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Early life adversity (ELA) produces long lasting developmental changes to the postnatal brain, increasing predisposition to a number of physical and psychiatric disorders. The mechanisms through which ELA is able to create lasting detrimental changes to neuronal development remains unclear. This thesis tested the hypothesis that increases in fear generalization, a common symptom in psychiatric disorders, follows ELA exposure in age dependent and sexually dimorphic ways in alignment with the findings of clinical studies. The effects of ELA often impact fear circuitry and we confirmed, using electrophysiology and tissue imaging, that 5-HT circuitry from the median raphe nucleus (MRN), integral to fear response, was impaired following ELA. Using a transgenic mouse model that allows for modulation of serotonergic release, we showed that circumventing serotonergic pathways disrupted by ELA and increasing whole brain 5-HT release was enough to rescue hippocampal dependent fear responses and fear generalization. Involvement of the hippocampus in ELA effects, particularly the ventral dentate gyrus (vDG), in fear overgeneralization was confirmed as hyperactivity in thevDG following exposure to novel contexts was rescued by increased 5-HT release. In addition to ELA-induced hyperactivity of the vDG, known to potentiate stress susceptibility, I demonstrated that ELA resulted in an increase in passive coping strategies, HPA axis dysfunction and elevated stress hormone release. These effects were seen predominantly in adult females and rescued in those with increased 5-HT release. Together these data suggest that increased predisposition to psychiatric disorders following ELA exposure involves the disruption of fear circuitry regulated by 5-HT activity. Identifying the underlying circuits altered by ELA not only provides insight about disrupted postnatal brain development, but also increases our knowledge of the timeline, trajectory and factors affecting healthy postnatal brain development.

Experiencing early life adversity (ELA) increases the risk of anxiety disorders, such as generalized anxiety disorder and post-traumatic stress disorder, with disproportionally higher risk in women compared to men. Neurodevelopmental and behavioral outcomes following ELA are multifaceted and are influenced heavily by the type of adversity experienced and sex of the individual. A major contributor to emotional dysfunction and anxiety disorders resulting from ELA are changes in fear and threat circuitry. Children who experienced ELA have been reported to show an accelerated development of the amygdala, a region involved in processing threat, and greater cerebrospinal levels of corticotrophin releasing hormone (Crh), an orchestrator of neuroendocrine and behavioral responses to stress. Work in rodents have linked Crh signaling within the lateral central amygdala (CeAL) with processing and responding to threat, core features disrupted in anxiety-related disorders. Further, sex biases in risk and symptom presentation have been proposed to be related to sexual dimorphic signaling of Crh across the brain that differentially influence a variety of Crh-dependent behaviors. However, it remains unclear what properties of ELA portend differential neurobiological risk, what is the basis of sex-differences for negative outcomes, and how specific mechanistic changes give rise to certain endophenotypes. In this work, I use genetic, cellular, and behavioral approaches to explore the impact of ELA and sex on perinatal development in mice and the functional consequences of altered Crh neuron activity in the CeAL on threat responding in adulthood. In Chapter 1, I review how factors such as sex and type of ELA influence amygdala development and Crh. In Chapter 2, I assess the impact of two forms of ELA, maternal separation (MS) and limited bedding and nesting (LBN) on perinatal development and anxiety-like behavior. Both forms of ELA shifted the timing of somatic maturation and basal CORT levels and led to increased anxiety-like behaviors, but the degree of the impact depended on the sex and type of adversity experienced. In Chapter 3, I demonstrate that a distinguishing feature between types of ELA was the predictability of maternal care. The type of ELA also contributed to sex-differences in Crh related gene expression in the perinatal amygdala. Increased expression was primarily observed in males following MS and in females following LBN. In Chapter 4, I investigate the functional consequences of ELA in the form of LBN on the activity of CeALCrh+ neurons in vivo and their causal role in threat reactivity indexed by the startle response. LBN rearing led to sustained activity of CeALCrh+ in female mice but diminished in male mice. Persistent activity of this population was necessary for and predicted the magnitude of startle responding. In Chapter 5, I discuss important considerations when integrating new advancements in the study of ELA and the use of sex as a biological variable. Collectively, this work deepens our understanding of the neurobiological mechanisms impacted by sex and ELA and holds promise for future strategies that may consider the sex and specific experiences of the individual to target specific endophenotypes and address the underlying root causes of anxiety disorders.

