Abnormal social behavior is a symptom of many human conditions, including Fetal Alcohol Spectrum Disorders (FASD). The zebrafish may be an excellent model to study embryonic alcohol effects, owing to the ease of drug administration. In recent decades, zebrafish have become increasingly popular in behavioral neuroscience, and their elaborate behavioral repertoire can provide insights in brain functioning and social behavior in response to teratogens or pharmaceutical agents. Shoaling is the zebrafish’s most notable behavioral feature, but has not been well characterized. I have started this characterization by describing the ontogeny of shoaling behavior. Embryonic exposure to low doses of ethanol has been shown to impair social behavior without any gross morphological alterations in zebrafish. However, this has not been studied in freely moving groups (shoals). Validation for using a shoaling task in behavioral testing, and potentially for high throughput analyses in the future, hinges on thorough characterization of the behavioral effects, however subtle in alcohol treated zebrafish. In my studies, I have shown that social behavior is impaired in zebrafish in a group setting after one time embryonic ethanol exposure. I have also discovered that this impairment is accompanied by a reduction of dopamine, serotonin, DOPAC and 5HIAA, neurochemicals measured in whole brain samples using HPLC. I have developed refined methods of measuring shoaling behavior in ten member zebrafish groups, laying the foundation for high throughput screening of adult zebrafish. Zebrafish are an economical model, and therefore lend themselves particularly well for high throughput screening. However, current paradigms are still labor intensive and require substantial human capital. By refining current behavioral tests and deploying new analytical tools, high throughput screening is starting to become within reach.

Abnormal social behavior is a symptom of many human conditions, including Fetal Alcohol Spectrum Disorders (FASD). The zebrafish may be an excellent model to study embryonic alcohol effects, owing to the ease of drug administration. In recent decades, zebrafish have become increasingly popular in behavioral neuroscience, and their elaborate behavioral repertoire can provide insights in brain functioning and social behavior in response to teratogens or pharmaceutical agents. Shoaling is the zebrafish’s most notable behavioral feature, but has not been well characterized. I have started this characterization by describing the ontogeny of shoaling behavior. Embryonic exposure to low doses of ethanol has been shown to impair social behavior without any gross morphological alterations in zebrafish. However, this has not been studied in freely moving groups (shoals). Validation for using a shoaling task in behavioral testing, and potentially for high throughput analyses in the future, hinges on thorough characterization of the behavioral effects, however subtle in alcohol treated zebrafish. In my studies, I have shown that social behavior is impaired in zebrafish in a group setting after one time embryonic ethanol exposure. I have also discovered that this impairment is accompanied by a reduction of dopamine, serotonin, DOPAC and 5HIAA, neurochemicals measured in whole brain samples using HPLC. I have developed refined methods of measuring shoaling behavior in ten member zebrafish groups, laying the foundation for high throughput screening of adult zebrafish. Zebrafish are an economical model, and therefore lend themselves particularly well for high throughput screening. However, current paradigms are still labor intensive and require substantial human capital. By refining current behavioral tests and deploying new analytical tools, high throughput screening is starting to become within reach.

Food choice and preference have been linked to post-ingestive consequences of food consumption. Many ultra-processed foods deliver calories rapidly and are highly rewarding. In literature surrounding substances of abuse, the speed at which a drug reaches the brain affects its abuse potential; this is known as the "rate hypothesis." Here, we test whether the rate hypothesis of addiction may apply to food, specifically whether caloric availability, or the speed at which carbohydrate becomes available for use, contributes to food reward and preference. To do this, we use beverages with novel flavors (conditioned stimulus (CS)) mixed with either a slow metabolizing carbohydrate (maltodextrin and inulin; CS+Slow), a fast-metabolizing carbohydrate (sucrose; CS+Fast), or no carbohydrate (sucralose; CS-). Participants are given each of these drinks 6 times to consume (conditioning period). 2 of these consumption periods occur during in-lab sessions. In one session, blood glucose is measured over one hour post-consumption. In another, we perform indirect calorimetry to assess post-consumption changes in substrate oxidation rates. At the post-testing session, changes in self-reported liking, wanting, and ad libitum intake of each beverage are recorded. Brain response to each flavor cue (without calories) is measured using fMRI at the post-test. We hypothesize the flavor paired with the CS+Fast will be the most liked, wanted, and consumed. We expect greater BOLD (blood oxygenated level dependent) activation to the CS+Fast relative to the CS+Slow and CS- in the nucleus accumbens and hypothalamus. This is an ongoing study and, here, we present our preliminary analysis of the data. / Doctor of Philosophy / People make food choices every day throughout their lives, but why? Research in the past has shown that there are aspects of an individual's life that may be affecting their preferences for foods. One of the aspects investigated in this analysis is metabolism. The way and speed that the body uses carbohydrates plays a large role in how an individual views food options. Here, we test if the speed at which the body is able to use carbohydrates affects their choices of food and if there are any neural components to these food options. To do this, we tested multiple carbohydrates to determine which were the best for comparisons of slow- and fast-metabolizing. These carbohydrate groups were tested against a drink containing no carbohydrates in two metabolic measurements: blood glucose and energy expenditure. We then used a magnetic resonance imaging scan to test brain activity when participants are given small amounts of each drink without carbohydrates. Each carbohydrate condition was paired with a novel flavor so participants wouldn't have a preconceived idea about the caloric load. We found drinks with sucrose, a common household sugar, had the fastest change in metabolic measures. Additionally, areas in the brain related to rewards and learning were activated by flavors associated with sucrose. This leads us to believe that carbohydrates that are quickly used by your body are more rewarding in the brain and may have implications for preferences down the line.

