Thesis advisor: John P. Christianson / The perception of others as safe or threatening informs how we respond to others in a social setting. These social affective behaviors require the detection of sensory stimuli and the appraisal of others’ affective states to orchestrate adaptive behavioral responses. This process is also informed by one’s own internal state and environment. The neural circuitry underlying this behavior consists of a wide network of brain regions that communicate to execute social behaviors. However, the neural mechanisms mediating social affective behavior require further investigation. Therefore, the objective of this dissertation is to add detail to our understanding of the specific brain circuits involved in social affective behavior. The insula is a key node within this circuitry, necessary for approach and avoidance behaviors in a social affective preference (SAP) test where adult rats prefer interactions with stressed juveniles but avoid interactions with stressed adults. Here, I investigated the roles of a basolateral amygdala projections to the insula and insular projections to the PL in SAP testing and present evidence indicating the necessity of both these tracts to social affective behaviors. The results described here along with the reviewed literature support a potential amygdalar-insular-prefrontal circuit responsible for detecting social valence, integrating external stimuli with internal states, and selecting and executing context-appropriate social affective behaviors. / Thesis (PhD) — Boston College, 2024. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology and Neuroscience.

Major depressive disorder (MDD) features symptoms spanning cognitive, affective, behavioral, and physiological domains. While many of the neural circuit disruptions mediating emotional and cognitive disturbances in depression have been described, far fewer studies have explored neurobiological mechanisms underlying its associated motor or physiological impairments. Emotionally motivated behaviors, including responses to stress, are characterized by concomitant somatomotor actions and autonomic changes that require intricate coordination of the motor and autonomic systems. Prior investigations by our group used a pseudorabies virus (PRV)-mediated retrograde tract-tracing approach to identify brain regions with parallel descending premotor and presympathetic efferents that play a role in integrating somatomotor and sympathetic functions. Several nodes of this circuitry, including the hypothalamic paraventricular nucleus (PVN), locus coeruleus (LC), and periaqueductal gray (PAG), are implicated in responses to stressful and emotionally salient stimuli. Based on this observation, it was hypothesized that these parallel descending circuits shape responses to diverse stressors and are altered in clinical depression and comorbid anxiety disorders. To explore this possibility, the experiments in this dissertation used two recombinant PRV strains to trace polysynaptic premotor and presympathetic pathways innervating sympathectomized skeletal muscle and adrenal gland, respectively, in two rat models with heritable differences in emotionality and stress reactivity: the Wistar-Kyoto (WKY) rat and the selectively bred Low Novelty Responder (bLR) rat. During our initial neuroanatomical investigations in the PVN, we observed that both WKY and bLR rats displayed significant decreases in the quantity of PVN neurons with premotor projections to skeletal muscle compared to their respective control strains. Labeling of neurons with presympathetic projections to adrenal gland or dual-labeled polysynaptic projections to both motor and sympathetic targets was not altered in either model. Our subsequent neuroanatomical studies focused on comparing premotor efferent projections from LC and PAG. In LC, fewer premotor efferent projections to skeletal muscle were observed in both models. There were also reductions in the number of premotor efferents in the four subdivisions of the PAG. WKY rats had significantly fewer premotor projections in the dorsomedial (DMPAG), lateral (LPAG), and ventrolateral (VLPAG) subdivisions, while bLR rats had significantly fewer premotor efferents in dorsolateral (DL)PAG. The final experiments in this dissertation sought to determine whether one potential therapeutic intervention, environmental enrichment during late childhood and adolescence, can improve emotional behavior disturbances and reverse premotor circuit alterations in bLR rats. Rearing young bLR rats in conditions with increased environmental complexity partially but incompletely improved aspects of depression- and anxiety-relevant behaviors and their corresponding PVN premotor circuit abnormalities. Cumulatively, these findings highlight somatomotor circuits in several brain structures involved in responses to stress and emotional stimuli that could be implicated in mediating motor-related impairments in clinical depression. / Doctor of Philosophy / Depression is a common and complex illness that features many types of impairing symptoms. Some of these symptoms involve functions regulated by the somatic motor system, which controls movement, and the autonomic nervous system, which regulates many basic bodily functions (for example, heart rate and blood pressure) that occur outside of our conscious control. The ability to coordinate the actions of these two systems is important for many behaviors, including how we respond to emotional or stressful situations. Past experiments in our laboratory used a type of virus (pseudorabies virus, PRV) that travels backwards through neural circuits containing multiple neurons and allows us to label parts of the brain that project to peripheral areas regulated by the somatic motor system (i.e., hindlimb skeletal muscle), the autonomic nervous system (i.e., adrenal gland), or both. These labeling experiments identified neurons in these motor and autonomic circuits in several parts of the brain, including the paraventricular nucleus of the hypothalamus (PVN), locus coeruleus (LC), and periaqueductal gray (PAG). Of note, all of these structures are involved in regulating responses to stressful or emotional situations. This observation led us to hypothesize that motor and autonomic projections from these areas of the brain are important for regulating how we respond to stress and might be altered in individuals suffering from depression. To test this idea, we labeled motor- and autonomic-projections with PRV in two separate rat models with a genetic disposition for emotional behaviors that resemble symptoms of clinical depression or anxiety. When we analyzed the PVN, LC, and PAG of rats with depression-relevant behaviors, we discovered that each of these brain areas contained fewer labeled neurons with motor projections to skeletal muscle. Based on these findings, we were interested in exploring whether enriching or stimulating experiences during early life had the potential to reverse deficits in the PVN motor projections and improve emotional behavior in one of our rat models for depression. Although enrichment partially improved behavioral and circuit-level outcomes, it was not fully effective. Taken together, our experimental findings highlight disruptions of motor projecting circuits in several brain structures implicated in mediating responses to stressful or emotional stimuli in two rat models relevant to depression and anxiety disorders. These motor circuit disruptions could be implicated in mediating motor-related symptoms observed in clinically depressed patients.

