<p>An animal's ability to make adaptive choices is key to its fitness. Thus, the process of determining options, making a decision, evaluating outcomes, and learning from those outcomes to adjust future behavior is a central function of our nervous system. Determining the neural mechanisms of these cognitive processes is a crucial goal. One brain region, the posterior cingulate cortex (CGp), a central hub within the default mode network, is prominently dysregulated in Alzheimer's Disease and schizophrenia. Despite its clinical importance, the posterior cingulate cortex remains an enigmatic nexus of attention, memory, and motivation, all pointing to a role in decision-making. This dissertation is concerned with the role of this brain region in the learning and valuation processes involved in making adaptive choices. Specifically, I used rhesus macaques (Macaca mulatta) to examine the neural activity in posterior cingulate associated with specific learning and valuation -related variables. In the first experiment, I showed that posterior cingulate neurons track decision salience--the degree to which an option differs from a standard--but not the subjective value of a decision. To do this, I recorded the spiking activity of CGp neurons in monkeys choosing between options varying in reward-related risk, delay to reward, and social outcomes, each of which varied in level of decision salience. Firing rates were higher when monkeys chose the risky option, consistent with their risk-seeking preferences, but were also higher when monkeys chose the delayed and social options, contradicting their preferences. Thus, across decision contexts, neuronal activity was uncorrelated with how much monkeys valued a given option, as inferred from choice. Instead, neuronal activity signaled the deviation of the chosen option from the standard, independently of how it differed. The observed decision salience signals suggest a role for CGp in the flexible allocation of neural resources to motivationally significant information, akin to the role of attention in selective processing of sensory inputs. This pointed to a role for CGp in learning rather than subjective value signaling, and the second set of experiments aimed to test the role of CGp in associative learning. I recorded from single CGp neurons in monkeys performing a simple conditional motor association task while varying stimulus familiarity and motivation. CGp neurons responded phasically following commission of errors, and this error signal was modulated by motivation and stimulus novelty. Moreover, slow variations in firing rates tracked variations in learning rate over the course of sessions. Silencing these signals with muscimol impaired learning in low motivational states but spared learning in high motivational states, and spared recall of familiar associations as well. These findings endorse a role for CGp in performance and environment monitoring to regulate learning rate. Collectively, these experiments reshape our understanding of the role of posterior cingulate cortex in cognition, integrate default mode and value-based theories of CGp function, and provide a potential foundation for a circuit-level explication of Alzheimer's Disease and schizophrenia.</p> / Dissertation

Emotion processing involves specialised brain regions allowing for effective evaluation of the social environment and for the acquisition of social skills that emerge over childhood. In humans, an important aspect of normal development is the ability to understand the facial expressions of others that signal the nature and safety of the environment. Existing functional data, however, have not characterised the developmental trajectories associated with the differing neural and cognitive-behavioural development. The current thesis investigates the functional specialisation and development of the spatial and temporal patterns in neural activities during implicit processing of facial emotions from early childhood through adulthood. The first study identified brain regions engaged in implicit processing of emotional expressions using a simple emotion-processing paradigm (target detection task) with fourteen healthy adults using magnetoencephalography (MEG) recordings. Participants responded to a non-face target (a scrambled pattern) while ignoring the emotional face presented in a different hemifield. Results showed ACC and right-lateralised amygdala activations in early latencies in response to the unattended emotional faces related to rapid and implicit attention to the task-irrelevant facial emotions, specifically during the processing of the fearful emotion. Based on the findings in the first study, the second study investigated the developmental patterns and age-related differences in brain activities associated with the rapid and automatic processing of the emotional expressions in MEG with twelve children 7 – 10 years old, twelve adolescents 12 – 15 years old and twelve young adults (mean age 24.4 years) using the same paradigm. The results showed that emotion processing developed early in childhood in the amygdalae, whereas the processing of fear had later maturation engaging the ACC. The results further demonstrated an age-correlated increase in development in ACC activity and an age-related laterality shift in the amygdalae related to fear processing. The present thesis provides new evidence contributing to the understanding of the protracted but differing normal development in the emotional brain over the childhood into adulthood, and offers critical insights into understanding possible dysfunctions of these brain regions during development.

