This dissertation serves three major purposes: (1) to create new knowledge in the domain of franchising research, (2) to assist future academic inquiry by advancing agency theoretical understanding, and (3) to serve members of the... more
This dissertation serves three major purposes: (1) to create new knowledge in the domain of franchising research, (2) to assist future academic inquiry by advancing agency theoretical understanding, and (3) to serve members of the franchising community by developing a framework for building franchisee trust. It is proposed that trust within the franchising relationship is important for overall franchisee performance, as well as necessary for uniting the franchisee and the franchisor in their mutually beneficial endeavours. Franchisee trust and franchisor trustworthiness are considered to have a central function within the franchising relationship and through empirical examination, both qualitative and quantitative data provided confirmation of this proposition. 30 interviews were conducted with franchising experts, franchisees, and franchisors, until data saturation was achieved. The interviews were audio recorded, with the permission of the interviewee, then transcribed. Analysis o...
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This paper contributes to existing franchising thought in three major ways. Firstly, synergy between the franchisee and the franchisor is achievable. Synergy occurs when the output of a group is greater than the sum of the individual... more
This paper contributes to existing franchising thought in three major ways. Firstly, synergy between the franchisee and the franchisor is achievable. Synergy occurs when the output of a group is greater than the sum of the individual effort. Secondly, the research reveals initial insight into how synergy can be achieved; synergy requires the essential elements of trust and good faith. Finally, the construct of good faith is compared with the construct of bad faith, compounded by the franchise culture. At one polar extreme, trust and good faith produce synergy. However, at the polar opposite, distrust and actions of bad faith result in dysfunction. Many authors have researched problems such as trust and distrust through the lens of agency theory (Jensen and Meckling, 1976) with the findings of this research building on existing thought. Qualitative data in the form of in-depth interviews with franchising experts. The overarching goal of this research is to gain further understanding ...
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Dysfunction within the dopamine system has been the predominant hypothesized cause of schizophrenia for some time; however, there is little anatomical or postmortem evidence showing that the roots of this disorder are to be found within... more
Dysfunction within the dopamine system has been the predominant hypothesized cause of schizophrenia for some time; however, there is little anatomical or postmortem evidence showing that the roots of this disorder are to be found within the dopaminergic neurons. Instead, the dopamine system appears to be dysregulated due to pathological influences from other structures. Recent postmortem and imaging studies have looked to the hippocampus as a potential site of this pathology. Our studies using a developmental animal model of schizophrenia found hyperactivity in the hippocampus likely drives the disruption in dopamine system function. This overactivity appears to be due to the functional loss of short axon interneurons that control the activity of the primary output neurons of the hippocampus. These data suggest that a more effective treatment of schizophrenia may be to normalize hippocampal function rather than block dopamine receptors. Moreover, given the high sensitivity of the hi...
This paper provides an in-depth qualitative investigation into the nature of the franchisee/franchiser relationship. The view that stable franchising relationships are formulated with the presence of trust and commitment is further... more
This paper provides an in-depth qualitative investigation into the nature of the franchisee/franchiser relationship. The view that stable franchising relationships are formulated with the presence of trust and commitment is further enhanced and developed upon Morgan & Hunt's (1994) foundational commitment-trust theory. Primary research in the form of face-to-face interviews with franchisees from four franchise systems was conducted using within and across case analysis. This exploratory research attempts to enhance franchising knowledge by shifting traditional transactional marketing (TM) focus toward relationship marketing (RM). The emphasis on relationships as apposed to transactional exchanges within franchising not only extends existing franchising literature but provides practical insight into the importance of stable personal relationships between franchisers and franchisees.
