Song production in songbirds is controlled by parts of the brain known as the song control regions (SCRs). During spring, gonads increase in size, males sing to attract mates, and SCRs become larger. This neuroplasticity is controlled by the change in day length and increased plasma testosterone (T) levels. Plasma T can be reduced by stress through the production of corticosterone (CORT), through the production of beta-endorphin, or through direct effects on the testes via the nervous system. We determined the T, estradiol, and CORT hormonal profiles of wild House Finches by capturing and sampling blood from the finches every season for two years. To track SCR neuroplasticity in the wild, we also measured the volume of two specific SCRs, the HVC and RA, every season. We then examined the effects of stress on the finch endocrine system in the wild by performing a 30-minute restraint stress protocol once every season and took blood samples before and after the restraint. To determine whether stress and/or CORT affect neuroplasticity in SCRs, we captured male house finches during winter and brought them into captivity. They were allowed to acclimate to captivity for one month on short days (8L:16D) before we transferred them to long days (16L:8D) and restraint stressed half the birds. We measured their gonads, plasma T and CORT levels, volumes of the HVC and RA, and the number of new neurons in the HVC. HVC volumes were smaller in stressed than non-stressed birds, while RA volumes did not differ. There was no difference in number of new neurons or estimated total number of neurons in the HVC between control and restrained birds. Because the HVC is involved in song production, it is possible that stress negatively impacts singing behavior and reproductive success in House Finches. Future work should address how natural stressors may affect neuroplasticity in birds.

The accessory olfactory bulb (AOB) processes pheromonal signals which in turn drive social behaviors. Here we identify a tract of aromatase-expressing (arom+) fibers in the dorsal lateral olfactory tract (dLOT) which terminate in the granule cell layer (GCL) of the AOB. We utilized a retrograde tracer in aromatase reporter animals to delineate the source of these fibers. We show that these input fibers emerge almost exclusively from a contiguous population of arom+ neurons that spans the bed nucleus of the accessory olfactory tract (BAOT) and posterioventral subnucleus of the medial amygdala (MeApv). This population of neurons expresses the estrogen receptor alpha and contains more aromatase neurons in male mice than female mice. Thus, this population of feedback neurons can detect neuroendocrine changes and modulate the output of AOB projection neurons in a way that is sexually dimorphic and could influence every downstream target of the AOB.

<p>Parkinson’s disease (PD) is characterized by progressive cell death of the dopaminergic neurons of nigrostriatal pathway. Several causes have been implicated for PD via neurochemical research including mitochondrial dysfunction, oxidative stress, and protein misfolding, to list a few. The novel Catecholamine Regulated Protein 40 (CRP40) has certain dopaminergic and neuroprotective features that implicate its importance for PD research. Recent studies using post-mortem brain tissue of patients with PD found MOT-2/CRP40 depletion in the frontal cortex and substantia nigra. MOT-2/CRP40 reduction is also observed in striatal brain tissue samples from a hemi-lesioned preclinical animal model of PD. Most recently, work done at the University of Laval in collaboration McMaster University suggests that levels of CRP40 mRNA are in deficit in blood platelet samples from a primate model of PD.</p> <p>The studies presented in this thesis suggest that the CRP40 protein has a dual function with regards to PD. The full-length CRP40 binds dopamine and, upon injection at the striatum of 6-hydroxydopamine hemi-lesioned rats, alleviates behavioural symptoms for up to 7 days. On the other hand, a 7kDA fragment of CRP40 does not bind dopamine, but does confer the same alleviatory effect upon intra-striatal injection in 6-hydroxydopamine hemi-lesioned rats. Not only has a protein now been identified with novel potential as a therapeutic agent for PD, but also the approximate region of the CRP40 protein responsible for behavioural effects.</p> <p>The later studies of this thesis show that CRP40 is found dysregulated in platelets of PD patients and lymphocytes of SCZ patients. This evidence has revealed CRP40 as a novel PD biomarker, for which on going studies are now in place to explore the potential of CRP40 as a diagnostic for PD.</p> / Doctor of Philosophy (PhD)

