<p>Preclinical rodent models were used to investigate the neural signatures of strategy change during the delay discounting decision making task. Neural signatures were assessed using advanced statistical techniques (de-mixed principal component analysis). </p>

<p>Parkinson’s Disease (PD) and Alcohol Use Disorder (AUD) are neurodegenerative conditions that involve similar neurobiological pathways and affect motivation and reward dysregulations. This project aims to explore whether PD-related insults affect alcohol-related motivation and reward. We utilized paraquat (PQ) exposure as a neurotoxicant-induced model for PD and mice selectively bred for a differential in alcohol preference as a model for genetic and neurobiological susceptibility for high/low alcohol consumption. In Experiment 1, binge-like alcohol drinking after three weeks of PQ exposure (10 mg/kg, i.p. once per week) or saline was assessed in HAP male and female mice. The four-day Drinking in the Dark (DID) procedure was used to induce binge-like alcohol drinking. Dorsal (DS) and ventral (VS) striatal catecholamines were analyzed after DID. Overall, PQ-treated HAP males had significantly lower alcohol intake than saline-treated males. This effect was absent in female HAP mice. Catecholamine quantification showed lower DOPAC levels in VS of PQ-treated vs. saline-treated HAP male mice. Experiment 2 assessed alcohol-induced locomotor sensitization in adult male and female high (HAP) and low-alcohol-preferring (LAP) mice after PQ exposure. Following the same 3 weeks of PQ or saline exposure, mice received 6 sensitization induction days with either 3 g/kg i.p. EtOH or saline. On test day, an alcohol challenge dose of 2 g/kg in all mice was used to determine the expression of locomotor sensitization. PQ exposure had no significant effect on locomotor activity and sensitization. However, PQ-treated mice showed great variability in their alcohol-induced locomotor activity compared to other groups. These data suggest a sex difference in PQ’s effect on alcohol binge-like drinking. However, PQ’s effect on alcohol-induced locomotor sensitization is not conclusive. This project will elucidate potential mechanisms behind PD-related neuropsychiatric comorbid conditions like AUD. Such findings may assist in early diagnosis and treatment refinement, as these comorbidities precede the motor manifestation of PD by decades and significantly impact the quality of life.</p>

<p dir="ltr">Traditional methods of behavior classification on videos of mice often rely on manually annotated datasets, which can be labor-intensive and resource-demanding to create. This research aims to address the challenges of behavior classification in mouse studies by leveraging an algorithmic framework employing self-supervised learning techniques capable of analyzing unlabeled datasets. This research seeks to develop a novel approach that eliminates the need for extensive manual annotation, making behavioral analysis more accessible and cost-effective for researchers, especially those in laboratories with limited access to annotated datasets.</p>

The gut-brain axis describes a paradigm wherein the trillions of microorganisms inhabiting the gastrointestinal tract engage in bidirectional communication with the host central nervous system. Adaptive immunity represents an important intermediate in this dynamic crosstalk; previous work in our lab has demonstrated that T-lymphocytes, a main class of immune effector cells, contribute to neurodevelopmental processes and behavioral outcomes across the lifespan. Parallels between the phenotype of T-cell deficient and germ free mice led us to hypothesize that bidirectional T-cell-microbe communication is critical for normal neurodevelopment, and that T-cell deficiency impacts the neural circuitry underpinning behavior via disruption of the gut-brain axis. The main objective of this thesis was to elucidate the mechanisms by which T-cells mediate developmental gut-brain signalling. The first installation examined the gut microbiome, gut metabolome, and neurochemical profile in wild-type and T-cell deficient mice from adolescence to adulthood, demonstrating that absence of T-cells impacts the developmental trajectory of functional microbiome output and levels of neuroactive molecules in the brain. Experiment two investigated the impact of T-cell deficiency on gut-brain communication through the lens of host gene expression in the parenchyma and the intestine. T-cell deficient mice showed significant changes in genes related to intestinal immunity and barrier function, in addition to decreases in microglia-related genes in the prefrontal cortex during early life. The final experiment transitioned into a wild-type model to measure the co-evolution of T-cell subsets in mucosal and central immune compartments with composition and diversity of the microbiota. We demonstrated a parallel diversification of the gut microbiome and the functional T-cell repertoire, whereby emergence and proliferation of specific T-cell subsets is linked to compositional shifts in dominant microbial communities across development. Together, our results demonstrate the importance of T-cells for normal development of the holo-organism, with implications for the developmental wiring of functional brain circuitry. / Thesis / Doctor of Philosophy (PhD) / Modern medicine has increasingly placed emphasis on the mind-body connection. This has been exemplified by a series of recent discoveries surrounding the importance of the gut microbiome in maintaining our physical and mental health. One of the key channels through which the microbiome communicates with the host is through the immune system, an equally complex network of cells and proteins that protect the body against invading pathogens. Indeed, these systems evolve alongside each other and engage in constant crosstalk throughout the lifespan, with downstream impacts on the developing brain. This thesis sought to further explore the role of T-cells, a key component of the adaptive immune system, in coordinating gut-microbiome-brain interactions across development. The first experiment examined the microbiome as well as small molecules in the gut and brain of normal mice and mice lacking T-cells. The second experiment built on this work to examine how T-cells influence the expression of different genes in the gut and brain. Finally, the third experiment mapped different populations of T-cells and microbiome composition from the first week of life to adulthood, to better understand how they interact at different stages of development. This work will offer insight into how T-cells talk to the microbiome and how they transmit signals from the gut to the brain, with implications for understanding neurodevelopmental disorders and how they arise.

