Traditional studies of simple perceptual choice tasks in vertebrates identified behavioural characteristics of deliberate decision-making that guided the development of general mathematical models, and the search for neurophysiological correlates. Current experimental and modelling efforts aim to uncover biophysical and circuit level mechanisms of decision-making processes. However, genetic manipulability constraints and lack of high-throughput assays make further progress in vertebrate studies a steep endeavour. In this thesis I studied decision-making in Drosophila melanogaster in trained two-alternative forced-choice olfactory tasks with varying stimulus contrast, using a high-resolution single fly behavioural assay. Analysing accuracy and reaction time as a function of task difficulty (i.e., stimulus contrast) showed that flies display behavioural characteristics of evidence accumulation processes, a signature of vertebrate decision-making: reaction times increased and perceptual accuracy declined as stimulus contrast decreased. Mutants for the gene encoding the transcription factor FoxP took longer than wild-type flies to form decisions of similar or reduced accuracy, especially in difficult tasks. Using the putative FoxP promoter to ascertain FoxP expression identified subsets of mushroom body intrinsic Kenyon cells, in αβ core and γ neurons, as potential sites of FoxP action. Disrupting FoxP expression or decreasing neuronal excitability specifically in αβ core neurons mimicked the phenotype observed in FoxP mutants. FoxP expression therefore affects the development or function of αβ core neurons in the progression of a decision process towards commitment. To identify molecular processes involved in evidence integration regulated by FoxP I further screened 2nd and 3rd chromosome deficiency lines in a sensitised FoxP mutant background, uncovering genomic regions of interest for further study. Finally, analysing naive performance in tasks of increasing difficulty showed that naive discriminations are faster and less accurate than trained ones, pointing to the existence of two decision-making systems. FoxP mutants appear to engage the slower, more accurate decision making system and the mushroom body seems to be involved in naive discriminations. The molecular and neuronal players involved in olfactory decision making in Drosophila melanogaster uncovered in this thesis will allow researching decision making systems to an unprecedented level of detail.

Functional MRI technique is vital in investigating the effect of an intervention on cortical activation in normal and patient population. In many such investigations, block stimulation paradigms are still the preferred method of inducing brain activation during functional imaging sessions because of the high BOLD response, ease in implementation and subject compliance especially in patient population. However, effect of an intervention can be validly interpreted only after reproducibility of a detectable BOLD response evoked by the stimulation paradigm is first verified in the absence of the intervention. Detecting a large BOLD response that is also reproducible is a difficult task particularly in olfactory Functional MRI studies due to the factors such as (a) susceptibility-induced signal loss in olfactory related brain areas and (b) desensitization to odors due to prolonged odor stimulation, which is typical when block paradigms are used. Therefore, when block paradigms are used in olfactory interventional Functional MRI studies, the effect of the intervention may not be easily interpretable due to the factors mentioned above. The first task of this thesis was to select a block stimulation paradigm that would produce a large and reproducible BOLD response. It was hypothesized that a BOLD response of this nature could be produced if within-block and across-session desensitization could be minimized and further, that desensitization could be minimized by reducing the amount of odor by pulsing the odor stimulus within a block instead of providing a continuous odor throughout the block duration. Once the best paradigm was selected, the second task of the thesis was to select the best model for use in general linear model (GLM) analysis of the functional data, so that robust activation is detected in olfactory related brain areas. Finally, the third task was to apply the paradigm and model that were selected as the best among the ones tested in this thesis, to an olfactory interventional Functional MRI study investigating the effect of food (bananas) eaten to satiety on the brain activation to the odor related to that food. The methods used in this thesis to ensure valid interpretation of an interventional effect, can serve as a template for the experimental design of future interventional Functional MRI studies.

