Parkinson’s disease (PD) and autism are prevalent diseases in two disparate age groups. The neuropathology underlying these diseases involves the major neurotransmitters, dopamine and GABA, and/ or their receptors. The current study investigated mRNA gene expressions of the GAD67 in autistic striatum and the DRD1 in the Parkinsonian dorsolateral prefrontal cortex. In situ hybridization histochemistry for GAD67 mRNA levels in postmortem striatal specimens from autistic individuals was compared to those of normal controls. Similarly, a nonradioactive in situ hybridization newly emerging method, RNAscope, was used to assess the D1 receptor mRNA gene expression in postmortem specimens of the dorsolateral prefrontal cortex of PD and control brains. The GAD67 mRNA labeling intensity that was measured on X-ray films and on emulsion radioautograph sections did not vary significantly between the autistic samples and the normal control samples. On the other hand, DRD1 mRNA levels showed a significant increase in the Parkinsonian dorsolateral prefrontal cortex specimens as compared to their normal counterparts. The GAD65 mRNA labeling results corresponded with the GAD67 mRNA levels. The similar GAD67 and GAD65 mRNA patterns in the autism group and the control group may suggest that the hyper-excitability hypothesis can be accounted for by an increase in the glutamatergic activity rather than a decrease in the GABAergic system. The increase in the DRD1 mRNA in the Parkinson’s disease dorsolateral prefrontal cortex may be interpreted in light of the expected upregulation of the D1 receptor in cases of dopamine depletion as the treatment-status was unknown. In conclusion, research investigating the neurotransmitters’ gene expression in Parkinson’s disease and in autism spectrum disorder needs more neurobiological studies in order to establish some knowledge regarding the temporality, and the genetic profile mapping of the diseases. Likewise, more research is encouraged to relate the symptoms and behaviors associated with disease to their anatomical origins.

The present thesis investigates the role of the prefrontal cortex and cholinergic modulation in attentional performance, and to a lesser extent, inhibitory response control, in rats. A greater understanding of these functions is important for the effective treatment of attentional and impulsive control deficits, present in a range of neuropsychiatric disorders. For this field to progress, the assessment of attentional performance in a similar manner across humans and animals is crucial. In the present thesis, attentional performance was assessed on the novel, touchscreen-based rodent continuous performance task (rCPT), which assesses sustained, focused attention in essentially an identical manner to CPTs commonly used in the clinic. Findings were compared to performance on the well-characterised 5-choice serial reaction time task (5-CSRTT), which assesses sustained, spatial divided attention and shares some, but not all characteristics of CPTs. The series of experiments described in this thesis contributes to the understanding of the role of the prefrontal cortex and cholinergic modulation in attentional performance; they also highlight differences between the two tasks in behaviour, brain functions and networks. Excitotoxic lesions of the medial prefrontal cortex (mPFC) and a range of cholinergic systemic pharmacology validated the role of the prefrontal cortex and cholinergic modulation in rCPT performance. A chemogenetic study also validated the role of the ascending cholinergic basal forebrain system in 5-CSRTT performance. These findings support 1. the idea of the relationship between cholinergic system activation and attentional performance to resemble an ‘inverted-U’ shaped function; 2. a double dissociation of mPFC sub-regions on attentional performance, in which the prelimbic cortex (PL) appears to play a role in rCPT performance, compared with a role of the anterior cingulate cortex (ACC) in 5-CSRTT performance; and 3. a role of ascending cholinergic projections from the basal forebrain to the ACC in 5-CSRTT performance. These findings also establish the development of a successful flanker distractor probe in rodents on the rCPT. This thesis concludes with an important comparison of the attentional and impulsivity measures in the rCPT compared to the 5-CSRTT, to help provide guidelines as to which task is most appropriate to use for particular research questions.

