The Involvement of the Anterior Cingulate Cortex in the Cognitive Dysfunction of Patients with Multiple Sclerosis: A Structural MRI Study

Meredith Anderson (Neuroscience ’07)

Advisor: Nancy Koven

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. Up to 65% of the MS population suffers cognitive deficits, a major determinant of quality of life. Such deficits include, but are not limited to, deficits in attention, concentration, abstract reasoning, and memory retrieval. Cognitive dysfunction may be caused by atrophy to areas of the brain involved in executive control. Carter et al. (2000) hypothesized that the anterior cingulate cortex (ACC) is part of a circuit involved in executive processes and cognitive function with reciprocal interconnections with the lateral prefrontal cortex, which modulates attention and executive functions. Although the ACC is implicated in cognitive function, very little research has been conducted on its effects in MS patients. By using structural MRI to examine volumetry, as well as neuropsychological assessment to index associated cognitive deficits, I examined structural abnormalities in four functionally relevant ACC subregions: dorsal, rostral, subcallosal, and subgenual. Three groups were studied: healthy volunteers, low disability, and high disability MS patients. I hypothesized that MS patients, relative to control subjects, would show decreased volumes in all subregions, but that a decreased volume of the dorsal subregion would correlate best with cognitive impairment due to its proposed role in cognitive control (Bush et al., 2000). Results indicated that the dorsal subregion volume of high disability MS patients was significantly reduced relative to that of healthy subjects. Sobel mediation analyses revealed a trend for dorsal ACC volume to mediate between diagnostic status and performance on the Reverse Digit Span test. In conclusion, the dorsal ACC is an important region of interest in the cognitive dysfunction of MS patients, but is not critical.

Failure to Disrupt Reconsolidation of a Morphine- and a Cocaine-Induced Conditioned Place Preference with MK-801 and Cycloheximide, Respectively

Aleksandra L. Brakalova (Neuroscience ’07)

Advisor: John Kelsey

Drug-related memories are known to maintain addictions and to induce relapse. Recent evidence suggests that the active retrieval of some memories makes them labile to impairment by disruption of a process referred to as reconsolidation. However, only a few recent experiments have attempted to disrupt drug-related memories after reactivation, and most of them use the conditioned place preference (CPP) paradigm to do so. In my two initial experiments, I used an antagonist of the glutamate NMDA receptor, MK-801, to disrupt reconsolidation of a CPP created by morphine and retrieved by re-exposure to both the drug and the drug context, as MK-801 had been shown to disrupt the reconsolidation of fear-related memories. Unfortunately, I found no disruption of the drug-related memory, i.e., the animals given MK-801 following retrieval of a morphine-induced CPP subsequently continued to prefer the morphine-paired chamber as much as animals given saline following initial retrieval. In a third experiment, I tried to replicate the findings that a protein synthesis inhibitor would disrupt reconsolidation of a CPP produced by cocaine but unlike my previous studies, I attempted to retrieve the drug memory by re-exposing the rats to both sides of the CPP apparatus in the absence of cocaine. However, cocaine did not produce a CPP that could be disrupted, and cycloheximide made the animals ill. Thus, contrary to the findings of previous experiments, my results suggest that drug memories are not easily susceptible to impairment after retrieval and that, therefore, they may not undergo robust reconsolidation.

Effects of a Dopamine D1 Antagonist, Adenosine A1 Agonist, and Caffeine on L-DOPA- Induced Dyskinesia in a 6-OHDA Rat Model of Parkinson’s Disease

Melissa Chen (Neuroscience ’07)