Self-injurious behavior (SIB) is a behavioral pathology seen in a small percentage of humans and non-human primates. In one previous study, macaques with SIB had more sleep disruption than controls, but observations were limited. Two studies were conducted: a baseline study to investigate nighttime activity in rhesus macaques (Macaca mulatta) displaying SIB and controls, and a probiotic study to assess probiotic Bifidobacterium infantis 35624 for high nighttime activity. Subjects were 13 rhesus macaques, 5 with SIB (3 females; 1 SIB). Videocapture of Nighttime Activity (VNRA) was developed to record in complete darkness. IR-receptive webcams were connected to a laptop running ISPYCONNECT, software which recorded movement. Subjects were observed during the entire lights-off period (8pm-7am). Measures included total movement time (TMT), movement in hour 1 (HR1) and hour 11 (HR11), and number of videos. In the baseline, SIB subjects had higher TMT (pBifidobacterium infantis 35624 had no effect on sleep disruption, and also that increased nighttime activity seems to be a persistent characteristic of SIB subjects. It is unknown if increased nighttime activity affects SIB subjects; it may result in elevated SIB, or the SIB pathology could result in sleep disruption.

<p>The gut and brain are involved in a bi-directional communication system, referred to as the gut-brain axis. While it has been established that antimicrobials induce dysbiosis in the gut, which further disrupts immune and metabolic homeostasis, research on brain and behaviour development is becoming a topic of interest. We propose that alterations via antibiotics at the level of the gut microbiota impacts the gut-brain axis. The primary interest of this thesis is to understand the effects that antibiotics have on brain and behaviour development in conjunction with changes in the immune system and metabolism using the antibiotic mouse model. Mice treated with antibiotics revealed behavioural differences in the open field apparatus and three-chamber social behaviour apparatus, but not in the elevated plus maze and auditory fear conditionings enclosures. Evaluation of intestinal permeability revealed that female Balb/C mice administered a combination of bacitracin, neomycin and primaricin and another group administered a combination of ampicillin, neomycin and primaricin showed reduced intestinal permeability. Furthermore, the immune system condition was evaluated using flow cytometric analysis of spleens, which revealed no effect of treatment on immune cell profiles in CD1 mice treated with ampicillin. Evaluation of serum cytokine levels showed minimal differences in Balb/C and C57Bl/6 mice treated with antibiotics. Body weight and water and food consumption were evaluated in mice administered antibiotics. Weight loss differences were observed in two groups of female Balb/C mice, with the first group administered bacitracin, neomycin and primaricin and the second group administered ampicillin , neomycin and primaricin. Antibiotic treatment dependent differences in water and food consumption were observed. Serum insulin and leptin level investigation revealed that female Balb/C mice administered ampicillin, neomycin and primaricin had reduced serum insulin levels compared to strain matched controls. These findings indicate that antibiotic treatment impact metabolic function. This pilot study using antibiotic treated mouse models provides insight on the microbiota’s effects on the gut-brain axis, which can help to potentially identify methods of preventing gut microbiota mediated pathology in humans.</p> / Master of Science (MSc)