Antipsychotic drugs are known to block dopamine receptors soon after their administration, resulting in an increase in dopamine neuron firing and dopamine turnover. Nonetheless, antipsychotic drugs must be administered repeatedly to... more
Antipsychotic drugs are known to block dopamine receptors soon after their administration, resulting in an increase in dopamine neuron firing and dopamine turnover. Nonetheless, antipsychotic drugs must be administered repeatedly to schizophrenics before therapeutic benefits are produced. Recordings from dopamine neurons in rats have revealed that chronic antipsychotic drug treatment results in the time-dependent inactivation of dopamine neuron firing via over-excitation, or depolarization block. Furthermore, the clinical profile of the response to antipsychotic drugs appears to correspond to the dopamine system affected: antipsychotic drugs that exert therapeutic actions in schizophrenics inactivate dopamine neuron firing in the limbic-related ventral tegmental area, whereas drugs that precipitate extrapyramidal side effects cause depolarization block of the motor-related substantia nigra dopamine cells. One factor that remains unresolved with regard to the actions of antipsychotic drugs is the relationship between dopamine turnover and depolarization block--i.e., why does a significant level of dopamine release or turnover remain after antipsychotic drug treatment if dopamine cells are no longer firing? We addressed this question using an acute model of neuroleptic-induced depolarization block. In this model, dopamine cells recorded in rats one month after partial dopamine lesions could be driven into depolarization block by the acute administration of moderate doses of haloperidol. However, similar doses of haloperidol, which were effective at increasing dopamine levels in the striatum of intact rats, failed to change dopamine levels in lesioned rats. This is consistent with a model in which neuroleptic drugs exert their therapeutic effects in schizophrenics by causing depolarization block in DA cells, thereby preventing further activation of dopamine neuron firing in response to external stimuli. Thus, attenuating the responsivity of the dopamine system to stimuli may be more relevant to the therapeutic actions of antipsychotic drugs than receptor blockade or decreases in absolute levels of dopamine, which could presumably be circumvented by homeostatic adaptations in this highly plastic system.
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ABSTRACT Introduction: Antipsychotic drugs are central to the treatment of schizophrenia, but their limitations necessitate improved treatment strategies. Multiple lines of research have implicated glutamatergic dysfunction in the... more
ABSTRACT Introduction: Antipsychotic drugs are central to the treatment of schizophrenia, but their limitations necessitate improved treatment strategies. Multiple lines of research have implicated glutamatergic dysfunction in the hippocampus as an early source of pathophysiology in schizophrenia. Novel compounds have been designed to treat glutamatergic dysfunction, but they have produced inconsistent results in clinical trials. Areas covered: This review discusses how the hippocampus is thought to drive psychotic symptoms through its influence on the dopamine system. It offers the reader an evaluation of proposed treatment strategies including direct modulation of GABA or glutamate neurotransmission or reducing the deleterious impact of stress on circuit development. Finally, we offer a perspective on aspects of future research that will advance our knowledge and may create new therapeutic opportunities. PubMed was searched for relevant literature between 2010 and 2020 and related studies. Expert opinion: Targeting aberrant excitatory-inhibitory neurotransmission in the hippocampus and its related circuits has the potential to alleviate symptoms and reduce the risk of transition to psychosis if implemented as an early intervention. Longitudinal multimodal brain imaging combined with mechanistic theories generated from animal models can be used to better understand the progression of hippocampal-dopamine circuit dysfunction and heterogeneity in treatment response.
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Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics... more
Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importan...
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Drawing on the four dimensions of justice: distributive, procedural, interactional, and informational justice, this research examines justice as an antecedent of franchisee performance. Empirical r...
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Research Interests: Neuroscience, Chemistry, Medicine, Animals, Male, and 15 moreMicroelectrodes, Neurons, Iontophoresis, Motor System, Globus Pallidus, Basal ganglia, Limbic System, Action Potentials, Excitatory Amino Acids, Excitatory Postsynaptic Potentials, NMDA receptor, Intracellular recording, extracellular recording, Medical and Health Sciences, and Electric stimulation
Research Interests: Neuroscience, Chemistry, Electrophysiology, Medicine, Dopamine, and 15 moreAnimals, Male, Microelectrodes, Neurons, Haloperidol, Microdialysis, Baclofen, Rats, Extracellular Space, Functional Laterality, Dopamine antagonists, Corpus striatum, Antipsychotic agents, Psychology and Cognitive Sciences, and Medical and Health Sciences
