SummaryPlace cell firing relies on information about self-motion and the external environment, which may be conveyed by grid and border cells, respectively. Here, we investigate the possible contributions of these cell types to place cell firing, taking advantage of a developmental time window during which stable border cell, but not grid cell, inputs are available. We find that before weaning, the place cell representation of space is denser, more stable, and more accurate close to environmental boundaries. Boundary-responsive neurons such as border cells may, therefore, contribute to stable and accurate place fields in pre-weanling rats. By contrast, place cells become equally stable and accurate throughout the environment after weaning and in adulthood. This developmental switch in place cell accuracy coincides with the emergence of the grid cell network in the entorhinal cortex, raising the possibility that grid cells contribute to stable place fields when an organism is far from environmental boundaries.
Summary Hippocampal place cells encode an animal’s current position in space during exploration [ 1 ]. During sleep, hippocampal network activity recapitulates patterns observed during recent experience: place cells with overlapping spatial fields show a greater tendency to co-fire (“reactivation”) [ 2 ], and temporally ordered and compressed sequences of place cell firing observed during wakefulness are reinstated (“replay”) [ 3 , 4 , 5 ]. Reactivation and replay may underlie memory consolidation [ 6 , 7 , 8 , 9 , 10 ]. Compressed sequences of place cell firing also occur during exploration: during each cycle of the theta oscillation, the set of active place cells shifts from those signaling positions behind to those signaling positions ahead of an animal’s current location [ 11 , 12 ]. These “theta sequences” have been linked to spatial planning [ 13 ]. Here, we demonstrate that, before weaning (post-natal day [P]21), offline place cell activity associated with sharp-wave ripples (SWRs) reflects predominantly stationary locations in recently visited environments. By contrast, sequential place cell firing, describing extended trajectories through space during exploration (theta sequences) and subsequent rest (replay), emerge gradually after weaning in a coordinated fashion, possibly due to a progressive decrease in the threshold for experience-driven plasticity. Hippocampus-dependent learning and memory emerge late in altricial mammals [ 14 , 15 , 16 , 17 ], appearing around weaning in rats and slowly maturing thereafter [ 14 , 15 ]. In contrast, spatially localized firing is observed 1 week earlier (with reduced spatial tuning and stability) [ 18 , 19 , 20 , 21 ]. By examining the development of hippocampal reactivation, replay, and theta sequences, we show that the coordinated maturation of offline consolidation and online sequence generation parallels the late emergence of hippocampal memory in the rat.
The role of the hippocampal formation in spatial cognition is thought to be supported by distinct classes of neurons whose firing is tuned to an organism's position and orientation in space. In this article, we review recent research focused on how and when this neural representation of space emerges during development: each class of spatially tuned neurons appears at a different age, and matures at a different rate, but all the main spatial responses tested so far are present by three weeks of age in the rat. We also summarize the development of spatial behaviour in the rat, describing how active exploration of space emerges during the third week of life, the first evidence of learning in formal tests of hippocampus-dependent spatial cognition is observed in the fourth week, whereas fully adult-like spatial cognitive abilities require another few weeks to be achieved. We argue that the development of spatially tuned neurons needs to be considered within the context of the development of spatial behaviour in order to achieve an integrated understanding of the emergence of hippocampal function and spatial cognition.
BackgroundProgression of Alzheimer's disease is thought initially to depend on rising amyloidβ and its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered synaptic transmission, compatible with increased physiological function of amyloidβ, before plaques are detected. Recently, the importance of microglia has become apparent in the human disease. Similarly, TASTPM show a close association of plaque load with upregulated microglial genes.MethodsCA1 synaptic transmission and plasticity were investigated using in vitro electrophysiology. Microglial relationship to plaques was examined with immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open field, light/dark box and elevated plus maze.FindingsThe most striking finding is the increase in microglial numbers in TASTPM, which, like synaptic changes, begins before plaques are detected. Further increases and a reactive phenotype occur later, concurrent with development of larger plaques. Long-term potentiation is initially enhanced at pre-plaque stages but decrements with the initial appearance of plaques. Finally, despite altered plasticity, TASTPM have little cognitive deficit, even with a heavy plaque load, although they show altered non-cognitive behaviours.InterpretationThe pre-plaque synaptic changes and microglial proliferation are presumably related to low, non-toxic amyloidβ levels in the general neuropil and not directly associated with plaques. However, as plaques grow, microglia proliferate further, clustering around plaques and becoming phagocytic. Like in humans, even when plaque load is heavy, without development of neurofibrillary tangles and neurodegeneration, these alterations do not result in cognitive deficits. Behaviours are seen that could be consistent with pre-diagnosis changes in the human condition.FundingGlaxoSmithKline; BBSRC; UCL; ARUK; MRC.
Place cells are hippocampal pyramidal cells that are active when an animal visits a restricted area of the environment, and collectively their activity constitutes a neural representation of space. Place cell populations in the adult rat hippocampus display fundamental properties consistent with an associative memory network: the ability to 1) generate new and distinct spatial firing patterns when encountering novel spatial contexts or changes in sensory input (“remapping”) and 2) reinstate previously stored firing patterns when encountering a familiar context, including on the basis of an incomplete/degraded set of sensory cues (“pattern completion”). To date, it is unknown when these spatial memory responses emerge during brain development. Here, we show that, from the age of first exploration (postnatal day 16) onwards, place cell populations already exhibit these key features: they generate new representations upon exposure to a novel context and can reactivate familiar representations on the basis of an incomplete set of sensory cues. These results demonstrate that, as early as exploratory behaviors emerge, and despite the absence of an adult-like grid cell network, the developing hippocampus processes incoming sensory information as an associative memory network.