<p dir="ltr"><b>ABSTRACT</b></p><p dir="ltr"><b>Background</b></p><p dir="ltr">Alcohol use disorder (AUD) poses negative health and social consequences, and is costly to affected individuals, loved ones, and society (Whiteford et al., 2013). It is a chronic neuropsychiatric disorder, associated with impaired decision making and altered functional connectivity patterns in the brain. Many studies have shown changes in the brain and behaviors after sustained abstinence using within-participant design or between-participant design comparing participants in recovery versus healthy controls (Muller & Meyerhoff, 2021; Wilcox et al., 2019). The purpose of this study was to investigate brain differences between participants in recovery and participants who are actively drinking. Specifically, this study evaluated within- and between-network resting-state functional connectivity (rsFC) strengths in the context of the triple network model, which focuses on three key networks for complex perceptual, emotional and behavior processing as well as introspection, theory of mind and self-awareness; the salience network (SN), the central executive network (CEN), and the default mode network (DMN) (Menon, 2019). Moreover, this study assessed the relationship between impulsive choices in temporal decision-making and changes in resting-state functional connectivity patterns in these networks.</p><p dir="ltr"><b>Methods</b></p><p dir="ltr">This study included two groups: the Recovery Group and the Drinking Group. The Recovery Group included participants who were starting recovery (within one year), met AUD diagnosis criteria or showed lifetime heavy drinking behaviors during a 12-month period, received treatment for substance use disorder for alcohol and/or illicit drugs, and showed ongoing intentions and efforts to maintain recovery (n=18, 6 females, mean age=32.4±7.4, 17 White, mean years of education=14.5±3.1, average days of abstinence prior to interview days=78.2±45.7). The Drinking Group included participants who were currently drinking that met diagnosis criteria for AUD or showed heavy drinking behaviors (n=49, 24 females, mean age=31.7±6.4, 29 White, mean years of education=13.6±2.3). Participants underwent an initial screen day where structured interviews were conducted to evaluate the number of lifetime AUD criteria and prior drinking patterns. On the study day, participants completed computer tasks and questionnaires prior to their functional Magnetic Resonance Imaging (fMRI) sessions. Participants in the Recovery Group received a virtual reality (VR) intervention targeting future self-continuity where they interacted with avatars that are versions of themselves (present self and future selves in recovery and relapsed) prior to MRI sessions. All participants completed baseline Delay Discounting (DD) to measure intertemporal choice preferences prior to the fMRI sessions and prior to the VR intervention for the Recovery Group.</p><p dir="ltr"><b>Results</b></p><p dir="ltr">This study did not find any significant differences in within- and between-network rsFC strength of regions of interest of this study within the triple networks between participants in recovery and those who were actively drinking. The study found that participants in recovery showed a greater preference for delayed rewards (measured by DD task) compared to participants who are actively drinking. Additionally, measures of self-reported impulsivity and impulsive decision-making were associated with resting state functional connectivity (rsFC) strength between regions within the Salience Network (SN), and between the SN and Central Executive Network (CEN). Specifically, baseline delayed reward preference was positively associated with the rsFC between two SN hubs: left dorsal anterior insula (dAIC) and dorsal anterior cingulate cortex (dACC). The rsFC between the left dACC (SN) and dorsolateral prefrontal cortex (dlPFC; CEN) negatively associated with subscales (including negative urgency, lack of perseverance, and lack of premeditation) of self-reported impulsivity measured by the Urgency-Premeditation-Perseverance-Sensation Seeking-Positive Urgency (UPPS-P) impulsive behavior scale. Together, these results suggested that there was an emerging pattern where enhanced the rsFC strength in these regions associated with higher impulsive tendencies. The exploratory analysis showed that the rsFC strength between the right precuneus and ventromedial prefrontal cortex (vmPFC) was related to abstinence length in participants in recovery.</p><p dir="ltr"><b>Conclusions</b></p><p dir="ltr">These findings indicated that participants in recovery exhibited higher delayed reward preference compared to participants who were actively drinking, alongside a significant relationship between measures of impulsivity and the rsFC within the SN and between the SN and CEN. These results highlighted the importance of the SN and its dynamic interaction with the CEN in self-reported impulsivity and impulsive decision making in addiction. Additionally, this study found that within-network functional connectivity strength in the DMN was related to abstinence length, suggesting that repairment in the rsFC strength within DMN might be integral to the process of addiction recovery.</p><p><br></p>

