Indiana University-Purdue University Indianapolis (IUPUI) / Alcoholics often experience difficulties ceasing drinking, potentially related to excessive behavioral inflexibility that either precedes or results from high alcohol consumption. Components of the Wisconsin Card-Sorting Task (WCST) a type of Attentional Set-Shifting (AttSS) task measuring impairments in behavioral flexibility have been modified to measure similar constructs within animals. Previous work has shown impaired AttSS in abstinent alcoholics and nonalcoholic individuals with a family history of alcoholism, as well as in mice exposed to chronic-intermittent alcohol vapor (Gierski et al., 2013; Hu et al., 2015; Oscar-Berman et al., 2009). The aim of the current study was to assess whether selectively-bred High- vs. Low- Alcohol Preferring (HAP vs LAP) mice display behavioral inflexibility as measured by an operant AttSS task, and furthermore, whether a history of voluntary drinking in cross-bred HAP (cHAP) mice further increases inflexibility. Impairments in the AttSS task are assessed by evaluating the number of trials to reach criterion, as well as the number and types of errors committed during the second experimental phase. In Experiment 1, male and female HAP and LAP mice first learned to press one of two levers signaled by a visual cue, but random with respect to spatial orientation, for a 0.1% saccharin solution reward. The following experimental phase consisted of an egocentric discrimination, such that side (left or right) now signaled correct reinforcement and the location of the visual cue was irrelevant. In Experiment 2, prior to identical operant procedures as Experiment 1, male and female cHAP mice were given free-choice access to 10% alcohol or water for seven weeks. Ethanol-exposed animals drank an average of 29.6 g/kg/day.

Yes / It has been suggested that the isolation rearing paradigm models certain aspects of schizophrenia symptomatology. This study aimed to investigate whether isolation rearing impairs rats’ performance in two models of cognition: the novel object recognition (NOR) and attentional set-shifting tasks, tests of episodic memory and executive function, respectively. Two cohorts of female Hooded-Lister rats were used in these experiments. Animals were housed in social isolation or in groups of five from weaning, post-natal day 28. The first cohort was tested in the NOR test with inter-trial intervals (ITIs) of 1 min up to 6 h. The second cohort was trained and tested in the attentional set-shifting task. In the NOR test, isolates were only able to discriminate between the novel and familiar objects up to 1-h ITI, whereas socially reared animals remembered the familiar object up to a 4-h ITI. In the attentional set-shifting task, isolates were significantly and selectively impaired in the extra-dimensional shift phase of the task (P < 0.01). Rats reared in isolation show impaired episodic memory in the NOR task and reduced ability to shift attention between stimulus dimensions in the attentional set-shifting task. Because schizophrenic patients show similar deficits in performance in these cognitive domains, these data further support isolation rearing as a putative preclinical model of the cognitive deficits associated with schizophrenia.

The ability to selectively attend to aspects of the environment which signal opportunity or danger, while marginalising irrelevant stimuli is critical to an animal's survival. With finite cognitive resources, the brain must dedicate resources to only those stimuli that are biologically significant. Incoming thalamic information must therefore be filtered. The thalamic reticular nucleus has long been considered critically involved in modulating thalamic sensory processing. Sharing connections with both the thalamus and cortex, it is ideally located to modulate the transfer of pertinent incoming sensory information. This thesis sought to determine the functional role of the thalamic reticular nucleus in attentional processes by combining lesion techniques and well established behavioural paradigms. Chapter 3 examined the role of visual thalamic reticular nucleus lesions on performance in a two-alternative forced choice reaction time task when auditory distractors were presented. No effect of the lesion was found. Chapter 4 examined excitotoxic lesions of thalamic retlcular nucleus on performance in the 7-stage attentional set shifting task. No effect of lesion on performance was found. Chapter 5 examined mediodorsal thalamus and rostral thalamic reticular nucleus lesions on performance in the attentional set shifting task. Despite strong connectivity with prefrontal regions known to be involved in this task, there was no effect of either lesion. Finally, chapter 6 examined the effects of reducing dopamine input into the thalamic reticular nucleus on a two alternative forced choice reaction time task. Following bilateral lesions the animals were impaired in the re-orientation of attention – suggesting a critical role for both the thalamic reticular nucleus and dopamine in attentional processes. Taken together, these results suggest that while the thalamic reticular nucleus is involved in attention, it is not involved in every aspect.