Research Interests: Neuroscience, Chemistry, Medicine, Prefrontal Cortex, Executive Function, and 15 moreDopamine, Hippocampus, Animals, Male, Neurons, Frequency Dependence, Rats, Neural pathways, Action Potentials, Single Unit Recording, Dopamine antagonists, Cortical neurons, Psychology and Cognitive Sciences, Medical and Health Sciences, and Electric stimulation
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Research Interests: Neuroscience, Electrophysiology, Dopamine, Antibodies, Nitric oxide, and 15 moreAnimals, Male, Amphetamine, Nitric Oxide Synthase, Degeneration, Neural pathways, Action Potentials, Brain Chemistry, Interneurons, Corpus striatum, Cortical neurons, Intracellular recording, fluorescent dyes, Central nervous system stimulants, and Medical and Health Sciences
Research Interests: Electrophysiology, Dopamine, Animals, Male, Microelectrodes, and 15 moreNeurons, Microdialysis, Neuronal Activity, Action potential, Membrane Potential, Action Potentials, Chloral Hydrate, Infusion Pumps, Excitatory Postsynaptic Potentials, Dopamine antagonists, Cell Membrane, Corpus striatum, Intracellular recording, Medical and Health Sciences, and Electric stimulation
Research Interests: Neuroscience, Chemistry, System Integration, Medicine, Patch-clamp and imaging techniques, and 15 moreDopamine, Thalamus, Animals, Quinpirole, Haloperidol, Low Threshold Spike, Rats, Action Potentials, Resting Membrane Potential, Cell Size, Dopamine antagonists, Antipsychotic agents, Psychology and Cognitive Sciences, Medical and Health Sciences, and In Vitro Techniques
Research Interests: Neuroscience, Chemistry, Medicine, Prefrontal Cortex, Nucleus Accumbens, and 15 moreDopamine, Hippocampus, Glutamate, Animals, Male, Neurons, Rats, Neuronal Activity, Action Potentials, Glutamic Acid, Glutamate Receptor, Cell count, Psychology and Cognitive Sciences, Kynurenic acid, and Medical and Health Sciences
Research Interests: Neuroscience, Polymorphism, Biology, Medicine, Prefrontal Cortex, and 14 moreNucleus Accumbens, Thalamus, Animals, Male, Basal forebrain, The, Pseudorabies virus, Second Order, Rats, Globus Pallidus, Neural pathways, Ventral Pallidum, Psychology and Cognitive Sciences, and Medical and Health Sciences
Research Interests: Neuroscience, Psychology, Medicine, Prefrontal Cortex, Dopamine, and 15 moreAnimals, Male, Amygdala, Neurons, Haloperidol, Action Potentials, Interneurons, Apomorphine, Medial Prefrontal Cortex, Basolateral Amygdala, Dopamine antagonists, Psychology and Cognitive Sciences, extracellular recording, Medical and Health Sciences, and Electric stimulation
Research Interests: Neuroscience, Chemistry, Electrophysiology, Medicine, Dopamine, and 15 moreAnimals, Male, Amygdala, Substantia nigra, Neurons, Iontophoresis, Rats, Single Unit Recording, Glutamic Acid, Medial Prefrontal Cortex, Basolateral Amygdala, Dopamine antagonists, Psychology and Cognitive Sciences, Medical and Health Sciences, and Electric stimulation
Research Interests: Neuroscience, Chemistry, Medicine, Prefrontal Cortex, Dopamine, and 15 moreEvoked Potentials, Animals, Male, Amygdala, Neurons, Neuronal Activity, Limbic System, Action Potentials, Basolateral Amygdala, Excitatory Postsynaptic Potentials, Dopamine antagonists, Psychology and Cognitive Sciences, Intracellular recording, Medical and Health Sciences, and Electric stimulation
Research Interests: Neuroscience, Psychology, Medicine, Prefrontal Cortex, Learning and Memory, and 15 moreClassical Conditioning, Animals, Male, Pavlovian conditioning, Neuronal Plasticity, Amygdala, Neurons, Odors, Neuronal Activity, Lateral Amygdala, Excitatory Postsynaptic Potentials, Psychology and Cognitive Sciences, Intracellular recording, Medical and Health Sciences, and Electric stimulation
Research Interests: Neuroscience, Chemistry, Medicine, Prefrontal Cortex, Nucleus Accumbens, and 15 moreHippocampus, Evoked Potentials, Animals, Male, Synaptic Transmission, Neurons, Steady state, Rats, SYNAPSES, Membrane Potential, Action Potentials, Psychology and Cognitive Sciences, Intracellular recording, Medical and Health Sciences, and Electric stimulation
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Clinical evidence supports the use of second-generation dopamine D2 receptor antagonists (D2RAs) as adjunctive therapy or in some cases monotherapy in patients with depression. However, the mechanism for the clinical antidepressant effect... more
Clinical evidence supports the use of second-generation dopamine D2 receptor antagonists (D2RAs) as adjunctive therapy or in some cases monotherapy in patients with depression. However, the mechanism for the clinical antidepressant effect of D2RAs remains unclear. Specifically, given accumulating evidence for decreased ventral tegmental area (VTA) dopamine system function in depression, an antidepressant effect of a medication that is expected to further reduce dopamine system activity seems paradoxical. In the present paper we used electrophysiological single unit recordings of identified VTA dopamine neurons to characterize the impact of acute and repeated administration of the D2RA quetiapine at antidepressant doses in non-stressed rats and those exposed to the chronic mild stress (CMS) rodent depression model, the latter modeling the hypodopaminergic state observed in patients with depression. We found that acute quetiapine increased dopamine neuron population activity in non-st...
