A significant number of individuals begin drinking alcohol early in life during adolescence, a period in which their brain is developing. Drinking alcohol at an early age is linked to a greater likelihood that a person will become an alcoholic later in life. Levels of Glutamate (GLU), a major neurotransmitter, in the medial prefrontal cortex (mPFC) has been directly linked to the expression of alcohol-use disorders. Thus, a better understanding of how childhood drinking produces alterations in the brain, thereby contributing to alcoholism, is needed. The current research utilized an animal model of alcoholism to examine the long range consequences of alcohol consumption during adolescence on GLU functioning within the mPFC in adulthood. It was hypothesized, adolescent drinking would lead to a higher levels of GLU in the mPFC in adulthood. Two groups of alcohol-preferring (P) rats received either free-access to alcohol (15% v/v) and water or water alone in their home cage (24 hrs a day; 7 days a week) during their adolescent period. At the end of the adolescent period, alcohol was removed and all animals were provided only water to drink for approximately 21 days. Next, animals were implanted with guide cannula aimed at infralimbic and prelimbic regions of the mPFC and provided one-week to recover before undergoing quantitative microdialysis, a method that allows for the direct sampling of GLU from brain tissue. During testing, samples were collected every 10 minutes and animals were first exposed to artificial cerebral spinal fluid (aCSF) followed by aCSF containing three GLU concentrations (1 µM, 5 µM , and 10 µM; presented in randomized order across rats). By exposing the animals to different levels of GLU, the average brain level of GLU can be established as well as how fast the brain is removing/clearing GLU. Samples were analyzed using high-pressure liquid chromatography a method that quantifies GLU levels in each sample. Analyses revealed a significantly lower level of GLU removal/clearance in the prelimbic region of the mPFC of the alcohol-drinking group compared to the water group. Analyses also revealed a significantly higher average level of GLU in the alcohol-drinking group compared to the water drinking control group. There were no differences between groups in average GLU levels or GLU clearance in the infralimbic region of the mPFC. Overall, the data from the current study suggest that the consumption of alcohol during adolescence may produce a long-lasting reduction of GLU removal/clearance thereby resulting in increased GLU levels within the prelimbic region of the mPFC. The current findings may represent a long-lasting change that happens in the brain when an individual consumes alcohol during adolescence which could then contribute to the development of an alcohol-use disorder later in life.

The medial prefrontal cortex (mPFC) is a cortical brain region involved in the evaluation and selection of motivationally relevant outcomes. mPFC-mediated cognitive functions are impaired following acute alcohol exposure. In rodent models, ethanol (EtOH) doses as low as 0.75 g/kg yield deficits in cognitive functions. These deficits following acute EtOH are thought to be mediated, at least in part, by decreases in mPFC firing rates. However, these data have been generated exclusively in anesthetized rodents. To eliminate the potentially confounding role of anesthesia on EtOH modulated mPFC activity, the present study investigated the effects of acute EtOH injections on mPFC neural activity in awake-behaving rodents. We utilized three groups: the first group received 2 saline injections during the recording. The second group received a saline injection followed 30 minutes later by a 1.0 g/kg EtOH injection. The last group received a saline injection followed 30 minutes later by a 2.0 g/kg EtOH injection. One week following the awake-behaving recording, an anesthetized recording was performed using one dose of saline followed 30 minutes later by one dose of 1.0 g/kg EtOH in order to replicate previous studies. Firing rates were normalized to a baseline period that occurred 5 minutes prior to each injection. A 5-minute time period 30 minutes following the injection was used to compare across groups. There were no significant differences across the awake-behaving saline-saline group, indicating no major effect on mPFC neural activity as a result of repeated injections. There was a significant main effect across treatment & behavioral groups in the saline-EtOH 1.0 g/kg group with reductions in the EtOH & Sleep condition. In the saline-EtOH 2.0 g/kg, mPFC neural activity was only reduced in lowered states of vigilance. This suggests that EtOH only causes gross changes on neural activity when the animal is not active and behaving. Ultimately this means that EtOH’s impact on decision making is not due to gross changes in mPFC neural activity and future work should investigate its mechanism.

