Indiana University-Purdue University Indianapolis (IUPUI) / Increased delay discounting (DD) has been associated with and is theorized to contribute to alcoholism and substance abuse. It is also been associated with numerous other mental disorders and is believed to be a trans-disease process (i.e., a process that occurs in and contributes to multiple different pathologies). Consequently insights gained from studying DD are likely to apply to many different diseases. Studies on the neurobiological underpinnings of DD have two main interpretations. The first interpretation is that two different neurobehavioral systems exist, one favoring delayed rewards (executive system) and one favoring immediate rewards (impulsive system), and the system with the greater relative activation determines choice made by an individual. Alternatively, a single valuation system may exist. This system integrates different information about outcomes and generates a value signal that then guides decision making. Preclinical investigations have steered clear of these two different interpretations and rather focused on the role of individual structures in DD. One such structure, the rat mPFC, may generate an outcome representation of delayed rewards that is critically involved in attributing value to delayed rewards. Moreover, there is evidence indicating the rat mPFC may correspond to the primate dlPFC, an executive system structure. The current body of work set about testing the hypotheses that the mPFC is necessary for attributing value to delayed rewards and that decreasing the activity in an executive system area, and thus the executive system, shifts inter-temporal preference towards immediate rewards. To this end the rat mPFC was inactivated using an hM4Di inhibitory designer receptor exclusively activated by designer drugs (DREADD; experiment 1) or microinjections of tetrodotoxin (TTX; experiment 2) while animals completed an adjusting amount DD task. Activation of the hM4Di inhibitory DREADD receptor caused a decrease in DD, opposite of what was predicted. Electrophysiological recordings revealed a subpopulation of neurons actually increased their firing in response to hM4Di receptor activation, potentially explaining the unpredicted results. Microinjections of TTX to completely silence neural activity in the mPFC failed to produce a change in DD. Together both results indicate that mPFC activity is capable of manipulating but is not necessary for DD and the attribution of value to the delayed reward. Consequently, a secondary role for the rat mPFC in DD is proposed in line with single valuation system accounts of DD. Further investigations determining the primary structures responsible for sustaining delayed reward valuation and how manipulating the mPFC may be a means to decrease DD are warranted, and continued investigation that delineates the neurobiological processes of delayed reward valuation may provide valuable insight to both addiction and psychopathology.

In this study, I investigate how serotonergic modulation of the medial prefrontal cortex (mPFC) affects neuronal activity and impacts cognitive flexibility, anxiety, and fear extinction (Figure 1). I begin in Chapter 1 with general information on the PFC with a focus on the mPFC, then discuss the role and complexity of serotonin and how manipulation of serotonin affects behavior. I, finally, introduce what is understood about how serotonin modulates the mPFC, the significance of which has implications for cognitive and emotional behaviors. In Chapter 2, I studied the role of serotonin in cognitive flexibility. Specifically, I used retrograde tracing to determine the origin of mPFC and assessed how terminal release of 5-HT affects mPFC pyramidal neuron activity using whole-cell electrophysiology in acute brain slices. Furthermore, through in vivo fiber photometry, I evaluated the activity of 5-HTergic neurons projecting to the mPFC during cognitive flexibility behavior. Lastly, by selectively increasing or decreasing mPFC 5-HTergic terminal release through in vivo optogenetics, I assessed the modulatory role of 5-HTergic input into the mPFC on intradimensional rule reversal and extradimensional rule shift performance in the cognitive flexibility task. Furthermore, I evaluated the activity of 5-HTergic neurons projecting to the mPFC during an open field task using in vivo fiber photometry and, in Chapter 3, used in vivo optogenetics to determine the role 5-HT in the mPFC plays in modulating fear-related behavior. In Chapter 4, I examined a pharmacological screen of a psychedelic drug in the cognitive flexibility task outlined in Chapter 2. I conclude in Chapter 5 with a discussion of the study implications and future directions.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20803号 / 医博第4303号 / 新制||医||1025(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 今中 雄一, 教授 伊達 洋至 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第20813号 / 人健博第50号 / 新制||人健||4(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 三谷 章, 教授 二木 淑子, 教授 村井 俊哉 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DGAM

京都大学 / 0048 / 新制・論文博士 / 博士(人間健康科学) / 乙第13171号 / 論人健博第5号 / 新制||人健||4(附属図書館) / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 十一 元三, 教授 木下 彩栄, 教授 伊佐 正 / 学位規則第4条第2項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(人間健康科学) / 甲第21422号 / 人健博第63号 / 京都大学大学院医学研究科人間健康科学系専攻 / (主査)教授 稲富 宏之, 教授 澤本 伸克, 教授 伊佐 正 / 学位規則第4条第1項該当 / Doctor of Human Health Sciences / Kyoto University / DFAM

