Indiana University-Purdue University Indianapolis (IUPUI) / Background Compulsive alcohol drinking is a defining characteristic of alcohol use disorder and the dorsolateral striatum (DLS) is implicated in regulating this inflexible behavior. AMPA receptors have been implicated in both goal-directed (dorsomedial striatal dependent) and DLS dependent inflexible behaviors with antagonism in the DLS and general DLS inhibition altering inflexible behavior including habit and compulsion. Discrepancies exist in the preclinical models used to investigate compulsive-like alcohol. The purpose of these experiments was to establish a robust model of compulsive-like quinine adulterated alcohol (QuA) drinking in C57BL/6J male and female mice, assess associated AMPA receptor protein expression in the dorsal striatum, and to antagonize DLS AMPA receptors during compulsive-like QuA drinking using a model of binge-like alcohol drinking, Drinking-in-the-Dark (DID). Methods In aim 1, C57BL/6J mice were allowed free access to 20% (v/v) alcohol (alcohol history), or water (water history) for two hours each day beginning three hours into the dark cycle for 23 days. On days 15 and 22 mice were given QuA to test for compulsive-like QuA drinking. 24-hours following the last DID session brain slices were taking for DLS and DMS AMPA receptor western blot. In aim 2, C57BL/6J mice were given a total of 21 days alcohol history, to establish a compulsive-like phenotype, or water history, prior to infusion. On days 22 and 24 mice were given a bilateral infusion of one of three concentrations of NBQX, an AMPA receptor antagonist, into the DLS, immediately prior to DID where the DID solution was either alcohol or QuA. Results We found that three weeks, not two, is sufficient to produce robust compulsive-like QuA drinking in C57BL/6J mice. We failed to replicate our compulsive-like DID model in aim 2 and found that infusion of NBQX reduced 2-hour alcohol drinking and reduced 2-hour QuA drinking when QuA was the second solution presented on infusion days in male water history mice only. We also found that NBQX reduced 20-minute front-loading in female alcohol history mice on alcohol intake and trended toward QuA intake. Overall locomotor activity was affected by drug infusions. Conclusions Together, these data suggest that compulsive-like alcohol drinking can be achieved following three-weeks DID and DLS infusion of NBQX reduces both alcohol and QuA drinking in a sex and drinking history dependent way, and these effects may be reliant on an initial single QuA or alcohol exposure.

No description available.

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.

No description available.

A displasia coxofemoral é a afecção ortopédica mais frequente na espécie canina e, pela estatística apresentada pela Orthopaedic Foundation for Animals o buldogue inglês é a raça com maior acometimento proporcionalmente. Entretanto carece em literatura dados sobre o desenvolvimento e morbidade desta doença na raça. O objetivo desse estudo foi avaliar a morfologia e morfometria da articulação coxofemoral de cães da raça buldogue inglês por meio de exame radiográfico e por tomografia computadorizada comparando-os com achados da avaliação ortopédica e cinética. A hipótese proposta é de que buldogues podem apresentar alterações radiográficas compatíveis com a displasia coxofemoral sem apresentar manifestações clínicas da doença. De cada articulação avaliada foram adquiridos dados por meio de exame ortopédico, avaliação cinética, radiográfica e por tomografia computadorizada. Foram feitas avaliação subjetiva das alterações morfológicas radiográficas e aferição do ângulo de Norberg, ângulo de inclinação do colo femoral e o escore de subluxação dorsolateral. Os dados obtidos foram correlacionados por meio dos coeficiêntes de Spearman. Trinta cães foram avaliados, 20 machos e 10 fêmeas. As médias de idade e peso dos participantes do estudo foram de 3,5 anos e 26,1 kg respectivamente. 76,6% dos animais apresentaram escore de condição corporal acima do considerado ideal e 63,3% viviam em ambiente de piso liso. Entretanto esses fatores de risco avaliados não apresentaram correlação com nenhuma alteração pesquisada. 