Mitochondrial and Autophagic Regulation of Adult Neurogenesis in the Healthy and Diseased Brain

Adult neurogenesis is a highly regulated process during which new neurons are generated from neural stem cells in two discrete regions of the adult brain: the subventricular zone of the lateral ventricle and the subgranular zone of the dentate gyrus in the hippocampus. Defects of adult hippocampal neurogenesis have been linked to cognitive decline and dysfunction during natural aging and in neurodegenerative diseases, as well as psychological stress-induced mood disorders. Understanding the mechanisms and pathways that regulate adult neurogenesis is crucial to improving preventative measures and therapies for these conditions. Accumulating evidence shows that mitochondria directly regulate various steps and phases of adult neurogenesis. This review summarizes recent findings on how mitochondrial metabolism, dynamics, and reactive oxygen species control several aspects of adult neural stem cell function and their differentiation to newborn neurons. It also discusses the importance of autophagy for adult neurogenesis, and how mitochondrial and autophagic dysfunction may contribute to cognitive defects and stress-induced mood disorders by compromising adult neurogenesis. Finally, I suggest possible ways to target mitochondrial function as a strategy for stem cell-based interventions and treatments for cognitive and mood disorders.     

Hippocampal theta-band activity and trace eyeblink conditioning in rabbits.

The authors examined the relationship between hippocampal theta activity and trace eyeblink conditioning. Hippocampal electrophysiological local field potentials were recorded before, during, and after conditioning or explicitly unpaired training sessions in adult male New Zealand White rabbits. As expected, a high relative power of theta activity (theta ratio) in the hippocampus predicted faster acquisition of the conditioned response during trace conditioning but, contrary to previous results obtained using the delay paradigm, only in the initial stage of learning. The presentation of the conditioned stimulus overall elicited an increase in the hippocampal theta ratio. The theta ratio decreased in the unpaired group as a function of training, remained high throughout conditioning in the fast learners, and rapidly increased in the slow learners initially showing a low theta ratio. Our results indicate a reciprocal connection between the hippocampal oscillatory activity and associative learning. The hippocampal theta ratio seems to reflect changes and differences in the subjects’ alertness and responsiveness to external stimuli, which affect the rate of learning and are, in turn, affected by both conditioning and unpaired training. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Classical tone-shock conditioning induces zenk expression in the pigeon (Columba livia) hippocampus.

The hippocampus is involved in fear conditioning, although the molecular events underlying this function are still under investigation. The authors analyzed the expression of the Zenk proto-oncogene product within the pigeon (Columba livia) hippocampus after training with a classical aversive conditioning protocol using tone-shock associations. Control groups were trained with shock or tone alone or were only exposed to the experimental chamber and manipulated. Experimental pigeons showed significant increases of Zenk expression in the ventromedial region of the hippocampus, whereas both the experimental and shock groups had increased Zenk expression in the dorsal region. The expression of Zenk in specific neuronal populations within the pigeon hippocampus may be indicative of plasticity-associated aversive classical conditioning. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Growth points in research on memory and hippocampus.

We present an overview of two of our ongoing projects relating processes in the hippocampus to memory. We are trying to understand why retrograde amnesia occurs after damage to the hippocampus. Our experiments establish the generality of several new retrograde amnesia phenomena that are at odds with the consensus view of the role of the hippocampus in memory. We show in many memory tasks that complete damage to the hippocampus produces retrograde amnesia that is equivalent for recent and remote memories. Retrograde amnesia affects a much wider range of memory tasks than anterograde amnesia. Normal hippocampal processes can interfere with retention of a long-term memory stored outside the hippocampus. We conclude that the hippocampus competes with nonhippocampal systems during memory encoding and retrieval. Finally, we outline a project to understand and manipulate adult hippocampal neurogenesis in order to repair damaged hippocampal circuitry to recover lost cognitive functions. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Context- but not familiarity-dependent forms of object recognition are impaired following excitotoxic hippocampal lesions in rats.

Dual-process models of recognition memory in animals propose that recognition memory is supported by two independent processes that reflect the operation of distinct brain structures: a familiarity process that operates independently of the hippocampus and a context-dependent (episodic) memory process that is dependent on the hippocampus. A novel variant of an object recognition procedure was used to examine this proposal. Healthy rats showed a preference for exploring a novel object rather than a familiar object: a familiarity-dependent recognition effect. They also showed a preference for exploring a familiar object that was presented in a different spatiotemporal context rather than a familiar object that was presented either in a different spatial or temporal context: a context-dependent form of recognition that is sensitive to "what" object has been presented "where" and "when." Rats with excitotoxic hippocampal lesions showed the familiarity-dependent but not the context-dependent form of recognition. The results provide support for dual-process theories of recognition memory. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Exposure to enriched environment improves spatial learning performances and enhances cell density but not choline acetyltransferase activity in the hippocampus of ventral subicular-lesioned rats.