Patients with antisocial personality disorder (ASPD) are deceptive, apathetic, and impulsive. Their social behavior is often inappropriate, and they fail to follow social norms, leading to frequent criminal behavior. Understanding the neural correlates of ASPD could alleviate issues for the patients, such as unstable living conditions, as well as financial costs for the justice system and society. Due to previous research and theoretical implications of the prefrontal cortex (PFC) and its role in emotion-regulation and decision-making, it is likely that ASPD patients would show differences in the PFC relative to healthy individuals. Therefore, emphasis is placed on this region. By systematically reviewing articles which used fMRI to examine ASPD patients, this paper aims to understand if the brain activity in the PFC or functional connectivity within these regions differs between ASPD patients and healthy controls. Decreased activity was found in the anterior cingulate cortex (ACC) and dorsolateral PFC (dlPFC) in ASPD patients compared to healthy controls. Further, decreased functional connectivity was found in the frontoparietal control network, default modenetwork, and attentional network. Other prefrontal regions implicated include the medial frontal cortex, orbitofrontal cortex, and medial prefrontal cortex. Most of these regions are important for cognitive control, enabling integration of information regarding, e.g., errors and conflict. Abnormal processing of such information can lead to the impulsive or inappropriate actions often seen in ASPD patients. The PFC seems to play an important functional role in ASPD, mainly the regions responsible for cognitive control, such as the ACC and dlPFC.

Synapses are a fundamental unit of computation in the brain. Far from being passive connections between spiking neurons, synapses display striking short-term dynamics, undergo long-term changes in strength, and sculpt network-level processes in a complex manner. These synaptic dynamics, both in time and across space, may be a fundamental determinant of population-level computations and behavioral output of the brain, yet their role in neuromodulatory circuits is relatively under-explored. First, I developed and validated a set of likelihood-based inference tools to quantify the dynamics of synaptic ensemble composition throughout development. Second, I examined network computations in the serotonergic dorsal raphe nucleus through a dynamical lens, exploring the role of short-term synaptic dynamics at sparse recurrent connections, and of distinct long-range synaptic inputs, in shaping the output of spiking populations. 1. Simulation-based inference of synaptic ensembles. Functional features of synapses are typically inferred by sampling small ensembles of synapses, yet it is unclear if such subsamples exhibit biases. I developed a statistical framework to address this question, using it to demonstrate that common bulk electrical stimulation methods for characterizing the fraction of silent synapses exhibit high bias and variance, and using typical sample sizes, possess insufficient statistical power for accurate inference. I developed and validated a novel synthetic likelihood-based inference approach based on a simulator of the underlying experimental methodology. This new estimator, made available in an object-oriented Python toolbox, reduces bias and variance compared to previously reported methods, and provides a scalable method for examining synaptic dynamics throughout development. These tools were validated by targeted recording from hippocampal CA1 neurons in juvenile mice, where they reveal fundamental tradeoffs between release probability, number of synapses sampled, and statistical power. 2. Synaptic dynamics and population computations in the serotonin system. This part is comprised of two manuscripts. First, in the dorsal raphe nucleus, I uncovered slow, inhibitory recurrent interactions between serotonin neurons that are generated by local serotonin release. These connections were probabilistic, displayed striking short-term facilitation, gated the spiking output of serotonin neurons, and could be activated by long-range excitatory input from lateral habenula, representing threat signals. Targeted physiology and modeling revealed that these recurrent short-term facilitation features generated paradoxical excitation-driven inhibition in response to high-frequency habenula input. These facilitation rules additionally supported winner-take-all dynamics at the population level, providing a contrastive operation between functionally distinct serotonergic ensembles. Behaviorally, activating long-range lateral habenula input to dorsal raphe nucleus generated a transient, frequency-dependent suppression of reward anticipation consistent with these recurrent dynamics, without modulating the underlying reward association itself. These dynamics, we suggest, support sharp behavioral state transitions in changing environments. In a second manuscript, I explored the multiplexing of distinct long-range inputs in serotonergic circuits through spike synchrony. I demonstrated that a population of serotonergic neurons receives input from both lateral habenula and prefrontal cortex. These inputs produced similar subthreshold events, but prefrontal cortex triggered spikes with much higher latencies, supporting a population synchrony code for input identity. These input-specific spike timing patterns could be read out by simple linear decoders with high accuracy, suggesting they could be demultiplexed by downstream circuits receiving sparse innervation by serotonergic axons. We uncovered a novel intracellular calcium conductance in serotonergic neurons that altered the spectral characteristics of membrane voltage in a manner sufficient to generate long-latency, power law-distributed spike times, suggesting a simple dynamical origin for the production of synchronous or asynchronous spiking. This work indicates that serotonergic circuits can multiplex distinct informational streams through population spike synchrony mechanisms. Together, these investigations reveal that the dynamics of short-term facilitation and synaptic ensemble composition can act as the fundamental substrate for flexible computation by spiking networks across the brain.

