We humans depend heavily on cognitive control to make decision and execute goal-directed behaviors, without which our behavior would be overpowered by automatic, stimulus-driven responses. In my dissertation, I focus on a brain region most implicated in this crucial process: the anterior cingulate cortex (ACC). The importance of this region is highlighted by lesion studies demonstrating diminished self-initiated behavior, or apathy, following ACC damage, the most severe form of which results in the near complete absence of speech production and willed actions in the presence of intact motor ability. Despite decades of research, however, its precise function is still highly debated, due particularly to ACC’s observed involvement in multiple aspects of cognition. In my dissertation I examine ACC function according to recent developments in reinforcement learning theory that posit a key role for ACC in motivating extended behavior. According to this theory, ACC is responsible for learning task values and motivating effortful control over extended behaviors based on those learned task values. The aim of my dissertation is two-fold: 1) to improve understanding of ACC function, and 2) to elucidate the contribution of ACC to depression, as revealed by individual differences in several personality traits related to motivation and reward sensitivity in a population of healthy college students. It was hypothesized that these different personality traits express, to greater or lesser degrees across individuals, ACC function, and that their abnormal expression (in particular, atypically low motivation and reward sensitivity) constitute hallmark characteristics of depression. First, this dissertation reveals that reward positivity (RewP), a key electrophysiological signature of reward processing that is believed to index the impact of reinforcement learning signals carried by the midbrain dopamine system on to ACC, is sensitive to individual differences in reward valuation, being larger for those high in reward sensitivity and smaller for those high in depression scores. Second, consistent with a previous suggestion that people high in depression or depression scores have difficulty using reward information to motivate behavior, I find these individuals to exhibit relatively poor prolonged task performance despite an apparently greater investment of cognitive control, and a reduced willingness to expend effort to obtain probable rewards, a behavior that was stable with time on task. In contrast, individuals characterized by high persistence, which is indicative of good ACC function, exhibited high self-reported task engagement and increasing effortful behaviors with time on task, particularly for trials in which reward receipt was unlikely, suggesting increased motivational control. In sum, this dissertation emphasizes the importance of understanding the basic function of ACC as assessed by individual differences in personality, which is then used to understand the impact of its dysfunction in relation to mental illnesses. / Graduate

Convergent evidence suggests that the dorsal medial prefrontal cortex (dmPFC) makes an important contribution to goal-directed action selection. The dmPFC is also part of a network of brain regions that becomes compromised in old age. It was hypothesized that during decision-making, some process of comparison takes place in the dmPFC between the representation of available actions and associated values, and that this process is changed with aging. These hypotheses were tested in aged and young adult rats performing a novel 3-choice, 2-cue decision task. Neuron and local field potential activity revealed that the dmPFC experienced different states during decision and outcome phases of the task, with increased local inhibition and oscillatory (gamma and theta) activity during cue presentation, and increased excitatory neuron activity (among regular firing neurons) at goal zones. Although excitatory and inhibitory activity appeared anti-correlated over phases of the decision task, cross-correlations and the prominent gamma oscillation revealed that excitation and inhibition were highly correlated on the millisecond scale. This "micro-scale" coupling between excitation and inhibition was altered in aged rats and the observed changes were correlated with changes in decision and movement speeds of the aged animals, suggesting a putative mechanism for age-related behavioral slowing. With respect to decision-making, both aged and young adult rats learned over multiple days to follow the rewarded cue in the 3-choice, 2-cue task. Support for the hypothesis that the dmPFC simultaneously represents alternative actions was not found; however, neuron activity selective for particular goal zones was observed. Interestingly, goal-selective neural activity during the decision period was more likely to take place on error trials, particularly on high-performing sessions and when rats exhibited a preference for a particular feeder. A possible interpretation of these patterns is that goal representations in the dmPFC might have sometimes overruled learned habits, which are likely to be involved in following the correct cue and which are known to be supported by other brain regions. These results describe fundamental properties of network dynamics and neural coding in the dmPFC, and have important implications for the neural basis of processing speed and goal-directed action.