Infant vocalisations are uniquely salient sounds in the environment. They universally attract attention and compel the listener to respond with speed and care. They provide a wealth of information to parents about their infant’s needs and affective state. There is a scientific consensus that early parenting has a profound impact on child development. In particular, the sensitivity with which parents respond to their infant’s communicative cues has been shown to affect cognitive and socio-emotional outcomes. The mechanisms underlying such sensitivity are not well understood. In this thesis, adults’ sensitivity to infant cues will be considered in terms of two components, the ‘promptness’ and ‘appropriateness’ of responses, as originally conceptualised by Bell and Ainsworth (1972). Promptness of responses is considered in terms of adults’ ability to move with speed and effort after listening to infant vocalisations. Appropriateness, on the other hand, is considered in terms of adults’ ability to differentiate between functionally significant parameters in infant vocalisations. The effect of modifiable environmental factors on the promptness and appropriateness of responses is also investigated. Finally, a focused investigation of the brain basis of responses to infant vocalisations is presented. Overall, findings demonstrated that infant vocalisations undergo privileged, specialised processing in the adult brain. After hearing an infant cry, adults with and without depression were found to move with greater coordination and effort. Adults were also found to be attuned to subtle parameters in infant cries. This sensitivity was shown to be affected by two participant-level factors, depression and previous musical training. Furthermore, this sensitivity could be enhanced through intervention, as evidenced by findings from short-term, perceptual discrimination training. The notion of privileged processing of infant vocalisations is further supported by evidence of early discrimination of infant sounds in a survival-related subcortical brain structure. Future directions for this work include directly relating current experimental measures of adults’ responses to infant cues with parental sensitivity to infant communication during dynamic interactions. Translating current findings into applied settings would require an investigation of the effects of factors such as musical and perceptual training on sensitivity to infant cues in at-risk populations, such as mothers and fathers with depression. Lastly, an increased understanding of the brain basis of adults’ sensitivity to infant cues will provide insight into our greatest challenge: parenting our young.

Humans effortlessly and accurately judge their subjective probability of being correct in a given decision, leading to the view that metacognition is integral to decision making. This thesis reports a series of experiments assessing people’s confidence and error-detection judgements. These different types of metacognitive judgements are highly similar with regard to their methodology, but have been studied largely separately. I provide data indicating that these judgements are fundamentally linked and that they rely on shared cognitive and neural mechanisms. As a first step towards such a joint account of confidence and error detection, I present simulations from a computational model that is based on the notion these judgements are based on the same underlying processes. I next focus on how metacognitive signals are utilised to enhance cognitive control by means of a modulation of information seeking. I report data from a study in which participants received performance feedback, testing the hypothesis that participants will focus more on feedback when they are uncertain whether they were correct in the current trial, whilst ignoring feedback when they are certain regarding their accuracy. A final question addressed in this thesis asks which information contributes internally to the formation of metacognitive judgements, given that it remains a challenge for most models of confidence to explain the precise mechanisms by which confidence reflects accuracy, under which circumstances this correlation is reduced, and the role other influences might have, such as the inherent reliability of a source of evidence. The results reported here suggest that multiple variables – such as response time and reliability of evidence – play a role in the generation of metacognitive judgements. Inter-individual differences with regard to the utilisation of these cues to confidence are tested. Taken together, my results suggest that metacognition is crucially involved in decision making and cognitive control.