Indiana University-Purdue University Indianapolis (IUPUI) / Although marijuana and alcohol are two of the most commonly used drugs in the United States, relatively little is understood about how these drugs interact to effect drug use, cognitive behaviors, and neurophysiological changes. Specific drug use patterns such as simultaneous use may produce differential effects for consumption and other behaviors in addition to unique neurobiological changes compared to singular drug use. In order to better understand the effects of simultaneous alcohol and marijuana (SAM) use, we used the selectively bred crossed High Alcohol Preferring mice to examine consummatory, cognitive, and neurobiological changes following chronic alcohol and THC self-administration. We hypothesized that SAM mice would consume more drug than animals exposed to either substance alone. We used an operant behavioral flexibility paradigm to assess cognitive impairments believing that drug-exposed animals would show deficits relative to Control animals, with SAM mice being the most impaired of all drug conditions. Finally, we assessed CB1 receptor changes in the dorsal striatum, as this region is critical for behavioral flexibility (Bissonette & Powell, 2012; Ragozzino, 2007), CB1 receptors are the primary target of THC and these receptors are involved in numerous alcohol related behaviors (Maldonado et al., 2006; Pava & Woodward, 2012). Contrary to our hypothesis, SAM animals did not consume higher levels of drug compared to mice exposed to only THC or alcohol. Interestingly, female THC consumption was robust when THC was consumed alone but was reduced when simultaneous access to alcohol was available. Surprisingly, although we speculated that drug-exposed mice would be impaired compared to Control animals, and that SAM animals would likely be more compromised than THC and alcohol for Reversal Learning and Attentional Set-Shifting respectively, behavioral flexibility deficits were absent in our paradigm. Finally, alterations to dorsal striatal CB1 receptor expression were observed following a Short Abstinence period. Despite an absence of cognitive behavioral effects, this research contributes to furthering our understanding of co-drug use for consummatory and neurobiological changes, both of which are critically necessary given the evolving landscape surrounding simultaneous alcohol and recreational marijuana use.

y / The α7 nicotinic acetylcholine receptors (nAChRs) have been highlighted as a target for cognitive enhancement in schizophrenia. Adult female hooded Lister rats received sub-chronic phencyclidine (PCP) (2mg/kg) or vehicle i.p. twice daily for 7 days, followed by 7 days’ washout. PCP-treated rats then received PNU-120596 (10mg/kg; s.c.) or saline and were tested in the attentional set-shifting task. Sub-chronic PCP produced a significant cognitive deficit in the extra-dimensional shift (EDS) phase of the task (p < 0.001, compared with vehicle). PNU-120596 significantly improved performance of PCP-treated rats in the EDS phase of the attentional set-shifting task (p < 0.001). In conclusion, these data demonstrate that PNU-120596 improves cognitive dysfunction in our animal model of cognitive dysfunction in schizophrenia, most likely via modulation of α7 nACh receptors. / This work was partially funded by Johnson & Johnson Pharmaceutical Research and Development.

No description available.

在探討注意力的選擇基礎時，一般可區分為空間為基、物體為基、特徵為基以及面為基四類論點。直至目前為止，各類注意力選擇基礎的論點，都有其支持證據以及可解釋之處。本研究的主要目的在探討，當實驗操弄較適合面為基的注意力選擇時，內因性與外因性導引線索的注意力作用情況為何？本研究採用快速物體運動改變(RSOT)實驗典範，此乃由於該典範的刺激呈現方式，能排除空間為基以及特徵為基的解釋，並且受試者實際上是知覺到兩個重疊面，所以適合作為討論面為基注意力的實驗典範。 　　在探討注意力選擇的議題上，導引線索的內因性與外因性，常被用以觀察注意力選擇的作用情況。由於內因性與外因性導引線索的注意力控制機制是不同的，而且在時間向度的發展也不一樣，故本研究欲觀察內因性與外因性導引線索，在重疊面的情況下，注意力控制的作用情形。 　　實驗一主要探討外因性導引線索之攫取注意力的作用以及在時間向度上的發展情況，並為RSOT實驗典範提供在反應時間面向上的資料。實驗二則是以目標刺激與干擾刺激同時呈現的方式，探討內因性導引線索的集中注意力效果，在時間向度上的發展情況，並進一步觀察不同的目標刺激與干擾刺激相對關係所造成的影響。 　　研究結果發現，在重疊面的實驗典範中，以反應時間為依變項，外因性導引線索須在持續時間方面符合注意力設定(attentional set)的情況下，才能發揮攫取注意力的效果。而內因性導引線索則須在SOA的時間間隔夠長時，才會發揮集中注意力的效果，而可排除另一面上的干擾刺激所產生的干擾作用，研究結果顯示適當的SOA時間間隔約為300毫秒。而此內因性與外因性注意力控制的作用情況，與空間為基以及物體為基的相關研究結果相符合。

