Despite virtually identical genomes, inbred animals often vary in phenotype, including behaviour, but the molecular basis of this phenomenon is unknown. Our hypothesis is that differences in behaviour between inbred rats are correlated with differential cortical mRNA transcript levels. 40 Lewis rats were subjected to 5 behavioural tests: two were used to categorize 10 animals into either “high” or “low” phenotype groups. Microarray gene expression profiling was performed for 5 rats from each group. Three main analyses were performed to: (1) identify differential expression between the high and low groups, (2) identify correlations between transcript levels and individual behaviour scores, and (3) determine if the results of this replicate experiment overlapped with a previous pilot experiment. Some array results were confirmed by RT-PCR. We found that this experiment did not replicate the findings from the pilot, however several genes of interest were determined and were validated by RT-PCR.

Thesis (M.S. in Computer Science)--Vanderbilt University, May 2005. / Title from title screen. Includes bibliographical references.

Thesis (M.A.)--Miami University, Dept. of Psychology, 2005. / Title from first page of PDF document. Document formatted into pages; contains [1], v, 48 p. : ill. Includes bibliographical references (p. 16-20).

The hippocampal to medial prefrontal cortex (HPC-mPFC) pathway has a role in mnemonic processing. A key function of the hippocampus (HPC) is to organize contextual memories by how they were experienced, and the prefrontal cortex (PFC) retrieves contextual memories by sorting and suppressing irrelevant memories for the task at hand. Studies have highlighted the HPC-mPFC connection in rodents, however, there is a relative paucity of primate studies. The present study addressed this issue by investigating the connection from the HPC to anterior cingulate cortex (ACC; areas 24a, 25 and 32) of the mPFC in rhesus monkeys (Macaca mulatta). The distribution of hippocampal axons and terminals (boutons) was largest in area 25. Bouton diameter was largest in the deep layers of area 25, suggesting an efficient transmission system from the HPC. The robust projections from the HPC terminated most densely in the superficial layers of area 25. The HPC pathway also innervated some inhibitory neurons, labeled for the calcium binding proteins calbindin or calretinin in the superficial layers of the ACC, whereas axons innervated parvalbumin inhibitory neurons in the deep layers of the ACC. The findings suggest that area 25 may be a fundamental pathway from the HPC for memory processing and can be a focal point in therapeutic interventions in neurological and psychiatric diseases.

The activity of neurons in the prefrontal cortex (PFC) may underlie working memory processes in the brain. Both the performance of working memory tasks and the activity of PFC neurons are modulated by dopamine. The goal of the present thesis was to gain insight into the neural basis of working memory by studying the PFC, and the DA system in the PFC, from both a behavioral and cellular perspective. The functional contribution of the PFC to working memory processes in the rat was assessed in Chapter 2 of the present thesis using memory-based foraging tasks on an 8-arm radial maze. The results of these studies indicated that lidocaine-induced inactivations of the PFC selectively disrupted the ability to use mnemonic information to guide foraging, but not the ability to acquire or retain such information. The ability to use mnemonic information to guide foraging was also disrupted by microinjection of a D1 but not D2 receptor antagonist into the PFC. Chapters 3-5 investigated how PFC neurons process synaptic inputs to their dendrites to produce spike output. The intrinsic membrane properties and synaptic responses at the soma and dendrites of deep layer PFC pyramidal neurons were recorded using sharp intracellular or whole-cell patch-clamp techniques in a brain-slice preparation. Different passive and active membrane properties of the soma and dendrites of PFC neurons were observed. The distal dendrites of PFC neurons responded most effectively to strong, highly coincident synaptic inputs. Ca²⁺currents near the soma both amplified the effects of these inputs and modulated the spike output pattern. Spike output at the soma was also controlled by the interplay of slowly-inactivating Na⁺ and K⁺ currents. Chapter 6 investigated the modulation of PFC neurons by DA. DA or a D1 but not D2 receptor agonist increased the evoked firing of PFC neurons via a D1- mediated modulation of slowly-inactivating Na⁺ and K⁺ currents. Concurrently, D1 receptor activation reduced burst firing in PFC neurons, due to a attenuation of Ca²⁺ currents. D1 receptor activation also increased both GABA[sub A] IPSPs and NMDA EPSPs. The final chapter of this thesis integrated these data into a cellular model of PFC function and its modulation by DA. It is proposed that DA may tune PFC neurons such that they respond selectively to strong synchronized inputs from other cortical areas. In the presence of DA, working memory processes mediated by the PFC may be influenced selectively by stimuli of behavioral significance. / Arts, Faculty of / Psychology, Department of / Graduate

