For many organisms the sense of smell is critical to survival. Some olfactory stimuli elicit innate responses that are mediated through hardwired circuits that have developed over long periods of evolutionary time. Most olfactory stimuli, however, have no inherent meaning. Instead, meaning must be imposed by learning during the lifetime of an organism. Despite the dominance of olfactory stimuli on animal behavior, the mechanisms by which odorants elicit learned behavioral responses remain poorly understood. All odor-evoked behaviors are initiated by the binding of an odorant to olfactory receptors located on sensory neurons in the nasal epithelium. Olfactory sensory neurons transmit this information to the olfactory bulb via spatially organized axonal projections such that individual odorants evoke a stereotyped map of bulbar activity. A subset of bulbar neurons, the mitral and tufted cells, relay olfactory information to higher brain structures that have been implicated in the generation of innate and learned behavioral responses, including the cortical amygdala and piriform cortex. Anatomical studies have demonstrated that the spatial stereotypy of the olfactory bulb is maintained in projections to the posterolateral cortical amygdala, a structure that is involved in the generation of innate odor-evoked responses. The projections of mitral and tufted cells to piriform cortex however appear to discard the spatial order of the olfactory bulb: each glomerulus sends spatially diffuse, apparently random projections across the entire cortex. This anatomy appears to constrain odor-evoked responses in piriform cortex: electrophysiological and imaging studies demonstrate that individual odorants activate sparse ensembles that are distributed across the extent of cortex, and individual piriform neurons exhibit discontinuous receptive fields such that they respond to structurally and perceptually similar and dissimilar odorants. It is therefore unlikely that olfactory representations in piriform have inherent meaning. Instead, these representations have been proposed to mediate olfactory learning. In accord with this, lesions of posterior piriform cortex prevent the expression of a previously acquired olfactory fear memory and photoactivation of a random ensemble of piriform neurons can become entrained to both appetitive and aversive outcomes. Piriform cortex therefore plays a central role in olfactory fear learning. However, how meaning is imparted on olfactory representations in piriform remains largely unknown. We developed a strategy to manipulate the neural activity of representations of conditioned and unconditioned stimuli in the basolateral amygdala (BLA), a downstream target of piriform cortex that has been implicated in the generation of learned responses. This strategy allowed us to demonstrate that distinct neural ensembles represent an appetitive and an aversive unconditioned stimulus (US) in the BLA. Moreover, the activity of these representations can elicit innate responses as well as direct Pavlovian and instrumental learning. Finally activity of an aversive US representation in the basolateral amygdala is required for learned olfactory and auditory fear responses. These data suggest that both olfactory and auditory stimuli converge on US representations in the BLA to generate learned behavioral responses. Having identified a US representation in the BLA that receives convergent olfactory information to generate learned fear responses, we were then able to step back into the olfactory system and demonstrate that the BLA receives olfactory input via the monosynaptic projection from piriform cortex. These data suggest that aversive meaning is imparted on an olfactory representation in piriform cortex via reinforcement of its projections onto a US representation in the BLA. The work described in this thesis has identified mechanisms by which sensory stimuli generate appropriate behavioral responses. Manipulations of representations of unconditioned stimuli have identified a central role for US representations in the BLA in connecting sensory stimuli to both innate and learned behavioral responses. In addition, these experiments have suggested local mechanisms by which fear learning might be implemented in the BLA. Finally, we have identified a fundamental transformation through which a disordered olfactory representation in piriform cortex acquires meaning. Strikingly this transformation appears to occur within 3 synapses of the periphery. These data, and the techniques we employ, therefore have the potential to significantly impact upon our understanding of the neural origins of motivated behavior.