The aims of the thesis were to examine i) whether the endogenous opioid system (EOS) is lateralized in human brain areas involved in processing of emotions and pain; ii) whether EOS responses to unilateral brain injury depend on side of lesion, and iii) whether in human alcoholics, this system is involved in molecular adaptations in brain areas relevant for cognitive control of addictive behavior and habit formation. The main findings were that (1) opioid peptides but not opioid receptors and classic neurotransmitters are markedly lateralized in the anterior cingulate cortex involved in processing of  positive and negative emotions and affective component of pain. The region-specific lateralization of neuronal networks expressing opioid peptides may underlie in part lateralization of higher functions in the human brain including emotions and pain. (2) Analysis of the effects of traumatic brain injury (TBI) demonstrated predominant alteration of dynorphin levels in the hippocampus ipsilateral to the injury, while injury to the right hemisphere affected dynorphin levels in the striatum and frontal cortex to a greater extent than that to the left hemisphere. Thus, trauma reveals a lateralization in the mechanisms mediating the response of dynorphin expressing neuronal networks in the brain. These networks may differentially mediate effects of left or right brain injury on lateralized brain functions. (3) In human alcoholics, the enkephalin and dynorphin systems were found to be downregulated in the caudate nucleus and / or putamen that may underlie in part changes in goal directed behavior and formation of a compulsive habit in alcoholics. In contrast to downregulation in these areas, PDYN mRNA and dynorphins in dorsolateral prefrontal cortex, k-opioid receptor mRNA in orbitofrontal cortex, and dynorphins in hippocampus were upregulated in alcoholics. Activation of the k-opioid receptor by upregulated dynorphins may underlie in part neurocognitive dysfunctions relevant for addiction and disrupted inhibitory control. We conclude that the EOS exhibits region-specific lateralization in human brain and brain-area specific lateralized response after unilateral TBI in mice; and that the EOS is involved in adaptive processes associated with specific aspects of alcohol dependence.

A dor é um fenômeno multidimensional, que geralmente desencadeia reações emocionais desconfortáveis quando identificada. Sua relação com injúria tecidual pode ser interpretado como um mecanismo adaptativo de defesa à integridade do organismo, tendo em vista sua preservação evolutiva. Porém, o substrato neurobiológico do organismo parece determinar a complexificação do repertório comportamental em diferentes espécies. Nesse sentido, o córtex cingulado anterior (CCA) tem sido amplamente descrito em mamíferos modulando diferentes aspectos da dor. O presente trabalho utilizou os testes algesimétricos de vocalização e da formalina em cobaias, para se avaliar o decurso temporal do efeito da microinjeção de agonistas e antagonistas GABAérgico (muscimol e bicuculina); colinérgico (carbacol e atropina) e opioidérgico (morfina e naloxona). A microinjeção de bicuculina (1 nmol / 0,2 µl) exacerbou as respostas nociceptivas em ambos os testes, porém diferentes doses de muscimol (0,5, 1 e 2 nmol / 0,2 µl), não modificaram as respostas. O efeito da bicuculina foi bloqueado em ambos os testes pela microinjeção prévia de muscimol (1 nmol/ 0,2 µl) no CCA. A microinjeção de carbacol (2,7 nmol /0,2 µl) neste substrato promoveu antinocicepção, evidenciada por meio da atenuação da amplitude das vocalizações, mas não pelo teste da formalina. Esse efeito foi bloqueado pela administração prévia de atropina (0,7 nmol /0,2 µl) e de naloxona (2,7 nmol /0,2 µl). A microinjeção de morfina (4,4 nmol /0,2 µl) promoveu antinocicepção em ambos os testes. Concluímos que a inibição do tônus GABAérgico no CCA exacerba os comportamentos nociceptivos e que a antinocicepção promovida por carbacol pode ter sido mediada pelo sistema de opióides endógenos, tendo em 9 vista o bloqueio do seu efeito com naloxona. Além disso, a estimulação opióide promove uma contundente antinocicepção. / Pain is a multidimensional phenomenon which usually triggers uncomfortable emotional reactions when identified. Its relation injury can be interpreted as an adaptive mechanism to defend the integrity of the body given its evolutionary conservation. However the neurobiological substrate of the body seems to determine the complexification of behavioral repertoire in different species. Thus, the anterior cingulated cortex (ACC) has been widely described in mammals by modulating different cognitive aspects of pain. This study used algesimetric tests of vocalization and formalin in guinea pigs to evaluate the time course of the effect of microinjection of GABA agonists and antagonists (bicuculline and muscimol) and cholinergic (carbachol and atropine) beyond the opioid antagonist naloxone. The microinjection of bicuculline (1 nmol / 0,2 µl) exacerbated the nociceptive behavior in both tests but different doses of muscimol (0,5; 1 e 2 nmol / 0,2 µl) did not change the responses. The effect of bicuculline was blocked in both tests by prior microinjection of muscimol (1 nmol / 0,2 µl) in the ACC. The microinjection of carbachol (2,7 nmol / 0,2 µl) on this substrate promoted antinociception as evidenced by attenuation of the amplitude of the vocalizations, but not by the formalin test. This effect was blocked by prior administration of atropine (0,7 / 0,2 µl) and naloxone (0,7 nmol / 0, 2 µl). The microinjection of morphine (4,4 nmol / 0,2 µl) promoted antinociception in both tests. We conclude that inhibition of GABAergic tone in the ACC exacerbates nociceptive behaviors and that the antinociception promoted by carbachol may 11 have been mediated by endogenous opioid system in order blocking its effect with naloxone. In addition opioid stimulation promotes a striking antinociception.