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Recent evidence has emerged supporting a role for the cholinergic system in schizophrenia, including the potential of α7 modulators as a treatment strategy. However, preclinical studies to date have relied on studies in normal systems... more
Recent evidence has emerged supporting a role for the cholinergic system in schizophrenia, including the potential of α7 modulators as a treatment strategy. However, preclinical studies to date have relied on studies in normal systems rather than on a validated developmental model of schizophrenia. Furthermore, there have been only few studies on whether orthosteric and allosteric modulators have differential impacts in such models. Thus, we investigated the effects of α7 agonists and positive allosteric modulators (PAMs) on dopamine (DA) neuron activity in the ventral tegmental area (VTA) in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. Four different drugs were evaluated: PNU282987 (full agonist), SSR180711 (partial agonist) NS1738 (PAM type I) and PNU120596 (PAM type II). PNU120596 increased the number of spontaneously active VTA DA neurons in normal rats. In contrast, PNU282987 and SSR180711 reduced the hyperdopaminergic tone in MAM rats....
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Altered cannabinoid 1 receptor (CB1R) expression has been reported in the brain of subjects with schizophrenia, a developmental mental illness that usually emerges in late adolescence/early adulthood. However, the developmental period at... more
Altered cannabinoid 1 receptor (CB1R) expression has been reported in the brain of subjects with schizophrenia, a developmental mental illness that usually emerges in late adolescence/early adulthood. However, the developmental period at which changes in the CB1R expression appear in schizophrenia is unknown. To gain insight into this factor, we assessed the postnatal developmental trajectory of CB1R expression in the methylazoxymethanol (MAM) model of schizophrenia. Using in situ hybridization with film and grain analyses, CB1R messenger RNA (mRNA) levels were quantified in multiple brain regions, including the medial prefrontal cortex (mPFC), secondary motor cortex, dorsomedial and dorsolateral striatum, dorsal subregions and ventral subiculum of the hippocampus, of MAM-treated rats and normal controls at three developmental periods [juvenile - postnatal day (PD) 30; adolescence - PD45; and adulthood - PD85]. In all brain regions studied, CB1R mRNA levels were highest in juveniles...
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Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data... more
Despite evidence for a role of the dopamine system in the pathophysiology of schizophrenia, there has not been substantial evidence that this disorder originates from a pathological change within the dopamine system itself. Current data from human imaging studies and preclinical investigations instead point to a disruption in afferent regulation of the dopamine system, with a focus on the hippocampus. We found that the hippocampus in the methylazoxymethanol acetate (MAM) rodent developmental disruption model of schizophrenia is hyperactive and dysrhythmic, possibly due to loss of parvalbumin interneurons, leading to a hyperresponsive dopamine system. Whereas current therapeutic approaches target dopamine receptor blockade, treatment at the site of pathology may be a more effective therapeutic avenue. This model also provided insights into potential means for prevention of schizophrenia. Specifically, given that stress is a risk factor in schizophrenia, and that stress can damage hip...