Stroke is the third leading cause of death and the primary cause of adult long-term disability in Canada. Despite advances in rehabilitation research, stroke survivors experience an unusually high incidence of depressive symptoms which undermine recovery outcomes by reducing patient motivation levels. Human and animal studies have linked the incidence of post-stroke depression and the extent of prefrontal cortex (PFC) damage. The PFC and the lateral habenula (LHb) are limbic structures that are strongly connected to the serotonergic dorsal raphe nucleus (DRN), a key neuronal hub for mood regulation. We hypothesized that PFC stroke produces a depressive phenotype by triggering maladaptive reorganization in mood-related networks. We used viral and optogenetic strategies to functionally characterize PFC and LHb projections to DRN. Moreover, we found that PFC stroke causes a time-dependent remodeling of LHb inputs to DRN 5-HT neurons which results in altered postsynaptic glutamate receptor number and subunit composition. This remodeling likely reflects a homeostatic upregulation of LHb-DRN synapses in response to stroke-induced challenge to network activity. Since these synapses encode stress and aversion, potentiation of this pathway could contribute to depressive symptoms following stroke. However, more work will be needed to identify the behavioral and network-level consequences of altered LHb-DRN dynamics. Thus, a deeper understanding of circuit mechanisms implicated in post-stroke depression will provide insights into this disease and open new treatment avenues to improve recovery.

The feasibility of using real-time functional magnetic resonance imaging (fMRI) feedback regarding the level of activation in rostromedial prefrontal cortex (rMPFC) to learn improved regulation of this brain area was examined in a group of 5 young adults. Subjects received real-time feedback from the target brain region while engaging in a blocked-design task involving alternating blocks of attempted up-regulation and down-regulation of the target brain region. A transient negative emotional state was induced prior to each scanning session. Subjects completed 6 scanning sessions (a pre-training session, 4 feedback sessions and a post-training session - no feedback was provided for pre and post-training sessions). The guideline strategy provided to subjects of engaging in emotional awareness during up-regulation and bodily awareness during down-regulation was found to consistently regulate the region in the pre-training session prior to the fMRI feedback sessions. This finding is in line with the previously proposed role of the rMPFC in emotional awareness. In contrast to previous real-time fMRI findings, greater recruitment of the region was observed in the pre-training session compared to the post-training session, with a non-significant negative trend observed across feedback sessions. These results suggest that there may be limitations to which the feedback techniques successfully employed for other brain regions extend to yet unexplored brain regions. / Arts, Faculty of / Psychology, Department of / Graduate

This dissertation investigates the fronto-parietal representation of the structure of organised mental episodes by studying its effect on the representation of cognitive events occurring at various positions within it. The experiments in chapter 2 look at the completion of hierarchically organized mental (task/subtask) episodes. Multiple identical target-detection events were organized into a sequential task episode, and the individual events were connected in a means-to-end relationship. It is shown that events that are conceptualized as completing defined task episodes elicit greater activity compared to identical events lying within the episode; the magnitude of the end of episode activity depended on the hierarchical abstraction of the episode. In chapter 3, the effect of ordinal position of the cognitive events, making up the task episode, on their representation is investigated in the context of a biphasic task episode. The design further manipulated the cognitive load of the two phases independently. This allowed for a direct comparison of the effect of phase vis-à-vis the effect of cognitive load. The results showed that fronto-parietal regions that increased their activity in response to cognitive load, also increased their activity for the later phases of the task episode, even though the cognitive load associated with the later phase was, arguably, lower than the previous phase. Chapter 4 investigates if the characteristics of the higher-level representations, like organization of task descriptions, have a causal role in determining the structure of the ensuing mental episode. Results show this to be true. They also confirm the results of earlier chapters in a different framework. Chapter 5 shows that the effect of episode structure is not limited to the elicited activity, but also affects the information content of the representation of the events composing the episode. Specifically, the information content in many regions of later steps is higher than that of earlier steps. Together, the results show widespread representation of the structure of organised mental episodes.