<p>Aging erodes motivation, cognition, sensory modalities and physical capacities, effectively depleting quality of life. Declining sensory, cognitive and motor function are reliable biomarkers of aging and mortality risk. These declines are associated with dysregulation of systemic and cellular processes. We developed a complex dietary supplement (DSP) designed to ameliorate five mechanisms of aging (oxidative processes, inflammation, mitochondrial function, insulin resistance and membrane integrity). Remarkably, normal mice fed the DSP retained youthful functionality into old ages, reflecting slower aging rates. Marked improvements in motor function, memory capacity, spatial learning, muscle strength, visual acuity, olfaction, fecundity and important behavioral functions were observed in aging supplemented mice. Conversely, untreated control animals showed age-related declines in all of the above. Functional improvements were associated with reduced oxidative damage, elevated mitochondrial activity, positive cellular energy balance, improved glucose tolerance, boosted neurotransmitters, greater synaptic density and higher neuronal numbers throughout the brain. A 30% reduction in cancer rates was also documented for DSP treated p53+/- mice. The vast functional benefits greatly exceed the modest longevity extension (11%) in normal supplemented mice. For aging humans, maintaining functionality and performance into later years may provide greater socioeconomic and health benefits than simply prolonging lifespan. Implications of these findings extend to common age-related pathologies including dementia and neurodegenerative diseases, diabetes, cancer, sarcopenia and age-related macular degeneration. Although identifying the role of specific ingredients remains outstanding, results provide proof of principle that complex dietary cocktails can powerfully ameliorate biomarkers of aging and modulate mechanisms considered ultimate goals for aging interventions.</p> / Doctor of Philosophy (PhD)

Attention uses sensory inputs and goals to select information from our environment. Monkey electrophysiological literature demonstrates that visuo-tactile bimodal neurons (respond to visual and tactile stimuli presented on/near the hand) facilitate multisensory integration. Human behavioral studies show that hand position/function bias visual attention. Event-related potentials (ERPs) reveal the cortical dynamics coordinating visual inputs, body position, and action goals. Early, sensory ERPs (N1) indicate multisensory integration. Later, cognitive ERPs (P3) reflect task-related processing. Study 1 investigates a discrepancy between monkey and human literatures. Monkey studies demonstrate bimodal neuron responses equidistantly around the whole hand, but human studies demonstrate attentional bias for grasping space. In a visual detection paradigm, participants positioned their hand so target and non-target stimuli appeared near the palm or back of the hand; ERPs were measured. N1 components indicated no amplitude differences between Palm vs. Back conditions, but P3 components revealed greater target vs. non-target differentiation for Palm conditions. Results suggest cortical timing underlies grasping vs. whole hand bias differences: early processing does not differentiate using hand function, but cognitive processing does when stimuli are discriminated for action. Study 2 investigates whether proprioceptive inputs facilitate visual processing. In a visual detection paradigm, participants viewed stimuli presented between occluders blocking view of a hand positioned either near or far from the stimuli. N1 amplitudes were similar for near and far conditions, but P3 amplitudes for target/non-target differences were accentuated for near conditions. Proprioceptive effects emerge later in processing. ERP reveals the cortical dynamics underlying hand position effects on vision.

Obesity and drug abuse share common neural circuitries including the mesocoticolimbic and striatal dopamine reward system. In the current study, a rat model of diet-induced obesity (DIO) was used to determine striatal dopamine function, impulsivity and motivation as neurobehavioral outcomes and predictors of obesity. For the outcome study, rats were randomly assigned a high-fat (HF) or a low-fat (LF) diet for 8 wk. Following the 8-wk HF-diet exposure, rats were segregated into obesity-prone and obesity-resistant groups based on maximum and minimum body weight gain, respectively, and neurobehavioral outcomes were evaluated. For the predictor study, neurobehavioral antecedents were evaluated prior to an 8-wk high-fat diet exposure and were correlated with subsequent body weight gain. Striatal D2 receptor density was determined by in vitro kinetic analysis of [3H]raclopride binding. DAT function was determined using in vitro kinetic analysis of [3H]dopamine uptake, methamphetamine-evoked [3H]dopamine overflow and no net flux in vivo microdialysis. DAT cell-surface expression was determined using biotinylation and Western blotting. Impulsivity and food-motivated behavior were determined using a delay discounting task and progressive ratio schedule for food-reinforcers, respectively. Relative to obesity-resistant, obesity-prone rats exhibited 18% greater body weight, 42% lower striatal D2 receptor density, 30% lower total DAT expression, 40% lower in vitro and in vivo DAT function, 45% greater extracellular dopamine concentration, and 2-fold greater methamphetamine-evoked [3H]dopamine overflow. Obesity-prone rats exhibited higher motivation for food, but were less impulsive relative to obesity-resistant rats. Neurobehavioral antecedents of DIO included greater motivation for high-fat reinforcers in rats subsequently shown to be obesity-prone relative to obesity-resistant. Impulsivity, DAT function and extracellular dopamine concentration did not predict the DIO-phenotype. Thus, motivation for food is linked to both initiation and maintenance of obesity. Importantly, obesity results in decreased striatal DAT function, which may underlie the maintenance of compulsive food intake in obesity.