Neurosteroids are naturally-occurring molecules in the brain that modulate neurotransmission.They are physiologically important since disrupting their biosynthesis precipitates neurological disorders, such as anxiety and depression. The endogenous neurosteroids, allopregnanolone and tetrahydro-deoxycorticosterone are derived from sex and stress hormones respectively, and exhibit therapeutically-useful anxiolytic, analgesic, sedative, anticonvulsant and antidepressant properties. Their main target is the γ-aminobutyric acid type-A inhibitory neurotransmitter receptor (GABA A R), whose activation they potentiate. However, whether specific GABA A R isoforms and neural circuits differentially mediate endogenous neurosteroid effects is unknown. By creating a knock-in mouse that removes neurosteroid potentiation from α2-GABA A R subunits, we reveal that this isoform is a key target for neurosteroid modulation of phasic and tonic inhibition, and is essential for the anxiolytic role of endogenous neurosteroids, but not for their anti-depressant or analgesic properties. Overall, α2-GABA A R targeting neurosteroids may act as selective anxiolytics for the treatment of anxiety disorders, providing new therapeutic opportunities for drug development.
29 Background 30 Progression of Alzheimer's disease is thought initially to depend on rising amyloidβ and 31 its synaptic interactions. Transgenic mice (TASTPM; APPSwe/PSEN1M146V) show altered 32 synaptic transmission, compatible with increased physiological function of amyloidβ, 33 before plaques are detected. Recently, the importance of microglia has become apparent 34 in the human disease. Similarly, TASTPM show a close association of plaque load with 35 upregulated microglial genes. 36 37 Methods 38 CA1 Synaptic transmission and plasticity were investigated using in vitro 39 electrophysiology. Migroglial relationship to plaques was examined with 40 immunohistochemistry. Behaviour was assessed with a forced-alternation T-maze, open 41 field, light/dark box and elevated plus maze. 42 43 Findings 44 The most striking finding is the increase in microglial numbers in TASTPM, which, like 45 synaptic changes, begins before plaques are detected. Further increases and a reactive 46 phenotype occur later, concurrent with development of larger plaques. Long-term 47 62 GlaxoSmithKline; BBSRC; UCL; ARUK; MRC. 63 64 Keywords 65 Alzheimer's disease; dementia; mouse model; synaptic transmission; microglia; plaque; 66 neurodegeneration. 67 68 Research in context 69Evidence before this study 70There is a large body of research examining many aspects of phenotypes associated with 71 mouse models of Alzheimer's disease -a PubMed search for the terms Alzheimer* AND 72 mouse returns in excess of 21000 articles. However, there are few systematic articles 73 pulling together pathological, functional (electrophysiological), and behavioural 74 analyses across the life-span of such models. There is also a number of conflicting 75 outcomes, for example reports of impaired versus enhanced synaptic plasticity; 76 cognitive impairments or not. 77 78Recently, the importance of microglia in Alzheimer's disease has come to the fore in 79 human Genome Wide Association Studies (GWAS), with variants of a number of 80 microglial genes identified as risk-factors for developing the disease. Interestingly, we 81 have recently reported that Trem2 and other genes identified as risk-factors in humans 82 are strongly up regulated in close association to plaque development in the mouse 83 model used in this study. Moreover, this previous study predicted two of the most 84 recently identified genes that were identified in GWAS since the publication of our 85 paper. 86 87We have previously used this model to identify the earliest synaptic changes and shown 88 changes in release of glutamate, the primary excitatory neurotransmitter in the brain, to 89 occur even before plaques are detectable. 90 91Added value of this study 92By studying this transgenic mouse model of Alzheimer's disease, throughout the 93 development of plaques, from prior to detection through to heavy plaque loads, we have been able to identify a clear time course of key phenotypic changes associated with early 95 disease. In particular, this study identifies the very early changes in micr...
Hippocampal place cells encode an animal's current position in space during exploration[1]. During subsequent sleep, hippocampal network activity recapitulates patterns observed during recent experience: place cells with overlapping spatial firing fields during locomotion show a greater tendency to co-fire ('reactivation') [2] and temporally ordered and compressed sequences of place cell firing observed during wakefulness are reinstated ('replay') [3-5]. Reactivation and replay are thought to be network mechanisms underlying memory consolidation [6-10].Compressed sequences of place cell firing also occur during exploration: during each cycle of the theta oscillation, the set of active place cells shifts from those signalling positions behind to those signalling positions ahead of an animal's current location [11,12]. These 'theta sequences' have been linked to spatial planning [13].Here we demonstrate that, before weaning (post-natal day 21, P21), offline place cell activity reflects predominantly stationary locations in recently visited environments. By contrast, sequential place cell firing, describing extended trajectories through space during exploration ('theta sequences') and subsequent sleep ('replay'), emerge gradually after weaning in a coordinated fashion, possibly due to a protracted decrease in the threshold for experiencedriven plasticity.
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