Role of Tyrosine Kinase B (TrkB) Signaling in the Regulation of Carotid Body Development by Hyperoxia of Carotid Body Development by Hyperoxia

Diane Grace Brackett (Neuroscience)

Advisor: Ryan Bavis

There is a strong correlation between perinatal exposure to hyperoxia (highoxygen, > 21% O2) and a reduction in the size of the carotid body (CB), a peripheral sensory organ important in respiratory control. This morphological change is associated with a blunted hypoxic ventilatory response (HVR) in mammals such as rats and mice. The HVR is a reflexive increase in breathing that occurs during exposure to acute hypoxia (low oxygen, < 21% O2) in order to compensate for low blood oxygen. The mechanism by which hyperoxia affects CB morphology and function is largely unknown, but recent studies have provided important clues. Brain-derived neurotrophic factor (BDNF) signaling via the tyrosine kinase B (TrkB) receptor has been shown to be crucial in the proper development of the CB and consequently, respiratory control. In a recent study, BDNF expression was reduced about 70% in the CBs of hyperoxia-treated rats. The purpose of the present study was to determine if inhibition of TrkB cell surfacereceptors in the CB has the same effect as perinatal hyperoxia. To test the hypothesis, we studied mice with a mutated form of the TrkB receptor. The mutation causes TrkB to be susceptible to blockade by the drug 1NMPP1. Groups of wild-type and mutant mice were treated with either 1NMPP1 or a vehicle for the first seven postnatal days. Reversible inhibition of TrkB in mutant mice did not result in significant differences in CB volume or the HVR relative to control mice. While this may indicate that our original hypothesis is incorrect, several methodological issues likely obscured the results; sample sizes for mutant mice were low and mice treated with 1NMPP1 may not have received sufficient doses. Analysis of ventilation and metabolism in three-month-old mice revealed that stress associated with daily injections and handling during the neonatal period contributed to higher metabolic rate, as manifested by increased O2 consumption. This finding implicates neonatal stress in the development of abnormal respiratory patterns that persist in adulthood. Results from this study contribute to an active area of research that seeks to identify the molecular contributors of the developmental plasticity inherent in the respiratory control system.

The Relationship among Vitamin D Blood Serum Levels, Cognition and Midsagittal Corpus Callosum Area in Individuals with Multiple Sclerosis

Meg Cadden  (Neuroscience-Honors)

Advisor: Nancy Koven

Multiple Sclerosis, a disease with no available cure, is marked by both physical and cognitive deficits. Symptoms, associated with white matter lesions present in the brain and spinal cord, include fatigue, loss of sensation, and weakness of the limbs as well as slowed processing speed and impaired memory. Data collected over the last ten years have started to uncover a relationship between vitamin D and MS susceptibility and severity. This study looks specifically at the relationships among vitamin D blood serum levels, cognition, and mid-saggital corpus callosum area. Mid-saggital corpus callosum area has been found to correlate to overall white matter lesion burden in the brain and is thus a reliable measure of disease progression. Cognition, including long-term memory, working memory, processing speed, language skills, visuospatial skills, sensorimotor skills, and executive functions, was assessed with neuropsychological tests. Vitamin D levels and structural MRI data, through which corpus callosum areas were calculated, were collected from participants medical records. Correlation analyses were used to test the hypothesis that higher vitamin D blood serum levels are associated with better cognitive performance and larger corpus callosum areas. Results of this study may indicate a beneficial role of vitamin D as an accessible and inexpensive supplement to MS medication.

Response Inhibition in Subclinical OCD and Subclinical AD/HD

Matt Chance (Psychology)

Advisor: Nancy Koven

Literature has been mixed on possible impairments in response inhibition, or more broadly, the emotional regulation strategy of suppression, and it is role in OCD and AD/HD populations. The current study examined the role of response inhibition in subclinical OCD and AD/HD populations compared to normal controls by surveying 94 undergraduates from a small liberal arts college in the Northeast, and utilizing known measures of OCD, AD/HD, response inhibition, and emotional regulation. Results indicate that, although some factors of OCD and AD/HD are significantly correlated with higher self-reported use of suppression, there is no
significant difference between the groups. Findings suggest that specific subscales may be more telling of impairments in response inhibition than a diagnosis as a whole. The results suggest that future research should more closely examine the relationship between response inhibition, OCD, and AD/HD, particularly using emotionally charged stimuli.

