Chronic or repeated exposure to stressful stimuli can result in several maladaptive consequences, including increased anxiety-like behaviors and altered peptide expression in brain structures involved in emotion. Among these structures, the bed nucleus of the stria terminalis (BNST) has been implicated in emotional behaviors as well as regulation of hypothalamic-pituitary-adrenal (HPA) axis activity. In rodents, chronic variate stress (CVS) has been shown to increase BNST pituitary adenylate cyclase activating polypeptide (PACAP) and its cognate PAC1 receptor transcript, and BNST PACAP signaling may mediate the maladaptive changes associated with chronic stress. In order to determine whether chronic stress would potentiate the behavioral and/or endocrine response to subthreshold BNST PACAP infusion, rats were exposed to a 7 day CVS paradigm previously shown to upregulate BNST PAC1 receptor transcripts; control rats were not stressed. Twenty-four hours following the last stressor, stressed and control rats were bilaterally infused into the BNST with 0.5 µg PACAP. Startle response to intra-BNST PACAP infusion was assessed post-infusion in Experiment 1. In Experiments 2 and 3, blood was sampled via a tail nick 30 min following PACAP infusion to assess the corticosterone response to PACAP following CVS. We found an increase in startle amplitude and an increase in plasma corticosterone levels 30 minutes following BNST PACAP infusion only in rats that had been previously exposed to CVS. These results were likely mediated via PAC1 receptors, as equimolar infusion of the VPAC1/2 receptor ligand vasoactive intestinal polypeptide (VIP) had no effect on plasma corticosterone levels. These results suggest that repeated exposure to stressors sensitizes the neural circuits underlying the behavioral and endocrine responses to BNST PACAP infusion and BNST PACAP/PAC1 receptor signaling likely plays a critical role in mediating stress responses.

Millions of people suffer from tinnitus, a disorder for which there is currently no effective treatment or cure. My dissertation work provides insight into the neural correlates of this pervasive hearing disorder and examines how a newly emerging therapy, transcranial magnetic stimulation (TMS), affects the central auditory system in the generation of the tinnitus percept. This work has a multifold focus of: i) developing and modeling the function of a miniature magnetic coil that can be used for TMS in rodents, ii) establishing a reliable mouse model of tinnitus that can be used for assessing TMS treatment-induced changes, iii) measuring the behavioral alterations and neural changes induced by TMS throughout the auditory system in mice with tinnitus, and iv) to assay underling molecular changes in the auditory cortex (AC) related to TMS and tinnitus. Chapter 1 gives an overview of the current research on tinnitus and TMS. Chapter 2 establishes a reliable neural and behavioral assay of verifying tinnitus in a mouse model and provides further evidence that the underlying hyperactivity associated with tinnitus is initiated in the brainstem following reduced afferent input. The remainder of the dissertation examines the modulation of tinnitus in the auditory central nervous system using a miniature TMS coil. Chapter 3 of the dissertation details the creation and evaluation of a rodent-sized TMS coil, which could increase the overall effectiveness and applicability for human treatment. TMS is currently an FDA approved treatment of depression and has been shown to decrease tinnitus perception in human clinical trials, albeit with variable results. There have been few published studies of tinnitus modulation by TMS using animal models and therefore little is known about the molecular and neural bases of this potential tinnitus treatment. TMS is thought to be therapeutic because the magnetic flux generated from the electromagnetic coil induces an electric field in the brain, altering ion flow and subsequently neural function, as the excitation and inhibition of cortical networks become synchronized to the magnetic pulse. Chapter 4 demonstrates that TMS with our custom-designed miniature rodent coil can successfully reduce behavioral evidence of tinnitus in a mouse model, mainly through activating inhibitory networks in the AC. It also shows that presynaptic activity is altered in the upper layers of the AC responsible for intralaminar processing and sound perception. Finally, chapter 5 describes an in-depth proteomic analysis of over 3000 proteins from the AC, which shows that TMS and noise-induced tinnitus alter the expression of several key proteins and pathways that play a critical role in cortical excitatory and inhibitory activation. The results of this work are also important because they are the first animal model to demonstrate neural changes during TMS-treated tinnitus, creating a paradigm that can be used for optimizing parameters to improve clinical outcomes in human trials.