<p>The human brain is possibly the most complicated structure in the known world. It contains 100 billion neurons, each making contact with 1,000 to 10,000 other neurons. The neurons themselves have hundreds of excitatory and inhibitory neurotransmitters / receptors with which to use to activate or de-activate other neighbouring neurons. Ultimately these neurons are organized into locally defined functional neural networks, which in turn connect with other neural networks to create non-localized highly-complex brain circuits. These brain circuits are responsible for the higher order functions such as perception, emotions, learning, language and conscious thought. In healthy brain states, these networks and circuits are communicating and signalling appropriately. With mental illness, or in an intoxicated brain state, however, this network and circuit functioning can become disrupted: either in a very specific manner, or in a generalized form. Alcohol (in the form of ethanol) is one of the oldest and most widely used psychoactive drugs in the world. In recreational doses, it can have drastic effects on how a person thinks and behaves. Small doses will lead to feelings of euphoria, increased sociability, and impaired judgement, while larger doses will lead to impaired memory and comprehension, and at extreme doses will lead from confusion and stupor to coma and death. The current understanding of alcohol’s effects on the brain is that it acts in a very specific way on a variety of brain enzymes and receptors. This in turn affects specific brain circuitries, making alcohol intoxication a promising model of pharmacological neural network and brain circuit modulation. Obsessive-compulsive disorder (OCD) is a major psychiatric disorder that affects many (lifetime prevalence of between 1-2.5%) and can cause significant disability and impairment in one’s life. The onset of OCD is usually during childhood and adolescence, with more than 50% of adults with OCD reporting its onset occurring before the age of 18. The etiological origin of OCD lies ultimately in specific neuropathological processes, with current theories postulating either a neurochemical model that emphasizes the dysfunction of the serotonergic and possibly dopaminergic systems; or a neuroanatomical model that emphasizes the dysfunction of a specific corticostriatal pathway; or both. Magnetic resonance imaging (MRI), with its safe, non-invasive ability to image both anatomy, brain function and brain metabolism, provides a unique tool with which to probe brain circuit changes, such as in healthy subjects under a pharmacological challenge (ethyl alcohol), or in medication naïve children with OCD. In the ethanol intoxicated brain, functional MRI can be used to probe specific resting state networks (RSN; functionally connected networks that exhibit low frequency blood oxygen level dependent (BOLD) fluctuations), measure brain BOLD time-signal complexity using fractal analysis, and to correlate these findings with measured alcohol levels in the brain in vivo using magnetic resonance spectroscopy (MRS). In subjects with OCD, functional MRI can be used to once again probe RSNs, and as well, MRS can be used to look at potential differences in brain metabolites in axonal projections that connect OCD relevant brain circuits. It is the purpose of this thesis to show how brain circuits and neural networks in atypical brain states (such as intoxication or mental illness) can be probed and better understood using advanced MRI techniques, such as resting state fMRI. Over a series of three studies, one involving MRI scans of healthy male adults before and after drinking a substantial amount of ethanol, and two others comparing RSNs in children with OCD versus healthy matched controls, and MRS differences in prefrontal white matter between the same two groups, we examined brain circuit changes using advanced MRI techniques. In the alcohol study, evidence was found of brain signal complexity decreasing after 60min and 90min post alcohol consumption. Simultaneously, a mixture of increased and decreased functional connectivity in the default mode network was found after 60min post alcohol consumption, which became general decreased functional connectivity after 90min post alcohol consumption. These changes took place while alcohol in the brain increased substantially after 60min. These findings may help provide insight into the neurofunctional underpinnings of the cognitive and behavioural changes observed during acute alcohol intoxication. In the first study on medication naïve children with OCD, we observed increased connectivity (OCD>control) in the right section of Brodmann area 43 of the auditory cortex, as well as decreased connectivity in the right section of Brodmann area 8 and Brodmann area 40 in the cingulate network. In the second study looking at medication naïve children with OCD, we observed higher levels of N-acetyl-aspartate (NAA) and choline in the right prefrontal white matter (RPFWM) in children with OCD compared to healthy controls, as well as a positive correlation of creatine, NAA, and myo-inositol levels in the RPFWM and OCD symptom severity. Both studies lend further support to the cortico-striatal-thalamiccortical hypothesis of OCD, while the first study further implicates other regions of the brain outside of the CSTC. Both of these OCD studies further demonstrated the differences in brain circuits of neuropsychiatric disorders between children and adults.</p> / Doctor of Philosophy (PhD)