63,3% dos cães apresentaram alterações nas articulações dos joelhos e 40% nas articulações coxofemorais pela avaliação ortopédica. Pela palpação da articulação coxofemoral foram observadas alterações em 50% dos animais, sendo a crepitação leve representando 86,6% das alterações, e crepitação de grau moderado e discreta manifestação de dor em 13,3%. A frequência de alterações morfológicas radiográficas observada foi de 98,3% para subluxação coxofemoral, 81,6% para o achatamento da cabeça do fêmur, 70% para presença de osteófitos ou entesófitos periarticulares e 61,1% para o arrasamento acetabular. A conformação radiográfica da articulação coxofemoral mais frequente foi de cabeça femoral com formato discretamente elíptico e discretamente subluxada, bordas acetabulares craniolateral arredondada e dorsal encurtada com discreta presença de osteófitos. A média das mensurações morfológicas obtidas no estudo foram abaixo dos valores considerado de normalidade, sendo de 94,94° para o ângulo de Norberg, 27,13% para o escore de subluxação dorsolateral e 128,53° para o ângulo de inclinação do colo femoral. A presença de osteófitos periarticulares obteve correlação estatística com presença de crepitação à palpação da coxofemoral, assim como o arrasamento acetabular com a presença de dor ao exame ortopédico. Entretanto as manifestações clínicas não coincidiram proporcionalmente às alterações observadas pelos métodos de diagnóstico por imagem. É questionado se a conformação muscular da raça pode contribuir para contrabalancear a instabilidade articular apresentada pelos métodos avaliados / Hip dysplasia is the most common orthopedic disorder in dogs, and the statistics presented by the Orthopedic Foundation for Animals English Bulldog is the race with most animals affected proportionately. However it lacks in literature data of the development and morbidity of this disease in the race. The aim of this study was to evaluate the morphology and morphometry of the hip joint of English Bulldogs through radiographic examination and computed tomography comparing them with findings from orthopedic and kinetic evaluation. The hypothesis proposed is that Bulldogs may have radiographic changes compatible with hip dysplasia without showing clinical symptoms of the disease. From each joint evaluated were acquired data through orthopedic examination, and kinetics, radiographic and computed tomography evaluations. They were made subjective evaluation of radiographic morphological changes and measuring the Norberg angle, femoral neck inclination angle and the dorsolateral subluxation score. The data were correlated by the Spearman\'s rank. Thirty dogs were evaluated, 20 males and 10 females. The mean age and weight of the study participants was 3.5 years and 26.1 kg respectively. 76.6% of the animals had a body condition score considered above ideal and 63.3% lived in flat floor environment. However, these risk factors evaluated were not correlated with any changes searched. 63.3% of dogs showed changes in knee joints and 40% in hip joints by the orthopedic evaluation. Abnormalities were observed in 50% of animals by palpation of the hip joint, the slight crackle representing 86.6% of the changes, and moderate crackle and mild degree manifestation of pain in 13.3%. The frequency of morphological radiographic changes observed was 98.3% for hip subluxation, 81.6% for the femoral head flattening, 70% for the presence of periarticular osteophytes or entesophytes and 61.1% for the acetabular razing. The most common radiographic conformation of the hip joint was femoral head slightly elliptical shape and discreetly subdisluxated, rounded craniolateral acetabular edge and shrtened dorsal edge with discreet presence of osteophytes. The average morphological measurements obtained in the study were below the values considered normal, being 94.94° for the angle of Norberg, 27.13% for dorsolateral subluxation score and 128.53° for inclination angle of the femoral neck. The presence of periarticular osteophytes have statistical correlation with the presence of ckakle on palpation of the hip joint, as well as the acetabular razing with the presence of painful on orthopedic examination. However the clinical manifestations were not proportionaly coincidence with the changes observed by the diagnostic imaging methods. It questioned whether the muscle conformation of the race can help to counteract the instability joint presented by the evaluated methods