The behavioral effects of drugs that act on the brain’s dopamine (DA) system change with repeated exposure to the drug. Antipsychotic drugs, that block DA receptors, produce progressively greater effects on behavior with repeated testing. For example, rats repeatedly treated with a low dose of the D2 receptor-preferring antagonist haloperidol do not initially exhibit catalepsy, a response quantified by time spent on a horizontal bar without active movement. However, with repeated drug-environment pairings animals show a reduction in exploration and increases in catalepsy. The current thesis examined the drug-environment relationship in catalepsy sensitization, and how different DA receptor subtypes control this phenomenon. Treatment with a D2, but not D3 or D1-like receptor-preferring antagonist produced catalepsy sensitization. Catalepsy sensitization developed in one test environment did not transfer to another environment. Similarly, rats with a history of haloperidol treatments outside of the test environment (unpaired group) did not exhibit significant catalepsy when given haloperidol for the first time prior to catalepsy testing. Previous exposure to the catalepsy test environment led to a more rapid development of catalepsy sensitization. Thus, drug-environment interaction is critical for the development and expression of catalepsy sensitization. Rats previously given haloperidol and tested with saline in the drug paired environment exhibited conditioned catalepsy. The acquisition of conditioned catalepsy is dependent on D1-like receptors, while its expression is dependent on D3 receptors. Conditioned catalepsy showed gradual day-to-day extinction with repeated saline treatment in the previously haloperidol-paired environment. Following extinction, the response to haloperidol in previously sensitized rats shifted from environment-specific to environment-independent suggesting that a putative haloperidol drug cue alone can elicit conditioned catalepsy. In summary, treatment with a D2, but not D1-like or D3 receptor-preferring antagonist in a particular test environment produces catalepsy sensitization, while acquisition of conditioned catalepsy is dependent on D1-like receptors, and its expression is dependent on D3 receptors. Importantly, the acquisition and expression of sensitization to haloperidol is conditional on the presence of drug-associated environmental stimuli. Our findings provide further insight into the current understanding of learning processes involved in the action of antipsychotic drugs and the dissociable effects of D1-like, D2 and D3 receptors controlling this phenomenon. / Thesis (Ph.D, Neuroscience Studies) -- Queen's University, 2012-08-12 15:51:00.467

Feature binding refers to the fundamental challenge of the brain to integrate sensory information registered by distinct brain regions to form a unified neural representation of a stimulus. While the human cognitive literature has established that attentional processes in a frontoparietal cortical network support feature binding, the neurochemical contributions to this attentional process remain unknown. Using systemic administration of the cholinergic muscarinic receptor antagonist scopolamine and a digging-based rat feature binding task that used both odor and texture stimuli, it was demonstrated that blockade of acetylcholine (ACh) at the muscarinic receptors impaired rats’ ability to feature bind at encoding, and it was proposed that ACh may support the attentional processes necessary for feature binding (Botly & De Rosa, 2007). This series of experiments further investigated a role for ACh and the cholinergic basal forebrain (BF) in feature binding. In Experiment 1, a cross-species experimental design was employed in which rats under the systemic influence of scopolamine and human participants under divided-attention performed comparable feature binding tasks using odor stimuli for rats and coloured-shape visual stimuli for humans. Given the comparable performance impairments demonstrated by both species, Experiment 1 suggested that ACh acting at muscarinic receptors supports the attentional processes necessary for feature binding at encoding. Experiments 2-4 investigated the functional neuroanatomy of feature binding using bilateral quisqualic acid excitotoxic (Experiment 2) and 192 IgG-saporin cholinergic immunotoxic (Experiments 3 and 4) brain lesions that were assessed for completeness using histological and immunohistological analyses. Using the crossmodal digging-based rat feature binding task, Experiment 2 revealed that the nucleus basalis magnocellularis (NBM) of the BF is critically involved in feature binding, and Experiment 3 revealed that cholinergic neurons in the NBM are necessary for feature binding at encoding. Lastly, in Experiment 4, rats performed visual search, the standard test of feature binding in humans, with touchscreen-equipped operant chambers. Here it was also revealed that cholinergic neurons in the NBM of the BF are critical for efficient visual search. Taken together, these behavioural, pharmacological, and brain-lesion findings have provided insights into the neurochemical contributions to the fundamental attentional process of feature binding.

