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Depression is a complex psychiatric illness that affects a large proportion of the population. Many researchers make use of preclinical animal models to study the behavioural and neurobiological characteristics of this disease. However, although a bias towards maladaptive thinking patterns and emotional responses is a cardinal symptom of depression, these symptoms have been rarely considered in preclinical models. One way to investigate maladaptive thinking is through the use of fear conditioning paradigms. Fear conditioning evaluates emotional memory by assessing a rodent’s ability to associate neutral cues with an aversive experience. It requires the activation of brain structures critically involved in emotion-related learning and memory processes, most notably the hippocampus and amygdala, to successfully learn the task. The primary goal of this dissertation was to gain a better understanding of the consequences of repeated corticosterone injections—a validated preclinical model of depression-- on emotionally driven behaviour, the involvement of the hippocampus and amygdala in mediating these behaviours, and whether the antidepressant, fluoxetine, can prevent the effects of corticosterone on these behaviours. To begin, in Chapter 2 I confirmed that the depressogenic effects of corticosterone in the forced swim test, which is a traditional behavioural assay for depression in rodents, are not due to procedural differences or non-specific motor effects. I then investigated the impact of repeated corticosterone injections on the learning and memory of delay and contextual fear conditioning. I examined whether altering the order in which rats recall context versus tone cued fear associations determines the magnitude of corticosterone’s effect on conditioned fear. I found that corticosterone dose-dependently increased freezing to contextual cues whereas freezing to tone cues was increased regardless of dose. Furthermore, the order of the presentation of context versus tone cues during recall determined whether corticosterone produced significant enhancements in freezing. In Chapter 4, I investigated whether neuronal activity in the hippocampus and amygdala after recall of contextual or tone cued fear was associated with the effects of corticosterone found in Chapter 3. Recall of contextual cues was associated with neuronal activity in specific sub regions of the amygdala without any observed changes in the hippocampus. In Chapter 5, I investigated whether repeated corticosterone injections would also enhance the learning and memory of trace fear conditioning, a task that is heavily reliant on the hippocampus. I found that corticosterone increased freezing during recall of trace cues and enhanced the acquisition of trace cues. The results from this chapter, taken together with the results from chapters 3 and 4, suggest that repeated corticosterone exposure readily enhances learning and memory processes that evoke emotional arousal. In Chapter 6, I asked whether repeated treatment with the antidepressant, fluoxetine, could prevent increased fear learning produced by repeated corticosterone injections. I found that fluoxetine decreased freezing behaviour in corticosterone rats during recall of tone cues. Overall, the results of this dissertation further our understanding of the effects of corticosterone on learning and memory tasks that evoke emotional arousal, support the use of fear conditioning as a measure of depression-like behaviour, and demonstrate that repeated corticosterone injections reliably produce a depressive phenotype in rats.

Synaptic plasticity, which is thought to represent the neuronal substrate for learning and memory is influenced by the degree of GABAergic inhibitory tone. In particular, γ-aminobutyric acid subtype A receptors (GABAARs), which mediate the majority of inhibitory neurotransmission in the mammalian brain regulate learning and plasticity. In these studies I examined a subpopulation of α5 subunit-containing GABAA receptors (α5GABAARs), which are preferentially expressed in the hippocampus, to determine whether they have a specific role in memory processes. I hypothesized that α5GABAAR-activity constrains hippocampus-dependent learning and CA1 synaptic plasticity. The main research objective of this thesis was to investigate the electrophysiological changes within the hippocampus that accompany genetic and pharmacological targeting of α5GABAARs and how these changes impact behaviour. I found that the general anesthetic etomidate enhanced a tonic inhibitory conductance generated by α5GABAARs, and this action correlated with an impairment of long-term potentiation (LTP) and hippocampus-dependent memory performance for fear-associated memory and spatial navigation. Mice with a genetic deletion of the α5 subunit gene (Gabra5–/–) were resistant to the LTP- and memory-impairing effects of etomidate. Additionally, the LTP- and memory-impairing effects of etomidate were rescued by pharmacologically inhibiting α5GABAARs. Genetic and pharmacological inhibition of α5GABAARs enhanced associative learning in trace fear but not contextual fear conditioning tasks. Interestingly, genetic deletion and pharmacological inhibition of α5GABAARs did not result in the common adverse side-effects associated with non-selective inhibition of GABAARs such as anxiogenesis or seizures. Further, I found that blocking the tonic inhibition generated by α5GABAARs lowered the threshold for LTP, such that lower stimulation frequencies enhanced LTP. Synaptic changes within this frequency band were modified independently of phasic GABAAR inhibition. Inhibiting the α5GABAAR-dependent membrane conductance was associated with an increase in the depolarizing envelope during 10 Hz stimulation. These experiments provide new insights into the in vitro and in vivo physiology of α5GABAARs and suggest that a tonic inhibition generated by α5GABAARs constrains learning and glutamate plasticity through regulation of the membrane’s electrical properties.