A displasia coxofemoral é a afecção ortopédica mais frequente na espécie canina e, pela estatística apresentada pela Orthopaedic Foundation for Animals o buldogue inglês é a raça com maior acometimento proporcionalmente. Entretanto carece em literatura dados sobre o desenvolvimento e morbidade desta doença na raça. O objetivo desse estudo foi avaliar a morfologia e morfometria da articulação coxofemoral de cães da raça buldogue inglês por meio de exame radiográfico e por tomografia computadorizada comparando-os com achados da avaliação ortopédica e cinética. A hipótese proposta é de que buldogues podem apresentar alterações radiográficas compatíveis com a displasia coxofemoral sem apresentar manifestações clínicas da doença. De cada articulação avaliada foram adquiridos dados por meio de exame ortopédico, avaliação cinética, radiográfica e por tomografia computadorizada. Foram feitas avaliação subjetiva das alterações morfológicas radiográficas e aferição do ângulo de Norberg, ângulo de inclinação do colo femoral e o escore de subluxação dorsolateral. Os dados obtidos foram correlacionados por meio dos coeficiêntes de Spearman. Trinta cães foram avaliados, 20 machos e 10 fêmeas. As médias de idade e peso dos participantes do estudo foram de 3,5 anos e 26,1 kg respectivamente. 76,6% dos animais apresentaram escore de condição corporal acima do considerado ideal e 63,3% viviam em ambiente de piso liso. Entretanto esses fatores de risco avaliados não apresentaram correlação com nenhuma alteração pesquisada. 63,3% dos cães apresentaram alterações nas articulações dos joelhos e 40% nas articulações coxofemorais pela avaliação ortopédica. Pela palpação da articulação coxofemoral foram observadas alterações em 50% dos animais, sendo a crepitação leve representando 86,6% das alterações, e crepitação de grau moderado e discreta manifestação de dor em 13,3%. A frequência de alterações morfológicas radiográficas observada foi de 98,3% para subluxação coxofemoral, 81,6% para o achatamento da cabeça do fêmur, 70% para presença de osteófitos ou entesófitos periarticulares e 61,1% para o arrasamento acetabular. A conformação radiográfica da articulação coxofemoral mais frequente foi de cabeça femoral com formato discretamente elíptico e discretamente subluxada, bordas acetabulares craniolateral arredondada e dorsal encurtada com discreta presença de osteófitos. A média das mensurações morfológicas obtidas no estudo foram abaixo dos valores considerado de normalidade, sendo de 94,94° para o ângulo de Norberg, 27,13% para o escore de subluxação dorsolateral e 128,53° para o ângulo de inclinação do colo femoral. A presença de osteófitos periarticulares obteve correlação estatística com presença de crepitação à palpação da coxofemoral, assim como o arrasamento acetabular com a presença de dor ao exame ortopédico. Entretanto as manifestações clínicas não coincidiram proporcionalmente às alterações observadas pelos métodos de diagnóstico por imagem. É questionado se a conformação muscular da raça pode contribuir para contrabalancear a instabilidade articular apresentada pelos métodos avaliados / Hip dysplasia is the most common orthopedic disorder in dogs, and the statistics presented by the Orthopedic Foundation for Animals English Bulldog is the race with most animals affected proportionately. However it lacks in literature data of the development and morbidity of this disease in the race. The aim of this study was to evaluate the morphology and morphometry of the hip joint of English Bulldogs through radiographic examination and computed tomography comparing them with findings from orthopedic and kinetic evaluation. The hypothesis proposed is that Bulldogs may have radiographic changes compatible with hip dysplasia without showing clinical symptoms of the disease. From each joint evaluated were acquired data through orthopedic examination, and kinetics, radiographic and computed tomography evaluations. They were made subjective evaluation of radiographic morphological changes and measuring the Norberg angle, femoral neck inclination angle and the dorsolateral subluxation score. The data were correlated by the Spearman\'s rank. Thirty dogs were evaluated, 20 males and 10 females. The mean age and weight of the study participants was 3.5 years and 26.1 kg respectively. 76.6% of the animals had a body condition score considered above ideal and 63.3% lived in flat floor environment. However, these risk factors evaluated were not correlated with any changes searched. 63.3% of dogs showed changes in knee joints and 40% in hip joints by the orthopedic evaluation. Abnormalities were observed in 50% of animals by palpation of the hip joint, the slight crackle representing 86.6% of the changes, and moderate crackle and mild degree manifestation of pain in 13.3%. The frequency of morphological radiographic changes observed was 98.3% for hip subluxation, 81.6% for the femoral head flattening, 70% for the presence of periarticular osteophytes or entesophytes and 61.1% for the acetabular razing. The most common radiographic conformation of the hip joint was femoral head slightly elliptical shape and discreetly subdisluxated, rounded craniolateral acetabular edge and shrtened