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A significant subpopulation of neurons in rat nucleus accumbens (NAc) coexpress dopamine D1 and D2 receptors, which can form a D1-D2 receptor complex, but their relevance in addiction is not known. The existence of the D1-D2 heteromer in... more
A significant subpopulation of neurons in rat nucleus accumbens (NAc) coexpress dopamine D1 and D2 receptors, which can form a D1-D2 receptor complex, but their relevance in addiction is not known. The existence of the D1-D2 heteromer in the striatum of rat and monkey was established using in situ PLA, in situ FRET and co-immunoprecipitation. In rat, D1-D2 receptor heteromer activation led to place aversion and abolished cocaine CPP and locomotor sensitization, cocaine intravenous self-administration and reinstatement of cocaine seeking, as well as inhibited sucrose preference and abolished the motivation to seek palatable food. Selective disruption of this heteromer by a specific interfering peptide induced reward-like effects and enhanced the above cocaine-induced effects, including at a subthreshold dose of cocaine. The D1-D2 heteromer activated Cdk5/Thr75-DARPP-32 and attenuated cocaine-induced pERK and ΔFosB accumulation, together with inhibition of cocaine-enhanced local field...
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There is common agreement that many disorders of the central nervous system are 'complex', that is, there are many potential factors that influence the development of the disease, underlying mechanisms, and successful treatment.... more
There is common agreement that many disorders of the central nervous system are 'complex', that is, there are many potential factors that influence the development of the disease, underlying mechanisms, and successful treatment. Most of these disorders, unfortunately, have no cure at the present time, and therapeutic strategies often have debilitating side effects. Interestingly, some of the 'complexities' of one disorder are found in another, and the similarities are often network defects. It seems likely that more discussions of these commonalities could advance our understanding and, therefore, have clinical implications or translational impact. With this in mind, the Fourth International Halifax Epilepsy Conference and Retreat was held as described in the prior paper, and this companion paper focuses on the second half of the meeting. Leaders in various subspecialties of epilepsy research were asked to address aging and dementia or psychosis in people with epilep...
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We recently reported that resting hippocampal, basal ganglia and midbrain perfusion is elevated in people at ultra high risk (UHR) for psychosis. The present study sought to replicate our previous finding in an independent UHR cohort, and... more
We recently reported that resting hippocampal, basal ganglia and midbrain perfusion is elevated in people at ultra high risk (UHR) for psychosis. The present study sought to replicate our previous finding in an independent UHR cohort, and examined the relationship between resting perfusion in these regions, psychosis and depression symptoms, and traumatic experiences in childhood. Pseudo-Continuous Arterial Spin Labelling (p-CASL) imaging was used to measure resting cerebral blood flow (rCBF) in 77 UHR for psychosis individuals and 25 healthy volunteers in a case-control design. UHR participants were recruited from clinical early detection services at 3 sites in the South of England. Symptoms levels were assessed using the Comprehensive Assessment of At Risk Mental States (CAARMS), the Hamilton Depression Scale (HAM-D), and childhood trauma was assessed retrospectively using the Childhood Trauma Questionnaire (CTQ). Right hippocampal and basal ganglia rCBF were significantly increas...
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A novel mechanism for regulating dopamine activity in subcortical sites and its possible relevance to schizophrenia is proposed. This hypothesis is based on the regulation of dopamine release into subcortical regions occurring via two... more
A novel mechanism for regulating dopamine activity in subcortical sites and its possible relevance to schizophrenia is proposed. This hypothesis is based on the regulation of dopamine release into subcortical regions occurring via two independent mechanisms: (1) transient or phasic dopamine release caused by dopamine neuron firing, and (2) sustained, "background" tonic dopamine release regulated by prefrontal cortical afferents. Behaviorally relevant stimuli are proposed to cause short-term activation of dopamine cell firing to trigger the phasic component of dopamine release. In contrast, tonic dopamine release is proposed to regulate the intensity of the phasic dopamine response through its effect on extracellular dopamine levels. In this way, tonic dopamine release would set the background level of dopamine receptor stimulation (both autoreceptor and postsynaptic) and, through homeostatic mechanisms, the responsivity of the system to dopamine in these sites. In schizophrenics, a prolonged decrease in prefrontal cortical activity is proposed to reduce tonic dopamine release. Over time, this would elicit homeostatic compensations that would increase overall dopamine responsivity and thereby cause subsequent phasic dopamine release to elicit abnormally large responses.