Synaptic plasticity, which is thought to represent the neuronal substrate for learning and memory is influenced by the degree of GABAergic inhibitory tone. In particular, γ-aminobutyric acid subtype A receptors (GABAARs), which mediate the majority of inhibitory neurotransmission in the mammalian brain regulate learning and plasticity. In these studies I examined a subpopulation of α5 subunit-containing GABAA receptors (α5GABAARs), which are preferentially expressed in the hippocampus, to determine whether they have a specific role in memory processes. I hypothesized that α5GABAAR-activity constrains hippocampus-dependent learning and CA1 synaptic plasticity. The main research objective of this thesis was to investigate the electrophysiological changes within the hippocampus that accompany genetic and pharmacological targeting of α5GABAARs and how these changes impact behaviour. I found that the general anesthetic etomidate enhanced a tonic inhibitory conductance generated by α5GABAARs, and this action correlated with an impairment of long-term potentiation (LTP) and hippocampus-dependent memory performance for fear-associated memory and spatial navigation. Mice with a genetic deletion of the α5 subunit gene (Gabra5–/–) were resistant to the LTP- and memory-impairing effects of etomidate. Additionally, the LTP- and memory-impairing effects of etomidate were rescued by pharmacologically inhibiting α5GABAARs. Genetic and pharmacological inhibition of α5GABAARs enhanced associative learning in trace fear but not contextual fear conditioning tasks. Interestingly, genetic deletion and pharmacological inhibition of α5GABAARs did not result in the common adverse side-effects associated with non-selective inhibition of GABAARs such as anxiogenesis or seizures. Further, I found that blocking the tonic inhibition generated by α5GABAARs lowered the threshold for LTP, such that lower stimulation frequencies enhanced LTP. Synaptic changes within this frequency band were modified independently of phasic GABAAR inhibition. Inhibiting the α5GABAAR-dependent membrane conductance was associated with an increase in the depolarizing envelope during 10 Hz stimulation. These experiments provide new insights into the in vitro and in vivo physiology of α5GABAARs and suggest that a tonic inhibition generated by α5GABAARs constrains learning and glutamate plasticity through regulation of the membrane’s electrical properties.

Skin conductance responses were used to assess the effects of THC on conditioned fear response amplitude and extinction using a fear conditioning and extinction paradigm that paired an aversive unconditioned stimulus (shock) with a conditioned stimulus (angry face). Participants (N = 10 males) exhibited conditioning to the CS+, as indicated by a larger CR to the CS+ than to the CS-. THC did not have a significant effect on extinction of the CR across trials, but there was a significant interaction of social anxiety with drug that suggests that THC may facilitate extinction of CR to fear-conditioned stimuli in more socially anxious individuals. These results provide support for the hypothesis that THC may act as an anxiolytic in fear-eliciting situations. The current study was limited by a small sample size and a potential confound that may have influenced the SCL during conditioned responding.

In the present study, footshock, which produces a powerful aversive emotional response was used in a Pavlovian conditioning experiment as an unconditioned stimulis (UCS), and was paired with the presentation of a light used as a conditioned stimulis (CS). There is an accumulation of evidence that supports the assertion that dopaminergic (DA) neurons within the ventral tegmental area (VTA) are active in processes that contribute to the amygdala-based circuitry involved in regulating emotionally salient responses. To build upon findings implicating VTA DA, excitatory glutamate (Glu), NMDA and AMPA receptors, were examined with respect to their role in Pavlovian conditioned fear responding. Fear potentiated startle (FPS) was used to assess the effects of intra-VTA infused AP5, and intra-VTA infused CNQX on conditioned fear responding in laboratory rats. The administration of the NMDA receptor antagonist AP5 (at 1.0, 2.5, and 5.0ug doses), blocked the ability of a conditioned stimulus (CS) previously paired with footshock to become conditioned to the UCS. Similarly, administration of the AMPA receptor antagonist CNQX (at 1.0, 2.5, 5.0ug doses), inhibited the ability of the CS to become conditioned to the UCS. The results of this study indicate the VTA is an important site for synaptic modifications associated with fear learning, and that activation of excitatory Glutamatergic receptors in the VTA play a necessary part of the processing underlying fear conditioning. Measures of shock reactivity demonstrated that the infusion of AP5 and CNQX into the VTA did not inhibit baseline startle amplitudes. The administration of AP5 and CNQX did not suppress the perception of footshock as an aversive stimulus. This study provides further definition to established knowledge surrounding the neural processes whereby neutral environmental cues gain negative emotional salience as occurs in fear conditioning. It was hypothesised that the action of excitatory glutamatergic transmission within the VTA acts on NMDA and AMPA receptors is to assist in the acquisition of Pavlovian conditioned fear, possibly through the same synaptic mechanisms that govern LTP.