The aim of this thesis is to overview studies examining the effect ethnicity has on the neural and physiological responses associated with empathy and the underlying mechanisms behind this effect.  It has been revealed that ethnicity can modulate the empathic responses in that faster physiological arousal and greater sensorimotor resonance occurs during the perception of own ethnic members in suffering. A reduction and even total absence of activity in empathy-associated brain regions such as anterior cingulate cortex, anterior insula, temporo partial junction and medial prefrontal cortex has further been seen during the perception of other ethnic members in pain. There have however been studies where ethnicity has not had an effect on empathic responses, indicating that it might not be ethnicity per se but instead other underlying mechanisms that causes the difference in empathic responses. There is an ongoing debate on which these mechanisms might be. It has been suggested that it might be attitudes, similarity and familiarity with the target, general ingroup bias, differences in perceptual processes and culture. The thesis will end with a discussion on how the results can be interpreted, the implications of the results, proposals for future research directions and a conclusion.

No description available.

This thesis examines the functional connectivity of the hippocampus with the rest of the brain, with a focus on the neocortex. The hypothesis explored, in an animal model, is whether the frequency-dependent behaviour of certain brain connectivity relationships applies to hippocampal-neocortical connections. To encompass the temporal and spatial resolution necessary to do this, two main techniques are used in combination in most of the experimental work hereby presented: (1) electrophysiological recordings of local field potentials (LFPs), and (2) functional activity recordings of blood oxygenation level dependent (BOLD) signal using functional magnetic resonance imaging (fMRI). The main hypothesis is that the frequency-dependent behaviour of specific hippocampal synapses imposes the rules of extra-hippocampal activity propagation and hippocampal-neocortical interactions. The main discovery is that short and long-term plasticity modulates network activation, a finding suggesting a possible mechanism that could mediate the encoding and consolidation of memory traces. Chapters 1 to 3 introduce the vast literature review in which this project lies, and the general methods utilised. Chapter 4 (first experimental chapter) describes, using electrophysiology in rats, the evoked response of the main hippocampal output (CA1 neurons) when its major input (CA3 pyramidal cells) is activated at frequencies that in subsequent experiments were used to build brain-wide functional maps. CA1 spiking activity is found to be optimal in maintaining the amplitude of the population spike (PS) at beta frequencies (10-20 Hz), whereas lower (< 10 Hz) and higher (> 20 Hz) frequencies are normally less effective. Chapter 5 describes, using fMRI, how these intra-hippocampal activity patterns relate to long-range activity propagation in fMRI experiments. Hippocampal activation exhibits a linear monotonic increase with evoked frequency, whilst a network of selected structures is activated preferentially when beta frequencies are applied (mainly neocortical structures like the prefrontal and parietal cortices, motor and sensory cortices, and some subcortical structures like the nucleus accumbens and the striatum). This data is highly correlated with the PS recorded in CA1 and with multi-unit activity (MUA) and single-unit activity (SUA) simultaneously recorded in the medial prefrontal cortex (mPFC), one of the structures receiving propagated activity at beta frequencies, as described in Chapter 6. As mPFC also receives hippocampal input at a restricted beta frequency range stimulation of the dorsal hippocampus, Chapter 7 describes the use of a combined electrophysiology/fMRI approach to identify the pathway responsible for activity propagation. We performed microsurgery lesions to investigate the pathway responsible for the polysynaptic propagation of activity. Findings indicate that the septo-temporal longitudinal pathway is the one leading information transfer from dorsal to ventral hippocampus in the rat, and from there directly to the ventral subiculum, apparently by-passing entorhinal cortex. Last, in Chapter 8 the effect of durable modifications of synaptic weights by long-term potentiation (LTP) in the previously described frequency-dependent activity propagation is also described and contextualized in the memory trace consolidation framework, both electrophysiologically (Chapter 5) and with fMRI (Chapter 6). LTP is a long-lasting change in synaptic weights that, at the CA3-CA1 synapse, is capable of modifying hippocampal-neocortical connections such as to open the opportunity for higher frequency patterns (> 40 Hz) to propagate to neocortical structures. These results suggest that, by means of frequency-coding, the hippocampus normally regulates propagation of selected information to the neocortex, but that at specific moments (e.g. when the hippocampus undergoes LTP) this regulation broadens to permit high-frequency information to pass through and affect neural activity in the cortex. It is a beautifully simple mechanism that merits further detailed examination in a multi-disciplinary manner as outlined in Chapters 9 and 10.