GABA is the main inhibitory neurotransmitter of the central nervous system. GABA[subscript A]Rs are multimeric transmembrane receptors, which are composed of 5 subunits. It is known that there are 19 subunits that can make up the GABA[subscript A]Rs, allowing for a vast array of receptor subtypes. In addition to the GABA binding site GABA[subscript A]Rs have distinct allosteric binding sites for benzodiazepines, barbiturates, ethanol, certain general anaesthetics and neuroactive steroids. The molecular heterogeneity of the GABA[subscript A]R is accompanied by distinct pharmacological profiles of the different receptor subtypes. The advance of transgenic mouse models has allowed the functional significance of this heterogeneity to be studied in vivo. Therefore, this thesis utilises a variety of transgenic mouse models carrying either mutations or deletions of certain subunits to study the functional significance of the receptor heterogeneity. Mice lacking the α1 subunit (α1[superscript(-/-)]), carrying a point mutation of the α1 subunit (α1H101R), and mice lacking the δ subunit (δ[superscript(-/-)]) have been utilised to investigate the role of these subunits in the sedative actions of benzodiazepines and the GABA[subscript A]R agonist THIP. Although there are limitations to the interpretation of these results due genetic background of the α1[superscript(-/-)] and α1H101R, experiments suggest that the α1H101R mutation is not behaviourally silent as previously suggested and provide further evidence that the α1 subunit mediates the sedative properties of benzodiazepines. These experiments also reveal that the extrasynaptic δ containing receptors are responsible for mediating the sedative effects of THIP, and these findings combined with evidence from collaborators, implicates the thalamus as an anatomical mediator of these effects. An investigation of the putative cognitive enhancing effects of THIP using an attentional set-shifting task for mice suggested that pre-treatment with THIP reduces the number of errors to reach criterion. δ[superscript(-/-)] mice could not be trained to perform the task, therefore further behavioural investigation of these mice was performed, which suggested a heightened level of anxiety and reduced motivation for a food reward. This thesis has furthered our understanding of the functional role of GABA[subscript A]R subtypes. With the advance in genetic manipulations that allow for regionally selective mutations of the receptor the anatomical structures involved in these functions can be identified.

<div><div><div><p>Although marijuana and alcohol are two of the most commonly used drugs in the United States, relatively little is understood about how these drugs interact to effect drug use, cognitive behaviors, and neurophysiological changes. Specific drug use patterns such as simultaneous use may produce differential effects for consumption and other behaviors in addition to unique neurobiological changes compared to singular drug use. In order to better understand the effects of simultaneous alcohol and marijuana (SAM) use, we used the selectively bred crossed High Alcohol Preferring mice to examine consummatory, cognitive, and neurobiological changes following chronic alcohol and THC self-administration. We hypothesized that SAM mice would consume more drug than animals exposed to either substance alone. We used an operant behavioral flexibility paradigm to assess cognitive impairments believing that drug-exposed animals would show deficits relative to Control animals, with SAM mice being the most impaired of all drug conditions. Finally, we assessed CB1 receptor changes in the dorsal striatum, as this region is critical for behavioral flexibility (Bissonette & Powell, 2012; Ragozzino, 2007), CB1 receptors are the primary target of THC and these receptors are involved in numerous alcohol related behaviors (Maldonado et al., 2006; Pava & Woodward, 2012). Contrary to our hypothesis, SAM animals did not consume higher levels of drug compared to mice exposed to only THC or alcohol. Interestingly, female THC consumption was robust when THC was consumed alone but was reduced when simultaneous access to alcohol was available. Surprisingly, although we speculated that drug- exposed mice would be impaired compared to Control animals, and that SAM animals would likely be more compromised than THC and alcohol for Reversal Learning and Attentional Set-Shifting respectively, behavioral flexibility deficits were absent in our paradigm. Finally, alterations to dorsal striatal CB1 receptor expression were observed following a Short Abstinence period. Despite an absence of cognitive behavioral effects, this research contributes to furthering our understanding of co-drug use for consummatory and neurobiological changes, both of which are critically necessary given the evolving landscape surrounding simultaneous alcohol and recreational marijuana use.</p></div></div></div>