Cognitive impairments and changes in the structure and function of related brain regions, namely the prefrontal cortex and striatum, have long been implicated in drug addiction. However, it is unknown whether these abnormalities predate substance abuse, potentially serving as risk factors for dependence, or if they are the consequence of protracted use. To address this question, endophenotype research using stimulant-dependent individuals’ biological siblings has been used to investigate traits implicated in the pathology of addiction. Impairments present in both groups suggest an underlying risk-state for dependence, while additional abnormalities present only in stimulant-dependent individuals reflect potential effects of the drugs themselves. Contrastingly, there are also individuals who use stimulant drugs in a controlled manner without developing dependence. These ‘recreational users’ may lack the underlying traits that comprise a greater risk for dependence, or they might maintain additional protective factors against the development of addiction. Experiments in the first half of this dissertation used functional magnetic resonance imaging to investigate neurocognitive similarities and differences between dependent stimulant users, their non-dependent siblings, recreational users of cocaine, and unrelated healthy control volunteers. In Chapter 2, performance on a colour-word Stroop task was impaired in both stimulant-dependent individuals and their siblings, suggesting an endophenotype of cognitive inefficiency. However, neural activity significantly differed between the groups, indicating additional changes specific to the use of stimulant drugs. In Chapter 3, dependent users showed significant attentional bias to salient stimuli on a cocaine-word Stroop task, with a concurrent increase in prefrontal activation. Conversely, recreational users showed resilience in the face of cocaine cues and a decrease in arousal. Finally, Chapter 4 explored differences in reward sensitivity to both generic and drug-specific reinforcers, comparing the effects of personal and family history of stimulant exposure on a monetary incentive delay task. It is also under debate whether the neurocognitive differences seen in stimulant-dependent individuals are unique to substance abuse, or if parallel changes in behaviour and neurobiology are present in similar addiction-spectrum disorders, such as binge eating leading to obesity. In Chapter 5, stimulant-dependent and obese individuals with binge-eating behaviours showed differences in their substance-specific and general reward responsivity on a novel reward-valuation task. However, in Chapter 6 a similar decline in orbitofrontal cortex grey matter volume in relation to both years of stimulant use and body mass index was identified, implicating an overlap in this area between both conditions. These findings are integrated in Chapter 7, discussing the neurocognitive risk and protective factors that underlie an individual’s vulnerability for addiction, not only to stimulant drugs, but also potentially for other addictive behaviours.

Cognitive impairments are a hallmark of many, if not all, psychiatric disorders. They include deficits in working memory, attention, and cognitive flexibility. The prefrontal cortex (PFC) is essential for these cognitive functions and has been implicated in psychiatric disorders, including schizophrenia. The PFC receives reciprocal inputs from the thalamus, and this thalamo-PFC circuitry supports cognition. In patients with schizophrenia, who have impaired cognitive functioning, thalamo-PFC connectivity is disrupted. This finding is also seen in adolescents at high risk for the disorder, even before diagnosis.While impaired cortical maturation has been postulated as a mechanism in the etiology of schizophrenia, the postnatal development of thalamo-PFC circuitry is still poorly understood. In sensory cortex, activity relayed by the thalamus during a postnatal sensitive period is essential for proper cortical maturation. However, whether thalamic activity also shapes maturation of the PFC is unknown. Here, I will present evidence to support the hypothesis that adolescence represents a sensitive period, during which the PFC is susceptible to transient perturbations in thalamic input activity, resulting in persistent changes in circuitry. In Chapter 1, I present the existing literature on schizophrenia and our current understanding of its etiology. I then review the structure and connectivity of the PFC and its inputs, including the thalamus, in the context of schizophrenia and cognition. Next, I discuss the role of adolescence in the development of these structures and circuits. Finally, I introduce the concept of sensitive periods and outline the hypothesis that a similar process may occur in the context of the adolescent development of thalamo-PFC circuitry. To assess cognitive functioning in mouse models, I developed an operant-based working memory task. In Chapter 2, I describe this newly developed task and demonstrate that behavioral performance in the task is susceptible to PFC lesions. Thus, the task offers a new approach to studying PFC cognitive function. In Chapter 3, I discuss work done to address the hypothesis of adolescence as a sensitive period in the development of thalamo-PFC circuitry. I established an approach whereby I can transiently reduce activity in the thalamus during specific time windows. In this way, I compared the persistent effects of transient thalamic inhibition during adolescence and adulthood. I found that adolescent thalamic inhibition causes long-lasting deficits in cognitive behavioral performance, including the operant-based working memory task described in Chapter 2 and a cognitive flexibility task, decreased PFC cellular excitability, and reduced thalamo-PFC projection density. Meanwhile, adult thalamic inhibition has no persistent consequences on behavior or PFC excitability. Adolescent thalamic inhibition also results in disrupted PFC cellular cross-correlations and task outcome encoding during the cognitive flexibility task. Strikingly, exciting the thalamus in adulthood during the behavioral task rescues PFC cross-correlations, task outcome encoding, and the cognitive deficit. These data support the hypothesis that adolescence is a sensitive period in thalamo-PFC circuit maturation as adolescent thalamic inhibition has long-lasting consequences on PFC circuitry, while adult thalamic inhibition has no persistent effects. Moreover, these results highlight the role of the thalamus as a non-specific facilitator of PFC activity, expanding our understanding of this thalamic function to additional cognitive contexts. By supporting PFC network activity, boosting thalamic activity provides a potential therapeutic strategy for rescuing cognitive deficits in neurodevelopmental disorders. Finally, in Chapter 4, I conclude with a general discussion. I highlight major take-aways from this work as well as next steps in our exploration of these crucial neural circuits. Together, the findings outlined here offer new promise for early diagnosis and treatment options for patients with cognitive impairments and psychiatric disorders.

