<p> Behavioral sensitization is an increase in a behavioral response (e.g., locomotor activity or stereotypy) induced by previous drug exposure. The present study examined one-trial methamphetamine behavioral sensitization in male and female rats during early or late adolescence. During pretreatment, male and female rats received methamphetamine (0.0&ndash;6.0 mg/kg) in the home or in a novel chamber during early (PD 38) or late (PD 48) adolescence. After 24 hours, rats received a 1 mg/kg methamphetamine challenge test dose in the novel chamber to assess for sensitization. The results showed that rats in both age groups exhibited robust locomotor activity to the acute effects of methamphetamine. However, male and female rats at either age group did not exhibit one-trial methamphetamine behavioral sensitization. Overall, females exhibited greater locomotor activity than males, while males exhibited greater stereotypy. These findings do not provide evidence that the ontogeny of one-trial methamphetamine sensitization emerges during adolescence.</p>

<p>An interesting unsolved case in cognitive science, and one that impacts education and decision-making, is the whole number bias: when people compare fractions they rely on the numerical values of the components (numerator or denominator). A handful of theories have been proposed to explain the bias in Arabic formats, all sharing the assumption of some fundamental difficulty in estimating ratio magnitudes. This thesis contrasts them in a perceptual setting by means of a cognitive model of ratio comparisons. Contrary to the assumption, for the visual system the bias is automatic even when fraction magnitudes are mentally available (Chapter 2a). Moreover, it is present in indigenous populations living in the Amazon, suggesting a limited role of culture and a more generic feature of cognition (Chapter 2b). The automatic activation of numerical magnitude can impact confidence (Chapter 2c), visual selection (Chapter 3) and modulate how the motor system displaces effectors (Chapter 4). The overall results are consistent with the view that the whole number bias is part of a larger phenomenon: people spontaneously and robustly represent numerical value across a variety of perceptual decision tasks.

Cocaine abuse and addiction are widespread problems with profound medical and socioeconomic consequences. At present, the neurobiological adaptations associated with short- and long-term cocaine abuse are not well understood, which contributes to the lack of availability of broadly effective treatments for this type of addiction. Recently, some studies have implicated GABAA receptor subtypes in the neuroadaptations underlying addiction. To explore the contributions of GABAA receptors to the neurobiological basis of cocaine abuse, we utilized a non-human primate model of cocaine self-administration and examined changes in species typical behaviors, and corresponding alterations in three GABAA receptor subtypes within five reward-related areas of the brain. Sixteen rhesus monkeys either self-administered cocaine intravenously (1-hr/day, 0.03 mg/kg/injection of cocaine) or received passive infusions of saline yoked to the cocaine injections (yoked control). Monkeys either self-administered cocaine for ~10 days (short-term group) or ~100 days (long-term group). Twenty-four hours after the last session, animals were sacrificed and brains were removed. We examined alterations in &agr;1, &agr;2, and &agr;3 subunit-containing GABAA receptors (&agr;1, &agr;2, and &agr;3GABAA receptors) using immunohistochemistry (IHC), in situ hybridization (ISH), and real-time PCR experiments (RTPCR) within reward-related areas of the brain including the nucleus accumbens, ventral tegmental area, caudate, putamen, and anterior cingulate cortex. Long-term cocaine taking animals self-administered cocaine in a cyclical pattern, and increased number of cocaine injections taken within the initial portion of daily self-administration sessions. We observed behavioral alterations in behaviors including locomotor, stereotypic, scratching and affiliative behaviors. IHC results demonstrated alterations in &agr;1GABAA receptors within all regions of interest after long-term self-administration. After short-term cocaine self-administration decreases in &agr;3GABAA receptors were observed in all regions examined. When examining transcript levels using ISH and RTPCR, we found relatively few changes in comparison to protein alterations. The notable change was a decrease of all three receptor mRNAs within the anterior cingulate cortex after short-term cocaine exposure. The present model of drug may expand our understanding of addiction-related behaviors and the role of GABA in addiction. Furthermore, our findings suggest GABAA receptors may serve as viable targets for pharmacotherapeutic approaches to treat addiction.