Research Interests: Neuroscience, Psychology, Materials Science, Medicine, Nucleus Accumbens, and 15 moreDopamine, Humans, Cerebral Cortex, Glutamate receptors, Animals, Dopamine Receptors, Hallucinogens, Neurons, Rats, Homeostasis, Psychological Models, Neurosciences, Glutamic Acid, Corpus striatum, and Antipsychotic agents
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Deficits in neuronal network synchrony in hippocampus and prefrontal cortex have been widely demonstrated in disorders of cognitive dysfunction, including schizophrenia and Alzheimer's disease. The atypical dopamine agonist SKF 83959... more
Deficits in neuronal network synchrony in hippocampus and prefrontal cortex have been widely demonstrated in disorders of cognitive dysfunction, including schizophrenia and Alzheimer's disease. The atypical dopamine agonist SKF 83959 has been shown to increase brain-derived neurotrophic factor signalling and suppress activity of glycogen synthase kinase-3 in PFC, two processes important to learning and memory. The purpose of this study was to therefore evaluate the impact of SKF 83959 on oscillatory deficits in methylazoxymethanol acetate (MAM) rat model of schizophrenia. To achieve this, local field potentials were recorded simultaneously from the hippocampus and prefrontal cortex of anesthetized rats at 15 and 90 min following both acute and repeated administration of SKF 83959 (0.4 mg/kg). In MAM rats, but not controls, repeated SKF 83959 treatment increased signal amplitude in hippocampus and enhanced the spectral power of low frequency delta and theta oscillations in this r...
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Stress constitutes a risk factor across several psychiatric disorders. Moreover, females are more susceptible to stress-related disorders, such as depression, than males. Although dopamine (DA) system underactivation is implicated in the... more
Stress constitutes a risk factor across several psychiatric disorders. Moreover, females are more susceptible to stress-related disorders, such as depression, than males. Although dopamine (DA) system underactivation is implicated in the pathophysiology of depression, little is known about the female DA system at baseline and post-stress. The effects of chronic mild stress (CMS) were examined on ventral tegmental area (VTA) DA neuron activity and forced swim test (FST) immobility by comparing male and female rats. The impact of a single dose of the rapid antidepressant ketamine (10mg/kg, i.p.) on FST immobility and VTA function was then tested. Baseline VTA DA activity was comparable in both sexes. At baseline, females exhibited roughly double the FST immobility duration than males, which corresponded to ~50% decrease in VTA DA population activity compared with similarly treated (i.e. post-FST) males. Following CMS, there was greater immobility duration in both sexes and reduced VTA...
Research Interests: Neuropsychopharmacology, Medicine, Chronic Disease, Female, Animals, and 12 moreMale, Ketamine, Ventral Tegmental Area, Action Potentials, Psychological Stress, Dopaminergic Neurons, Motor activity, Acute Disease, Sex Characteristics, Psychology and Cognitive Sciences, Medical and Health Sciences, and Antidepressive agents
The article by Hashemiyoon et al. is a masterful synthesis of the clinical, genetic, and neurobiological aspects of Gilles de la Tourette's syndrome that provides unique insights into the neural state dysfunctions that underlie this... more
The article by Hashemiyoon et al. is a masterful synthesis of the clinical, genetic, and neurobiological aspects of Gilles de la Tourette's syndrome that provides unique insights into the neural state dysfunctions that underlie this enigmatic disorder. In particular, the authors make a powerful argument for the disorder arising from hyposynchronization within cortico-basal ganglia-thalamocortical systems which may result from a genetically-driven developmental insult to interneuron regulation, and suggest deep brain stimulation as a valuable tool to assess how balance may be restored to the system and reverse the pathological state.
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Schizophrenia has been associated with heightened stress responsivity in adolescence that precedes onset of psychosis. We now report that multiple stressors during adolescence in normal rats leads to deficits in adults analogous to that... more
Schizophrenia has been associated with heightened stress responsivity in adolescence that precedes onset of psychosis. We now report that multiple stressors during adolescence in normal rats leads to deficits in adults analogous to that seen in schizophrenia patients. Moreover, impairment of stress control by lesion of the prelimbic prefontal cortex in adolescence caused previously subthreshold levels of stress to induce these deficit states when tested as adults. Thus, predisposition to stress hyper-responsivity, or exposure to substantial stressors, during adolescence can trigger a cascade of events that result in a schizophrenia-like profile in adults. This data can provide crucial information with respect to identifying markers for schizophrenia vulnerability early in life and, by mitigating the impact of stressors, prevent the transition to psychosis.