Advisor: John Kelsey

Chronic L-DOPA therapy effectively reduces the akinesic symptoms of most patients with Parkinson’s disease (PD), but also causes debilitating dyskinesic side effects in many patients. Blockade of dopamine D1 receptors attenuates L-DOPA-induced dyskinesia (LID) in animal models of PD, but also blocks the therapeutic effects of L-DOPA. Because D1 and adenosine A1 receptors have been reported to interact antagonistically, A1 receptor stimulation would be predicted to have similar effects. Given the evidence that caffeine and selective adenosine A2A receptor antagonists can potentiate the therapeutic effects of L-DOPA without exacerbating LID in animal models, I examined the possibility that caffeine might reduce the anti-therapeutic effects of a D1 antagonist and A1 agonist without affecting its anti-dyskinesic effects. In rats with a unilateral 6-OHDA lesion, an acute injection of a high dose of L-DOPA (35 mg/kg) was used to produce LID as measured by the abnormal involuntary movements (AIMs) scale. As expected, 0.1 mg/kg of the D1 antagonist SCH 23390 and, to a lesser extent, 0.05 and 0.1 mg/kg of the A1 agonist CPA reduced total AIMs scores and the therapeutic effects of L-DOPA, as measured in a forepaw stepping paradigm. While having no effects by itself, the addition of 15 mg/kg caffeine to the combination of SCH 23390 and L-DOPA and to the combination of CPA and L-DOPA largely reversed the impairment in stepping produced by the D1 antagonist and A1 agonist without affecting the beneficial reduction of LID produced by these drugs. Collectively, this study demonstrates that the combination of caffeine and a D1 antagonist or an A1 agonist may be beneficial in the treatment of PD patients with LID.

Schizophrenia and the Biological Vulnerability to Abuse Substances: An MRI Study Investigating Four Subregions of the Anterior Cingulate Gyrus

Melissa Coito (Neuroscience ’07)

Advisor: Nancy Koven

Over the course of their lifetime, a majority of patients with schizophrenia will experience a co-occurring substance use disorder (Regier et al., 1990). This recurrent comorbidity has led some theorists to believe that patients with schizophrenia have a biologic vulnerability to substance abuse. There is one brain region that stands out as being both central in theories of addiction and consistently noted as dysfunctional in schizophrenics, the anterior cingulate gyrus. The anterior cingulate gyrus appears to mediate inhibitory decision-making processes, specifically response selection and response inhibition, particularly when involving reward related behaviors (Elliot et al., 2002; Fan et al., 2003). Working with fMRI data of patients with schizophrenia and comorbid cannabis abuse as well as data from healthy control participants, I analyzed the relationships between the volumes of four cingulate subregions (dorsal, rostral, subcallosal, and subgenual) and performance on neuropsychological tests of response inhibition that are known the activate the anterior cingulate gyrus. Of the four regions of interest, MANOVA revealed that volumes of the left and right dorsal and right rostral regions were significantly reduced in dual diagnosis patients. A separate MANOVA revealed a trend for these patients to score lower a measure of response inhibition. Upon further analysis, however, the dorsal and rostral subregions were not found to mediate inhibitory control. The data did indicate that these subregions are involved in dissociable processes involved in decision-making.

The Effect of Priming on Executive Functioning

Ryan Griffin (Psychology ’07)

Advisor: Nancy Koven

Response inhibition refers to the ability to suppress behaviors when they are inappropriate. While response inhibition is significantly impaired in clinical conditions such as ADHD, bipolar disorder, and OCD, this skill varies considerably across non-pathological individuals. This project examined the role of priming stimuli in response inhibition, specifically how presentation of supraliminal and subliminal stimuli affect unconscious memories such that behaviors and cognitions change as a result. Priming appears to be a ubiquitous phenomenon in that it is known to affect aspects of social cognition and intellectual performance. However, the effect of priming on response inhibition in particular remains unclear. In this study, healthy college students were randomly assigned to one of three lexical priming conditions: primes that were hypothesized to increase response inhibition (e.g., “focus”), primes hypothesized to decrease response inhibition (e.g., “error”), and neutral primes (e.g., “secretary”). A neuropsychological measure of sustained attention and response inhibition was utilized to examine relative changes that may have resulted from exposure to the primes. The implications of this study could mean that cues in a person’s environment affect the ability to suppress inappropriate behaviors, which is of particular interest to those who work with individuals diagnosed with ADHD, bipolar, or OCD.