Inhalants are a loosely defined diverse group of volatile substances which people abuse. Despite widespread misuse of inhalants, there are limited preclinical methods available to study the reinforcement-like properties of inhalants. One procedure which has demonstrated substantial promise as a tool to investigate inhalant pharmacology is the intracranial self-stimulation (ICSS) procedure. ICSS utilizes pulses of electrical stimulation to the mesolimbic reward pathway to serve as a temporally defined and controlled operant reinforcer with a highly adjustable efficacy. The first aim of the project was to characterize the effects of commonly abused inhalants: including toluene, trichloroethane, nitrous oxide, isoflurane and R134a in ICSS. The second aim was to attenuate inhalant-facilitated ICSS by utilization of compounds which would attenuate the pharmacological actions of toluene on GABAA receptors. The low efficacy benzodiazepine negative modulator Ro15-4513 significantly attenuated the ability of toluene to facilitate ICSS without itself significantly altering baseline ICSS responding. Pretreatment with Ro15-4513 also attenuated methamphetamine ICSS even though there is no evidence of methamphetamine interacting with GABAA receptors. Given these unexpected results, I employed a microdialysis procedure to examine the effect of Ro15-4513 on methamphetamine stimulated dopamine release in the nucleus accumbens. Pretreatment with Ro15-4513 significantly attenuated methamphetamine stimulated dopamine release while having a negligible effect on dopamine release when administered alone. These results suggest that a modest level of benzodiazepine-site negative modulation can reduce the reinforcement enhancing effects of abused drugs regardless of their primary mechanism of action through allosteric modulation of GABAergic neurons within the mesolimbic pathway. Further, these results may have implications for expanding the examination of GABAA negative modulator medications beyond those trials currently being conducted with alcohol. Finally, the effects of chronic intermittent toluene exposure on ICSS and nesting behaviors were examined. Subjects were systemically exposed to air, chronic intermittent toluene (CIT), or escalating chronic intermittent (ECIT) toluene for 15 min at 3300 PPM toluene vapor per exposure. The results show that ECIT resulted in decreased overall responding in ICSS relative to air control and showed a tolerance-like effect to facilitatory effects of 3300 ppm toluene during ICSS compared to CIT group. These results indicate that escalating use of toluene produces reductions in its reward-like effects and may contribute to escalation to other drugs of abuse.

Stress has been widely shown to directly influence people’s emotional and behavioral processing as well as their underlying biological systems. This project examined physiological and behavioral responses as indicators of stress and coping in the context of a psychosocial stressor in a controlled laboratory setting. We examined the association between indicators of behavioral coping and underlying physiological reactivity within participants while experiencing stress. Participants included 68 emerging adults. Physiological measures include autonomic biomarkers (e.g., heart-rate, skin conductance) at rest and during the stressor while behavioral indicators that were coded include acute verbal and non-verbal actions exhibited by participants during the stressor. Results supported the efficacy of a modified social stressor at eliciting stress responding in participants. In addition, behavioral coping was found to be associated with autonomic responding to the stressor. Exploring these associations has important implications for understanding the interaction between biological and behavioral responding to stress.