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Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural... more
Dopaminergic medications used in the treatment of patients with Parkinson's disease are associated with motor and non-motor behavioural side-effects, such as dyskinesias and impulse control disorders also known as behavioural addictions. Levodopa-induced dyskinesias occur in up to 80% of patients with Parkinson's after a few years of chronic treatment. Impulse control disorders, including gambling disorder, binge eating disorder, compulsive sexual behaviour, and compulsive shopping occur in about 17% of patients with Parkinson's disease on dopamine agonists. These behaviours reflect the interactions of the dopaminergic medications with the individual's susceptibility, and the underlying neurobiology of Parkinson's disease. Parkinsonian rodent models show enhanced reinforcing effects of chronic dopaminergic medication, and a potential role for individual susceptibility. In patients with Parkinson's disease and impulse control disorders, impairments are observe...
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Stress during adolescence is a risk factor for schizophrenia, and medial prefrontal cortex (mPFC) dysfunction is proposed to interfere with stress control, increasing the susceptibility to stress. We evaluated the impact of different... more
Stress during adolescence is a risk factor for schizophrenia, and medial prefrontal cortex (mPFC) dysfunction is proposed to interfere with stress control, increasing the susceptibility to stress. We evaluated the impact of different stressful events during adolescence (restraint stress [RS], footshock [FS], or the combination of FS and RS) on behaviors correlated with schizophrenia in rats as adults. At adulthood, animals were tested for anxiety responses (elevated plus-maze), cognitive function (novel-object recognition test) and dopamine (DA) system responsivity (locomotor response to amphetamine and DA neuron activity in the ventral tegmental area (VTA) using in vivo electrophysiology). All adolescent stressors impaired weight gain and induced anxiety-like responses in adults. FS and FS + RS also disrupted cognitive function. Interestingly, only the combination of FS and RS induced a DA hyper-responsivity as indicated by augmented locomotor response to amphetamine and increased ...
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The circuitry mediating top-down control of dopamine (DA) neurons in the ventral tegmental area (VTA) is exceedingly complex. Characterizing these networks will be critical to our understanding of fundamental behaviors, such as motivation... more
The circuitry mediating top-down control of dopamine (DA) neurons in the ventral tegmental area (VTA) is exceedingly complex. Characterizing these networks will be critical to our understanding of fundamental behaviors, such as motivation and reward processing, as well as several disease states. Previous work suggests that the medial prefrontal cortex (mPFC) exerts a profound influence on VTA DA neuron firing. Recently, our group reported that inhibition of the infralimbic subdivision of the medial prefrontal cortex (ilPFC) increases the proportion of VTA DA neurons that are spontaneously active (i.e., "population activity") and that this effect depends on activity in the ventral subiculum of the hippocampus (vSub). However, there is no direct projection from the mPFC to the vSub. Anatomical evidence suggests that communication between the two structures is mediated by the nucleus reuniens of the midline thalamus (RE). Here, we used in vivo electrophysiological and behavio...
Research Interests: Neuroscience, Prefrontal Cortex, Patch-clamp and imaging techniques, Hippocampus, Animals, and 13 moreMale, Amphetamine, Rats, Tetrodotoxin, Hyperkinesis, Neural pathways, Ventral Tegmental Area, Isoflurane, Action Potentials, Dopaminergic Neurons, Psychology and Cognitive Sciences, Central nervous system stimulants, and Medical and Health Sciences
Loss of parvalbumin interneurons in the hippocampus is a robust finding in schizophrenia brains. Rats exposed during embryonic day 17 to methylazoxymethanol acetate exhibit characteristics consistent with an animal model of schizophrenia,... more
Loss of parvalbumin interneurons in the hippocampus is a robust finding in schizophrenia brains. Rats exposed during embryonic day 17 to methylazoxymethanol acetate exhibit characteristics consistent with an animal model of schizophrenia, including decreased parvalbumin interneurons in the ventral hippocampus. We reported previously that peripubertal administration of diazepam prevented the emergence of pathophysiology in adult methylazoxymethanol acetate rats. We used an unbiased stereological method to examine the impact of peripubertal diazepam treatment on parvalbumin interneuron number in the ventral subiculum, dentate gyrus of the hippocampus and the basolateral amygdala. Methylazoxymethanol acetate rats with peripubertal diazepam showed significantly more parvalbumin interneurons (3355±173 in the ventral subiculum, 1211±76 in the dentate gyrus) than methylazoxymethanol acetate without diazepam (2375±109 and 824±54, respectively). No change was found in the basolateral amygdal...