Inhibition of Corticotropin Releasing Factor (CRF) Reduces Both the Somatic and Motivational Components of Precipitated Nicotine Withdrawal in Rats

Stephanie LeBourdais (Neuroscience ’07)

Advisor: John Kelsey

Corticotropin-releasing factor (CRF), a neuropeptide involved in mediating neuroendocrine and behavioral responses to stress, has recently been implicated in withdrawal from opiates, alcohol, and cocaine. CRF levels have been shown to increase when rats are in withdrawal and the somatic and behavioral symptoms of withdrawal are attenuated with CRF1 receptor antagonists. This thesis investigates CRF’s role in mediating nicotine withdrawal in rats. Rats were addicted to nicotine over a 7-day period through the use of nicotine injections or implanted osmotic minipumps, and withdrawal was precipitated by injections of the nicotinic antagonist mecamylamine. Although the withdrawal symptoms were rather mild, injections of antalarmin, a CRF1 receptor antagonist prior to precipitated withdrawal reduced the somatic symptoms of nicotine withdrawal and also attenuated the development of a nicotine withdrawal-induced conditioned place aversion. Taken together, these results indicate that CRF does appear to mediate some of the symptoms and aversive consequences of nicotine withdrawal in rats.

Orbitofrontal Correlates of Neuropsychological Performance and Mood in Schizophrenic Patients Comorbid for Substance Use Disorder

Chris Leonards (Neuroscience ’07)

Advisor: Nancy Koven

Immense comorbidity exists between schizophrenia and substance use disorder (SUD).  Because imaging studies have suggested that orbitofrontal cortex (OFC) gray matter anomalies may mediate schizophrenia and SUD vis-à-vis reduced response inhibition, this study examined OFC gray matter (GM) volumetry in schizophrenic, comorbid, and healthy participants, using structural magnetic resonance imaging.  It further assessed the role of OFC volumetry in response inhibition, perseveration, and attention by measuring perseverative error in the Wisconsin Card Sorting Test, false positive errors on the Continuous Performance Test, inhibition on the Delis-Kaplan Executive Function System Color-Word Test and mood, as assessed by the Beck Depression Inventory (Second Edition) and the State-Trait Anxiety Inventory.  Results showed that healthy controls had larger total OFC volumes than schizophrenic patients, and that smaller OFC volumes were associated with poorer neuropsychological performance.  Among comorbid patients, smaller right OFC volumes were associated with increased distraction, and increased right OFC volumes were associated with increased depression and anxiety.  In schizophrenic patients, decreased left OFC volumes were associated with increased perseveration, while increased left OFC volumes were associated with inhibition and decreased levels of depression.  These findings are discussed in the context of approach-withdrawal behavior and possible iatrogenic effects.

Mapping of Glutamate Receptor-Containing Neurons in the Pond Snail, Helisoma trivolvus

Neil Marya (Neuroscience ‘ 07)

Advisor: Nancy Kleckner

Central pattern generators are essential for the function of several types of behaviors (e.g., walking, breathing, swimming, digestion) in both vertebrate and invertebrate systems. This thesis focuses on characterizing the central pattern generator that controls the feeding behavior of the pond snail Helisoma trivolvis. Previous studies have helped characterize this particular CPG, and have identified glutamate as a neurotransmitter that controls and modulates neuronal cells that are integral to the function of this particular system. This thesis focuses on identifying a glutamate-receptor subtype?GluR5,6,7?that previous evidence has suggested as being pertinent to modulating this same feeding behavior. Immunocytochemistry procedures were used to identify cells that contain the GluR5,6,7 receptor subtype through application of a fluorescently-labeled GluR5,6,7 monoclonal antisera to the ganglia of the central nervous system of Helisoma trivolvis. Images taken indicate highly specific staining of the GluR5,6,7 receptor subtype on the dorsal surface of both the left and right buccal ganglia of the central system. Furthermore, staining for this receptor subtype was also seen in the underlying neuropil beneath the dorsal surface of the buccal ganglia. Further research should be pursued in order to further characterize the neurons that have been specified in this thesis. Specifically, double stain experiments should attempt to inject Lucifer Yellow into neurons that are concurrently labeled for the GluR5,6,7 receptor subtype.