Arthropod predators often use prey and conspecific cues to make foraging decisions. Calosoma wilcoxi (Leconte) is a voracious predatory beetle that specializes on lepidopteran larvae often found in the forest canopy, including the fall cankerworm. This study tested the hypothesis that C. wilcoxi uses olfactory cues to detect prey and conspecifics. A Y-tube olfactometer was used to test attractiveness to larvae, larval frass, conspecific cues, and volatiles from herbivore-damaged white oak leaves. C. wilcoxi did not preferentially choose the treatment in any of the experiments. There was no difference in mean time spent in the treatment or control arm for any of the cues assayed. The time to choose the treatment was significantly shorter in the female conspecific experiment only. I found no evidence that C. wilcoxi uses olfaction to locate prey; however, C. wilcoxi is attracted to conspecifics. C. wilcoxi may use conspecific cues to make informed foraging decisions.

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Doctor of Philosophy (PhD) / Abstract Olfactory tasks are used very often with laboratory animals in studies of the neurobiology of learning and memory. Rats and mice are extremely sensitive in their detection and discrimination of odours, learn olfactory tasks rapidly, and can display higher order cognitive functions in olfactory tasks. This cognitive capacity may rival the ability of primates to learn analogous tasks with visual cues and most likely reflects strong anatomical connections between the olfactory bulbs and higher brain regions such as the piriform cortex, orbitofrontal cortex and hippocampus. The current thesis explored olfactory discrimination learning and performance in rats and had two principal aims. The first part of the thesis was oriented around odour masking phenomena in rats: the ability of one odour in a mixture to suppress detection of a second odour in that mixture. A specialized behavioural paradigm was developed to allow the study of odour masking in the rat. The second part of the thesis was pharmacological and determined whether the acquisition, reversal and performance of olfactory discriminations, and analogous auditory discriminations, are affected by two commonly used classes of drugs (benzodiazepines and cannabinoids). Together, these studies attempt to gain a better understanding of the nature of olfactory discrimination learning in rats, by using both psychophysical and pharmacological approaches, and to develop behavioural paradigms which may be used in future psychophysical and pharmacological studies. Following an introduction and review of olfactory and auditory studies in rat (Chapter 1), odour masking phenomena were studied in Chapter 2. The aliphatic aldehydes butanal (C4) and heptanal (C7) were used in the study. Aldehydes were of interest as this class of odorants abound in nature and may be important for rodents’ species-specific communication. Thirsty rats were initially trained to discriminate C4 and C7 in the olfactometer, using a go/no-go olfactory discrimination task. This involved rats learning to nose poke in an odour port and to lick a tube for a water reward on presentation of the rewarded component S+, while withholding licking at the tube when the other, unrewarded, aldehyde (S-) was presented. Odour mixtures (C4C7 or C7C4) were then introduced into the task as an additional non-rewarded condition (mixture S-). The concentration of the non-rewarded aldehyde in the mixture was then systematically decreased, while the concentration of the rewarded aldehyde was kept constant. When the non-rewarded aldehyde reached a critical low level in the mixture, rats started to make responses to the non-rewarded mixture (false alarms) showing that the S+ odour was suppressing the S- odour in the mixture, so the mixture was being responded to in the same manner as the S+ odour presented alone. Results also showed asymmetric suppression in the mixture condition, such that butanal suppressed detection of heptanal at a much lower concentration than vice versa. A second experiment demonstrated that when both butanal and heptanal were present in a binary mixture at the same concentration (10-6 volume %), rats responded to the mixture as if only butanal was present. Our findings are in agreement with human studies showing component interactions in binary mixtures of aldehydes. The molecular feature of carbon chain length appears to be a critical factor in determining the outcome of interactions between aldehydes at peripheral olfactory receptors, with smaller chain aldehydes better able to compete for receptor occupancy. Subsequent chapters explored the effects of two classes of commonly used drugs - benzodiazepines and cannabinoids - on olfactory and auditory discrimination in rats. Animal models such as the radial arm maze, Morris water maze and object recognition test are routinely used to test adverse and facilitatory effects of drugs on cognition in rodents. However, comparatively few pharmacological studies employ olfactory or auditory go/no-go paradigms. Thus, an important part of the present thesis was to assess the viability of using such paradigms in detecting pharmacological effects, and to identify whether such effects may be modality specific (i.e. whether a drug has a greater effect on olfactory or auditory tasks). In Chapter 3, the effects of benzodiazepines on olfactory discrimination tasks were explored. Rats were injected with the benzodiazepine drugs midazolam or diazepam and tested on discrimination tasks involving either the auditory and olfactory modality. Results showed that midazolam (0.5–2 mg/kg sc) did not affect the performance of a well-learned two-odour olfactory discrimination task, and moderately facilitated the performance of a go/no-go auditory discrimination task. On the contrary, midazolam (1 mg/kg) impaired the acquisition of a novel go/no-go olfactory discrimination task, as well as the reversal of a previously well-learned olfactory discrimination. However, midazolam did not affect the acquisition or reversal of an equivalent auditory discrimination task. The olfactory bulb and the piriform cortex are intimately involved in associative learning and behavioural aspects of olfactory performance, and have high concentrations of benzodiazepine receptors. These may therefore be possible neural substrates for the disruptive effects of benzodiazepines on olfactory learning. Findings from Chapter 4 indicated that the prototypical cannabinoid agonist delta-9-tetrahydrocanabinol (Δ9 THC) (0.3, 1 and 3 mg/kg) impairs auditory discrimination performance, but had no effect on equivalent olfactory discriminations. This is in marked contrast to the effects of benzodiazepines. Residual effects were observed, such that auditory discrimination performance was still impaired on the day following Δ9 THC administration. Delta-9-tetrahydrocanabinol effects were prevented by co-administration of the cannabinoid antagonist rimonabant (3 mg/kg). In addition, the anandamide hydrolysis inhibitor URB597 (0.1 and 0.3 mg/kg), which boosts levels of endogenous cannabinoids in the synapse, also impaired auditory discrimination performance, and this effect was also reversed by rimonabant. This study also assessed the effects of Δ9 THC (0.3, 1 and 3 mg/kg) and URB597 (0.1 and 0.3 mg/kg) on acquisition and reversal of novel olfactory discriminations. Results showed that Δ9 THC impairs olfactory reversal learning without affecting acquisition of the original discrimination. It is argued that this reversal deficit may be part of a wider capacity for cannabinoids to impair cognitive flexibility. The final Chapter (General Discussion) discusses the relevance and implications of the combined findings. The results add significantly to our current understanding of perceptual, learning and memory processes involving the olfactory modality in rats. With respect to olfactory perception, this thesis introduced a new behavioural paradigm, which can be used to assess component suppression in mixtures, and may be of use in future psychophysical studies involving rodents or other species. With respect to learning and memory, the thesis provides novel information on the disruptive effects of benzodiazepines and cannabinoids on olfactory and auditory tasks. It is concluded that go/no-go olfactory and auditory discrimination tasks in rats can provide a useful platform for assessing the disruptive and modality-specific effects of drugs on learning, performance and cognitive flexibility. Future studies might expand the range of drugs tested on these paradigms and might consider chronic as well as acute drug effects.