Spatial attention enhances perception at specific locations in the visual field, measured behaviorally as improved task performance and faster reaction times. In visual cortex, neurons with receptive fields at attended locations display enhanced responses. This neural modulation is presumed to underlie the associated behavioral benefit, although the mechanisms linking sensory cortical modulation to perceptual enhancement remain unclear. In studies of spatial attention, experimentalists persuade animals to attend to particular locations by associating them with a higher probability or magnitude of reward. Notably, these manipulations alter in tandem both the absolute expectation of reward at a particular location, as well as the expectation of reward relative to other locations in the visual field. We reasoned that independently changing absolute and relative reward expectations could provide insight into the mechanisms of attention. We trained monkeys to discriminate the orientation of two stimuli presented simultaneously in different hemifields while independently varying the reward magnitude associated with correct discrimination at each location. Behavioral measures of attention were controlled by the relative value of each location. By contrast, neurons in visual area V4 were consistently modulated by absolute reward value, exhibiting increased firing rates, increased gamma-band power, and decreased trial-to-trial variability whenever receptive field locations were associated with large rewards. Thus, neural modulation in V4 can be robustly dissociated from the perceptual benefits of spatial attention; performance could be enhanced without neural modulation, and neural activity could be modulated without substantial perceptual improvement. These data challenge the notion that the perceptual benefits of spatial attention rely on increased signal-to-noise in V4. Instead, these benefits likely derive from downstream selection mechanisms. In identifying brain areas involved with attention, a distinction is generally made between sensory areas like V4— where the representation of the visual field is modulated by attentional state— and attentional “source" areas, primarily in the oculomotor system, that determine and control the locus of attention. The amygdala, long recognized for its role in mediating emotional responses, may also play a role in the control of attention. The amygdala sends prominent feedback projections to visual cortex, and recent physiological studies demonstrate that amygdala neurons carry spatial signals sufficient to guide attention. To characterize the role of the amygdala in the control of attention, we recorded neural activity in the amygdala and V4 simultaneously during performance of the orientation discrimination task. In preliminary data analysis, we note two sets of findings. First, consistent with prior work, we found that amygdala neurons combine information about space and value. Rewards both contralateral and ipsilateral to amygdala neurons modulated responses, but contralateral rewards had a larger effect. Therefore, notably distinct from known attentional control sources in the oculomotor system, spatial-reward responses in the amygdala do not reflect the relative value of locations. Second, we found signatures of functional connectivity between the amygdala and V4 during task performance. Reward cue presentation was associated with elevated alpha and beta coherence, and attention to locations contralateral to the amygdala and inside the receptive field of V4 neurons was associated with elevated inter-area gamma coherence. These results suggest that the amygdala may serve a unique role in the control of spatial attention. Together, these experiments contribute towards an understanding of the brain-to-behavior mechanisms linking neural activity in V4 and the amygdala to the dramatic perceptual and behavioral improvement associated with attention.

Dramatic changes occur across childhood and adolescence in the activity and connectivity of an amygdala-medial prefrontal cortex circuit critical for emotional learning and regulation. However, little is currently known about how neuroplasticity within the circuit changes during development in the human. Experiences that occur during developmental sensitive periods of increased neuroplasticity have the capacity to sculpt neural function with lifelong consequences for cognition and behavior, though. This dissertation will therefore investigate when and how experience may shape amygdala-medial prefrontal cortex functional circuitry (Aim 1) and what the implications of experience-dependent circuitry development are for emotion regulation behaviors (Aim 2) across childhood, adolescence, and adulthood in three studies. Study 1 (previously published as Gabard-Durnam, Gee et al., 2016) posits and tests the long-term phasic molding hypothesis that tonic amygdala-prefrontal cortex functional connectivity, the functional architecture of the brain, is shaped during development by recurring stimulus-elicited connectivity in the circuitry using prospective examination of these connectivities’ development across childhood and adolescence. Study 1 also tests whether the ability of amygdala-prefrontal cortex stimulus-elicited connectivity to shape the amygdala-prefrontal cortex resting-state functional architecture changes across development, reflecting changing plasticity of the circuitry. Study 2 examines how the timing and duration of an early adverse experience, parental deprivation, interacts with genetically-driven differences in neuroplasticity levels indexed by the Brain-Derived Neurotrophic Factor val66met polymorphism to influence the developmental trajectory of amygdala-prefrontal cortex functional architecture using a population of previously-institutionalized children and adolescents and a never-institutionalized comparison sample. Study 2 further examines how the experience- and plasticity-related changes to the functional architecture influence both concurrent and future internalizing symptomatology across childhood and adolescence. Study 3 builds on the first two developmental studies by explicitly testing whether childhood is a sensitive period for medial prefrontal cortex-mediated regulatory signal learning through a retrospective design in adults. Study 3 additionally assesses the effects of developmental experience on adult emotion regulation behavior and physiology. My findings at the levels of brain circuitry, behavior, physiology, and genetics together delineate a period of increased sensitivity to the environment within prefrontal cortex-amygdala functional circuitry from infancy through childhood, modifiable by genetically-conferred variation in plasticity and the nature of the early environment. Moreover, experiences occurring during the sensitive period have consequences for future emotion regulation behavior both during development and lasting into young adulthood. Together, these findings demonstrate how experience-dependent development has enduring effects on amygdala-prefrontal cortex circuitry function and affective behavior.