This would allow for a greater understanding of the location and orientation of the cells that have been stained. By understanding the exact locations of these cells, future electrophysiological studies can be pursued in order to characterize the polarizing effects of exogenously applied chemicals. Such studies are vital to extending our comprehension of the feeding behavior CPG in Helisoma trivolvis and CPGs in general.

The Atypical Antipsychotic Clozapine Blocks PCP-induced Impairment of Working Memory in Rats

Maddy O’Donnell (Neuroscience ’07)

Advisor: John Kelsey

Schizophrenia is a gravely debilitating disease known to affect an estimated one percent of the world’s population.  Among the different symptoms characteristic of the disease, many would argue that the most functionally incapacitating are the cognitive symptoms.  While these symptoms are untreatable with the older typical antipsychotics which act as D2 receptor antagonists (haloperidol), they are mildly improved by the use of atypical antipsychotics which interact with DA and 5HT receptors.  Currently there are many animal models for studying schizophrenia in rats with the use of PCP, which has been documented to induce schizophrenic-like behaviors in humans and rats.  However, there is a need for a well established cognitive model.  In this study I used an operant delayed non-matched to sample test of working memory in which the rats had to remember which of two levers it pressed over a variable retention interval. PCP (4-7.5 mg/kg) produced a deficit on the task that was partially delay-dependent.  The atypical antipsychotic clozapine (2.5-5 mg/kg) reversed the PCP-induced deficit in working memory.  Thus it appears as though the PCP-induced deficit in the task may provide a good animal model of the cognitive deficits in schizophrenia, that may be useful in developing even more effective therapies.

Caffeine, an Adenosine A1 and A2A Antagonist, Delays the Expression of Nicotine-Induced Locomotor Sensitization in Rats

Jessie Ricker (Neuroscience ’07)

Advisor John Kelsey

Caffeine and nicotine are frequently co-administered in the human population, but there is not yet a complete understanding of how their co-administration influences behavior. Because both drugs increase dopamine in the nucleus accumbens and because adenosine antagonists such as caffeine enhance dopamine receptor affinity, it might be expected that caffeine would enhance the rewarding effects of nicotine, explaining the frequent co-administration. On he other hand, there is evidence that elimination of the A2A adenosine receptor by genetic knockouts reduces the development of locomotor sensitization to repeated injections of a variety of drugs. Because locomotor sensitization is often used as an indirect measure of reward, these latter findings suggest that caffeine may reduce the reward value of other drugs. Consequently, the current study investigated the effect of co-administration of caffeine (15 mg/kg) on the development of nicotine- (0.4 mg/kg) induced locomotion sensitization in rats. Data indicate that the development of locomotor sensitization in animals receiving both nicotine and caffeine over four, but not six, sessions was reduced compared to animals only receiving nicotine. Furthermore, acute caffeine injections reduced the expression of already established nicotine sensitization. Thus, my data are consistent with the hypothesis that adenosine receptor antagonists and knockouts can delay the onset of locomotor sensitization to a variety of drugs. Thus, it is not clear from my study why there appears to be such a tight association between nicotine and caffeine consumption in humans.