Selective Attention, Memory, and Alexithymia: Performances on an Emotional Stroop Task and WMS-III Subtests

Rachael DiStefano (Psychology-Honors)

Advisor: Nancy Koven

Alexithymia, a personality construct in which an individual has difficulty processing and regulating emotions, results in a wide range of impairments. This pattern of dysfunction may be explained, in part, by a deficit in selective attention for emotional information, which may then lead to an impaired memory for emotional information. Currently, the role of attention and memory in alexithymia is unclear. In Study 1, participants (N = 72) completed self-report measures of alexithymia (TAS-20, MAS, TMMS), an emotional Stroop task, and an incidental memory task. Contrary to hypothesis, individuals who were more alexithymic responded more quickly when the eStroop stimulus was positive (but not negative) than when the stimulus was neutral. Principal components analysis produced two factors relevant to alexithymia: Emotional Monitoring (EM) and Emotional Clarity (EC). With regard to eStroop, high-EM individuals took longer to respond and made more errors than low-EM individuals, regardless of word type. With regard to incidental memory, high-EC individuals were better at disregarding negative distracters, but less proficient at recognizing negative targets than low-EC individuals. In Study 2, extreme groups formed using TAS-20 scores from a previous study (N = 101) underwent a neuropsychological assessment of memory (WMS-III). High-alexithymics (n = 12) and low-alexithymics (n = 12) performed equivalently on verbal subtests, offering evidence against an underlying verbal deficit. As compared to low-alexithymics, high-alexithymics demonstrated a deficit for a pair of visual subtests that involved remembering pictures of people in social situations. However, working memory represented an unexpected strength for high-alexithymics both within and between groups. Implications and ideas for future research are discussed.

The effect of 5-HT1A agonists and NMDA antagonists in Parkinson’s Disease and Dyskinesia in a Unilateral 6-OHDA Rat Model

Basil Ferenczi (Neuroscience)

Advisor: John Kelsey

Parkinson’s disease (PD) is the result of a lack of dopamine (DA) in the striatum. Treatment of PD with DA agonists such as apomorphine and L-DOPA often leads to dyskinetic motor complications caused by raising DA levels in the striatum too highly. However, there are two classes of drugs, serotonin (5-HT1A) agonists and glutamate (NMDA) antagonists that appear to ameliorate both symptoms. In Experiment 1, it was found that 0.2 mg/kg (but not others) of the 5HT1A agonist 8-OH-DPAT produced an 8.3% increase in contralateral forepaw stepping in rats with unilateral 6-OHDA lesions of the medial forebrain bundle, whereas 8 mg/kg L-DOPA improved forepaw stepping by 29.4%. In Experiment 2, 2 weeks of daily 0.05 mg/kg injections of the D2/D3 agonist apomorphine, sufficient to produce dyskinesia in half of the rats, increased contralateral stepping by 12.2%, but decreased ipsilateral by 30.7%. In these animals, 0.2 mg/kg 8-OH-DPAT increased contralateral stepping by 4.7% and 0.2 mg/kg of the NMDA receptor antagonist MK-801 increased stepping by 13.0%, in all rats, and by 23.1% and 41.1% respectively in rats that did not demonstrate an anti-PD effect of apomorphine. 0.3 mg/kg 8-OH-DPAT and 0.1 mg/kg MK-801 did not have an effect. 0.2 mg/kg 8-OH-DPAT also reduced the apomorohine-induced dyskinesia (measured by AIMs) by 21.9%, whereas 0.2 mg/kg MK-801 reduced AIMs by 39.1%. I argue that both of these drugs act to reduce PD and dyskinesia, by decreasing striatal glutamatergic transmission. 5-HT1A agonists likely act to reduce glutamate release from corticostriatal glutamate neurons, whereas NMDA antagonists antagonize postsynaptic NMDA receptors of medium spiny GABAergic neurons.

Orbitofrontal Cortex Correlates of Trait Emotional Intelligence

Katelyn Gilardi (Psychology)

Advisor: Nancy Koven

Coping with life’s daily stressors requires a certain degree of skill in the ability to understand and regulate one’s emotions.  People who are lacking in these skills are often labeled alexithymic.  Current research implicates frontal lobe abnormality in alexithymia, but it is unclear whether this accurately accounts for brain-related patterns associated with perceived emotional intelligence at the facet level.  A recent study found correlations between trait meta-mood facets (ability to attend to, have clarity of, and repair emotions) and gray matter volumes of different regions in the frontal lobe using voxel-based morphometry, a key finding of which was the relationship between Attention to Emotion and orbitofrontal cortex (OFC) volume.  The present study used manual volumetry, a more conventional neuroimaging method, to examine the relationship between Attention to Emotion and OFC volume.  This study used structural MRI scans and Trait Meta-Mood Scale (TMMS) scores from 30 healthy adults who participated in the aforementioned  study.  This is the first known study to examine OFC correlates (left and right lateral and medial regions) of emotional intelligence using manual volumetry.  During manual tracing, considerable variation in anterior OFC volume across participants prompted inclusion of left and right anterior OFC volume as separate variables.  Results indicated that the strongest correlations were those between the left and right anterior OFC volume and Attention to Emotion.  These results are discussed in the context of functional and structural connectivity between OFC and other brain regions.