Feature binding refers to the fundamental challenge of the brain to integrate sensory information registered by distinct brain regions to form a unified neural representation of a stimulus. While the human cognitive literature has established that attentional processes in a frontoparietal cortical network support feature binding, the neurochemical contributions to this attentional process remain unknown. Using systemic administration of the cholinergic muscarinic receptor antagonist scopolamine and a digging-based rat feature binding task that used both odor and texture stimuli, it was demonstrated that blockade of acetylcholine (ACh) at the muscarinic receptors impaired rats’ ability to feature bind at encoding, and it was proposed that ACh may support the attentional processes necessary for feature binding (Botly & De Rosa, 2007). This series of experiments further investigated a role for ACh and the cholinergic basal forebrain (BF) in feature binding. In Experiment 1, a cross-species experimental design was employed in which rats under the systemic influence of scopolamine and human participants under divided-attention performed comparable feature binding tasks using odor stimuli for rats and coloured-shape visual stimuli for humans. Given the comparable performance impairments demonstrated by both species, Experiment 1 suggested that ACh acting at muscarinic receptors supports the attentional processes necessary for feature binding at encoding. Experiments 2-4 investigated the functional neuroanatomy of feature binding using bilateral quisqualic acid excitotoxic (Experiment 2) and 192 IgG-saporin cholinergic immunotoxic (Experiments 3 and 4) brain lesions that were assessed for completeness using histological and immunohistological analyses. Using the crossmodal digging-based rat feature binding task, Experiment 2 revealed that the nucleus basalis magnocellularis (NBM) of the BF is critically involved in feature binding, and Experiment 3 revealed that cholinergic neurons in the NBM are necessary for feature binding at encoding. Lastly, in Experiment 4, rats performed visual search, the standard test of feature binding in humans, with touchscreen-equipped operant chambers. Here it was also revealed that cholinergic neurons in the NBM of the BF are critical for efficient visual search. Taken together, these behavioural, pharmacological, and brain-lesion findings have provided insights into the neurochemical contributions to the fundamental attentional process of feature binding.

Reduced activity of the N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a glycine site on the NR1 subunit that may be a promising therapeutic target for psychiatric illness. Recently, D-serine has been discovered to be a high-affinity endogenous activator of the NMDAR glycine site. Levels of D-serine in the brain are controlled by its synthesis enzyme serine racemase (Srr) and its catabolic enzyme D-amino acid oxidase (DAO). This work investigates the NMDAR glycine site, D-serine, and D-serine-regulatory enzymes Srr and DAO in the pathophysiology and treatment of symptomatology relevant to schizophrenia and other psychiatric disorders. Pharmacological and genetic mouse models were used to alter glycine site function and D-serine availability. Behavioral responses in these models were assessed. Administration of exogenous D-serine and the glycine transporter 1 (GlyT-1) inhibitor ALX-5407 improved performance of C57BL/6J mice in behavioral tests examining prepulse inhibition (PPI) or latent inhibition (LI). These compounds also reversed impairments induced by the NMDAR antagonist MK-801, and produced similar beneficial effects to the classical atypical antipsychotic clozapine. Mice carrying a point mutation that leads to diminished NMDAR glycine site function demonstrated abnormally persistent LI and deficits in social approach and spatial recognition that were reversible by D-serine or clozapine administration. Similarly, mutant mice that lacked Srr function and had a severe reduction in D-serine displayed impairments in sociability, PPI, spatial recognition and memory. Behavioral deficits in mice without Srr were exacerbated by MK-801 and rescued by treatment with D-serine or clozapine. A genetically-induced loss of DAO function in mice resulted in the elevation of brain D-serine levels, and produced improvements in spatial reversal memory and extinction of a learned response in the Morris water maze, consistent with the effects of exogenous D-serine application in wild-type mice. Thus, deficiencies in NMDAR glycine site function and D-serine availability produce behavioral disturbances that are relevant to the negative and cognitive symptoms of schizophrenia. Activation of the NMDAR glycine site by D-serine, GlyT-1 inhibition, or diminished DAO activity may be beneficial for the treatment of schizophrenia and other psychopathologies involving cognitive dysfunction and persistent repetitive behaviors.