The Relationship Between Orbitofrontal Cortical Subregion Volumes, Comorbid Mood Disorders and Verbal Learning and Memory Indices in Obsessive-Compulsive Disorder

Madelyn Nora Rubin (Psychology ’07)

Advisor: Nancy Koven

Previous research has provided strong evidence that the orbitofrontal cortex (OFC) may be involved in a neuronal circuit that modifies the expression of obsessive-compulsive disorder (OCD). More specifically, it has been postulated that the anterior subregion of the OFC is related to certain cognitive abilities termed executive functions. This study was designed to investigate the volumetric abnormality of the OFC by dividing it into anterior and posterior subregions using 3D magnetic resonance images (MRI). Grey matter volumes of bilateral anterior and posterior subregions in 10 patients with OCD were measured and compared to those of 10 healthy control patients. Clinical and cognitive assessments were employed including the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) to assess symptom severity, along with the California Verbal Learning Test – Second Edition (CVLT-II) to evaluate learning strategies and long-term verbal memory ability. Results indicated reduced left anterior OFC volume in OCD participants compared to control participants, with this reduced volume being marginally associated with compulsive behavior. Volume reduction was not correlated with organization strategies on the CVLT-II for the OCD group; however, OCD symptom severity, anxiety and depression were instead correlated with verbal memory ability. While the OFC may not be implicated in abnormal verbal memory in this OCD sample, OFC volume appears to be associated with compulsiveness and anxiety.

Pharmacological Characterization of Excitatory and Inhibitory Glutamate Receptors in Buccal Neurons B5, B19, and B27 in Helisoma trivolvis

Elizabeth Scannell (Neuroscience ’07)

Advisor: Nancy Kleckner

Glutamate is the primary neurotransmitter responsible for regulating the triphasic feeding central pattern generator in the neurons of the buccal ganglia in the pond snail, Helisoma trivolvis. Three different interneuronal subunits, referred to as S1, S2, and S3, act on different motor neurons to produce the phases of feeding behavior: protraction, retraction, and hyperretraction. The glutamatergic retraction interneuron B2 inhibits protraction neuron B5 and hyperretraction motor neuron, while B2 excited retraction motor neuron B27. This suggests that excitatory glutamate receptors may be found on B27, while inhibitory glutamate receptors may be present on B5 and B19. Evidence from previous studies suggests that excitatory glutamate receptors in Helisoma may resemble the KA/AMPA ionotropic glutamate receptor subtypes found in vertebrates, while inhibitory glutamate receptors in Helisoma may be similar to vertebrate metabotropic glutamate receptors. The purpose of this study was to classify the excitatory and inhibitory glutamate receptor subtypes in buccal neurons B5, B19, and B27 using a pharmacological approach using intracellular recording and the perfusion of whole-ganglia preparations with glutamate and agonists that are selective for different glutamate receptor subtypes. Data showed inhibition of neuronal firing rate in all three neurons in response to glutamate and quisqualate, a metabotropic glutamate receptor agonist, as well as excitation in all three neurons in response to kainate, an ionotropic glutamate receptor agonist that is selective for AMPA/KA subtypes. Experiments with more selective glutamate agonists to further characterize the inhibitory receptor subtypes showed inhibition of B19 in response to an mGluRII agonist, as well as trends toward inhibition in B5 in response to mGluRII and mGluRIII agonists. Selective mGluR agonists did not affect firing rate in B27, suggesting that the inhibitory GluRs on this neuron do not closely resemble any of the vertebrate mGluR subtypes. The occurrence of inhibition in B27 in response to 100 µM and 300 µM glutamate, and excitation in that same neuron in response to 1 mM and 5 mM glutamate, suggests that inhibitory GluRs have a greater affinity for glutamate, and that perhaps differential concentrations of glutamate, as well as the relative numbers of inhibitory and excitatory GluRs on a neuron, may modulate the effects of glutamate in the feeding CPG. These potential differential effects of varying glutamate concentrations may explain the presence of both excitatory and inhibitory GluRs on B5, B19, and B27. Future research using voltage clamp or patch clamp recording in isolated buccal neurons is needed to further the characterization of GluR pharmacology and associated intracellular mechanisms in order to more fully understand the role of GluRs in the buccal ganglia in Helisoma.

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