archives@tulane.edu / Autism spectrum disorders (ASD) are commonly characterized by abnormal social behaviors. Fragile X syndrome (FXS) is the most common inherited intellectual disability in humans and the most common single-gene cause of ASD symptoms. FXS is caused by the loss or malfunction of the fragile X mental retardation protein (FMRP), an mRNA-binding protein that regulates numerous synaptic proteins, both translationally and through direct protein-protein interactions. One direct-binding target is the large-conductance potassium (BK) channel. BK channels have been shown to be hypoactive in FXS, and represent possible targets for treatment in both general ASD and in FXS specifically. Also, two members of the KCNQ class of voltage-activated potassium channels, KV7.2 and KV7.3, have been identified as FMRP translation targets. Finally, a commonly observed abnormality in the ASD brain is an imbalance in the ratio of excitatory to inhibitory signaling (E/I balance) causing general hyperexcitability in numerous brain areas. One area in which altered E/I balance is often observed is the medial prefrontal cortex (mPFC), which is involved with the processing of social information. Therefore, the goal of this dissertation was to determine if stimulating potassium channel function in the mPFC of Fmr1 KO mice would correct abnormal social behavior. In addition, the possible mechanistic determinants and effects on E/I balance were investigated in WT and Fmr1 KO mice. Infusion of the potassium channel activator, BMS-204352, into the mPFC of KO mice had no effect on social approach behavior, but corrected social novelty impairments as measured by a 3-Chamber Test. Whole-cell patch clamp recordings of pyramidal neurons in layer V of the mPFC revealed no differences in mEPSCs between KO and WT mice, but did reveal higher frequency of mIPSCs in KO mice. Treatment with BMS-204352 resulted in a decrease in mEPSC amplitude in both genotypes, which was blocked by the BK channel antagonist, paxilline. Effects of BMS-204352 treatment on mIPSCs revealed two possible populations of cell types. One population of exhibited a decrease in frequency of mIPSCs, an effect seen in both genotypes. The other population exhibited a slight increase in frequency of mIPSCs, but this was seen only in KO cells. Treatment with paxilline caused a decrease in mIPSC frequency in both genotypes, which was not altered with subsequent BMS-204352 treatment. Pretreatment with the KV7 channel antagonist XE 991 prevented BMS-204352-induced cross-genotype decrease in mIPSC frequency, but did not prevent BMS-204352-induced frequency increase in KO cells. Western blot analyses revealed no changes between genotypes in BK channel expression, but a trend to increased KV7.3 expression in the PFC of KOs compared to WTs. With these data, it was concluded that aberrant activity of potassium channels in the mPFC of KOs mediates some of the social abnormalities observed in the phenotype, that KOs may exhibit increased KV7.3 expression as a potential compensatory mechanism for BK channel dysfunction, and that potassium channels are a promising potential target for future treatment of ASD symptoms / 1 / Ted Sawyer