When a human or animal is threatened or confronted with a stimuli signalling danger, internal defence mechanisms are activated that evoke feelings of fear and anxiety. These emotional responses promote the behaviour patterns necessary for an organism's survival. Animal research seeks to understand how these emotions affect behaviour both physiologically and neurologically in order to develop effective treatment for those suffering from severe anxiety disorders. The aim of this thesis was to examine the role of the amygdala, and dorsal and ventral hippocampus in relation to immediate fear arousal brought on by footshock. This was assessed by examining whether muscimol would interfere with the acoustic startle response before or after footshock presentation, and then comparing these reactions to a control group that received saline infusions. The results of this research are extremely important because they identify various brain structures involved in the fear-arousing effects of footshock as measured by the shock sensitization of acoustic startle. Laboratory rats received muscimol (0.1ug and 0.01ug) infusions into the basolateral amygdala, dorsal and ventral hippocampus. These three brain regions have been identified as playing a prominent role in fear neurocircuitry. The results demonstrated that the GABA A receptor agonist muscimol in doses of 0.1ug and 0.01ug reliably blocked shock sensitization of the acoustic startle response. The muscimol doses did not alter the shock reactivity amplitudes therefore indicating a normal perception of the fear arousing properties of footshock. Therefore, the present study's results suggest that a decrease of GABA activity in the amygdala, dorsal and ventral hippocampus may be essential for the neuronal basis of fear acquisition and expression of unconditioned and conditioned stimuli.

Thesis advisor: Gorica D. Petrovich / Thesis advisor: Christina Reppucci / We are interested in exploring the instances in which environmental controls can override physiologic or homeostatic cues, and additionally the areas of the brain that might be implicated in such behavioral effects. For this study, we replicated a previously established behavioral finding in which male and female rats show fear-cue induced inhibition of eating, and that female rats take longer than male rats to extinguish this behavior. We assessed brain activation via Fos-expression in the NTS and DMX in the brainstem and found that males had higher brainstem activation than females during extinction of fear-cue induced inhibition of eating. Additionally, female experimental rats had suppressed activity in the caudal NTS compared to female control rats. The data from this study support our hypotheses that there are distinct activation patterns in the brainstem during the extinguishing of inhibition of eating, and that there are sex differences in these activation patterns. / Thesis (BS) — Boston College, 2013. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: Psychology Honors Program. / Discipline: Psychology.

Thesis advisor: Gorica Petrovich / Thesis advisor: Christina Reppucci / In order to understand the neurobiological basis for the phenomenon in which environmental cues override physiological cues to influence the behavioral control of feeding, we utilized an animal model for fear-cue induced inhibition of eating. Female rats that had learned to associate a tone with foot-shocks showed inhibition of eating across three extinction tests, whereas male rats that had received tone-shock pairings extinguished their inhibition of eating after the first test day. We assessed activation of orexin (ORX), a neuropeptide involved in eating and arousal, in the lateral hypothalamic area (LHA) of the brains of male and female control and experimental rats during the final test day. Female rats exhibited greater recruitment of ORX neurons in the LHA than male rats; there was no difference in ORX activation between control and experimental groups of either sex, indicating that ORX is involved in sex differences in fear-cue induced inhibition of eating. / Thesis (BS) — Boston College, 2013. / Submitted to: Boston College. College of Arts and Sciences. / Discipline: College Honors Program. / Discipline: Psychology.

Aberrations in brain serotonin (5-HT) neurotransmission have been implicated in psychiatric disorders including anxiety, depression and deficits in learning and memory. Many of these disorders are treated with drugs which promote the availability of 5-HT in the synapse. Selective serotonin uptake inhibitors (SSRIs) are known to stimulate the production of new neurons in the hippocampus (HPC) by increasing synaptic concentration of serotonin (5-HT). However, it is not clear which of the 5-HT receptors are involved in behavioral improvements and enhanced neurogenesis. The current study aimed to investigate the effects of 5HT2A agonists psilocybin and 251-NBMeO and the 5HT2A/C antagonist ketanserin on neurogenesis and hippocampal-dependent learning. Agonists and an antagonist to the 5-HT2A receptor produced alterations in hippocampal neurogenesis and trace fear conditioning. Future studies should examine the temporal effects of acute and chronic psilocybin administration on hippocampal-dependent learning and neurogenesis.