The dorsal anterior cingulate cortex (dACC) has been implicated in a broad range of cognitive and emotional functions, including the processing of negative emotion. Furthermore, abnormalities in dACC activity have been associated with anxiety and depression, disorders in which negative emotion is dysregulated. Thus, a better understanding of the precise contributions of the dACC to negative emotion could give us important insights into the neurobiological mechanisms underlying these debilitating neuropsychiatric disorders. However, despite extensive study of the dACC, its precise role in negative emotion is unclear. Instead there is mounting evidence that rather than being one functionally homogeneous region, subregions of the dACC may have distinct functional roles. This evidence is largely correlational, and interventional studies in experimental animals are required to address this. Accordingly, the work in this thesis causally assessed the contributions of two spatially distinct subregions of the dACC (rostral and caudal) to the regulation of the behavioural and cardiovascular correlates of negative emotion in the common marmoset (Callithrix jacchus). These dACC subregions were targeted with indwelling cannulae to enable pharmacological manipulations to be carried out in a range of tasks, used to assess distinct components of negative emotion, such as conditioned fear and anxiety. The findings suggest that the rostral dACC and the caudal dACC do indeed have distinct contributions to the expression of negative emotion and the regulation of anxiety, respectively. Furthermore, an assessment of the anterograde projections of these subregions provides anatomical support for the observed functional differences.

L'adaptation comportementale est primordiale pour faire face à l'environnement flexible dans lequel les individus évoluent chaque Jour, notamment par l'élaboration de comportements d'exploration ou de vérification. Le cortex préfrontal a depuis longtemps été considéré comme le siège du contrôle exécutif nécessaire à la genèse de ces comportements. Deux régions semblent essentielles: le cortex préfrontal latéral (LPFC) et le cortex midcingulaire (MCC). Bien que diverses théories attribuent à ces régions les fonctions d'évaluation des performances et de contrôle cognitif respectivement, leurs rôles dans les comportements de recherche d'information restent imprécis, et cela malgré l'apport potentiel aussi bien dans un contexte normal que pathologique (i.e. troubles obsessionnels compulsifs). Pour mieux comprendre la spécificité de ces régions dans les comportements d’exploration, les travaux que nous avons menés au cours de cette thèse emploient différentes approches comportementales et électrophysiologiques chez les primates humains et non humains. Ils ont permis de (1) raffiner la compréhension de l'implication des régions frontales dans le contrôle cognitif et l'effort attentionnel, (2) développer des tâches comportementales induisant des vérifications, basées sur le Jugement des performances ou l'évaluation de l'environnement, et (3) souligner la spécificité des comportements de vérification. En particulier, nos enregistrements intracérébraux chez le singe en comportement montrent l'importance du MCC pour signaler le besoin d'explorer sur la base de l'évaluation des performances, tandis que le LPFC contribue à la mise en oeuvre de la conduite comportementale à adopter / Behavioural adaptation is an essential element of our quest to survive and flourish in a volatile environment, in particular by the use of exploration and verification behaviours. The prefrontal cortex has long been considered a critical source of these behaviours given it role in executive control. Two regions appear to be particularly critical – the lateral prefrontal cortex (LPFC), and the midcingulate cortex (MCC). Although numerous theories associate these regions with the functions of performance evaluation and cognitive control, the role of these regions in the search for information remains lacking, despite the importance of these behaviours and their apparent role in pathologies such as obsessive compulsive disorders. This thesis seeks to understand the specific roles of these regions in exploratory behaviours, employing a range of behavioural and electrophysiological techniques in both human and non human primates. The work here helps to refine our understanding of the role of frontal cortical regions in cognitive control and attentional effort. Moreover, we have developed a number of behavioural tasks that induce verification behavior based on subjects’ evaluation of their own performance or on an evaluation of the environment. Our work reveals the specificity of verification behaviour as well as specific roles for the MCC and LPFC in this search for information. Our intra cerebral recordings in monkeys working on such tasks underline the importance of the MCC for signalling the need to explore the environment on the basis of performance evaluation, whilst we have also shown the role of LPFC in the implementation of the necessary behavioural adaptations