Eleven experiments examined two late-developing learning and memory systems in rats: fear-potentiated startle (FPS) and the contextual regulation of latent inhibition and extinction. The first study was based on three previous developmental findings on FPS: (1) FPS to an odour CS emerges at postnatal day (PN) 23; Rats conditioned at PN16 to an odour CS express freezing but not FPS when tested at PN23, and (3) FPS to an odour CS trained at PN16 is activated if rats are also trained to a difference odour at PN23 (Yap, Stapinski, & Richardson, 2005). Yap et al. (2005) hypothesised that the activation effect only occurs if rats are given training to the second odour at an age when FPS has emerged. Study 1 assessed this hypothesis and trained the second odour CS at either PN23 or PN20. Contrary to expectations, the results of this study showed the activation effect for both groups of rats. Surprisingly, the results also revealed a significant FPS effect to the odour CS trained at PN20. Subsequent experiments examined this unexpected result, and found that learning to odour 1 at PN16 facilitated the age of onset for FPS at PN20. The results of Study 1 are discussed in relation to past findings on enrichment, cumulative learning, and neurobiological models of conditioned fear. The second section of this thesis (Studies 2 and 3) examined the context-specificity of two memory interference paradigms, latent inhibition and extinction, in developing rats. The studies found that both phenomena were context-specific at PN23-25 but not at PN16-18. Moreover, the results suggest that the context-specificity of both latent inhibition depended on the age of the rat during the second phase of training, but not their age during the first phase of training or their age at test. The implications of these findings for theoretical and neural models of learning, as well as the occurrence of latent inhibition and extinction during development are discussed.

Research has shown alcohol expectancies to be critically important in understanding maladaptive drinking patterns within alcohol use disorders. Alcohol expectancies, thought to be automatically elicited in the presence of environmental alcohol-related cues, represent both cognitive and affective associations with drinking behavior. However, the automatic and affective properties of alcohol expectancies have not yet been thoroughly measured in the literature. Psychophysiological measures, including skin conductance, heart rate, and the acoustic startle response in particular, offer a uniquely powerful set of indices for the automatic affective processing of alcohol-related cues. Therefore, the present study was designed to examine how alcohol expectancies moderate affective processing of alcohol cues and how they relate to other known risk variables for alcohol use disorders.Fifty-eight college-aged participants viewed pictures from three categories (neutral, alcohol-nonsocial, and alcohol-social) and gave subjective ratings of valence, arousal, dominance, and craving for each cue. Skin conductance, heart rate and startle responses were obtained during picture viewing. The startle eyeblink reflex was probed early in the picture viewing sequence to assess arousing and attentional cue properties and late in order to address affective and motivational cue properties.Analyses indicated that participants reporting more positive, arousing, and social alcohol expectancies rated alcohol cues as more pleasant, arousing and craving-inducing. Individuals with greater positive/arousing alcohol expectancies displayed blunted cardiac deceleration during alcohol-related cues, indicating that they processed these cues as less aversive than other participants. In addition, individuals with greater social alcohol expectancies displayed greater skin conductance response to alcohol-related cues, indicating increased arousal during alcohol pictures. Startle response patterns indicated that individuals at greater risk for alcohol use disorders (i.e. family history positive, greater positive/arousing alcohol expectancies) displayed blunted processing of alcohol-related cues, while individuals at lower risk processed alcohol-related cues as more pleasing and attention-grabbing. Ultimately, alcohol-related cues were processed as more pleasing and appetitive among lower-risk individuals, lending support to affective and automatic processing component of alcohol expectancy theory. This study also lends further evidence to support blunted affective processing of alcohol-related stimuli among high risk individuals.

Originally developed as an anti-depressant and later available as a ‘party-pill’ in New Zealand, methylone is currently classed as an illegal drug. This is due to findings of its similarity in chemical structure to that of Ecstasy (MDMA). Methylone is a relatively new drug into which little research has been conducted. Consequently, no known study has investigated the long-term effects on behavioural development arising from exposure during adolescence. The present thesis therefore aimed to identify long-term effects of chronic adolescent exposure to methylone on adult anxiety-like behaviours. This was achieved by the use of 80 rats (40 males: 40 females) and exposing them to either a methylone or saline treatment for ten consecutive days. Two different treatment age groups (early versus late adolescence) were examined and to ensure adequate comparisons could be made, two control groups were utilised. All rats were tested during adulthood in four specifically selected anxiety-measure tests; the open-field, preference for the light side of a light-dark box, acoustic startle and responsiveness to the novel arm of a Y-maze. The results suggested methylone-exposed rats displayed more anxiolytic behaviours than saline-treated rats. In the open field methylone exposed rats exhibited less ambulation than controls and those treated in early adolescence defecated more while rats treated in late adolescence occupied the corners of the apparatus more exhibiting higher anxiety-like behaviours. Exploratory behaviours in the Y-maze were decreased in methylone-treated rats, and those exposed in early adolescence entered the novel arm less often. However, acoustic startle results suggested methylone-exposed rats were less anxious as evidenced by a lower startle amplitude than controls. Overall, the results suggested differences in anxiety-like behaviours between methylone-exposed rats and controls. It did not appear that being exposed to methylone in early adolescence resulted in vast differences in anxiety-like behaviours than if exposure began in late adolescence.