dorsal edge with discreet presence of osteophytes. The average morphological measurements obtained in the study were below the values considered normal, being 94.94° for the angle of Norberg, 27.13% for dorsolateral subluxation score and 128.53° for inclination angle of the femoral neck. The presence of periarticular osteophytes have statistical correlation with the presence of ckakle on palpation of the hip joint, as well as the acetabular razing with the presence of painful on orthopedic examination. However the clinical manifestations were not proportionaly coincidence with the changes observed by the diagnostic imaging methods. It questioned whether the muscle conformation of the race can help to counteract the instability joint presented by the evaluated methods

L'un des aspects les plus problématiques de l’addiction est la vulnérabilité à la rechute qui persiste même longtemps après la disparition des symptômes de sevrage. Les modèles rongeurs d'auto-administration (AA) démontrent que la réexposition à la drogue, les stimuli associés à la drogue ou le stress sont des déclencheurs majeurs de la rechute. Bien que les différentes catégories de drogues varient dans leurs mécanismes pharmacologiques primaires, elles partagent toutes un effet aigu d'augmentation des niveaux de dopamine (DA) dans le striatum. Après une utilisation répétée, les propriétés addictives des psychostimulants tels que la cocaïne (COC) sont sous-tendues par la mise en place de neuroadaptations persistantes dans le système DA (SDA) mésocorticolimbique. Le striatum est une cible majeure du SDA et, dans cette région, la DA agit sur deux familles de récepteurs (D1R et D2R) séparées positionnées sur les neurones épineux moyens (NEM) et donnant naissance à deux voies de sorties striatales différenciées et ayant des rôles différents dans l’addiction.Des travaux antérieurs dans notre équipe ont montré une implication différentielle de ces deux sous-types de récepteurs DA sur le rétablissement du comportement de recherche de COC. Alors que l'administration systémique d'un agoniste D2R induisait de puissants effets de rétablissement de recherche de cocaïne sur des rats entraînés à s'autoadministrer de la COC, l'administration systémique de l'agoniste D1R n’avait aucun effet (Dias et al, 2003).Les sous-régions ventrale (noyau accumbens) et dorsale du striatum (caudate putamen) sont modulées par l’innervation dopaminergique du mésencéphale ventral (VTA, substance noire) et la plasticité induite par la cocaïne dans ces circuits est supposée sous-tendre plusieurs aspects du comportement de recherche de drogue (Pierce and Vanderschuren, 2010). C’est pourquoi la première section de ce travail comprend une description de trois expériences réalisées dans le but d'étudier la participation des récepteurs DA du striatum au niveau ventral et dorsal à la réinstallation du comportement de recherche de cocaïne. / For many, drug taking may continue on an occasional basis for a long time; however, some individuals lose control of their drug use and are unable to stop. The transition from casual use to addiction is accompanied by drug-induced changes in the brain, followed by associated changes in behavioral functions. One of the most problematic aspects of addiction is the enduring vulnerability to relapse that persists even long after withdrawal symptoms have abated. Rodent models of drug self-administration (SA) show that re-exposure to the drug itself, drug associated cues or stress are major triggers of relapse. While different classes of drugs vary in their primary pharmacological mechanisms, they all share an acute effect of raising dopamine (DA) levels in the striatum. Following repeated use, the addictive properties of psychostimulants such as cocaine (COC) are believed to take place through the induction of neuroadaptations within the mesocorticolimbic DA system.The striatum is a major target of the DA system, where DA acts on two families of metabotropic receptors (D1-like or D2-like) that are segregated into two pathways of medium spiny neurons (MSNs) and have different roles in addiction and relapse. For instance, while systemic D2 receptor (D2R) stimulation induces reinstatement of COC seeking in rats, D1 receptor (D1R) stimulation does not. DA signaling in the nucleus accumbens (NAcc) responds to rewarding and aversive stimuli; in turn, the dorsolateral striatum (DLS) plays a key role in the transition to compulsive use, and the habitual aspects of drug-seeking after prolonged drug SA. Despite several works examining their role in relapse, the results remain somewhat unclear. Given their critical but