Daoyun Ji - US grants

DESCRIPTION (provided by applicant): Understanding the neural mechanisms of episodic memory is fundamental to memory-related psychiatric and neurological disorders, such as post traumatic stress disorder and Alzheimer's disease. Although it is clear that the neocortex and hippocampus are important for episodic memories, how sensory contents of these memories are stored is unknown. According to current theories, sensory components are stored in the neocortex, whereas the role of hippocampus is to bind the components together. However, there is no evidence for the existence of such neocortical neurons that are involved in processing the sensory components but functionally bound by HP. Our preliminary studies revealed that many cells in the primary visual cortex of freely moving rats fired at specific places of an environment, a property thought to be unique to cells in the hippocampus and its surrounding cortical areas. We hypothesize that these visual cortical neurons are involved in processing the visual components of spatial memories and influenced by hippocampal cells. Using simultaneous tetrode recordings of visual cortical and hippocampal neurons in rats performing spatial navigation tasks, this proposal will investigate the place-specific visual cortical neurons and study whether they are related to spatial learning or memory and whether they depend on the hippocampus.

ABSTRACT A hallmark of Alzheimer's disease is the progressive appearance of hyper-phosphorylated tau protein, tau neurofibrillary tangles, and neuron loss in the memory-processing circuits including the hippocampus. The functional changes and adaptations in these altered neural circuits are what ultimately give rises to the cognitive symptoms such as memory loss. However, it is unknown what functional changes occur in the hippocampus of the living brain with ongoing tau pathology and what pathological features causes these changes. The development of tauopathy mouse models and the tetrode recording technique, which can record hippocampal neurons in freely moving mice, make it possible to address this question. This proposal will apply the tetrode technique to a tauopathy mouse model, the transgenic rTau4510 mice, in which the over- expression of a mutated version of human tau leads to age-dependent memory deficits. We focus on a hypothesis that tau pathology in this model disrupts neural mechanisms for memory consolidation and the disruption results in unstable hippocampal memory representations. Hippocampal neurons and local field potentials will be recorded while mice perform spatial navigation tasks and while they rest. The tau pathology in the recorded brains will be subsequently examined by biochemical and immunohistochemical methods. We will investigate how the electrophysiological markers related to memory consolidation, including ripples, neuronal synchrony, and place field stability, are altered at various pathological stages in the rTg4510 mice, and which pathological parameters are critical for these electrophysiological alterations.

? DESCRIPTION (provided by applicant): Observational learning, defined as learning by observing others' actions, is a fundamental behavior of human and animals and is impaired in patients with autism spectrum disorders (ASDs). How the neurons and circuits in the brain accomplish this remarkable function is unknown. In observational learning, the observer needs to actively understand and store others' actions from his own personnel perspective, and then utilize the information in later self-actions. This proposal studies the role of hippocampal neurons in this process of action understanding and how they mediate the learning effect of observation. We will test a hypothesis that observing others' actions triggers the hippocampal neuronal activity patterns that encode the observer's own execution of the same actions. According to the hypothesis, observation leads to learning by facilitating and strengthening the activity patterns encoding self-actions. Our main approach is to simultaneously record a large number of neurons in freely moving rats performing observational tasks. We will determine what activity patterns occur during observation and how they compare with the patterns during the observer's own actions. We will then determine whether the observation-induced activity patterns enhance the observer's learning behavior and whether the disruption of these patterns reduces the enhancement. In addition, we will determine whether the observation-induced neural activity patterns and their learning effects are impaired in a transgenic rat model with social dysfunction. The outcome of this proposal may reveal a novel neural circuit mechanism of observational learning and generate insights into how observational learning is impaired in ASDs at the neural circuit level in vivo.

