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Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy. TREM2 is a genetic risk factor for Alzheimer’s disease, and soluble TREM2 (sTREM2) in the CSF correlates with AD progression. Here the authors study the role of sTREM2 in a mouse model of Alzheimer’s disease, and find it reduces amyloid accumulation and increases the numbers of plaque-associated microglia which correlates with improved behavioural function in the mice.

Successful movement depends on an accurate sense of one's location within a particular environment. Neuroscientists distinguish self-centered and world-centered navigation and have been searching for a brain region where all ingredients of navigation come together. As rats foraged in an open field, LaChance et al. recorded activity from single neurons in an area called the postrhinal cortex. The authors found a population of cells that transform an animal's immediate sensory perception of its environment into a spatial map. This map is markedly different from the high-level representations observed in hippocampal place cells or entorhinal grid cells, but it is very flexible and is likely to provide the necessary building blocks for creating higher-level representations. Science , this issue p. eaax4192 Neurons in the rat postrhinal cortex provide a template for the formation of high-level topographic spatial maps. A topographic representation of local space is critical for navigation and spatial memory. In humans, topographic spatial learning relies upon the parahippocampal cortex, damage to which renders patients unable to navigate their surroundings or develop new spatial representations. Stable spatial signals have not yet been observed in its rat homolog, the postrhinal cortex. We recorded from single neurons in the rat postrhinal cortex whose firing reflects an animal’s egocentric relationship to the geometric center of the local environment, as well as the animal’s head direction in an allocentric reference frame. Combining these firing correlates revealed a population code for a stable topographic map of local space. This may form the basis for higher-order spatial maps such as those seen in the hippocampus and entorhinal cortex.

The observation of place cells has suggested that the hippocampus plays a special role in encoding spatial information. However, place cell responses are modulated by several nonspatial variables and reported to be rather unstable. Here, we propose a memory model of the hippocampus that provides an interpretation of place cells consistent with these observations. We hypothesize that the hippocampus is a memory device that takes advantage of the correlations between sensory experiences to generate compressed representations of the episodes that are stored in memory. A simple neural network model that can efficiently compress information naturally produces place cells that are similar to those observed in experiments. It predicts that the activity of these cells is variable and that the fluctuations of the place fields encode information about the recent history of sensory experiences. Place cells may simply be a consequence of a memory compression process implemented in the hippocampus.

Global Positioning System (GPS) navigation devices and applications have become ubiquitous over the last decade. However, it is unclear whether using GPS affects our own internal navigation system, or spatial memory, which critically relies on the hippocampus. We assessed the lifetime GPS experience of 50 regular drivers as well as various facets of spatial memory, including spatial memory strategy use, cognitive mapping, and landmark encoding using virtual navigation tasks. We first present cross-sectional results that show that people with greater lifetime GPS experience have worse spatial memory during self-guided navigation, i.e. when they are required to navigate without GPS. In a follow-up session, 13 participants were retested three years after initial testing. Although the longitudinal sample was small, we observed an important effect of GPS use over time, whereby greater GPS use since initial testing was associated with a steeper decline in hippocampal-dependent spatial memory. Importantly, we found that those who used GPS more did not do so because they felt they had a poor sense of direction, suggesting that extensive GPS use led to a decline in spatial memory rather than the other way around. These findings are significant in the context of society’s increasing reliance on GPS.

Slow gamma oscillations (30–60 Hz) correlate with retrieval of spatial memory. Altered slow gamma oscillations have been observed in Alzheimer’s disease. Here, we use the J20-APP AD mouse model that displays spatial memory loss as well as reduced slow gamma amplitude and phase-amplitude coupling to theta oscillations phase. To restore gamma oscillations in the hippocampus, we used optogenetics to activate medial septal parvalbumin neurons at different frequencies. We show that optogenetic stimulation of parvalbumin neurons at 40 Hz (but not 80 Hz) restores hippocampal slow gamma oscillations amplitude, and phase-amplitude coupling of the J20 AD mouse model. Restoration of slow gamma oscillations during retrieval rescued spatial memory in mice despite significant plaque deposition. These results support the role of slow gamma oscillations in memory and suggest that optogenetic stimulation of medial septal parvalbumin neurons at 40 Hz could provide a novel strategy for treating memory deficits in AD. Slow gamma oscillations are associated with memory and have been reported to be disrupted in patients with Alzheimer’s disease. Here the authors show that optogenetic stimulation of medial septum parvalbumin neurons at 40 Hz rescues memory retrieval in the J20 mouse model of Alzheimer’s disease.