Post-traumatic stress disorder (PTSD) is classified as an anxiety disorder in the Diagnostic and Statistical Manual IV of the American Psychiatric Association. It is characterised by three main symptom clusters: re-experiencing (of which flashbacks are the hallmark symptom); hyperarousal; and avoidance. Diagnosis requires not only the occurrence of a traumatic event but also an intense emotional (fear, horror, or helplessness) reaction to it. Epidemiological data suggest that 80% of people will experience at least one qualifying event in their lifetime. However, prevalence rates of PTSD are much lower. Additionally, individuals with PTSD tend to experience flashbacks of only two or three particular ‘hot-spots’ of the entire trauma. Therefore, the question arises: why do some moments of trauma flash back and not others? Clinical-cognitive theories of PTSD suggest that shifts in information processing at the time of the trauma (i.e. peri-traumatically) are the mechanism whereby flashbacks are created. However, for ethical and practical reasons peri-traumatic processes in real trauma are seldom studied. An analogue traumatic event has been developed to help study peri-traumatic processes – the trauma film paradigm. This paradigm is used through-out this thesis with the goal of investigating peri-traumatic cognitive mechanisms in flashback formation. Studies 1 and 2 extend previous work using dual tasks to manipulate intrusions in-line with clinical-cognitive theories. Studies 3 and 4 use neuroimaging techniques to investigate brain regions involved in real-time peri-traumatic encoding of analogue flashbacks. Chapter 9 presents heart rate data relating to peri-traumatic physiological response to flashback encoding. All of these studies support the notion that peri-traumatic shifts in processing are involved in flashback formation. In particular, Study 3 suggests that there may be a particular neural signature associated with the formation of flashbacks. Investigation of these brain areas may help solve the questions of why some individuals are more vulnerable to PTSD and why only a few specific moments of a trauma subsequently flashback. Furthermore, an improved understanding of the cognitive mechanisms involved in flashback formation may allow theory and evidence led improvements in PTSD treatments.

Background: Adolescence and young adulthood are particularly vulnerable periods for the development of mental health disorders, including bipolar disorder (BD). Mental health screening at universities could aid in the early identification of particularly at- risk individuals, with the long-term aim of providing early treatment interventions to improve clinical outcomes. However, further research into the identification of appropriate behavioral and biological markers for vulnerability to psychiatric disorders – as well as into the acceptability and efficacy of mental health screening - is warranted. Methods: Young adults were recruited via an already existing Internet-based mental health screening survey of undergraduate students at the University of Oxford. In Study 1, qualitative interviews of young adults with and without previous mental health problems were conducted to assess the acceptability and efficacy of mental health screening within a university setting. In Studies 2-5 we explored the hypotheses of altered emotional decision-making, reward processing and neurostructural integrity as behavioral and neurobiological markers for vulnerability to bipolar disorder via the study of young adults with a common bipolar phenotype (BPP) - some of whom meet diagnostic criteria for bipolar II or not-otherwise-specified disorder (BD II/NOS). To that end, we employed a diverse range of methodologies: alcohol challenge (Study 2); neuropsychological task performance (Study 3); functional magnetic resonance imaging (fMRI; Study 4); diffusion tensor imaging (DTI) and voxel-based morphometry (VBM; Study 5). Results: Findings from Study 1 suggest that young adults are willing to participate in mental health screening within a university setting, and that such screening may be used to offer subsequent treatment interventions. Taken together, findings from Studies 2 and 4 suggest a general blunted reward response among unmedicated young adults at increased risk for BD during euthymia, and additionally suggest pathophysiological similarities between BD and alcohol use disorders (AUDs) that may provide a causal link between the elevated co-occurrence rates of the two disorders. Finally, findings from Study 5 suggest widespread white matter microstructural alterations – which are likely to be neurodevelopmental in origin – among antipsychotic- and mood-stabilizer naïve young adults with BD II/NOS. Conclusions: These data support the hypothesis of neurodevelopmental alterations identifiable prior to significant clinical impairment among young adults at increased risk of – or already meeting DSM-IV criteria for – bipolar disorder. They also suggest that young adults in higher education are willing to participate in mental health screening. Future studies should aim to identify more specific markers for individual disorders such as BD.