This thesis research was designed to study the role of glucocorticoids in the central regulation of aggressive, submissive, and communicative behavior in male golden hamsters (Mesocricetus auratus). It represents the first time that site-, context-, dose-, and steroid-specific actions of glucocorticoids in behavioral regulation have been systematically examined within the central nervous system. Chronic implants of cortisol exerted site-specific and context-dependent effects on agonistic responding within the hypothalamus. In paired encounters with aggressive opponents, submissive responding was induced by cortisol implants in the medial preoptic area, anterior hypothalamus, and ventromedial hypothalamus; aggressive responding by implants in the paraventricular nucleus and third ventricle. Cortisol implants in the anterior hypothalamus induced submissive responding in paired encounters with aggressive opponents, aggressive responding in paired encounters with submissive opponents, and aggressive responding in territorial aggression tests with juvenile intruders. Acute microinjections of cortisol in the anterior hypothalamus exerted dose-dependent and steroid-specific effects on agonistic responding. High (10$\sp{-2}$M) doses of cortisol induced submissive responding; low (10$\sp{-6}$M) doses induced aggressive responding. The direction of these biphasic effects were unique to cortisol. High doses of deoxycorticosterone induced aggressive responding, while both high and low doses of testosterone, dihydrotestosterone, progesterone and estradiol had no effect. Low doses of deoxycorticosterone also had no effect. Acute peripheral administration of cortisol induced aggressive responding, as did chronic administration of the glucocorticoid synthesis inhibitor cyanoketone. In contrast, central and peripheral administration of the antiglucocorticoid RU486, had significant site- and dose-dependent effects hypothalamic-pituitary-adrenal axis function, but no effect on agonistic responding. In all cases, the effects of cortisol on flank marking behavior appeared to relate more to the social status of the cortisol-treated animal than a direct effect on the neural substrates of flank marking. Dominant animals flank marked at higher, and subordinate animals at lower levels than their opponents. In conclusion, glucocorticoids are prepotent modulators of agonistic responding within the medial hypothalamus. Both acute and chronic neuroendocrine regulation of agonistic responding by adrenal steroids appear to serve the function of promoting adaptive behavioral responses that minimize the risk of serious injury during competitive interactions.

<p> The ability to flexibly control or inhibit unwanted actions is critical for everyday behavior. Lack of this capacity is characteristic of numerous psychiatric diseases including attention deficit hyperactivity disorder (ADHD). My project is designed to study the neural underpinnings of response inhibition and to what extent these mechanisms are disrupted in animals with impaired impulse control. I therefore recorded single neurons from dorsal striatum, orbitofrontal cortex, and medial prefrontal cortex from rats performing a novel rodent variant of the classic "stop signal" task used in clinical settings. This task asks motivated rats to repeatedly produce simple actions to obtain rewards while needing to semi-occasionally inhibit an already initiated response. To take this a step further, I compared normal rats to rats prenatally exposed to nicotine in order to better understand the mechanism underlying inhibitory control. Rats exposed to nicotine before birth show abnormal attention, poor inhibitory control, and brain deficits consistent with impairments seen in humans prenatally exposed to nicotine and those with ADHD.</p><p> I found that dorsal striatum neurons tend to encode the direction of a response and the motor refinement necessary to guide behaviors within the task rather than playing a causal role in response inhibition. However the orbitofrontal cortex, a direct afferent of dorsal striatum, possesses the capacity to inform the striatum of the correct action during response inhibition within the critical time window required to flexibly alter an initiated movement. On the other hand, medial prefrontal cortex functions as a conflict &ldquo;monitor&rdquo; to broadly increase preparedness for flexible response inhibition by aggregating current and past conflict history. Lastly, rat pups exposed to nicotine during gestation exhibit faster movement speeds and reduced capacity for inhibitory behavior. Physiologically, prenatal nicotine exposure manifests in a hypoactive prefrontal cortex, diminished encoding of task parameters, and reduced capacity to maintain conflict information.</p>

<p> Basal forebrain corticopetal cholinergic neurons are critical for contextual and cued fear memory in the conditioned suppression paradigm, but neural mechanisms that alter these neurons in fear memory remain unknown. Interestingly, basal forebrain cholinergic lesions have no effect on behavioral performance in commonly-studied fear conditioning paradigms like Pavlovian conditioned freezing or fear-potentiated startle, yet impair fear memory in the conditioned suppression paradigm. Many studies conducted have experimented with lesions of cell bodies of corticopetal cholinergic neurons in the nucleus basalis magnocellularis (NBM), but there is a void in the literature defining which specific projections may be responsible for their discrepant role in different fear memory paradigms. The basal forebrain projects to the anterior cingulate cortex (ACC), a subregion of the medial prefrontal cortex. The ACC is a well-established portion of the fear circuit across all fear conditioning paradigms and has a clear role in decision-making in the conditioned suppression paradigm. Given the role in choice conflict that the ACC plays in operant tasks involved in the conditioned suppression paradigm, it is plausible that it may be a region that allows basal forebrain cholinergic neurons to alter a fear memory in the conditioned suppression paradigm. The goal of this study is to examine the specific roles that basal forebrain cholinergic projections to the ACC play in fear memory, specifically in the conditioned suppression paradigm. These lesions may target specific cholinergic input to the ACC from the NBM in the basal forebrain and this may isolate a specific fear circuit involved in fear memory in the conditioned suppression paradigm. Data have suggested that ACC lesioned animals demonstrate less fear-conditioned suppression over sham animals, but further experiments and cohorts of animals are required. If ACC cholinergic lesions are shown to produce deficits in fear memory in the conditioned suppression paradigm, it may suggest that the presence of the appetitive task, which only occurs in the conditioned suppression paradigm and not in any of the other commonly studied fear paradigms, may be able to elicit changes in functional connectivity to incorporate this projection from the NBM to the ACC to the fear circuit. Discrepancies in fear memory between fear conditioning paradigms demand to be addressed because assumptions about functional connectivity across different paradigms are assumed to be similar in the literature. If the notion of paradigmdependent functional connectivity presented here is true, deductions about this functional connectivity may only be made in the context of one fear paradigm and may not necessarily be applicable across paradigms. In other words, to say that Pavlovian fear conditioning and fear-potentiated startle are indicative of the broad neurobiology of fear memory would only be looking at a fraction of the reality behind how fear circuitry operates. In order to further the literature to propose holistic circuits, molecular processes and constructs that apply to all fear memory regardless of protocol or paradigm, it is necessary to investigate neural involvement across alternative fear paradigms, like conditioned suppression. This study supports the novel idea that neural circuitry that supports fear can expand with new learning tasks or events and therefore, may be more susceptible to change than previously considered, but future studies are required</p><p>