Stringent glucose demands render the brain susceptible to disturbances in the supply of this main source of energy, and chronic stress may constitute such a disruption. However, whether stress-associated cognitive impairments may arise from disturbed glucose regulation remains unclear. Here we show that chronic social defeat (CSD) stress in adult male mice induces hyperglycemia and directly affects spatial memory performance. Stressed mice developed hyperglycemia and impaired glucose metabolism peripherally as well as in the brain (demonstrated by PET and induced metabolic bioluminescence imaging), which was accompanied by hippocampus-related spatial memory impairments. Importantly, the cognitive and metabolic phenotype pertained to a subset of stressed mice and could be linked to early hyperglycemia 2 days post-CSD. Based on this criterion, ∼40% of the stressed mice had a high-glucose (glucose >150 mg/dL), stress-susceptible phenotype. The relevance of this biomarker emerges from the effects of the glucose-lowering sodium glucose cotransporter 2 inhibitor empagliflozin, because upon dietary treatment, mice identified as having high glucose demonstrated restored spatial memory and normalized glucose metabolism. Conversely, reducing glucose levels by empagliflozin in mice that did not display stress-induced hyperglycemia (resilient mice) impaired their default-intact spatial memory performance. We conclude that hyperglycemia developing early after chronic stress threatens long-term glucose homeostasis and causes spatial memory dysfunction. Our findings may explain the comorbidity between stress-related and metabolic disorders, such as depression and diabetes, and suggest that cognitive impairments in both types of disorders could originate from excessive cerebral glucose accumulation.

Ageing is characterized by the development of persistent pro-inflammatory responses that contribute to atherosclerosis, metabolic syndrome, cancer and frailty 1 – 3 . The ageing brain is also vulnerable to inflammation, as demonstrated by the high prevalence of age-associated cognitive decline and Alzheimer’s disease 4 – 6 . Systemically, circulating pro-inflammatory factors can promote cognitive decline 7 , 8 , and in the brain, microglia lose the ability to clear misfolded proteins that are associated with neurodegeneration 9 , 10 . However, the underlying mechanisms that initiate and sustain maladaptive inflammation with ageing are not well defined. Here we show that in ageing mice myeloid cell bioenergetics are suppressed in response to increased signalling by the lipid messenger prostaglandin E 2 (PGE 2 ), a major modulator of inflammation 11 . In ageing macrophages and microglia, PGE 2 signalling through its EP2 receptor promotes the sequestration of glucose into glycogen, reducing glucose flux and mitochondrial respiration. This energy-deficient state, which drives maladaptive pro-inflammatory responses, is further augmented by a dependence of aged myeloid cells on glucose as a principal fuel source. In aged mice, inhibition of myeloid EP2 signalling rejuvenates cellular bioenergetics, systemic and brain inflammatory states, hippocampal synaptic plasticity and spatial memory. Moreover, blockade of peripheral myeloid EP2 signalling is sufficient to restore cognition in aged mice. Our study suggests that cognitive ageing is not a static or irrevocable condition but can be reversed by reprogramming myeloid glucose metabolism to restore youthful immune functions. In aged mice, inhibition of prostaglandin E 2 (PGE 2 ) signalling through its receptor EP2 improves cellular bioenergetics, reduces inflammatory responses and restores hippocampal plasticity to youthful levels, resulting in an improvement in spatial memory and cognition.