Thesis advisor: Gorica D. Petrovich / Environmental cues that are neutral in respect to hunger and feeding can come to predict food through Pavlovian appetitive conditioning. These learned cues can drive food seeking and eating independent of physiological hunger leading to overeating and obesity. However, the food outcome, and thus the value of the cues, can change due to environmental alterations. A change in the values of learned cues requires altering behavioral responses to accurately reflect the cue’s new outcome. This behavioral flexibility is necessary to respond appropriately to changes in the environment and, as such, is an adaptive trait. The aim of this dissertation was to determine critical neural mechanisms specifically within the basolateral amygdala (BLA) and also with its interactions with the medial prefrontal cortex (mPFC) during behavioral flexibility when outcomes of learned appetitive cues change using the appetitive reversal learning paradigm. The main focus was on the BLA (Chapter 2) and its connection with the mPFC (Chapters 3 and 4) since both of these areas are critical in appetitive cue learning and valuation and subsequent behavioral modifications. The first study in this dissertation examined if separate neuronal ensembles within the BLA respond to different learned cues, a cue that signals food availability and a cue that does not. Additionally, we investigated if these potentially distinct neuronal ensembles are necessary during periods of behavioral flexibility when the value of the specific learned cues are changed during reversal learning. We determined that there are distinct neuronal ensembles within the BLA that respond to different learned cues, and that the cue-specific ensembles are necessary for updating the value of each specific cue (Chapter 2). Next, we examined a projection target of the BLA, the mPFC, to determine if BLA-projecting neurons are activated during learning (Chapter 3). Using retrograde tract tracing combined with Fos detection, we found recruitment of the anterior BLA to prelimbic area of the mPFC across cue-food learning, signifying that the BLA can inform the mPFC of the value of learned cues. Then to establish that communication between the BLA and mPFC is necessary for cue value learning and updating (Chapter 4), we functionally disconnected communication between these regions and examined appetitive learning using discriminative conditioning, reversal learning, and devaluation paradigms. We found impairments in cue value recall and subsequent updating of the cues’ values during reversal learning. Together, these studies indicate the BLA may be important in informing the mPFC of the value of learned cues, and their interaction is critical to optimally guide behavioral responding. The findings from these experiments are valuable for our understanding of the neural mechanisms that motivate eating behavior under the control of learned food cues and to understand the mechanisms necessary for behavioral flexibility when the outcomes of learned cues are changed. / Thesis (PhD) — Boston College, 2018. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