Neurabin, a cytoskeletal protein, has been shown to be required for normal dopamine signalling, and dopaminergic systems have been previously implicated in the pathophysiology of anxiety disorders, including generalized social anxiety disorder. And results from neuroimaging studies have implicated the anterior cingulate cortex (ACC) in depression and anxiety disorders. However, lesion studies have failed to produce the expected deficits. Here, we demonstrate that the injections of muscimol and midazolam into the ACC reduced anxiety- and depression-like behaviours, and that complete absence of neurabin reduced anxiety-like behaviour but increased depression-like behaviour. However, reduction of neurabin by injecting neurabin-targeted siRNA into the ACC reduced anxiety-like behaviour but did not affect depression-like behaviour. This study provides evidence that the imbalance of excitatory and inhibitory activity in the ACC alters affective disorders, and that neurabin may be critical for the modulation of these behaviours.

Neurabin, a cytoskeletal protein, has been shown to be required for normal dopamine signalling, and dopaminergic systems have been previously implicated in the pathophysiology of anxiety disorders, including generalized social anxiety disorder. And results from neuroimaging studies have implicated the anterior cingulate cortex (ACC) in depression and anxiety disorders. However, lesion studies have failed to produce the expected deficits. Here, we demonstrate that the injections of muscimol and midazolam into the ACC reduced anxiety- and depression-like behaviours, and that complete absence of neurabin reduced anxiety-like behaviour but increased depression-like behaviour. However, reduction of neurabin by injecting neurabin-targeted siRNA into the ACC reduced anxiety-like behaviour but did not affect depression-like behaviour. This study provides evidence that the imbalance of excitatory and inhibitory activity in the ACC alters affective disorders, and that neurabin may be critical for the modulation of these behaviours.

Emotion processing involves specialised brain regions allowing for effective evaluation of the social environment and for the acquisition of social skills that emerge over childhood. In humans, an important aspect of normal development is the ability to understand the facial expressions of others that signal the nature and safety of the environment. Existing functional data, however, have not characterised the developmental trajectories associated with the differing neural and cognitive-behavioural development. The current thesis investigates the functional specialisation and development of the spatial and temporal patterns in neural activities during implicit processing of facial emotions from early childhood through adulthood. The first study identified brain regions engaged in implicit processing of emotional expressions using a simple emotion-processing paradigm (target detection task) with fourteen healthy adults using magnetoencephalography (MEG) recordings. Participants responded to a non-face target (a scrambled pattern) while ignoring the emotional face presented in a different hemifield. Results showed ACC and right-lateralised amygdala activations in early latencies in response to the unattended emotional faces related to rapid and implicit attention to the task-irrelevant facial emotions, specifically during the processing of the fearful emotion. Based on the findings in the first study, the second study investigated the developmental patterns and age-related differences in brain activities associated with the rapid and automatic processing of the emotional expressions in MEG with twelve children 7 – 10 years old, twelve adolescents 12 – 15 years old and twelve young adults (mean age 24.4 years) using the same paradigm. The results showed that emotion processing developed early in childhood in the amygdalae, whereas the processing of fear had later maturation engaging the ACC. The results further demonstrated an age-correlated increase in development in ACC activity and an age-related laterality shift in the amygdalae related to fear processing. The present thesis provides new evidence contributing to the understanding of the protracted but differing normal development in the emotional brain over the childhood into adulthood, and offers critical insights into understanding possible dysfunctions of these brain regions during development.