No description available.

Reduced activity of the N-methyl-D-aspartate receptor (NMDAR) has been implicated in the pathophysiology of schizophrenia. The NMDAR contains a glycine site on the NR1 subunit that may be a promising therapeutic target for psychiatric illness. Recently, D-serine has been discovered to be a high-affinity endogenous activator of the NMDAR glycine site. Levels of D-serine in the brain are controlled by its synthesis enzyme serine racemase (Srr) and its catabolic enzyme D-amino acid oxidase (DAO). This work investigates the NMDAR glycine site, D-serine, and D-serine-regulatory enzymes Srr and DAO in the pathophysiology and treatment of symptomatology relevant to schizophrenia and other psychiatric disorders. Pharmacological and genetic mouse models were used to alter glycine site function and D-serine availability. Behavioral responses in these models were assessed. Administration of exogenous D-serine and the glycine transporter 1 (GlyT-1) inhibitor ALX-5407 improved performance of C57BL/6J mice in behavioral tests examining prepulse inhibition (PPI) or latent inhibition (LI). These compounds also reversed impairments induced by the NMDAR antagonist MK-801, and produced similar beneficial effects to the classical atypical antipsychotic clozapine. Mice carrying a point mutation that leads to diminished NMDAR glycine site function demonstrated abnormally persistent LI and deficits in social approach and spatial recognition that were reversible by D-serine or clozapine administration. Similarly, mutant mice that lacked Srr function and had a severe reduction in D-serine displayed impairments in sociability, PPI, spatial recognition and memory. Behavioral deficits in mice without Srr were exacerbated by MK-801 and rescued by treatment with D-serine or clozapine. A genetically-induced loss of DAO function in mice resulted in the elevation of brain D-serine levels, and produced improvements in spatial reversal memory and extinction of a learned response in the Morris water maze, consistent with the effects of exogenous D-serine application in wild-type mice. Thus, deficiencies in NMDAR glycine site function and D-serine availability produce behavioral disturbances that are relevant to the negative and cognitive symptoms of schizophrenia. Activation of the NMDAR glycine site by D-serine, GlyT-1 inhibition, or diminished DAO activity may be beneficial for the treatment of schizophrenia and other psychopathologies involving cognitive dysfunction and persistent repetitive behaviors.

abstract: Cognitive function is multidimensional and complex, and research indicates that it is impacted by age, lifetime experience, and ovarian hormone milieu. One particular domain of cognitive function that is susceptible to age-related decrements is spatial memory. Cognitive practice can affect spatial memory when aged in both males and females, and in females alone ovarian hormones have been found to alter spatial memory via modulating brain microstructure and function in many of the same brain areas affected by aging. The research in this dissertation has implications that promote an understanding of the effects of cognitive practice on aging memory, why males and females respond differently to cognitive practice, and the parameters and mechanisms underlying estrogen's effects on memory. This body of work suggests that cognitive practice can enhance memory when aged and that estrogen is a probable candidate facilitating the observed differences in the effects of cognitive practice depending on sex. This enhancement in cognitive practice effects via estrogen is supported by data demonstrating that estrogen enhances spatial memory and hippocampal synaptic plasticity. The estrogen-facilitated memory enhancements and alterations in hippocampal synaptic plasticity are at least partially facilitated via enhancements in cholinergic signaling from the basal forebrain. Finally, age, dose, and type of estrogen utilized are important factors to consider when evaluating estrogen's effects on memory and its underlying mechanisms, since age alters the responsiveness to estrogen treatment and the dose of estrogen needed, and small alterations in the molecular structure of estrogen can have a profound impact on estrogen's efficacy on memory. Collectively, this dissertation elucidates many parameters that dictate the outcome, and even the direction, of the effects that cognitive practice and estrogens have on cognition during aging. Indeed, many parameters including the ones described here are important considerations when designing future putative behavioral interventions, behavioral therapies, and hormone therapies. Ideally, the parameters described here will be used to help design the next generation of interventions, therapies, and nootropic agents that will allow individuals to maintain their cognitive capacity when aged, above and beyond what is currently possible, thus enacting lasting improvement in women's health and public health in general. / Dissertation/Thesis / Ph.D. Psychology 2011