning procedure induces the transition from an initially infrequent and irregular motor activity to a frequent and regular behavior. However the cellular and central network mechanisms that mediate this behavioral plasticity remain poorlyunderstood. Our study on the marine sea slug Aplysia has allowed us to analyze these mechanisms in an identified neuronal network that is responsible for generating the motor patterns of the animal's feeding behavior. Using in vitro neuronal preparations, we selectively controlled the frequency and regularity of the motor activity induced by operant learning with experimental manipulations of the functional plasticity in identified pacemaker neurons. We found for the first time a causal relationship between the learning-induced plasticity and (1) changes in pacemaker neuron membrane properties and the increased frequency of feeding motor activity, and (2), in the strength of their interconnecting electrical synapses and the regularized phenotype of this motor activity. We then addressed the role of the transmitterdopamine in the induction of this functional plasticity and specifically the expression of a frequent and stereotyped rhythmic feeding motor pattern. Finally, we analyzed the intrinsic membrane properties of the essential pacemaker neuron for generating the irregular motor drive in naïve animals. In conclusion, the data from this thesis work have provided novelinsights into the cellular and synaptic mechanisms underlying the intrinsic variability of a motivated behavior and its regulation by learning.