differential involvement in COC seeking, here we investigated the role of D1R and D2R receptors of the NAcc and DLS in relapse, employing pharmacological manipulations, as well as assessing their protein expression using an animal model of COC SA. Our results showed a double dissociation between the actions of both DA receptors (DARs) in the striatum. Pharmacological activation of the D1R, but not D2R of the NAcc induces reinstatement of COC seeking, whereas the same effect is triggered by the activation of D2R, but not D1R of the DLS. Also, the reinstating effects of the systemic D2R stimulation is blocked by D1R or D2R antagonists injected into the NAcc or D1R antagonist into the DLS, while being blunted by the D2R inhibition in the DLS. These results convey an interaction between both receptor subtypes, likely relying on ascending spiraling connections associating the ventral and the dorsal striatum through midbrain-reaching loops. Finally, we found the reinstatement of COC seeking elicited by D1R or D2R agonists in either region is not due to changes in DAr expression.These results enticed us to examine the behavioral mechanisms underpinning reinstating behavior. Though initially goal-directed, COC seeking is argued to become habitual after extended training. This progression is believed to initially elicit functional changes within the NAcc, and gradually hijack the circuitry of the dorsal striatum. The activation of D1R in the NAcc and D2R in the DLS has been associated with the processing of rewarding properties and habitual responding for drugs, respectively. Therefore, we aimed to assess whether the reinstatement of COC seeking triggered by the D2R stimulation within the DLS would involve incentive motivational or reinforcing processes likely underlying those induced by the D1R stimulation within the NAcc. Also, we aimed to assess whether the D1R stimulation within the NAcc involves the overtaking of the behavioral control by habitual stimulus-response mechanisms which may be involved in the reinstatement of drug-seeking after the D2R stimulation in the DLS.

Made available in DSpace on 2016-03-15T19:39:42Z (GMT). No. of bitstreams: 1 Ricardo Rafael de Araujo.pdf: 639007 bytes, checksum: 913741be473f0be64fda69ad9172445d (MD5) Previous issue date: 2011-02-25 / Fundo Mackenzie de Pesquisa / Attention can be understood as a set of neural mechanisms that enhance the processing of relevant information, thoughts or actions while ignoring irrelevant or scattered stimuli. Thus, attention allows the organism to interact in a proper way with the environment. Among the brain structures associated with the control of attention, the Dorsolateral Prefrontal Cortex (DLPFC) has a remarkable role in current literature as a region associated with behavioral control. Transcranial Direct Current Stimulation (TDCS) is based on the application of a low intensity electric current through electrodes placed in the scalp, aimed at modulating the activity of different brain areas. This technique has been used to study brain functions. This study has the objective of verifying how attention can be modulated through the application of bilateral tDCS on DLPFC using measures of reaction time (RT) in tasks of temporal and spatial orientation. To accomplish that, two experiments were planned and executed. In the first one, which focused on the voluntary orienting of spatial attention, each participant had to orient attention to the position indicated by an arrow; in the second, on voluntary orienting of temporal attention, each participant had to orient attention to the most frequent time interval of visual targets. In both cases, participants had to respond as fast as possible when the target was displayed by pressing a joystick key. RTs were registered. The sample was composed of 18 undergraduate students, age range 19-25 years old (12 for the first experiment and 6 more for the second). In each experiment, subjects were submitted to three tDCS conditions (anodal, cathodal and sham) on the DLPFC during the undertaking of tests. Analyses of variance were made, in order to compare the involved factors. For the experiment of spatial orientation, the anodal condition produced lower RTs, when compared to sham. For the temporal orienting experiment it was observed that, in the anodal modulation, RTs were increased for the less frequent interval (500 ms), indicating that the anodal tDCS can have influenced in a more effective way attentional orienting to the most frequent intervals. Therefore it is possible to postulate the existence of a facilitating effect of anodal tDCS in the modulation of DLPFC, which