The overall goal of this dissertation is to elucidate the cellular and circuit mechanisms underlying flexible behavior in the prefrontal cortex. We are often faced with situations in which the appropriate behavior in one context is inappropriate in others. If these situations are familiar, we can perform the appropriate behavior without relearning how the context relates to the behavior — an important hallmark of intelligence. Neuroimaging and lesion studies have shown that this dynamic, flexible process of remapping context to behavior (task switching) is dependent on prefrontal cortex, but the precise contributions and interactions of prefrontal subdivisions are still unknown. This dissertation investigates two prefrontal areas that are thought to be involved in distinct, but complementary executive roles in task switching — the dorsolateral prefrontal cortex (dlPFC) and the anterior cingulate cortex (ACC). Using electrophysiological recordings from macaque monkeys, I show that synchronous network oscillations in the dlPFC provide a mechanism to flexibly coordinate context representations (rules) between groups of neurons during task switching. Then, I show that, wheras the ACC neurons can represent rules at the cellular level, they do not play a significant role in switching between contexts — rather they seem to be more related to errors and motivational drive. Finally, I develop a set of web-enabled interactive visualization tools designed to provide a multi-dimensional integrated view of electrophysiological datasets. Taken together, these results contribute to our understanding of task switching by investigating new mechanisms for coordination of neurons in prefrontal cortex, clarifying the roles of prefrontal subdivisions during task switching, and providing visualization tools that enhance exploration and understanding of large, complex and multi-scale electrophysiological data.

How is the brain capable of mediating pain relief via the mind alone? Placebo analgesia is just such a case, wherein an inert substance yields relief from a number of pain inducing stimuli. Scholars typically separate several factors thought to contribute to the placebo effect into psychological and neurobiological influences. Psychological mechanisms include expectation and conditioning of analgesic effects, while neurobiological mechanisms implicate the opioidergic descending pain system. The current paper proposes an integrative model in which the rostral anterior cingulate cortex (rACC), implicated in cognitive-affective modulation, receives goal-directed input (i.e., expected pain relief) from the prefrontal cortex. As the rACC processes the cognitive difference between expected and actual pain, it recruits a critical descending pain pathway by means of modulating the periaqueductal gray area (PAG). The PAG is a key relay station that connects to other endogenous subsystems of opioidergic pain relief. Whether the rACC and its connection to the PAG are necessary for the placebo effect is a question future research will have to address.

Cognitive dissonance has traditionally been defined as the negative affective state which accompanies inconsistent cognitions and motivates one to make the cognitions consistent. This thesis critically evaluates two theories about cognitive dissonance. The action-based model of dissonance argues that inconsistent cognitions have the potential to interfere with effective and unconflicted action. The new look model of dissonance, contradicting the traditional definition of dissonance, argues that it is aversive consequences rather than inconsistent cognitions that cause dissonance. Recent studies investigating the neural correlates of dissonance show that parts of anterior cingulate cortex and prefrontal cortex seem to be involved in the dissonance process. One of the major predictions of the new look model of dissonance has been undermined by recent evidence. In contrast, the action-based model of dissonance is supported by recent studies.

Vocal plasticity is presumed to be a key element underlying the evolution of human speech and language, but the mechanisms and neuroanatomical basis for this plasticity remain largely unknown. The Mexican free-tailed bat, Tadarida brasiliensis, presents a unique opportunity to advance our understanding of the evolution and neurobiology of mammalian vocal communication because this animal displays elements of vocal complexity and plasticity that are more sophisticated than any mammal other than humans, including non-human primates. Current models of vocal control in mammals do not account for the vocal complexity of free-tailed bats. The purpose of this dissertation is to fill that gap in knowledge by identifying a possible neuronal basis for vocal complexity in free-tailed bats. This will be achieved by 1) providing a detailed analysis of the free-tailed bat’s vocal behaviors, 2) mapping the distribution of neurotransmitter receptor types suspected of involvement in vocal control, 3) identifying brain regions that exhibit increased neuronal activity during vocalizing, and 4) pharmacologically manipulating putative vocal control regions to confirm and characterize their function in vocalizing. Analysis of Tadarida’s vocal behavior indicated that they have a vast vocal repertoire, including many different call types, context-dependent sensory-feedback driven vocal plasticity, and syntactically-organized stereotyped songs. Their vocal behavior changed seasonally, so I mapped the distribution of melatonin binding sites in the brain, finding high densities in the striatum, similar to dopamine receptor distribution. I then used immunohistochemical labeling of the immediate early gene cfos to map neuronal activation in brains of highly vocal bats to find ROIs activated by vocal production. This technique not only identified all previously known regions of the mammalian vocal motor pathway but also revealed activity in novel brain regions that could potentially account for vocal plasticity, including a localized region of the basal ganglia, the dorsolateral caudate nucleus, and the anterior cingulate region of the frontal cortex. Pharmacological excitation of these regions evoked complex vocal sequences similar to the songs recorded in the field and lab. These results support the hypothesis that the mammalian basal ganglia may play a crucial role in the plasticity and complexity of mammalian vocal behaviors.