Hippocampus最新文献

Glutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary DG cell type, granule cells (GCs). Numerous MC synapses are on GC proximal dendrites in the inner molecular layer (IML). However, field recordings of the GC excitatory postsynaptic potential (fEPSPs) have not been used to study this pathway selectively. Here we describe methods to selectively activate MC axons in the IML using mice with Cre recombinase expressed in MCs. Slices were made after injecting adeno-associated virus (AAV) encoding channelrhodopsin (ChR2) in the DG. In these slices, we show that fEPSPs could be recorded reliably in the IML in response to optogenetic stimulation of MC axons. Furthermore, fEPSPs were widespread across the septotemporal axis. However, fEPSPs were relatively weak because they were small in amplitude and did not elicit a significant population spike in GCs. They also showed little paired pulse facilitation. We confirmed the extracellular findings with patch clamp recordings of GCs despite different recording chambers and other differences in methods. Together the results provide a simple method for studying MC activation of GCs and add to the evidence that this input is normally weak but widespread across the GC population.

When I began my career, I had no idea that much of it would center around the hippocampus. Here I discuss some of the history of how this happened. I briefly mention my early undergraduate life and the problems it posed for getting into graduate school. I describe the unique circumstances that led me to Allan Wagner's laboratory and changed my career trajectory. My path to the hippocampus began with a decision to study memory development. This led to a collaboration with Rob Sutherland that produced the configural theory of the hippocampus. The idea was that the hippocampus facilitated the construction of representations of the co-occurring stimulus elements currently experienced by the organism. Thus, if two elements, A and B, occurred together, a representation, AB, could be constructed that could be discriminated from its elements, A and B. This idea was partially correct, but we missed an important property of the hippocampal system that was recognized by O'Keefe and Nadel, 1978 that is, that the hippocampus is an unmotivated, rapid learning system. Randy O'Reilly and I addressed this issue in what we called conjunctive representation theory and put forth a detailed cortical-hippocampus computational theory to explain how this could work I later realized that our ideas were remarkably like Tim Teyler's indexing theory of how the hippocampal system supports memory. At a Park City meeting, a chance encounter with Tim (whom I had never met) resulted in the opportunity to write a paper with Tim updating the indexing theory, It is my favorite theoretical paper.

My most important contribution to research on the hippocampus was the discovery that certain phylogenetically ancient subcortical nuclei that carry information about motivation, emotions and autonomic state exert their profound effects on hippocampal functions by selectively innervating interneurons. Diverse effects on network activity patterns and plasticity can be achieved via activating or inhibiting these functionally distinct interneuron types. In the following, I will present the series of serendipitous events that prompted me to shift my research interest from the visual cortex and the basal ganglia to the hippocampus and its subcortical control.

In the adult dentate gyrus of the hippocampus there are neuronal stem cells that give rise to immature neurons and subsequently to mature functional granule neurons. The rate of proliferation, differentiation, and survival is regulated intrinsically and extrinsically. For example, Wnt, BMP, TLX, and BDNF all regulate adult neurogenesis intrinsically, while exercise, environmental enrichment, stress, and epilepsy are some of the extrinsic factors that regulate adult neurogenesis. A clearer picture is emerging for the functional role of these newly born neurons in behavior, demonstrating that adult neurogenesis plays a role in recognizing events, places, objects, or people as unique when comparing options that are very similar, but that these newly born cells play little role in recognition when differences are greater. Most of the research on adult neurogenesis is conducted in experimental mammals, including mice and rats. The first evidence for adult neurogenesis in humans was reported in 1998, when postmortem brains from cancer patients injected with bromodeoxyuridine (BrdU) were examined and cells were found that had divided and differentiated into mature neurons. Subsequently, additional evidence using other techniques has confirmed human adult neurogenesis. Additional in vivo live reports will be needed to monitor the effects of changes in human adult neurogenesis with age and disease.

Serotonin (5-HT) has long been involved in response to stress and its effect may be, in part, mediated by 5-HT1a and 5-HT7 receptor subtypes in different brain structures. Both pre- and post-synaptic activation of 5-HT1a receptor, respectively, in the rat median raphe nucleus (MnRN) and hippocampus, lead to adaptation to acute inescapable stressors such as restraint and forced swim. 5-HT7 receptor (5HT7r), a stimulatory G-protein coupled receptor, has also been investigated as a possible candidate for mediating stress response. In the MnRN, activation of 5-HT7r has antidepressant effects, while in the hippocampus, 5HT7r mRNA expression is increased after exposure to restraint stress, but the functional significance of these receptors remains to be determined. Therefore, the aim of this study was to investigate whether blockade of hippocampal 5HT7r would prevent and/or attenuate the behavioral effects of stress. Male adult Wistar rats with bilateral cannulas aimed at the dorsal hippocampus were restrained for 2 h and tested in the elevated plus maze (EPM) 24 h later. SB 258741 (3 nmoles/0.5 μL/side; selective 5HT7r antagonist) was administered bilateraly into the hippocampus according to the experimental protocol: immediately before or after stress, or 24 h after it (immediately before the test). In a second experiment, rats were exposed to 15 min. of forced swim, and tested 24 h later. Intra-hippocampal treatment was performed as described for the restraint stress protocol. We found that blockade of hippocampal 5-HT7r immediately after, but not before, the exposure to restraint or forced swim attenuated stress-induced behavioral changes. Similar results were obtained when SB was administered before the test in previously stressed rats. Our data suggest that activation of hippocampal 5-HT7r is crucial for the consolidation and retrieval of aversive stimulus-related memories, such as those caused by a stressful experience, probably through mechanisms involving stress-induced changes in 5-HT7r expression.

During the 1980s and 1990s, much memory research focused on the differential role of the hippocampus in various forms of memory. My work on the distinction between explicit and implicit memory led me to become involved in several early neuroimaging studies that made use of cognitive paradigms to investigate the conditions in which hippocampal activity does and does not occur, and to address the theoretical implications of these findings. Here, I summarize two such projects and some of the personal backstory associated with them.

Early influences that led to the development of the cognitive map theory of hippocampal function, and the multiple trace theory, are discussed. Some details are provided, many are left out.