generated an impact in attentional orienting, lowering RTs to the valid condition (spatial) when compared to sham tDCS. / A atenção pode ser compreendida como um conjunto de mecanismos neurais que facilitam o processamento de informações, pensamentos ou ações relevantes enquanto ignoram outros irrelevantes ou dispersos. Deste modo a atenção permite que o organismo interaja de maneira adequada com o ambiente. Dentre as estruturas cerebrais associados ao controle da atenção, o Córtex Prefrontal Dorsolateral (CPFDL) tem tomado papel de destaque na literatura atual como uma região associada ao controle comportamental. A Estimulação Transcraniana por Corrente Contínua (ETCC) se baseia na aplicação de corrente elétrica de baixa intensidade por meio de eletrodos posicionados no escalpe com o objetivo de modular a atividade de diferentes regiões cerebrais e tem sido utilizada como modo de estudo da função cerebral. Esse trabalho tem como objetivo verificar como a atenção pode ser modulada a partir da aplicação ETCC bilateral sobre o CPFDL, utilizando medidas de tempo de reação (TR) em tarefas de orientação temporal e espacial. Para Tanto foram planejados e executados dois experimentos. No primeiro experimento, relativo à orientação voluntária da atenção espacial, cada participante deveria orientar a atenção para a posição do espaço indicada por uma seta. O segundo experimento, relativo à orientação voluntária da atenção temporal, cada participante deveria orientar a atenção para o intervalo temporal de maior recorrência. Em ambos os casos os participantes deveriam responder o mais rapidamente possível ao aparecimento do alvo pressionado uma tecla de joystick registrando-se assim o seu TR. Participaram desse estudo 18 alunos de graduação (12 no primeiro desenho experimental, e para o segundo desenho experimental foram adicionados mais 6 colaboradores) na faixa etária de 19 à 25 anos. A cada sessão os colaboradores deveriam responder a ambos os experimento enquanto eram submetidos a diferentes polaridades de ETCC (anódica, catódica e placebo) sobre o CPFDL. Foram feitas análises de variância para comparar os fatores estudados. No experimento de orientação espacial a condição anódica produziu TR menores em comparação à condição placebo. No caso do experimento de orientação temporal foi observado que na modulação anódica houve um aumento nos TR no intervalo menos recorrente de 500 ms, indicando que a ETCC anódica pode ter influenciado de modo mais efetivo o direcionamento atencional aos intervalos mais freqüentes. Neste sentido é possível sugerir a existência de um efeito facilitatório da ETCC anódica na moducalçao do CPFDL, o que gerou um impacto no direcionamento atencional, diminuindo os TR para a condição valida (orientação espacial) quando comparados a ETCC placebo.

Traditionally, working memory and its neural underpinnings have been studied in the visual domain. A rich and diverse amount of research has investigated the lateral prefrontal cortex (lPFC) as a primary area for visual working memory, while another line of research has found the neurotransmitter acetylcholine (ACh) to be involved. This dissertation used auditory cues and found similar patterns of activity for processing auditory working memory information within a task compared to visual working memory processes. The first two experimental chapters demonstrated that the cholinergic system is involved in auditory working memory in a comparable fashion to its role in visual working memory. In chapter 2, blocking ACh impaired performance on an auditory working memory task in a dose dependent manner. Chapter 3 investigated the specificity of the effect of blocking ACh by administering an ACh agonist (physostigmine) at the same time as an ACh antagonist (scopolamine). When both drugs were administered together performance on the delayed matching-to-sample task (DMTS) task improved compared to performance on scopolamine alone. These results support the hypothesis that ACh is involved in auditory working memory. Chapter 4 investigated the neural correlates of auditory working memory in area 46 and found that this region of the lPFC contains neurons that are responsive to auditory working memory components in a very similar way to how it this region encodes information during visual working memory tasks. Neurons in the lPFC are responsive to visual or auditory cues, the delay portion of tasks, the wait time (i.e. decision making period), response, and reward times. This type of coding provides support for the theories that position the lPFC as a key player in recognition and working memory regardless of modality.

