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.
| Identifer | oai:union.ndltd.org:VTETD/oai:vtechworks.lib.vt.edu:10919/115887 |
| Date | 27 July 2023 |
| Creators | Shupe, Elizabeth Anne |
| Contributors | Neuroscience, Clinton, Sarah, Olsen, Michelle Lynne, Thompson, Christopher, Hodes, Georgia E., Jarome, Timothy J. |
| Publisher | Virginia Tech |
| Source Sets | Virginia Tech Theses and Dissertation |
| Language | English |
| Detected Language | English |
| Type | Dissertation |
| Format | ETD, application/pdf |
| Rights | Creative Commons Attribution-NonCommercial 4.0 International, http://creativecommons.org/licenses/by-nc/4.0/ |
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