The authors demonstrated the efficacy of enriched housing conditions in promoting the behavioral recovery and neuronal survival following subicular lesion in rats. Chemical lesioning of the ventral subiculum impaired the spatial learning performances in rats. The lesion also induced a significant degree of neurodegeneration in the CA1 and CA3 areas of the hippocampus and entorhinal cortex. Exposure to enriched housing conditions improved the behavioral performance and partially attenuated the neurodegeneration in the hippocampus. The choline acetyl transferase (ChAT) activity in the hippocampus remained unchanged following ventral subicular lesion and also following exposure to an enriched environment. The study implicates the effectiveness of activity-dependent neuronal plasticity induced by environmental enrichment in adulthood following brain insult. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The role of dorsal hippocampus and basolateral amygdala NMDA receptors in the acquisition and retrieval of context and contextual fear memories.

The authors used 3-phase context preexposure facilitation methodology to study the contribution of N-methyl-D-aspartate (NMDA) receptors in dorsal hippocampus (DH) and the basal lateral region of the amygdala (BLA) to (a) acquisition of the context memory, (b) retrieval of the context memory, (c) acquisition of context-shock association, and (d) retrieval of the context-shock association. The NMDA receptor antagonist D-2-amino-5 phosphonopentanoic acid (D-AP5) was injected into either the DH or BLA prior to (a) the context preexposure phase, (b) the immediate shock phase, or (c) the test for contextual fear. Antagonizing NMDA receptors in the DH impaired the acquisition of the context memory but did not affect its retrieval or retrieval of the fear memory. Antagonizing NMDA receptors with D-AP5 in the BLA impaired acquisition of the context-shock association but had no effect on the expression of fear. However, both DL-AP5 and L-AP5 reduced the expression of fear when they were injected into the amygdala prior to testing for contextual fear. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Changes in goal selection induced by cue conflicts are in register with predictions from changes in place cell field locations.

In the cognitive mapping theory of hippocampal function, currently active place cells represent a rat's spatial location (J. O'Keefe & L. Nadel, 1978). A systematic shift of firing field locations should therefore produce a similar shift in a rat's judgment of its location. A. A. Fenton, G. Csizmadia, and R. U. Muller (2000a) recorded place cells in cylinders with 2 cue cards separated by 135°. When the separation was changed, firing fields moved systematically, as described by a vector-field equation (A. A. Fenton, G. Csizmadia, & R. U. Muller, 2000b). Given this cohesive movement of firing fields, the mapping theory predicts that a rat's decisions about the location of an unmarked goal should move after card separation changes, as described by the vector-field equation. The authors tested this reasoning with a task in which the rat earned a food reward by pausing in a small, unmarked goal zone. When cues were shifted in the absence of reward, goal choice shifts were accurately predicted by the vector-field equation, providing strong support for the notion that a rat's judgment of its spatial location is intimately related to the across-cell discharge pattern of simultaneously active place cells. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Impaired processing of local geometric features during navigation in a water maze following hippocampal lesions in rats.

Hippocampal damage impairs navigation with respect to information provided by the shape of an arena. Recent evidence has suggested that normal rats use local geometric information, as opposed to a global geometric representation, to navigate to a correct corner. One implication of this pattern of results is that hippocampal lesions may impair processing of 1 or more of the local geometric features of an environment. The authors therefore investigated the effects of hippocampal cell loss in rats on navigation to a hidden goal with respect to a variety of local cues in an environment with a distinctive shape. Rats with lesions of the hippocampus were impaired in discriminating a right-angled corner from its mirror image. However, they were able to use cues provided by an acute-angled corner (Experiment 1) or a local polarizing cue (Experiment 2). In contrast, lesioned rats were impaired in discriminating long versus short walls (Experiment 3). Results indicate that the hippocampus plays a role in disambiguating locations by processing (metric) information related to the distance between corners. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

基于改进水平集和区域生长的轮廓提取方法

以人体大脑海马切片序列为研究对象,提出了基于目标灰度差异的水平集方法,该方法克服了水平集方法用于提取海马轮廓时边界易停留在背景梯度局部极值处的问题。同时为了避免传统区域生长人工定义阈值的盲目性,将水平集分割后的图像的标准差作为阈值进行自适应区域生长,获得了海马的轮廓。通过理论分析与实验验证,提出的方法能够有效地滤除非目标区域对海马目标的干扰,获得了较好的分割效果。