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Neonatal administration of quinpirole produces significant increases in D2 receptor sensitivity that persists into adulthood. This phenomenon, known as D2 receptor priming, is consistent with pathology in schizophrenia. Rats were administered quinpirole or saline postnatally and raised to adulthood. In adulthood, rats were administered d-amphetamine sulfate or saline every other day and were placed in a locomotor arena where activity was measured over 7 trials. Results showed that D2-primed rats receiving amphetamine were higher in locomotor activity across all days of testing compared to other groups. This effect was more prominent in males than in females. After sensitization, cerebrospinal fluid was taken via microdialysis from the nucleus accumbens core and was analyzed for dopamine content. Analysis revealed D2 priming produced a 300% increase of dopamine release in the nucleus accumbens core in response to amphetamine compared to controls. These results suggest that increases in D2 sensitivity may lead to increased reaction to amphetamine in psychotic individuals.

The synthetic cathinones, 3,4- methylenedioxypyrovalerone (MDPV), 4-methylmethcathinone (mephedrone), and 3,4- methylenedioxymethcathinone (methylone), gained worldwide notoriety as the psychoactive components of ‘bath salts;’ a marketing term used to circumvent federal drug laws and permit their legal sale. Previous studies have shown that these drugs share pharmacological characteristics with cocaine and the amphetamines, however, descriptions of their neurotoxic properties are limited. Moreover, while forensic analysis has revealed that the most frequently abused bath salts ‘brands’ contain binary and ternary mixtures of MDPV, mephedrone, and methylone, the majority of preclinical research has focused on explicating the individual effects of these drugs. Therefore, the present dissertation aimed to address this limitation and characterize the acute and chronic effects of combined synthetic cathinone exposure on dopaminergic tone in mesolimbic and nigrostriatal brain regions. To accomplish this, male Swiss-Webster mice were administered MDPV, mephedrone, and methylone, individually or concomitantly, 1 time or 7 times over the course of two weeks and the corresponding effects of each treatment on mesolimbic and nigrostriatal brain tissue levels of dopamine (DA) and DA metabolites were analyzed using a high performance liquid chromatography – electrochemical detection (HPLC-ECD) assay. Additionally, motor-stimulant activity was evaluated after both dosing regimens using locomotor activity assays, while immunoblot and immunostaining techniques were used to evaluate the chronic effects of co-synthetic cathinone exposure on tissue levels of tyrosine hydroxylase (TH), dopamine transporter (DAT), monoamine oxidase B (MAO-B), catechol-O-methyltransferase (COMT), and glial fibrillary acidic protein (GFAP). Results from these studies provide evidence of a significant pharmacological interaction among major bath salt constituents, MDPV, mephedrone, and methylone. This was observed acutely as enhanced DA responses and chronically as functional toxicity at the DA synapse. Furthermore, such interactions may contribute to the deleterious effects reported by bath salt users. Together, these findings have shown that the composition of bath salts preparations can significantly influence their psychostimulant and toxic effects, substantiating the importance of modeling bath salts as drug mixtures.

Quantifying individual differences in behavior and the extent that behavior is influenced by circadian control is of paramount importance in behavioral ecology. In addition, the proximate mechanisms underlying behavior are also critical in order to obtain a more complete picture of how behavior evolves. Biogenic amines (BAs) are simple nitrogenous compounds derived from amino acids and have been consistently and extensively linked to behavior. For this study, we analyzed temporal patterns of BAs in relation to the antipredator (boldness) and aggressive behavior in female Agelenopsis pennsylvanica, a funnel-web spider. Using HPLC-ED, we compared behavioral responses to temporal patterns of octopamine and serotonin, two BAs known to influence behavior in invertebrates. Our results suggest that, while there was a clear diel cycling pattern of both aggression and boldness, BAs do not follow this same pattern, suggesting that oscillations in absolute levels of BAs are not the underpinnings of behavioral oscillations.

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