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

Traumatic brain injury (TBI) is one of the leading causes of death and disability in children. The prefrontal cortex (PFC) is most susceptible to injury which leads to deficits in executive function, sociability, and cognitive flexibility. The oxytocin (OT) system plays a significant role in the modulation of species-typical social behaviors, such as social recognition and memory. Intranasal OT (IN-OT) has been shown to be neuroprotective against neuronal insults and social deficits through various mechanisms. Due to this and OT’s role in the modulation of social behaviors, it is possible that IN-OT could improve the social deficits caused by a PFC injury. The primary goal of this study was to determine the effects of a TBI on the development of the OT system. The secondary goal was to address the efficacy of IN-OT as a treatment for the social deficits observed following a TBI. For these studies, animals received a single cortical contusion injury bilaterally damaging the medial pre-frontal cortex. Immediately following injury (1-2 minutes), animals were given a single dose of IN-OT (20 μg, 1 μg/1 μl Ringer’s solution), placebo, or no treatment and sacrificed at days 1, 14, and 30 post-injury. Animals were assessed using behavioral and histological measures. It was predicted that animals that received IN-OT would demonstrate fewer social deficits on the behavioral measures and a smaller lesion size. Additionally, it was expected that a TBI would increase inflammation levels and decrease the levels of OT and OT receptors compared to sham animals. The results indicate that OT treatment did not significantly improve histopathological outcomes. However, the vehicle that was utilized impaired outcomes. Additionally, there was minimal changes to the OT system at the injury site, in the anterior olfactory nucleus, and in the caudate putamen due to injury. But vehicle treatment altered the expression levels of the OT peptide and receptors. Behaviorally, OT treatment improved performance in the Morris water maze in TBI animals compared to vehicle-treated and untreated TBI animals, but not other behaviors. However, vehicle-treated, and OT-treated animals were more likely to be aggressive than expected and untreated sham animals were less likely to be aggressive than expected. Taken together, it was observed that administration of a hypotonic saline solution following TBI significantly increases pathophysiology after TBI, and these effects translate into increased aggression levels. Although, learning and memory remained unaffected by the vehicle. Thus, further studies are needed to examine the effects of OT on TBI for behavioral and pathophysiological improvements.

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.

Social interactions between individuals, particularly within groups, constitute a vital aspect of animal survival across nearly all species. In particular, higher level, evolutionarily preserved processes and behaviors such as pro-sociality (e.g., recognition of another’s emotional state) and group interactions (e.g., competitive foraging) have been widely studied in fields of ethology, psychology, and economics. While recent neuroethological studies have examined interactive behaviors at extremes of dyads in artificial environments or herds in nature, gaining a full understanding of the neuronal mechanisms underlying these behaviors requires new approaches that examine freely behaving individuals within groups. Additionally, while there is mounting evidence pointing to the role that the dorsomedial prefrontal cortex (dmPFC) and the dACC (dorsal anterior cingulate cortex) play as a hub of the ‘social brain,’ the single-neuronal processes driving pro-social behaviors and naturalistic group interactions remain unknown. In this dissertation, I begin by reviewing previous work that has guided the study of social interactive behaviors and their neuronal mechanisms in animal models. Next, I present our novel findings and advances that combine a host of cutting-edge techniques to explore fundamental gaps in our understanding of pro-sociality and group interactions in male mice. Specifically, we find that 1) rodent dmPFC neurons differentially represent other- and self-experiences and drive prosocial ‘helping’ behaviors, and 2) the dmPFC uniquely drives competitive effort based on information about others during group foraging. I also discuss the impact of these results that may be translated to the clinic, where deficits in these behaviors are a hallmark of psychosocial illnesses such as autism spectrum disorders (ASD). Using a mouse Shank3 haploinsufficient model of ASD, I show that 3) proper Shank3 expression is necessary for prosocial decision making and that adult restoration of Shank3 expression reverses neuronal social-encoding imbalances in the dmPFC. Last, I forecast the future of social neuroethology by discussing recent technological advancements that will allow us to reveal the neural and molecular mechanisms of complex social behaviors emerging from groups of animals. Together, findings from this dissertation add to our fundamental understanding of the complex role that the dmPFC plays in social cognition and interactive behaviors. Data from these studies also reveal a remarkably rich neuronal process in the mouse prefrontal cortex that drives prosocial and competitive decision making in groups. The novel assays that I developed in these experiments also provide a unique framework to develop new treatments for psychosocial disorders in future studies. / 2024-02-03T00:00:00Z

No description available.

In this thesis, we look at evidence accumulated on the prefrontal cortical and hippocampal regions of the brain and review theories about the possible roles each structure has on human memory and behaviour. Aspects of these theories are tested via a self-reinforcing computational network model. We propose this model may simulate the underlying mechanisms or processes of the prefrontal-hippocampal interaction during performance of memory tasks that require intact prefrontal and hippocampal structures. / Thesis / Master of Science (MSc)

He Wu-jing. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2002. / Includes bibliographical references (leaves 48-57). / Abstracts in English and Chinese. / Abstract --- p.ii / Chinese Abstract (論文摘要) --- p.iv / Acknowledgements --- p.vi / Table of Contents --- p.vii / List of Tables --- p.viii / List of Figures --- p.ix / Chapter Chapter 1 - --- fMRI as a Neuroimaging Method --- p.1 / Chapter Chapter 2 - --- An Review of the Relationship Between Prefrontal Lobes and Memory --- p.6 / Chapter Chapter 3 - --- The Present Study --- p.12 / Chapter Chapter 4 - --- Method --- p.17 / Chapter Chapter 5 - --- Results --- p.25 / Chapter Chapter 6 - --- Discussion --- p.41 / References --- p.48

The current studies investigate the behavioral and anatomical changes after lesions at different ages of the cingulate cortex. Rats received lesions of the posterior cingulate cortex (PCing) or the anterior and posterior cingulate cortex (Total) at: postnatal day 4 (P4); day 10 (P10), or in adulthood (P120). Rats were trained in the Morris water maze, the Whishaw reaching task, conditioned taste aversion (CTA), and their activity was monitored over 48 hours. The general finding was a significant behavioral recovery on P10 animals regardless the size of the lesion. This recovery was associated with an increase in dendritic arborization in P10 animals with the PCing removed and a partial regeneration of the midline tissue in the Total P10 animals. These results suggest that damage to the cingulate cortex at P10 is associated with substantial behavioral and anatomical plasticity and that removal of the frontal midline tissue stimulates a regenerative process in more posterior cortex that does not occur otherwise. / ix, 111 leaves : ill. ; 29 cm.