Abstract Tau pathology, including tau protein hyperphosphorylation, neurofibrillary tangles and subsequent neurodegeneration, plays a key role in cognitive symptoms of tauopathies including Alzheimer?s disease. Recent studies using animal models have made rapid progress in understanding tau pathogenesis and its involvement in cognitive deficits. However, behavioral deficits are ultimately mediated by functional changes in neural circuits in vivo. An important question that has rarely been studied is how neural circuit functions are altered in the living brain with ongoing tau pathology and neurodegeneration. Here we propose to determine in vivo functional abnormalities caused by tau pathology and neurodegeneration in the neural circuits of hippocampus (HP) and entorhinal cortex, areas that are crucial for memory loss in tauopathies. Primarily using the tetrode recording technique, in combination with behavioral and pharmacological manipulations, we will simultaneously record a large number of neurons in freely moving animals of tauopathy mouse models, including the transgenic rTg4510 mouse and htau mouse. We will focus on a specific ?internal-external imbalance? hypothesis: The memory circuits in these mice cannot form normal memories because they are dominated by internal activities generated within the hippocampus and thus fail to respond to external sensory input. To test the hypothesis, we will aim to determine whether activities of HP neurons in tauopathy models are preferentially driven by internal activities more than those in control mice, how this abnormality is generated by the memory neural circuits, what computational process it alters, and how it is linked to behavioral memory deficits.

Project Summary The hallucinogenic drug lysergic acid diethylamide (LSD) is abused for its mind-altering effects such as vivid, surreal visual hallucinations. How LSD generates such abnormal perceptions is unknown. Because abnormal perceptions are mediated by altered activities in relevant neural circuits, investigating how LSD alters activity patterns of neural circuits in vivo is a critical step to understand the action of the drug. Here we propose a working hypothesis that LSD suppresses the ?top-down? mnemonic control of visual cortical activities from the memory areas hippocampus and medial prefrontal cortex in vivo. The suppression under LSD renders the visual cortical activities no longer influenced by recent or personal memories and therefore produces visual perceptions that no longer reflect reality or self-identify. To test the hypothesis, we will first determine whether LSD produces abnormal activity patterns in the hippocampus/medial prefrontal cortex that no longer reflect the memory of the animal?s recent behavior. Then we will examine how these abnormal mnemonic activity patterns are correlated with abnormal activities in the visual cortex and with behavioral responses to LSD. We will do so by simultaneous recording of a large number of individual neurons in rats during active tasks and during resting with and without the presence of LSD. Second, we will boost mnemonic activities in the hippocampus and medial prefrontal cortex by deep brain stimulations and determine whether the activity patterns in the visual cortex under LSD are rectified and whether behavioral responses are reduced. This project will study the neural circuit mechanism of how LSD produces its mind-altering effects and significantly advance our understanding of potential risks of recreational or medicinal use of LSD. Its outcomes will also generate insights into how hallucinations in psychiatric disorders such as schizophrenia are produced and may inspire novel treatment strategies.

Abstract Humans and animals can sense and respond to aversive experiences of others, an ability crucial for empathy, social bonding and important for survival. Here we study how neural circuits in the brain produce observational fear, a behavior of one subject displaying fearful responses to the observation of another subject in fear. Previous behavioral and human imaging studies have revealed a powerful influence of prior aversive experience on this behavior and have also identified several brain areas involved. However, what neuronal activity patterns in vivo allow one subject to subjectively perceive the others? experiences as aversive remains mysterious. Given the strong influence of prior experience on observational fear, we propose a hypothesis that the subjective sense of fear upon observation is represented by neurons in the anterior cingulate cortex (ACC), but strongly influenced by a particular neuronal activity pattern in the hippocampus (HP), called awake replay, that recalls prior fearful experiences. We will test the hypothesis by simultaneous recording of a large number of single neurons in ACC and HP in rats during observational fear tasks. We will first determine how HP awake replay and the associated ACC activity patterns are correlated with behavioral measures of observational fear and how they are generated within the HP and ACC neural circuits. Second, we will determine how key factors related to prior experience modulate the ACC/HP activity patterns underlying observational fear. In particular, we will study the effects of recency, valence, spatial and social contexts of prior experience. Finally, we will determine how the ACC/HP activity patterns are causally related to observational fear by disrupting these patterns and then examining its impacts on behavioral measures. The outcomes of this study will significantly advance our understanding of neural circuit computations in observational fear and may reveal a specific in vivo neural mechanism of how it can be produced by recalling prior fearful experiences. This study may open the door to understand antisocial symptoms in mental disorders such as antisocial personality disorder and schizophrenia and may inspire novel therapeutic strategies. 1