É crescente o interesse nos efeitos que o ambiente parental exerce sobre o fenótipo da prole, a chamada herança epigenética. Tem sido mostrado que essa herança ocorre especialmente para efeitos de plasticidade do desenvolvimento, os quais derivam de alteração ambiental durante o desenvolvimento parental. Dentre os estudados realizados em camundongos, várias estratégias ambientais foram abordadas, como o estresse durante a infância e o enriquecimento ambiental, com a avaliação da prole em relação a parâmetros comportamentais, fisiológicos e moleculares. De modo a estudar o fenômeno, o presente trabalho investigou, em camundongos Swiss machos, os efeitos de um estresse durante a infância, a Privação Materna em PND 9, com avaliação de comportamentos exploratório (Campo Aberto), do tipo ansioso (Labirinto em Cruz Elevado), depressivo (Nado Forçado) e relacionados ao álcool (Condicionamento Condicionado por Lugar e Sensibilização Comportamental), e, numa outra abordagem, do Enriquecimento Ambiental do desmame (PND 21) à idade adulta (PND 70), com avaliação de parâmetros fisiológicos diversos (peso corporal, de depósito de gordura, de baço e glândulas adrenais) e comportamentos exploratório (Campo Aberto), memória espacial (Labirinto de Barnes), dominância social (Tubo de Dominância Social), atratividade (Teste de Escolha de Parceiro), além de avaliação de corticosterona plasmática e BDNF hipocampal. A privação materna não promoveu diferenças para os parâmetros comportamentais avaliados. Optou-se pela utilização do paradigma do Enriquecimento Ambiental para investigação dos efeitos sobre o fenótipo da prole (machos e fêmeas). Foram observados nos filhotes machos resultados comportamentais opostos aos apresentados pela geração paterna. Porém, quando os filhos foram expostos a um período breve de enriquecimento durante a idade adulta, essas diferenças não foram mais encontradas. Portanto, conclui-se que o enriquecimento ambiental paterno foi capaz de gerar efeitos na prole, tornando os filhotes machos menos adaptados ao ambiente não enriquecido. / There is a growing interest in the effects of the parental environment on the offspring phenotype, the so-called epigenetic inheritance. It has been shown that this inheritance occurs especially for developmental plasticity effects, which stem from environmental changes during parental development. Studies carried out in mice have adopted several environmental strategies, such as early life stress and environmental enrichment, and the offspring have been assessed for behavioural, physiological and molecular parameters. In order to study the phenomenon, the present work investigated, in Swiss male mice, the effects of an early-life stress protocol, the Maternal Deprivation on PND 9, assessing behaviours such as exploratory (Open Field), anxiety-like (Elevated-Plus Maze), depressive-like (Forced Swim) and alcohol-related behaviours (Conditioned Place Preference and Behavioural Sensitisation) and, through a different approach, the environmental enrichment, from weaning (PND 21) to adulthood (PND 70), assessing diverse physiological parameters (body weight, fat pad weight, spleen and adrenal glands weights) and behaviours such as exploratory (Open Field), spatial memory (Barnes Maze), social dominance (Social Dominance Tube Test), attractiveness (Mate Choice Teste) as well as plasmatic corticosterone and hippocampal BDNF. The maternal deprivation did not yield any differences in the behavioural parameters assessed. The Environmental Enrichment paradigm was adopted for studying its effects on the offspring phenotype (males and females). Behavioural results were observed in the male offspring, which were the opposite of those found in the paternal generation. However, when the male offspring was exposed to a brief period of enrichment during adulthood, these differences were no longer found. Therefore, paternal environmental enrichment was able to induce effects on the offspring, turning male offspring less adapted to the non-enriched environment.