<p>Negotiating the complex decisions that we encounter daily requires coordinated neu- </p><p>ronal activity. The enormous variety of decisions we make, the intrinsic complexity </p><p>of the situations we encounter, and the extraordinary flexibility of our behaviors </p><p>suggest the existence of intricate neural mechanisms for negotiating contexts and </p><p>making choices. Further evidence for this prediction comes from the behavioral al- </p><p>terations observed in illness and after injury. Both clinical and scientific evidence </p><p>suggest that decision signals are carried by electrical neuronal activity and influenced </p><p>by neuromodulatory chemicals. This dissertation addresses the function of two puta- </p><p>tive contributors to decision-making: neuronal activity in posterior cingulate cortex </p><p>and modulatory effects of serotonin. I found that posterior cingulate neurons respond </p><p>phasically to salient events (informative cues; intentional saccades; and reward deliv- </p><p>ery) across multiple contexts. In addition, these neurons signal heuristically guided </p><p>choices across contexts in a gambling task. These observations suggest that posterior </p><p>cingulate neurons contribute to the detection and integration of salient information </p><p>necessary to transform event detection to expressed decisions. I also found that </p><p>lowering levels of the neuromodulator serotonin increased the probability of making </p><p>risky decisions in both monkeys and mice, suggesting that this neurotransmitter con- </p><p>tributes to preference formation across species. These results suggest that posterior </p><p>cingulate cortex and serotonin each contribute to decision formation. In addition, the </p><p>unique serotonergic pro jections to posterior cingulate cortex, as well as the frequent </p><p>implication of altered serotonergic and posterior cingulate function in psychiatric dis- </p><p>orders, suggest that the confluence of cingulate and serotonergic activity may offer </p><p>key insights into normal and pathological mechanisms of decision making.</p> / Dissertation

The current study is the first to demonstrate that structural deficits in the Anterior Cingulate Cortex (ACC) of the human brain may play a role in reading ability. Recent imaging work has indicated that the ACC is activated by tasks involving modulation of the fronto-temporal networks during language processing tasks and may be involved in anticipatory reactions and response preparation during reading. This study investigated the relationship between ACC volumetric measurements and reading ability in a sample of 68 individuals nested within 24 families with and without reading disorders. This sample allowed for examination of the effect of the volume of the ACC on reading, while controlling for normally occurring fluctuations in the size of the ACC due to heredity and shared environment. Forty-five linear models were conducted in SPSS on all 68 participants using the brain measurements (ACC, ACC with Paracingulate (PaC), and Putamen, separately) as well as control variables (gender, FSIQ, family membership) as predictors of the outcomes variables related to reading achievement (GORT Passage, rate, and accuracy) and reading processes (CTOPP phonological awareness and rapid naming). The use of family membership as a random effect predictor together with the specific brain volume as a predictor allowed for the effect of family on reading outcomes to be accounted for while, explicitly accounting for any relationships that may exist between family and brain volume. Additional sets of measurements, with PaC, were included in the final analyses to address the inconsistent inclusion of this tertiary structure in earlier research. Finally, a control region (putamen) was included to rule out whole brain effects and improve the specificity of the findings. The most significant findings were that the results varied systematically with inclusion or exclusion of the PaC. Measurements including the PaC were statistically significant for reading achievement for the left side of the ACC as expected. However, for the ACC volume without PaC, it was the right side that was related to reading measures. Neither set of measurements of the ACC were predictive of group membership. The current study supported a role for the ACC in reading and suggests a standardized method for inclusion of the PaC in the volumetric analysis of the ACC. / text