In most animal species, reproductive success depends critically on precopulatory or solicitational behaviors that occur prior to mating. The specific sensory systems and behavioral strategies employed in precopulatory behaviors vary across species; in all cases, however, animals must be able to identify potential mating partners and solicit sexual interest. Female Syrian hamsters (Mesocricetus auratus) engage in multiple forms of precopulatory behaviors that are preferentially expressed to males or their odors, including vaginal scent marking and sexual odor preference. Conspecific odors relevant for precopulatory behaviors are processed by a network of forebrain areas that includes the bed nucleus of the stria terminalis (BNST) and the medial preoptic area (MPOA). The precise functional and neurochemical mechanisms whereby these areas regulate the expression of precopulatory behaviors, however, are unknown. Therefore, the aim of this dissertation is to address the following research questions: (1) Is the neuropeptide oxytocin (OT), acting within BNST or MPOA, necessary for the normal expression of odor-­guided precopulatory behaviors? (2) Is BNST or (3) MPOA required for the preferential expression of vaginal marking or investigation towards male odors?, and (4) Does OT interact with social odor processing to regulate vaginal marking? We found that blockade of OT receptors (OTRs) in MPOA and BNST decreased vaginal marking to male odors. There was no effect of OTR blockade on sexual odor preference. Selective lesions of BNST also disrupted preferential vaginal marking responses to male odors, without affecting sexual odor preference. In contrast, lesions of MPOA disrupted odor preference without affecting vaginal marking responses. Finally, central blockade of OTRs eliminated the normal pattern of increased activation of neurons to male vs. female odors in BNST, but not MPOA. Considered together, these results suggest that OT normally acts within BNST to drive preferential vaginal marking responses to male odors via selective facilitation of neural responses to these odors, and further, that there are separate and distinct neural circuits that regulate different forms of odor-guided precopulatory behaviors in females.