付記する学位プログラム名: 京都大学卓越大学院プログラム「メディカルイノベーション大学院プログラム」 / 京都大学 / 新制・課程博士 / 博士(医学) / 甲第24509号 / 医博第4951号 / 新制||医||1064(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 林 康紀, 教授 渡邉 大, 教授 高橋 淳 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Many studies in affective neuroimaging have addressed the question of how the "self" is represented in brain activation. The medial prefrontal cortex (mPFC) is implicated in many of these studies and an essential component self-representation in the brain. In this study we looked at differences between men and women in the mPFC in terms of how they assessed comparisons of the body image. Participants viewed images of thin and overweight bodies and were asked to consider how they would feel if someone were to compare them to the image. Brain activations were measured using functional magnetic resonance imaging (fMRI). Results indicate that men did not react significantly differently to thin or overweight images while women showed increased mPFC activation when considering comparison to the overweight images. These findings provide some insight into the differences between men and women in terms of self-evaluation and body image.

Organisms can form safety associations with cues that predict the absence of an aversive event. This cognitive process, learned safety, is important for modulating emotional processing, as safety cues can decrease fear in the presence of previously learned danger cues. Further, there are clinical implications in understanding learned safety, as individuals with PTSD present with deficits in learned safety. Additionally, there is a well established relationship between smoking and PTSD. The link between smoking and PTSD is unclear, however one possibility is that nicotine-associated changes in cognition could facilitate PTSD symptoms, particularly by disrupting are altering learned safety. Considering that nicotine has been shown to modulate associative learning, including hippocampus-dependent forms of fear learning, we hypothesized that nicotine administration could cause maladaptive associative learning to occur, leading to altered safety learning. In the present study, mice were administered acute nicotine and trained and tested in two forms of cued safety learning, explicitly unpaired and backwards trace conditioning. To test for conditioned inhibition of fear by safety cues we performed summation testing. Summation testing indicated that acute nicotine did not impact unpaired learned safety, but did disrupt backwards trace conditioned safety. Additionally, chronic nicotine was found to have no effect on backwards trace conditioned safety, suggesting the development of tolerance. Importantly, on a separate test in which the backwards trace conditioned stimulus was presented alone in a novel context, acute nicotine administration was found to facilitate a fear association with the backwards trace conditioned stimulus. Therefore, acute nicotine prevented backwards trace conditioned safety, by facilitating the formation of a maladaptive fear association. Finally, we found that infusion of nicotine into the dorsal hippocampus and medial prefrontal cortex resulted in similar maladaptive behavioral patterns in summation testing. These findings are discussed with respect to how nicotine can alter cognition and the role alterations in cognition may play PTSD. / Psychology

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Indiana University-Purdue University Indianapolis (IUPUI) / Impulsivity, or the tendency to act prematurely without foresight, has been linked to a diverse range of pathological conditions. Foresight refers to the ability to envision future rewards and events (i.e. prospectively sample) and has been associated with decreased impulsivity. One form of impulsivity is measured by the ability to delay gratification and is often studied in the framework of Delay Discounting (DD). DD provides the means to study impulsivity in a number of pathological conditions. However, whether impulsivity precedes the development of pathological states or results from the pathological state itself is not fully understood. This necessitates an understanding of neurobiological mechanisms contributing to decision making in both non-impulsive as well as impulsive populations of individuals. Animal models allow invasive techniques to be used to dissect the neurocircuitry involved in decision making. Given that the decision-making process is an ongoing process rather than an isolated event, optogenetics provide the temporal and spatial specificity necessary for evaluating brain region specific contributions to decision making in DD. In the present study, optogenetics were used to assess the contribution of the medial Prefrontal Cortex (mPFC), a brain region involved in ‘goal-directed’ behavior, in the planning of future choices (i.e. prospective plans) and subsequent measures of impulsivity in an adjusting amount DD procedure. Optogenetic inhibition of mPFC was conducted in Wistar rats during different epochs of a DD task in order to assess how mPFC affects planning behavior in a population of rat not considered to be highly impulsive. Although no direct effects on planning behavior (e.g. consistency) were observed, inhibiting mPFC after a trial has been initiated and directly before a choice was made (Epoch 2) was observed to increase measures of impulsivity in comparison to days where no optogenetic manipulation occurred in a delay-specific manner. This suggests that mPFC differentially contributes to decision making at different delays. A pattern of associations between choice latency, impulsivity, and consistency began to emerge for inactivation occurring in Epoch 2, suggesting that mPFC contributes to some aspect of planning choices during this epoch. Moreover, these results indicate that mPFC is involved in decision making in Wistar Rats. Understanding the direct role that mPFC plays in promoting choices of delayed rewards provides a neurobiological target for treatment aimed at reducing impulsivity in the clinical population.