Hippocampus最新文献

Autophagy is a cellular protein degradation mechanism essential for neuronal function. Recent work has begun to implicate autophagy in cellular functions beyond preserving homeostasis, such as synaptic plasticity and the regulation of dendritic spines. Work from our lab and others demonstrates that synaptic plasticity in distinct dendritic compartments is in part regulated by the uneven distribution of autophagosomes in CA1 apical dendrites. However, it remains unclear whether autophagy contributes to dendritic spine regulation in different dendritic segments. Here, we investigated the role of autophagy and caspase-3, a protein inhibiting autophagy during NMDA receptor-dependent long-term depression, in the regulation of proximal and distal dendritic spines of CA1 pyramidal neurons. We conducted 3D neuron reconstruction of fluorescently labeled dendrites to analyze the volume, density, and subtype proportions of dendritic spines across compartments in ATG5 and caspase-3 knockout mice. ATG5 knockout mice had larger spines in distal dendrites as compared to proximal dendrites. Caspase-3 knockout mice did not display any difference between proximal and distal spine volume. Only ATG5 knockout mice exhibited reduced spine density as compared to controls. Both ATG5 and caspase-3 knockout mice possessed increased spine volume across all three spine subtypes: thin, stubby, and mushroom, along with a shift in spine subtypes with reduced proportions of thin and increased proportions of stubby and mushroom. These findings suggest that both autophagy and caspase-3 contribute to the regulation of spine volume and morphology. However, only autophagy appears to influence spine density. Moreover, autophagy uniquely regulates spine volume differently in proximal versus distal dendrites.

Morphological features within the hippocampal dentate gyrus (DG) granule cell layer (GCL) have been identified in some cases of sudden unexpected infant death (SUDI), including sudden infant death syndrome (SIDS). Reelin, an extracellular matrix protein, is critical in neuronal migration and cell positioning. An altered reelin expression is hypothesized as a contributor to altered DG morphology. This study aimed to determine whether the number of reelin-expressing cells within the infant hippocampus is altered in (1) SIDS, and according to the presence of (2) SIDS risk factors (age, cigarette smoke exposure [CSE], sleep position, bed sharing, and upper respiratory tract infection [URTI]), and (3) DG morphology. Immunohistochemical staining of reelin was quantified (measured as the number of positive reelin cells/mm²) within the layers of the DG, CA4/Hilus, CA3-CA1, and subiculum in cases of explained SUDI (eSUDI, n = 12), SIDS I (n = 7), and SIDS II (n = 33). Reelin was highly correlated with age. After adjusting for age, SIDS II infants had a lower number of reelin immunopositive cells in the CA1, a finding that was more pronounced in bed sharers. Analysis of risk factors indicated lower reelin in the DG and CA3 of males, and in the DG of infants with URTI (when excluding bed sharers). The presence of the DG morphological feature of cluster ectopic cells was associated with a lower number of reelin cells across several hippocampal layers, whereas gaps were associated with higher numbers, with layers predominantly affected being the DG molecular layer and CA2 stratum radiatum.

It has been established that aged rats are worse at learning the spatial version of the Morris watermaze task compared to their younger counterparts. It remains unclear, however, whether this poorer performance by the older rats can be attributed to the use of different behavioral strategies to solve the task. We trained young (6–9 months, n = 37) and old (19–22 months, n = 65) male Fischer 344 rats on the Morris watermaze for four consecutive days with six trials per day. Using Rtrack, an automated discriminant classifier, we analyzed each rat's swimming trajectory to estimate the probability of the rat using one of eight distinct navigation strategies on each given trial. Across acquisition, the behavioral strategy profiles diverged markedly by age. The use of both platform-independent and procedural strategy types declined across learning in young rats in favor of allocentric ones. In contrast, there was no decline in the old rats' use of procedural strategies across learning, although their use of allocentric strategies did increase across days. The allocentric strategies that older animals favored tended to be less accurate than those favored by young rats. To investigate the tendency to switch strategies between trials, the entropy of strategy transition matrices was calculated. Young rats exhibited lower entropy between trials, which reflects the fact that they tended to converge onto a restricted set of allocentric strategies by Day 4. Old rats, on the other hand, had higher entropy, reflecting the fact that they continued to interleave procedural and allocentric strategies throughout training. These results align with human literature that hypothesizes that aging shifts the balance of strategy selection from allocentric hippocampus-dependent circuits to procedural extra-hippocampal circuits.

While the hippocampus has intrigued generations of neuroscientists for its contributions to cognitive and emotional processing, functional specialization along its longitudinal axis confers particular importance to the ventral hippocampus (vHPC) in affective regulation under normal and pathological conditions. In particular, vHPC is extensively linked to the encoding, expression, and extinction of fear memories, which mediate behavioral adaptation to environmental threats. Despite decades of research, however, many questions remain about precisely what is encoded among specific populations of vHPC neurons and what brain systems cooperate in processing this information during fear regulation. Furthermore, as insights accumulate into the function of discrete afferent projections of vHPC, an important area of focus is how vHPC circuitry might be organized to support different output patterns through synaptic integration. Here, we summarize the current understanding of these issues based on contemporary circuit-based approaches and highlight potential clues to the anatomical and functional organization of synaptic networks that may help reconceptualize vHPC as a system of interacting modules.

This article is a personal history of the background, ideas, and motivations behind the major discoveries from my lab in the past 27 years. Tracing the main themes back to my training as a graduate student and a postdoc, I discuss how all of our work has been influenced by a desire to use anatomical and computational literature to inspire and constrain the experimental questions we have addressed. The backstory of two fundamental discoveries made in the early days on my independent research program are described: (a) differences between DG, CA3, and CA1 population dynamics in relation to computational theories of pattern separation and pattern completion and (b) differences in the types of information conveyed to the hippocampus from its lateral and medial entorhinal cortex inputs. Also described are how these initial findings set the foundation for numerous subsequent discoveries as we followed the data from one experiment to the next, with the goals of understanding how information is represented and transformed through the hippocampal formation in support of spatial learning and episodic memory.

Long-term potentiation (LTP) has had a major impact on neuroscience. In this review I use LTP citations from PubMed and LTP publications from the Web of Science to analyze the fascinating history of research on LTP. Interest gradually grew from a prolonged delay after its discovery, to its meteoric rise and mature growth, and finally to a recent steep decline. While such rise and fall is not unique in science, the sharpness and magnitude of the swings in LTP are unusually dramatic. I discuss factors that contributed to each phase and point to key developments that led to the inflection points, at times using my own work as illustrations. I call attention to several factors that contributed to the decline in interest and conclude that LTP is to a great extent a victim of its own success. Much of the community now accepts that LTP and CaMKII are the cellular and molecular underpinning of memory. However, a broad shift toward “systems neurosciences” has deflected attention away from crucial cellular and molecular issues still unaddressed in LTP. This neglect is regrettable and unwarranted. Neuroscience doesn't have to choose between mechanisms and behavior, and I describe two somewhat overlooked examples where notable progress is being made in combining the two approaches. Countless exciting opportunities exist for further advances along these lines.