<p>The visual world is full of potentially important information, but only a subset of the world can be evaluated at any time. An essential function of the central nervous system is to rapidly and adaptively select which stimuli warrant attention. Much of the time, attention is directed towards stimuli that are relevant for current goals. However, things that have proven important in an organisms' personal or evolutionary past effectively compete with goal-relevant targets for attention. In humans, one example of this attentional superset is faces: faces attract attention even when they are in competition with immediate goals. Using a combination of behavioral, pharmacological, and electrophysiological techniques in the rhesus macaque, I investigated the physiological, neurobiological, and evolutionary determinants of the attentional capture of faces. First, I show that the prioritization of faces is evolutionarily conserved in primates. Face distractors also capture attention in rhesus macaques, a species of old world monkey, successfully competing with task goals for limited attentional resources. Importantly, the same classes of faces have the greatest attentional effects in both monkeys and humans. Further, I describe behavioral evidence that subcortical systems contribute to the attentional salience of faces in this species, proving an initial characterization of the neural mechanisms that may mediate this effect. Next, I examine the interaction between pupil size and vigilance for faces. A focal increase in luminance has long been known to provoke pupil constriction, but here I show that the pupil response to a flashed distractor is proportional to the allocation of attention to that image. Pupil constriction may provide a novel implicit metric of stimulus attention. In particular, face images provoked greater pupil constriction than non-face images. Moreover, I also find that baseline pupil size is a strong predictor of distractor interference, suggesting that arousal may modulate social vigilance. Therefore, I next examined the activity of single neurons within dorsal anterior cingulate cortex (dACC), a region implicated in task performance across a wide variety of tasks, but which also has strong connections to subcortical neuromodulatory centers responsible for regulating arousal. I find that the dACC discriminates between social and nonsocial distractors, scales with distractor attention, and predicts adjustments in arousal and vigilance state on upcoming trials. This is consistent with a model in which dACC supports task performance through regulating arousal. Finally, I turn to oxytocin (OT), a neuromodulatory hormone released during affiliative social interactions that is also implicated in regulating arousal. Though typically thought to generally enhance social attention, I report multiple circumstances in which OT suppresses, rather than enhances, vigilance for faces. This suggests a mechanism through which affiliative social interactions can reduce social vigilance, permitting more relaxed social interactions. Together, these results highlight an evolutionarily conserved neural circuit important for the adaptive, contextual modulation of reflexive face attention, a behavior that is compromised in both anxiety disorders and autism.</p> / Dissertation

<p>It has been suggested that primate brains are inherently biased towards gathering and processing the social information present in the world. In fact, the neural network that mediates our engagement with the external world - the default mode network (DMN) ¬- is strongly convergent with the neural circuitry for social cognition. The posterior cingulate (PCC) is believed to be a key node in both the DMN and in social cognition. Human and non-human primate studies have demonstrated a role for the PCC in outcome monitoring: it tracks rewards, subjective values of choices, task engagement and global choice strategies. It is also implicated in social cognition. Human studies show that PCC activity varies with the recall of autobiographical memories and exposure to social stimuli. While several electrophysiological studies explicate the response of PCC neurons to non-social outcome monitoring and valuation, there is a lack of similar studies for social valuation. This thesis is concerned with characterizing the neuronal responses in the PCC to social stimuli and determining whether social valuation occurs in the PCC in a manner similar to that previously described for non-social outcomes. I recorded the single unit activity of neurons in the PCC of rhesus macaques while they performed behavioral tasks that required attending to the faces of high-status or low-status individuals. Monkeys valued the faces of high-status individuals more than low-status individuals, though they were equally likely to identity and overtly attend to faces of both social classes. This differential valuation of face stimuli was represented in the firing activity of PCC neurons, with higher neuronal activity seen in response to subordinate faces as compared to dominant ones. Cells in the PCC did not track the individual identity of the presented faces. Furthermore, neuronal activity in the PCC predominantly tracked social value, and not non-social reward delivery as previously reported. Neuronal activity also predicted task engagement, with higher firing rates being predictive of a decrease in task engagement. To summarize, the PCC is biased towards social information processing, and neuronal activity in the PCC tracks social category information and the level of task engagement.</p> / Dissertation