Modulation of the First Phase of Feeding Behavior of Helisoma trivolvis by Neuropeptide Phenylalanine (NPF) stimulation of Buccal A Cluster (BAC) Neurons

Quan Ho (Neuroscience)

Advisor: Nancy Kleckner

Feeding in Helisoma trivolvis is controlled by a central pattern generator (CPG) located in a pair of buccal ganglia of the central nervous system. The CPG is composed of neurons divided into three distinct subunits (S1-S2-S3) that correspond to protraction, retraction, and hyperretraction of the dentate radula, respectively. Each subunit is an independent conditional oscillator, becoming active when released from inhibition or when directly stimulated, and thus producing a cyclic feeding pattern. The feeding CPG can be modulated by a group of neurons termed the buccal A cluster (BAC) network, which can switch the normal feeding pattern from S1-S2-S3 to a S1-S2 regurgitation pattern. Aplysia neuropeptide phenylalanine (ApNPF) facilitates a gradual transition from standard feeding behavior (ingestive) to regurgitation (egestive) responses to satiation in Aplysia. The purpose of this study was to determine the effect of NPF stimulation of BAC neurons on phase 1 of the Helisoma trivolvis feeding pattern to see whether NPF causes a reconfiguration from a standard phase 1-2-3 to either phase 1-2 regurgitation or satiation. Simultaneous electrophysiological recordings were made from S1 motor neurons (MNs) and BAC neurons to characterize their interaction and connection to the CPG. Dopamine (DA) and neuropeptide phenylalaline (NPF) were perfused to evoke the BAC neurons. Targeted BAC and S1 neurons were injected with Neurobiotin and Alexa Fluor 555. Neurobiotin was visualized using Streptavidin-Alexa Fluor 488 conjugate. DA increased burst frequency in S1 MNs and increased frequency of BAC EPSPs, but did not cause them to fire. Hel-NPF evoked action potentials in type 2, 10, 12 and 16 BAC neurons but not in type 1, 8 and 13 BAC neurons. Hel-NPF enhanced burst frequency for all S1 motor neurons followed by inhibition in a limited number of B6 and B7 cells. There were little evidence to suggest a correlation between BAC activity and S1 motor neurons activity. Because of the small sample size, more research and data are required to verify these findings. This study suggests that Hel-NPF facilitates a transition to satiation through a phase resembling regurgitation in Helisoma trivolvis.

Repeated Doses of MK-801 Disrupts Reconsolidaton and Prevents Reinstatement of a Morphine Withdrawal-Induced Conditioned Place Aversion

Anna McGrath (Neuroscience)

Advisor: John Kelsey

Environmental cues that have been associated with drugs have a long lasting ability to evoke cravings in recovering addicts. In order to reduce the probability of relapse, extinction therapy has been used to disassociate the conditioned drug cues from the drug effects. While this is a useful technique it has not had tremendous clinical success because the effects of extinction are context-specific and prone to spontaneous recovery. D-cycloserine (DCS), a drug that enhances glutamate transmission and consolidation of new memories, including extinction, may reduce the probability of relapse. Other studies have shown that brief re-exposure to drug cues can return the memory induced by those cues to a labile form that reconsolidates. This reconsolidation can be disrupted by various amnesic drugs, such as propranolol or MK-801. This could be a superior treatment option to extinction, because blocking reconsolidation may erase, not just suppress, the original memory. In my first experiment, I found that DCS failed to facilitate extinction or block stress-induced reinstatement of a morphine withdrawal-induced conditioned place aversion (CPA) in rats. Subsequent attempts to block reconsolidation of the CPA using a single dose of propranolol and MK-801 were also unsuccessful. However, repeated doses of 0.2 mg/kg of the NMDA receptor antagonist MK-801 were able to partially block reconsolidation and prevent stress-induced reinstatement. Thus, repeated, brief reactivation of a well consolidated drug memory followed immediately by an amnesic agent, such as MK-801, would seem to hold promise as a means of potentially eliminating such memories.

GluR-5/6/7 and NPF like Immunoreactive (IR) Buccal A Cluster (BAC) Cells in the CNS of Pond Snail Helisoma trivolvis.