Thesis advisor: John P. Christianson / Stress is a risk factor for neuropsychiatric disorders such as post-traumatic stress disorder and depression, yet not all individuals who are exposed to stress develop such disorders. Several factors influence susceptibility versus resilience to the effects of stress, including coping strategy biological sex. A growing body of research in humans has demonstrated that active coping strategies – defined as using available resources to problem solve – are positively correlated with resilience. In rodents, resilience to a potent acute stressor can be achieved through active coping, such as controlling the termination of a stressor, but only in males. During controllable stress males engage a stress mitigating pathway between the prelimbic (PL) and dorsal raphe nucleus (DRN), but this pathway isn’t engaged by control in females or when stress is uncontrollable in both sexes. Thus, neural activity within the ventromedial prefrontal cortex (vmPFC) is a critical determinant of stressor-induced anxiety. The mechanism that engage vmPFC excitability are not well understood. Therefore, the goals of the dissertation were 1) determine if eCBs in the PL promote neuronal excitability and behavioral resilience 2) test if ES and IS result in differential activation PL afferents, and will specifically test if ES results in greater activation PL-inputs from action-outcome associated regions, while IS leads to greater engagement of stress/fear inputs to the PL, and 3) identify network-wide patterns of activation and test the hypothesis that the stress and action-outcome networks are differentially activated as a function of stressor controllability and/or sex. We’ve demonstrated that augmenting eCBs in the PL increased excitability through a CB1 and GABA receptor dependent mechanism and was sufficient to block the stress induced decrease in social exploration. Regarding goal 2, PL inputs from the orbitofrontal cortex and DRN were activated in response to stress per se, but were not sensitive to stressor controllability and did not differ between males and females. PL afferents from the basolateral amygdala and mediodorsally thalamus were not sensitive to stress. Lastly, we quantified Fos expression in response to controllable and uncontrollable stress in male and female rats in 24 brain regions associated with stress, action-outcome learning, and showing sex differences in response to stress. Using interregional correlations, we found differences in functional connectivity as a function of stressor controllability and sex when considering all 24 regions and when considering only stress associated regions. Females showed greater overall functional connectivity compared with males, and IS resulted in greater overall connectivity than ES. We also reveal potentially important nodes in functional connectivity networks using centrality measures to identify network hubs. The findings of this research emphasize the need to study differences between males and females across all realms of neuroscience, particularly in relation to disorders of stress and anxiety. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20998号 / 医博第4344号 / 新制||医||1027(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 伊佐 正, 教授 渡邊 直樹, 教授 髙橋 良輔 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Thesis advisor: Scott D. Slotnick / We are able to consciously remember an incredible amount of information for long periods of time (Brady et al., 2008, 2013). Furthermore, we often think about our memories in terms of how successful we are in retrieving them, such as vividly recalling the smell of your grandmother’s cooking. However, we can also identify the times when we have forgotten information, such as misremembering the name of an acquaintance or misplacing your car keys. Such instances of forgetting have been suggested to be caused by inhibitory processes acting on associated information, such as the inhibitory processing shown in retrieval-induced forgetting where the retrieval of specific items leads to forgetting related information (Anderson et al., 2004; Wimber et al., 2015). Thus, long-term memory is said to rely on both accurately retrieving specific details and inhibiting potentially distracting information. In Chapter 1, I demonstrate that specificity of long-term memory depends on inhibiting related information through a series of behavioral experiments investigating item memory for faces and abstract shapes. In Chapter 2 and Chapter 3, I examine the neural regions associated with long-term memory specificity and inhibitory processing by focusing on the functional roles of the hippocampus and the prefrontal cortex, two key regions associated with long-term memory. In Chapter 2, I provide evidence that the hippocampus is associated with memory specificity by demonstrating that distinct regions of the hippocampus are associated with memory for different visual field locations. Furthermore, I provide evidence that the hippocampus operates in continuous manner during recollection (i.e., conscious retrieval of details). In Chapter 3, I demonstrate that the prefrontal cortex can inhibit both the hippocampus and language processing regions during retrieval of distracting information during episodic and semantic memory, respectively. / Thesis (PhD) — Boston College, 2019. / Submitted to: Boston College. Graduate School of Arts and Sciences. / Discipline: Psychology.

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