A hipóxia-isquemia (HI) encefálica neonatal pode gerar sequelas neurológicas permanentes nos indivíduos que sobrevivem a este evento precoce. Dentre estas sequelas, o diagnóstico de Transtorno de déficit de atenção e hiperatividade (TDAH) já foi relacionado em pesquisa clínica. Sabendo que não há consenso de um modelo adequado para o estudo do TDAH em pesquisa experimental, novas abordagens que contribuam para o desenvolvimento desse modelo são necessárias. Assim, o objetivo do presente estudo foi investigar se a HI neonatal contribui para o desenvolvimento das características comportamentais relacionadas ao TDAH na fase adulta em ratos e correlacionar os resultados comportamentais com o volume da lesão encefálica. Para isso, ratos Wistar machos foram divididos em dois grupos: hipóxia-isquemia (HI, n=12) e controle (CT, n=10). O procedimento de HI consistiu na combinação da oclusão da artéria carótida comum direita no 7º dia pós-natal com exposição a uma atmosfera hipóxica (8% O2 e 92% N2, durante 90 minutos). Durante a fase adulta, ao atingir dois meses de idade, os animais foram testados no teste attentional set-shifting (ASS) para avaliar flexibilidade comportamental atencional e no teste de tolerância ao atraso da recompensa, para avaliação da escolha impulsiva. Os resultados mostraram que os animais submetidos à HI apresentaram prejuízo na função executiva, avaliado no ASS, evidenciado por uma inflexibilidade comportamental quando a regra para a execução da tarefa era mudada (p ≤ ,05 para o número de tentativas para passar dos estágios de Reversão 2 e Reversão 3, assim como o número de erros nesses estágios, além do estágio de mudança extradimensional – Teste t não-pareado). No teste de tolerância ao atraso da recompensa, não foi observada uma maior impulsividade dos animais HI, tendo os dois grupos um comportamento similar neste teste. Além disso, as avaliações do volume encefálico pelo Método de Cavalieri demonstraram uma atrofia no grupo HI no hemisfério total, córtex cerebral, substância branca, hipocampo e estriado, principalmente no lado ipsilateral à lesão (p ≤ ,05, Teste t não-pareado). Considerando esses resultados, podemos inferir que a HI neonatal é um fator ambiental que pode contribuir para o desenvolvimento das características comportamentais observadas no TDAH, e que estas são associadas a uma atrofia encefálica geral. / Neonatal hypoxic-ischemic encephalopathy (HI) can cause permanent neurological sequelae in survivors of this early event. Among these sequelae, the diagnosis of attention deficit hyperactivity disorder (ADHD) has already been linked in clinical research. There is no consensus about an ideal ADHD model in experimental research, being necessary new approaches that contribute to the development of this model. Thus, the aim of this study was to investigate whether HI contributes to the development of characteristics related to ADHD in adult rats and correlate the behavioral results with brain damage volume. Male Wistar rats were divided into two groups: hypoxia-ischemia (HI, n=12) and control (CT, n=10). The HI procedure consist of a permanent occlusion of the right common carotid artery followed by a period of hypoxia (90 min; 8% O2 and 92% N2), at seventh postnatal day (PND). Two months later, animals were evaluated in attentional set-shifting test (ASS) for assessment of attentional flexibility and in the tolerance to delay of reward, for evaluation of impulsivity choice. Our results demonstrated that animals submitted to HI manifest impairments in executive function, evidenced by a behavioral inflexibility when the rule for the execution of the ASS task was changed (p ≤ ,05 for number of trials to reach the criterion in Reversion 2 and 3 stages, as well as in number of erros in these stages, in addition to the Extradimensional shift stage – Unpaired t test). In the tolerance to delay of reward, no greater impulsivity of HI animals was observed, with both groups demonstrating similar behavior in this task. Moreover, the assessments of brain volume by Cavalieri method demonstrated atrophy in HI group in total hemisphere, cerebral cortex, white matter, hippocampus and striatum, especially on the side ipsilateral to the lesion (p ≤ ,05 – Unpaired t test). Considering these results, we can infer that neonatal HI is an environmental factor that could contribute to the development of behavioral characteristics observed in ADHD which are associated to general brain atrophy.