Nawshaba Nawreen (Biochemistry)

Advisor: Nancy Kleckner

Feeding in pond snail Helisoma trivolvis is under control of neuronal networks called Central Pattern Generators (CPG) capable of producing endogenous rhythmic activity to control feeding behavior. A group of about 17 different neurons called the Buccal A Cluster or ?BACs? play a crucial role in modulating such neuronal network in H.trivolvis. Neurons within the BAC cluster are thought be involved in distention induced satiation and regurgitation. Previous research using immunohistochemistry has shown that some BAC neurons express only glutamate (? -GluR5,6,7) receptors or Neuropeptide F (NPF) while some express both. So far no significant research has been done to study whether variation in immunoreactivities to BAC neurons might categorize them into unique groups which might explain their functional differences. The purpose of this thesis project was to systematically characterize the different kind of BAC neurons according to their respective immunoreactivities to NPF and GluR-5/6/7. BAC neurons were targeted by injection of Neurobiotin and then co-processed for GluR5/6/7 and NPF-like immunoreactivity. Results showed BAC neuron types 1, 4, 11 and 12 to be GluR5/6/7 IR while BAC neuron types 5, 10 and 14 were not.It was speculated that types 1,4,11 and 12 BAC cells being immunoreactive to GluR5/6/7 were under control of S2 interneuron which enabled the cells to undergo rapid modulation during regurgitation. Non GluR5/6/7 IR BAC types 5, 10 and 14 were speculated to play a role in satiation. The experimental findings of this study provide the first step towards understanding the mechanism of regulation of BAC neurons to modulate the CPG, and how glutamate and NPF might play a role in such feeding modulation. Further studies need to be done to establish a conclusive relationship between BAC neuron types and their respective functions.

Acute and Chronic Doses of Nicotine Increase Impulsive Responding in Rats

Anzela Niraula (Neuroscience)

Advisor: John Kelsey

Although cigarette smokers have been found to exhibit heightened impulsivity, whether increased impulsivity is a cause or consequence of nicotine abuse is unclear. Previous research on rats shows that highly -impulsive rats are more likely to self-administer nicotine, compared to their less impulsive counterparts. The present study employed a delay-discounting procedure to investigate whether acute and chronic nicotine increases impulsive responding. Rats were presented with two levers, one of which delivered an immediate water reward with a probability of 0.5 (probability lever), while the other lever delivered the same magnitude of reward with 100% certainty but at five varying delays (delay lever). In two separate experiments, acute injections of 1.2 mg/kg nicotine decreased the preference for the delayed reward lever at intermediate delays, while acute doses of 0.4 and 0.8 mg/kg had smaller effects. Similarly, in both experiments, twelve twice daily injections of 0.8 mg/kg nicotine progressively decreased the preference for the delayed reward lever across days. Although these findings are consistent with the hypothesis that nicotine increases impulsivity by increasing delay discounting, it is also possible that nicotine increases probability discounting. In either event, these data indicate that both acute and chronic nicotine may help maintain addiction to nicotine by increasing impulsivity.

Signal Transduction Mechanisms of Glutamate Mediated Inhibition of Phase 3 Motor Neurons in the Pond Snail, Helisoma trivolvis.

Dorian Tolis (Neuroscience)

Advisor: Nancy Kleckner

Glutamate is an important regulatory neurotransmitter in the triphasic feeding behavior in the pond snail, Helisoma trivolvis.  It excites phase two motor neurons while inhibiting those in phases one and three.  The receptors that mediate this regulation are only partially characterized.  One possible mechanism that has been proposed is that glutamate acts directly on motor neuron B19 to activate an inwardly rectifying potassium channel (Kir), possibly a GIRK subtype.  Using single and dual channel recordings from neurons involved in the swallowing phase of feeding, the purpose of this study was to determine the signal transduction mechanisms used by glutamate to inhibit the activity of these neurons.  This was done using a pharmacological approach with intracellular recordings and the perfusion of whole-ganglia preparation with metabotropic glutamate (mGluR) agonists and antagonists that are selective for different glutamate receptor subtypes, as well as ion channel blockers.  Quisqualate application (10 ?M) was sufficient to produce hyperpolarization in B19.  BaCl2 and CsCl, known inhibitors of Kir channels, did not block quisqualate-induced hyperpolarization at concentrations of 100 ?M, 300 ?M, and 1 mM in B19.  Kir subtype GIRK 1/4 blocker tertiapin-Q did not block quisqualate-induced hyperpolarization of B19, nor did it block phase-2 inhibition of B19.  Application of quisqualate produced a decrease in the highly concentrated rhythmic firing of B27, while application of DCG-IV, a mGluRII agonist, produced an increase in action potential frequency in B27.  In B19, DCG-IV produced a significant increase in burst rate and a near significant decrease in action potential frequency.  Future research using isolated neurons, as well as mGluRII agonists and antagonist is needed to further characterize the mGluR pharmacology responsible for S2-mediated inhibition of S3 motor neurons.

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