Antipsychotic drugs (typical and atypical) are used in the treatment of mental disorders such as schizophrenia. Typical antipsychotic drugs (such as haloperidol) specifically target dopamine D2 receptors and produce extrapyramidal side effects. Atypical antipsychotic drugs (such as risperidone and olanzapine) primarily target dopamine D2 and serotonin 5HT2A receptors and produce fewer extrapyramidal symptoms (EPS) than do the typical antipsychotic drugs at clinically effective doses (Meltzer and Nash, 1991). It has been proposed that the prefrontal cortex (a brain region implicated in the pathophysiology of schizophrenia) is the locus of antipsychotic drug action to improve cognitive dysfunction and negative symptoms of schizophrenia (Weinberger and Lipska, 1995; Jakab and Goldman-Rakic, 1998). Moreover, it is possible that the effects in the prefrontal cortex may contribute to the differences between typical and atypical antipsychotic drugs as well as differences among atypical antipsychotic drugs (Horacek et al., 2006). The core pathology associated with the dorsolateral prefrontal cortex includes reduced cerebral volume, increased ventricle size and deficits in neuronal morphology, including increased cell packing density, reduction in dendrites and its associated dendritic spines (Selemon and Goldman-Rakic, 1999). However, since most neuropathology data emerge from in vivo imaging and post-mortem studies of patients with schizophrenia, it is difficult to interpret and distinguish between findings that have an etiological or iatrogenic basis. Thus, the objective of the current study was to examine the effects of antipsychotic drugs, at therapeutically relevant concentrations, in a rat brain region that is homologous to that of the human dorsolateral prefrontal cortex. The hypothesis upon which this study was based is that haloperidol, risperidone and olanzapine (at 65 to 80% striatal dopamine D2 receptor occupancy) induce changes to pyramidal cell architecture in the rat anterior cingulate cortex (Vogt and Gabriel, 1993; Hoover and Vertes, 2007). This hypothesis was investigated by (a) determining doses that are within the therapeutic range (65 to 80% striatal dopamine D2 receptor occupancy) by measuring the occupancy of haloperidol, risperidone and olanzapine in the presence of 3H-raclopride ( a dopamine D2 receptor antagonist) at dopamine D2 receptors in the rat striatum; and (b) examining whether therapeutic doses of antipsychotic drugs in rats cause neuropathology comparable to that observed in human post-mortem brains of patients with schizophrenia. Antipsyhcotic drug doses were selected using an appropriate in vivo dopamine D2 receptor occupancy method. The findings from this study revealed that 0.25 mg/kg/day haloperidol, 5 mg/kg/day risperidone and 10 mg/kg/day olanzapine achieved therapeutically relevant rat striatal dopamine D2 receptor occupancy in the range of 65 to 80%. To determine whether antipsychotic drugs at therapeutic doses established above induce changes in neuronal cell density and morphology; immunohistochemistry, single cell injection of lucifer yellow dye and Golgi-Cox impregnation of layer II/III pyramidal cells was performed. The results from these experiments revealed that the density of cells expressing NeuN, parvalbumin, calretinin or calbindin is highly unlikely to be affected by chronic exposure to haloperidol, risperidone and olanzapine. The current study evaluated the effects of chronic antipsychotic drug exposure on spontaneous locomotor activity of a rat in a novel environment. The purpose of this study was to differentiate between a direct and an indirect drug effect. It was found that at the doses established above, risperidone and olanzapine did not overtly reduce spontaneous locomotor activity of a rat in a novel environment relative to controls. In contrast, haloperidol reduced spontaneous locomotor activity of rat in an open field, although this was not statistically significant. Nevertheless, the data reported here allowed us to conclude that the level of activity across groups is unlikely to affect the data obtained in subsequent studies investigating the effects of chronic antipsychotic drug treatment on pyramidal cell structure. Intracellular injection of lucifer yellow dye into pyramidal cells revealed that chronic haloperidol treatment (28 days) was associated with a relative increase in basal dendritic arborisation, but neither of these drug treatments induced changes in arborisation that were different from controls. No statistically significant change in the basal dendritic arbor was detected with animals treated with risperidone relative to controls. Similarly using the Golgi-impregnation method, changes in soma size, dendritic branching, total number of branches and the density of dendritic spines in antipsychotic drug treated groups were not significantly different to controls. Taken together, this finding indicates that only relatively subtle neuritic changes may be attributed to chronic treatment with typical or atypical antipsychotic drugs administered at doses that avhieved striatal dopamine D2 receptor occupancy in the range of 65 to 80%. In summary, this study confirms that antipsychotic drugs are unlikely to induce changes to neuronal cell density or morphology in the rat anterior cingulate cortex at therapeutically relevant doses. Hence, it can be concluded that the observed neuropathology, found in the brains of patients with schizophrenia that have undergone antipsychotic drug therapy, is more likely to be caused by the disease and not the effects of the concomitant drug therapy.