Previous research indicates that many important changes in executive functions, or higher cognitive capacities, occur between the ages of three and five years. Additionally, a distinction can be made between the cognitive functions associated with two different cortical regions. The functions of the dorsolateral prefrontal cortex (DL-PFC) are assessed using 'cool' tasks that are abstract and decontextualised. In contrast, the functions of the orbitofrontal cortex (OFC) are assessed using 'hot' tasks that require flexible appraisal of the affective significance of stimuli (Zelazo & Müller, 2002). Different clinical populations have been hypothesized to differ in terms of their impairment on tasks associated with each area of functioning. Current research conclusions regarding the primacy of hot versus cool executive function impairments are limited, however, as they have not taken complexity into account. That is, tasks currently used in investigations of hot and cool executive functions might differ in terms of the complexity of the cognitive processes that the tasks require. Therefore, comparisons across tasks may be misleading because these tasks vary in terms of the demands they place on participants as well as their hot versus cool status. While complexity theories have been applied to a number of cool tasks, only one hot task, those measuring theory-of-mind abilities, have been analysed in terms of complexity. One aim of the current research was to modify several tasks presumed to measure OFC performance to include a complexity manipulation. Tasks from three hot domains (conditional discrimination, the Children's Gambling Task, and future-oriented decision-making) were analysed in terms of their relational complexity, that is, the number of related entities or arguments inherent in a task or concept (Halford, 1993). Based on these complexity analyses, binary-relational and ternary-relational items of each of these tasks were developed or existing tasks were selected and/or modified. The binary-relational items were closely matched to the ternary-relational items in terms of stimuli and procedure, however, they were lower in complexity. After pilot testing, the three new measures of hot executive functioning were included in a larger test battery that was administered to a sample of 120 normally developing 3-, 4-, 5- and 6-year-old children. Existing binary- and ternary-relational items assessing theory-of-mind (a hot task) and three cool measures (transitivity, class inclusion and the Dimensional Change Card Sort test) were also included. The inclusion of measures of both hot and cool executive functions, each with complexity manipulated, allowed for the examination of a possible differential age of emergence of executive abilities associated with the DL-PFC versus the OFC. In support of the relational complexity approach, significant complexity effects were found across all seven tasks. Items at a higher level of complexity were experienced as relatively more difficult by children of all ages. Significant effects of age were also observed, with performance across all tasks increasing with age. The age effects were strongest on the ternary-relational items. The pass-fail data indicated that the majority of children in all age groups succeeded on the binary-relational items. However, it was not until a median of five years of age that children were able to process ternary relations. Consequently, the ternary-relational items produce the greatest differences in performance between the four age groups. The overall pattern of the results also suggested that a distinction can be made between the ages of emergence of abilities associated with the OFC versus the DL-PFC. The results of the pass-fail percentages, patterns of age-related change and age effects on domain factor scores all suggested that while hot executive functions may begin to develop around four years of age, similar levels of improvement are not seen in cool executive functions until five years of age. Thus, the ability to succeed on ternary-relational items of hot executive function tasks appeared to emerge slightly earlier than the cool executive function tasks. Complexity appears to be a critical factor underlying children's performance on executive function tasks, and future assessment regarding the development of executive abilities will benefit from keeping this in mind. While some refinement of new task items may be beneficial, the current test battery may have utility in further examinations of the executive profiles underlying clinical groups, such as children with autism and ADHD.