N-methyl-D-asparate (NMDA) receptors located within the basolateral complex of the amygdala are required for the consolidation and expression of Pavlovian conditioned fear. The events downstream of receptor activation that mediate these processes are not well defined. An intermediate step that may be of significance is the synthesis of the gas nitric oxide (NO). Nitric oxide is synthesised as a result of NMDA receptor activation and acts as an unconventional neurotransmitter freely diffusing across cell membranes interacting with its targets in a non-synaptic manner. The targets of NO include cellular components that play significant roles during the consolidation of conditioned fear and the neurotransmission associated with its expression. This implies that NO may be an important intermediary of NMDA receptor activation and both these processes. The current study sought to examine this possibility using fear potentiated startle to examine the expression of learned fear. Three experiments were conducted, fifty rats received intra-BSC microinfusions of the global nitric oxide synthase inhibitor L-NAME either prior to fear conditioning, fear testing, or examination of the shock sensitization of the acoustic startle affect. The results indicated that NO was indeed required for both the consolidation and expression of learned fear, whereas it was not required for shock enhanced startle responding. This study provides new information about the sub-cellular basis of conditioned fear, and highlights the pivotal role played by NO in processes associated with conditioned fear.

Thesis (Ph.D. in Human Medical Genetics) -- University of Colorado Denver, 2007. / Typescript. Includes bibliographical references (leaves 141-157). Free to UCD affiliates. Online version available via ProQuest Digital Dissertations;

Thesis (Ph.D.)--Uniformed Services University of the Health Sciences, 2006 / Typescript (photocopy)

abstract: Recently, it was demonstrated that startle-evoked-movements (SEMs) are present during individuated finger movements (index finger abduction), but only following intense training. This demonstrates that changes in motor planning, which occur through training (motor learning - a characteristic which can provide researchers and clinicians with information about overall rehabilitative effectiveness), can be analyzed with SEM. The objective here was to determine if SEM is a sensitive enough tool for differentiating expertise (task solidification) in a common everyday task (typing). If proven to be true, SEM may then be useful during rehabilitation for time-stamping when task-specific expertise has occurred, and possibly even when the sufficient dosage of motor training (although not tested here) has been delivered following impairment. It was hypothesized that SEM would be present for all fingers of an expert population, but no fingers of a non-expert population. A total of 9 expert (75.2 ± 9.8 WPM) and 8 non-expert typists, (41.6 ± 8.2 WPM) with right handed dominance and with no previous neurological or current upper extremity impairment were evaluated. SEM was robustly present (all p < 0.05) in all fingers of the experts (except the middle) and absent in all fingers of non-experts except the little (although less robust). Taken together, these results indicate that SEM is a measurable behavioral indicator of motor learning and that it is sensitive to task expertise, opening it for potential clinical utility. / Dissertation/Thesis / Masters Thesis Biomedical Engineering 2018

abstract: Stroke is a debilitating disorder and 75% of individuals with stroke (iwS) have upper extremity deficits. IwS are prescribed therapies to enhance upper-extremity mobility, but current most effective therapies have minimum requirements that the individuals with severe impairment do not meet. Thus, there is a need to enhance the therapies. Recent studies have shown that StartReact -the involuntary release of a planned movement, triggered by a startling stimulus (e.g., loud sound)- elicits faster and larger muscle activation in iwS compared to voluntary-initiated movement. However, StartReact has been only cursorily studied to date and there are some gaps in the StartReact knowledge. Previous studies have only evaluated StartReact on single-jointed movements in iwS, ignoring more functional tasks. IwS usually have abnormal flexor activity during extension tasks and abnormal muscle synergy especially during multi-jointed tasks; therefore, it is unknown 1) if more complex multi-jointed reach movements are susceptible to StartReact, and 2) if StartReact multi-jointed movements will be enhanced in the same way as single-jointed movements in iwS. In addition, previous studies showed that individuals with severe stroke, especially those with higher spasticity, experienced higher abnormal flexor muscle activation during StartReact trials. However, there is no study evaluating the impact of this elevated abnormal flexor activity on movement, muscle activation and muscle synergy alterations during voluntary-initiated movements after exposure to StartReact. This dissertation evaluates StartReact and the voluntary trials before and after exposure to StartReact during a point-to-point multi-jointed reach task to three different targets covering a large workspace. The results show that multi-jointed reach tasks are susceptible to StartReact in iwS and the distance, muscle and movement onset speed, and muscle activations percentages and amplitude increase during StartReact trials. In addition, the distance, accuracy, muscle and movement onsets speeds, and muscle synergy similarity indices to the norm synergies increase during the voluntary-initiated trials after exposure to StartReact. Overall, this dissertation shows that exposure to StartReact did not impair voluntary-initiated movement and muscle synergy, but even improved them. Therefore, this study suggests that StartReact is safe for more investigations in training studies and therapy. / Dissertation/Thesis / Doctoral Dissertation Mechanical Engineering 2020