Excitation and inhibition in the nervous system must be carefully balanced. I utilized the zebrafish (Danio rerio) in order to study this balance in the vertebrate motor system. Zebrafish (Danio rerio) can be used effectively for both forward and reverse genetics. My primary interest lies in genes involved in neural network development and function. Forward genetic mutagenesis screens are particularly powerful as they are unbiased. Using this approach we characterized a mutant based on its abnormal motor behavior. However, mutants identified with abnormal motor behavior may have mutations in muscle proteins. We identified a semi-dominant mutation in the atp2a1 gene, which encodes a protein vital for normal muscle function, from a previously completed mutagenesis screen. In order to investigate genes directly involved in neuronal signaling I used a reverse genetics approach to study GABAA receptors. γ-Aminobutyric acid (GABA) is a major source of inhibition in the motor system. In order to test the effect of blockade of GABAA receptors, I injected gabazine, a GABAA receptor antagonist, into zebrafish embryos. Injected embryos display an abnormal escape response later in development. To determine the GABAA receptor subunits responsible for the observed phenotype, I utilized RNA in situ hybridization to examine the expression of the &agr; class of GABAA receptor subunits. I found that the gabra5 gene, which encodes the GABAA &agr;5 subunit, was expressed in the hindbrain of larvae. To examine the role of the &agr;5 subunit I designed anti-sense morpholinos to target the start codon of the gabra5 gene. Knockdown of the gabra5 gene caused abnormal behavior in larvae similar to that seen in gabazine injected larvae. I have characterized a novel semi-dominant atp2a1 mutant in zebrafish. This mutant completes a zebrafish model system of the human disease Brody's disease. Turning toward a reverse genetic approach I investigated the expression of several GABAA receptor &agr; subunits. I have characterized the behavior of GABAA &agr;5 subunit knockdown embryos and larvae and begun work to generate a stable knockout line. This line will be useful in exploring the function of the &agr;5 subunit and compounds that interact with it.

Purpose. Sensory feedback from the vestibular system and neck muscle stretch receptors is critical for the regulation of posture. The relationship of the head to the trunk is a major factor determining the availability and integration of sensory feedback and can be interfered with by varying head orientation. The goal of this research was to assess (1) how adopting different head-on-trunk orientations would impact postural stability, particularly in relation to the stability boundary, during static balance tasks and (2) how adopting different head-on-trunk and head-in-space orientations would impact postural stability, movement characteristics, and multi-segmental torso coordination during a dynamic postural transition task in healthy, young participants. Methods. Healthy, young participants were asked to maintain 30 seconds of upright stance and forward lean or to move from sitting to standing with extended, flexed, and neutral head orientations. Dual force plates were used to assess postural stability from center of pressure variability, range, velocity, or time-to-contact. Six motion capture cameras were used to assess kinematics. During the sit-to-stand task, head velocities, trunk flexion, and movement phase durations were calculated. Segment cross-correlation and joint range of motion were calculated for six torso segments. Results. Extended head-on-trunk orientations decreased postural stability during upright stance, forward lean, and the sit-to-stand movement compared to flexed or neutral orientations. During the sit-to-stand task, head-on-trunk extension, with or without head-in-space extension, led to reduced head velocities, trunk flexion, movement duration, and transition phase duration. Head extension led to increased inter-segmental torso motion, and decreased temporal coordination of torso segments. Conclusions. This study demonstrated that interfering with head-trunk posture by adopting head extended orientations impairs balance and leads to sit-to-stand strategy changes that may interfere with movement and coordination. Results show that head-on-trunk extension is more critical than head-in-space extension for determining postural and movement changes. The findings suggest that vestibular system interference may not be the main route through which head extension impacts postural control, but that extensor muscle stretch receptors may be a factor in the posture and movement changes associated with head-on-trunk extension. It is possible tonic neck muscle activity is a critical factor for regulating balance and movement.