Olfactory sensing is ubiquitous across animals and important for survival. Yet, its characteristics, mechanisms, and functions in humans remain not well understood. In this dissertation, I present four studies on human olfactory perception. Study I investigates the impact of short-term exposures to an odorant on long-term olfactory learning and habituation, while Study II examines human ability to localize smells; Study III probes visual-olfactory integration of object representations, and Study IV explores the role of olfaction in sensing nutrients. Several conclusions are drawn from these studies. First, brief intermittent exposures to even a barely detectable odorant lead to long-term incremental odorant-specific habituation. Second, humans localize smells based on gradient cues between the nostrils. Third, there is a within-hemispheric advantage in the integration of visual-olfactory object representations. Fourth, olfaction partakes in nutrient-sensing and facilitates the detection of food. Some broader implications of our findings are discussed.

Primates have traditionally been considered having a poor sense of smell compared to other orders of mammals, like carnivores, due to reduced olfactory structures of the primate brain. This thought, however, is slowly changing. There are now a range of studies showing that primates do use their sense of smell, for example in chemical communication. However, few studies have been carried out on olfactory-related behaviors in Great Apes. The aim of this study was to assess the occurrence of olfactory-related behaviors in captive chimpanzees (Pan troglodytes). The results do not only show that chimpanzees use their sense of smell, but also a behavioral difference between male and female chimpanzees. There was a significant difference between male to female smelling of the anogenitals and male to male smelling of the anogenitals (p = 0.0001) and also a difference between the occurrences of males and females touching an object with the hand and then smelling at the hand (p = 0. 0007). There was a significant difference between male and female frequency of smelling at an object (p = 0.001) and a significant difference between the occurrences of male and female smelling at foods and liquids (p = 0.003). There were no observations of chimpanzees performing a scent-marking behavior. These results suggest that chimpanzees use their sense of smell, from investigating new objects to the inspection of food and other chimpanzees. It would be interesting in future studies to study the difference between male and female frequency of olfactory-related behaviors.

Having means to detect and avoid potential predators is a necessity for prey species. Most mammalian prey species are able to detect odours emitted by predators and to adapt their behaviour accordingly. These odour cues are therefore considered to act as semiochemicals. Predator odours consist of several dozen different odourants. In order to assess if single odourants elicit aversive behavioural reactions, predator-naïve CD-1 mice were presented with six odourants which are part of body-borne odours of different mammalian predator species. A two-compartment chamber was used in order to assess place-preference, motor activity and faecal excretions when the animals were simultaneously presented with a predator odourant and a blank control. Further trials were performed to assess whether the odourant concentrations had an influence on the behaviours. The only odourant that elicited a significant aversion was 3-methyl-1-butanethiol, a compound found in the anal gland secretion of skunks, when presented at a factor of 100 above the olfactory detection threshold of mice. Two other concentrations of 3-methyl-1-butanethiol did not elicit significant behavioural changes. Based on the present study, only one out of six selected predator odourants elicited a significant aversive response in CD-1 mice. This suggests that more than one odour component, or perhaps even the full mixture of odourants, may be necessary for CD-1 mice to respond to a predator odour with aversive behaviour.

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