Learning the location of relevant places in the environment is crucial for survival. Such capacity is supported by a distributed network comprising the prefrontal cortex and hippocampus, yet it is not fully understood how these structures cooperate during spatial reference memory formation. Hence, we examined neural activity in the prefrontal–hippocampal circuit in mice during acquisition of spatial reference memory. We found that interregional oscillatory coupling increased with learning, specifically in the slow-gamma frequency (20 to 40 Hz) band during spatial navigation. In addition, mice used both spatial and nonspatial strategies to navigate and solve the task, yet prefrontal neuronal spiking and oscillatory phase coupling were selectively enhanced in the spatial navigation strategy. Lastly, a representation of the behavioral goal emerged in prefrontal spiking patterns exclusively in the spatial navigation strategy. These results suggest that reference memory formation is supported by enhanced cortical connectivity and evolving prefrontal spiking representations of behavioral goals.

During our daily life, we depend on memories of past experiences to plan future behaviour. These memories are represented by the activity of specific neuronal groups or ‘engrams’ 1 , 2 . Neuronal engrams are assembled during learning by synaptic modification, and engram reactivation represents the memorized experience 1 . Engrams of conscious memories are initially stored in the hippocampus for several days and then transferred to cortical areas 2 . In the dentate gyrus of the hippocampus, granule cells transform rich inputs from the entorhinal cortex into a sparse output, which is forwarded to the highly interconnected pyramidal cell network in hippocampal area CA3 3 . This process is thought to support pattern separation 4 (but see refs. 5 , 6 ). CA3 pyramidal neurons project to CA1, the hippocampal output region. Consistent with the idea of transient memory storage in the hippocampus, engrams in CA1 and CA2 do not stabilize over time 7 – 10 . Nevertheless, reactivation of engrams in the dentate gyrus can induce recall of artificial memories even after weeks 2 . Reconciliation of this apparent paradox will require recordings from dentate gyrus granule cells throughout learning, which has so far not been performed for more than a single day 6 , 11 , 12 . Here, we use chronic two-photon calcium imaging in head-fixed mice performing a multiple-day spatial memory task in a virtual environment to record neuronal activity in all major hippocampal subfields. Whereas pyramidal neurons in CA1–CA3 show precise and highly context-specific, but continuously changing, representations of the learned spatial sceneries in our behavioural paradigm, granule cells in the dentate gyrus have a spatial code that is stable over many days, with low place- or context-specificity. Our results suggest that synaptic weights along the hippocampal trisynaptic loop are constantly reassigned to support the formation of dynamic representations in downstream hippocampal areas based on a stable code provided by the dentate gyrus. Imaging of hippocampal neuron activity in mice performing a memory task across several days identifies both stable and dynamic memory engrams.

Temporal lobe epilepsy is the most common form of epilepsy in adults. Patients have spontaneous seizures and risk developing serious cognitive impairment. Bui et al. studied an animal model of temporal lobe epilepsy (see the Perspective by Scharfman). Selective optogenetic inhibition of dentate gyrus mossy cells increased the likelihood of electrographic seizures generalizing to full behavioral convulsive seizures. Activation of mossy cells reduced the likelihood. Thus, the activity of mossy cells might serve to inhibit seizure propagation. Science , this issue p. 787 ; see also p. 740 There is a direct relationship between mossy cell activity in the dentate gyrus, convulsive seizures, and spatial memory formation in mice. Temporal lobe epilepsy (TLE) is characterized by debilitating, recurring seizures and an increased risk for cognitive deficits. Mossy cells (MCs) are key neurons in the hippocampal excitatory circuit, and the partial loss of MCs is a major hallmark of TLE. We investigated how MCs contribute to spontaneous ictal activity and to spatial contextual memory in a mouse model of TLE with hippocampal sclerosis, using a combination of optogenetic, electrophysiological, and behavioral approaches. In chronically epileptic mice, real-time optogenetic modulation of MCs during spontaneous hippocampal seizures controlled the progression of activity from an electrographic to convulsive seizure. Decreased MC activity is sufficient to impede encoding of spatial context, recapitulating observed cognitive deficits in chronically epileptic mice.