This dissertation aims to shed light on the ways in which our affective responses and subjective beliefs shape our reasoning about social events and targets. The human ability to reason about other people’s minds, and the social world in which we live, has been central to the field of psychology. However, that ability to make sense of the social world does not exist in isolation. Each social perceiver has idiosyncratic beliefs and identities. Perceivers also affectively respond to events and people in the world around them. Historically, the processes underlying affective processing, social cognition, and formed beliefs, have been studied in isolation, leading to a gap in our knowledge about their interactions. We conducted a set of experiments combining fMRI and behavioral methods to address this gap. The experiments used naturalistic stimuli, which allow related processes to co-occur in an ecologically valid way. The results of the experiments are described in three chapters, following a general introduction (Chapter 1). In Chapter 2, we show that the mentalizing regions of the brain represent a continuous affective response to social targets, and demonstrate a link between that response and the impression perceivers formed of those targets. In Chapter 3, we demonstrate that when presented with conflicting accounts of the same events, the subsequent event representation in participants medial prefrontal cortex is in concordance with perceivers’ beliefs about the events. In Chapter 4, we describe a cross-disciplinary study, informed by political scientific theories about the roots of polarization. In this study, we challenged partisan’s political beliefs and identities. We found that affective responding brain regions showed an effect of partisan information processing for both ideological beliefs and identity challenges. In addition, using two functional localizer tasks, we identified two sets of regions with differing functional profile within the mentalizing network. One set of regions showed the effect of partisan information processing only when perceivers’ ideology was challenged, while the other set showed the effect only when perceivers’ identity was challenged. Taken together, the results from these three studies expand our understanding of the mentalizing regions by suggesting that they represent not only the mental states of others, but also an affective response towards them. This work also reinforces our understanding of the differences in level of abstraction of the representation between prefrontal and parietal mentalizing regions. Lastly, the finding of different yet consequential activation profiles within the mentalizing network opens the door for further inquiries into the functional organization and representations within its constituting regions.

As humans we are not stuck in an everlasting present. Instead, we can project ourselves into both our personal past and future. Remembering the past and simulating the future are strongly interrelated processes. They are both supported by largely the same brain regions including the rostral and ventral medial prefrontal cortex (mPFC) but also the hippocampus, the posterior cingulate cortex (PCC), as well as other regions in the parietal and temporal cortices. Interestingly, this core network for episodic simulation and episodic memory partially overlaps with a brain network for evaluation and value-based decision making. This is particularly the case for the mPFC. This part of the brain has been associated both with a large number of different cognitive functions ranging from the representation of memory schemas and self-referential processing to the representation of value and affect. As a consequence, a unifying account of mPFC functioning has remained elusive. The present thesis investigates the unique contribution of the mPFC to episodic simulation by highlighting its role in the representation of memory schemas and value. In a first functional MRI and pre-registered behavioral replication study, we demonstrate that the mPFC encodes representations of known people as well as of known locations from participants’ everyday life. We demonstrate that merely imagined encounters with liked vs. disliked people at these locations can change our attitude toward the locations. The magnitude of this simulation-induced attitude change was predicted by activation in the mPFC during the simulations. Specifically, locations simulated with liked people exhibited significantly larger increases in liking than those simulated with disliked people. In a second behavioral study, we examined the mechanisms of simulation-based learning more closely. To this end, participants also simulated encounters with neutral people at neutral locations. Using repeated behavioral assessments of participants’ memory representations, we reveal that simulations cause an integration of memory representations for jointly simulated people and locations. Moreover, compared to the neutral baseline condition we demonstrate a transfer of positive valence from liked and of negative valence from disliked people to their paired locations. We also provide evidence that simulations induce an affective experience that aligns with the valence of the person and that this experience can account for the observed attitude change toward the location. In a final fMRI study, we examine the structure of memory representations encoded in the mPFC. Specifically, we provide evidence for the hypothesis that the mPFC encodes schematic representations of our social and physical environment. We demonstrate that representations of individual exemplars of these environments (i.e., individual people and locations) are closely intertwined with a representation of their value. In sum, our findings show that we can learn from imagined experience much as we learn from actual past experience and that the mPFC plays a key role in simulation-based learning. The mPFC encodes information about our environment in value-weighted schematic representations. These representations can account for the overlap of mnemonic and evaluative functions in the mPFC and might play a key role in simulation-based learning. Our results are in line with a view that our memories of the past serve us in ways that are oriented toward the future. Our ability to simulate potential scenarios allows us to anticipate the future consequences of our choices and thereby fosters farsighted decision making. Thus, our findings help to better characterize the functional role of the mPFC in episodic future simulation and valuation.