Orientador: Rodrigo Vitório / Resumo: Introdução: Apesar dos correlatos neurais dos comprometimentos do andar associados ao envelhecimento não serem completamente compreendidos, estudos recentes apontam que idosos apresentam maior ativação do córtex pré-frontal (via indireta) durante o andar. Entretanto, os estudos existentes não consideram o processo de envelhecimento em um espectro mais amplo e, ao contrário, apresentam comparações limitadas a extremos de idade (adulto jovem X idoso). A compreensão da atividade neural do controle do andar no envelhecimento é importante para a identificação do momento em que as alterações inerentes ao envelhecimento afetam a atividade do córtex cerebral. Assim os objetivos deste estudo foram: (i) investigar os efeitos do envelhecimento na atividade do córtex pré-frontal (CPF) durante o andar usual, adaptativo e com tarefa dupla; e (ii) analisar a associação entre a atividade cortical e medidas do andar e de funções cognitivas. Materiais e Método: Noventa participantes foram avaliados, sendo 15 participantes sadios em cada grupo etário: 20-25, 30-35, 40-45, 50-55, 60-65 e 70-75 anos. Foram realizadas avaliações cognitivas, do andar e da atividade do CPF. Um sistema portátil de espectroscopia funcional de luz próxima ao infravermelho foi utilizado para o registro da atividade do CPF enquanto os participantes andavam em um circuito em três condições: andar usual, adaptativo (ultrapassagem de obstáculos) e com tarefa dupla. Um carpete com sensores de pressão foi posicionado em uma d... (Resumo completo, clicar acesso eletrônico abaixo) / Abstract: Introduction: Although the neural correlates of walking impairments associated with aging are not fully understood, recent studies indicate that the older adults present greater activation of the prefrontal cortex during walking. However, existing studies do not consider the aging process in a broader spectrum and, on the contrary, present limited comparisons to extremes of age (younger X older adult). Understanding the neural activity of walking control in aging is important to identify when the inherent changes in aging affect the activity of the cerebral cortex. Thus, the aims of this study were: (i) to investigate the effects of aging on the activity of the prefrontal cortex (PFC) during usual, adaptive and dual task walking; and (ii) to analyze the association of cortical activity with walk measures and cognitive functions. Materials and Methods: Ninety participants were evaluated, with 15 healthy participants in each age group: 20-25, 30-35, 40-45, 50-55, 60-65 and 70-75 years. Cognitive, walking and PFC activity assessments were performed. A portable near infrared functional spectroscopy system was used to record PFC activity while participants walked on a circuit in three conditions: usual, adaptive (obstacle avoidance) and dual task walking. A carpet with pressure sensors was positioned in one of the straight lines of the circuit to record walk parameters. ANCOVAs were used to analyze differences in oxyhemoglobin concentrations between groups and conditions; Two-way ... (Complete abstract click electronic access below) / Mestre

The ability to recognize dangerous situations and environments is crucial for survival, but overestimating risk can lead to pathological avoidance of normal activities, potentially leading to anxiety disorders. Many studies over the past several decades have begun to identify the brain regions underlying threat detection and anxiety behavior. In particular, the ventral hippocampus has emerged as a critical structure for emotional behaviors, including innate anxiety. Recent work from our lab and others has shown that ventral CA1 pyramidal neurons encode information about anxiety, and these CA1 neurons preferentially target downstream structures such as hypothalamus and medial prefrontal cortex. However, the neural representation of anxiogenic environments in the initial stage of the trisynaptic circuit— the dentate gyrus— is unknown. Here, I use Dock10-Cre and Drd2-Cre mouse lines to gain optical access to granule cells and mossy cells, respectively, in the ventral dentate gyrus. Calcium activity was recorded during free exploration of the elevated plus maze (EPM) and open field test (OFT). Single cell activity and population coding were analyzed for mossy cells, granule cells, and CA1 pyramidal neurons. I found that anxiety-related activity was present in granule cells and vCA1, however mossy cells encoded novelty and spatial position. Furthermore, chemogenetic inhibition of mossy cells did not disrupt behavior in the EPM or OFT, but did disrupt acquisition of a contextual fear memory. These findings support the notion that different features of an anxiogenic environment are encoded by different cell types, and that anxiety information is present at the earliest stage of the trisynaptic circuit.