No description available.

The basolateral complex of the amygdala (BLA) is a key component of the neuronal circuitry underlying the acquisition and the extinction of Pavlovian conditioned fear. The present series of experiments examined the role of neuronal activity and NMDA receptors (NMDAr) activation in the BLA on learning and relearning context conditioned fear and its extinction. Disruption of neuronal activity in the BLA prevented the acquisition of fear responses to a novel, a moderately familiar or a highly familiar context. It also prevented the reacquisition of fear responses to a conditioned or an extinguished context. Local blockade of NMDAr containing the NR2B subunit prior to training extinction or re-extinction impaired the short- and long-term loss of fear responses. In contrast, a similar blockade subsequent to training extinction or re-extinction left the long-term loss of fear responses unaffected. Disruption of neuronal activity in the BLA prior to training extinction and re-extinction depressed fear responses. It impaired the long-term loss of fear produced by extinction training but spared and even facilitated the long-loss of fear produced by re-extinction training when extinction had already been learned. The exact same outcome was observed when neuronal activity in the BLA was disrupted subsequent to training extinction and re-extinction. These findings suggest that the BLA is critical for both learning and relearning context conditioned fear. In contrast, the BLA is necessary for learning but not relearning extinction of conditioned fear. This implies that once extinction has been learned, others structures support the retrieval and the expression of extinction memory. This is consistent with current neural model of extinction that involves interactions between several neural substrates including the BLA and the medial prefrontal cortex.

Thesis (M.Sc.)--Memorial University of Newfoundland, 2001. / Bibliography: leaves 47-54.

published_or_final_version / Medicine / Master / Doctor of Medicine

This thesis examined the involvement of the lateral, central and basolateral nuclei of the amygdala in both appetitive and aversive affective behavior. In Experiment I, using electrolytic lesions, it was found that damage to the lateral but not central or basolateral nuclei blocked a Conditioned Cue Preference (CCP) to food (Froot Loops) in rats that were not deprived of food. In Experiment II, also using electrolytic lesions, it was found that damage to the basolateral but not central or lateral nuclei blocked a Conditioned Cue Aversion (CCA) produced by a lithium chloride injection (42 mg/kg). In Experiment III results similar to those in Experiments I and II were obtained using axon-sparing NMDA lesions. The results of Experiments I-III demonstrate a double dissociation of affective memory with respect to the amygdala. The lateral nucleus of the amygdala mediated the memory of an appetitive affective experience and the basolateral nucleus mediated memory for an aversive affective experience. / In Experiment IV the contributions of appetitive and aversive affective states to a food CCP were examined. Lesions of the lateral but not the basolateral nucleus were found to attenuate but not completely eliminate a food CCP when the rats were food deprived in the Paired compartment and sated in the Unpaired compartment. Food deprivation alone produced a CCA and lesions of the basolateral but not the lateral nucleus blocked this effect. The possibility that both the appetitive and aversive behaviours are mediated through connections from the dopamine-reward centres in the ventral striatum is discussed.

The experiments in this thesis examined the roles of stimulus configuration on conditioned cue preference (CCP) learning by asking what information is processed and by which neural substrates. Results from Experiments 1 and 2 showed that lesions of the lateral nucleus of the amygdala (LNA) but not of fimbria-fornix (FF) impaired CCP learning when the cues paired with food during training were distinct from those not paired with food in either of two different apparatuses. In Experiments 3 and 4 LNA lesions increased the size of the CCP when the cues paired with food and no food were ambiguous in two different apparatuses. Learning the ambiguous cue CCP required at least one session of unreinforced pre-exposure to the cues and was eliminated by FF lesions. In the last series of experiments, a latent learning effect of unreinforced pre-exposure on ambiguous cue CCP learning on the radial maze was found in normal animals that received at least 3 sessions of unreinforced pre-exposure. FF lesions made before, but not after, pre-exposure eliminated the latent learning effect. Hippocampus lesions made either before or after pre-exposure eliminated the CCP learning. Taken together, the results are consistent with the hypothesis that distinct cue CCP learning is based on conditioned approach responses to cues paired with food, mediated by a neural system that includes the LNA. The results also suggest that ambiguous cue CCP learning takes place in two phases. First spatial learning occurs during unreinforced pre-exposure, a process that requires an intact FF. Subsequently, information about the location of the reinforcer is added to the spatial information during the reinforced training trials by a process of "reconsolidation". An intact hippocampus is required for this process. The implications of these results and interpretations for latent learning and latent inhibition are considered.

No description available.