Dissertation
An analysis of the bed nuclei of the Stria terminalis and related circuitry in the modulation of memory consolidation
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2022
DOI: 10.25820/etd.006478
Abstract
Memory consolidation following stressful experiences is a key means of adaptation, allowing a long-term representation of the event to facilitate evaluation of future threats. It is well documented that the consolidation process is enhanced by glucocorticoids, the end-products of the HPA cascade, via activation of cognate receptors in the basolateral amygdala. Nevertheless, there remain lingering questions concerning what changes in endogenous glucocorticoid activity are necessary to enhance memory, which neural systems are involved in this modulation, and whether they overlap with the neural systems implicated in memory generalization. The experiments described here attempt to address this by elucidating neural circuits involved in modulating endogenous glucocorticoid activity and their contribution to memory consolidation and generalization.
Prior work from our laboratory has established a role for the anteroventral subdivision of the bed nuclei of the stria terminalis (avBST) in the modulation of the HPA axis. Moreover, avBST maintains extensive connectivity with a network of limbic cortical circuitry canonically associated with memory consolidation. As such, avBST is well positioned to act within the traditional framework of the consolidation network and as a regulatory locus for the hormonal modulation of memory strength. In chapter 2 we show post-training optogenetic stimulation of avBST bi-directionally modulated long-term retention of a single-trial inhibitory avoidance task via connectivity with separate downstream effectors. Post-training photoinhibition of avBST soma, and its projection to the paraventricular hypothalamus was sufficient to augment long-term retention (by 200%), an effect contingent upon an increased availability of corticosterone produced by the optogenetic manipulation. Separately, post-training photoexcitation of avBST, and its projection to the ventrolateral periaqueductal gray could diminish long-term retention (by 50%), an effect independent of any changes in HPA activity. Together, these data support a role for divergent avBST centered circuits in the modulation of memory consolidation, whereby biasing avBST activity toward excitation or inhibition engages the capacity to restrict or augment consolidation, respectively.
Chapter 3 addresses the role of a discrete prefrontal projection to BST that is critical for preventing context fear generalization. Generalization of fear is a fundamental adaptive neurobiological process conserved across species that is critical for survival. Organisms utilize environmental information from previous fearful experiences to shape behavioral responses to novel situations where the presence of a threat is uncertain. Provided the perception of threat is high, organisms may express a range of defensive behaviors deemed most likely to navigate the threat successfully. Although generalization is necessary for an organism to predict the presence of threat and select the appropriate behavioral response, in humans, generalization of fear to environments or to cues that bear little similarity to previous fearful experiences is a hallmark of stress-related psychiatric disease. Given the necessity of generalization processes in adapting to complex environmental changes, there is a critical need to better understand the neural systems that restrict fear generalization during periods of uncertainty and the underlying perturbations that lead to the exaggeration of these responses.
Here we used intersectional viral approaches to characterize a subsection of prefrontal input to BST originating from the rostral end of the prelimbic region (rPL) and interrogate its involvement in regulating context fear generalization. We applied electrophysiological and optical methods for monitoring and manipulating neural activity immediately following training on a modified inhibitory avoidance (IA) procedure to target post-training consolidation processes, as this period is critical for mediating the emergence of long-term fear generalization. We found that rPL provides discrete input to the caudal end of the anterior BST and targets GAD1, but not vGlut2, expressing neurons that in turn provide input to a distributed network of threat processing regions. rPL neuronal ensembles were robustly mobilized following training and were differentially recruited during avoidance testing in a novel context. BST was similarly mobilized during training and avoidance testing. Post-training optical inhibition of the rPL-BST pathway with eNpHR3.0 exaggerated post-training CORT responses and was associated with increased avoidance to a novel chamber 48hrs later, an effect that was not dependent on the increased CORT availability. Separately, we used pre-exposure to a neutral context to encourage later generalization of fear. Here, post-training optical or chemogenetic activation of the rPL-BST pathway with ChR2 (E123A), or hM3dq prevented generalization 48hrs later to the neutral context without affecting avoidance to the training context. We also demonstrate these effects are specific to rPL-BST, and not an rPL-vlPAG projection that maintains collaterals with BST. Together, these data provide evidence for a novel circuit tasked with regulating post-training consolidation processes that contribute to the emergence of generalized fear.
These results outline a BST centric network that is differentially able to modulate the contribution of the neuroendocrine response during memory consolidation and separably capable of mediating the extent of memory consolidation that occurs and whether environmental features extend the generalization of fear to novel situations involving threat.
Details
- Title: Subtitle
- An analysis of the bed nuclei of the Stria terminalis and related circuitry in the modulation of memory consolidation
- Creators
- Ryan Thomas Lingg
- Contributors
- Jason Radley (Advisor)Ryan LaLumiere (Committee Member)Nandakumar Narayanan (Committee Member)Rainbo Hultman (Committee Member)John Freeman (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Psychology
- Date degree season
- Spring 2022
- Publisher
- University of Iowa
- DOI
- 10.25820/etd.006478
- Number of pages
- xiv, 176 pages
- Copyright
- Copyright 2022 Ryan Thomas Lingg
- Language
- English
- Description illustrations
- color illustrations
- Description bibliographic
- Includes bibliographical references (pages 148-176).
- Public Abstract (ETD)
Discrimination between threatening and non-threatening contexts is an adaptive neurobiological process. However, chronic or traumatic stressors may shift responses toward responding to non-threatening contexts as if they contained a threat, a response known as generalization. From a translational perspective, the loss of discrimination, or over-generalization, from a stressful to neutral context is one of the core features of stress-related psychiatric diseases. The general goal of this dissertation is to characterize the neural circuits modulating adaptation to environmental threats in the rodent brain and how these affect the ability to discriminate between neutral and threatening contexts in the future. In the first chapter I will discuss the primary research literature relevant to this topic. I will provide background on stress literature and neural circuitry in relation to memory consolidation, a critical process by which organisms create long-term memories. The hypothalamo-pituitary-adrenal (HPA) axis is the canonical neuroendocrine system for stress. Activation of this neuroendocrine cascade produces glucocorticoid hormone secretion that affects a variety of functions in the body and enhances memory consolidation through activation of the neural pathways to be studied in my dissertation. Much prior research has made inroads in understanding the neurobiology of discrimination, however, the neural circuits accounting for how stress perturbs these processes has received less attention. To address this, my work has investigated how a discrete region of the basal forebrain, the bed nucleus of the stria terminalis, mediates the extent with which glucocorticoid hormones contribute to memory consolidation and separably participates in a prefrontal cortex driven network responsible to preventing memory for aversive experiences from generalizing to distinct situations that do not involve a threat. In this way, the bed nucleus of the stria terminalis is a critical component of how an organism learns about a threat, the extent to which that learning is dependent upon the release of stress hormones, and whether that learning extends to situations of relative uncertainty.
- Academic Unit
- Psychological and Brain Sciences
- Record Identifier
- 9984271453202771
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