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Stress is assumed to cause a shift from flexible 'cognitive' memory to more rigid 'habit' memory. In the spatial memory domain, stress impairs place learning depending on the hippocampus whereas stimulus-response learning based on the striatum appears to be improved. While the neural basis of this shift is still unclear, previous evidence in rodents points towards cortisol interacting with the mineralocorticoid receptor (MR) to affect amygdala functioning. The amygdala is in turn assumed to orchestrate the stress-induced shift in memory processing. However, an integrative study testing these mechanisms in humans is lacking. Therefore, we combined functional neuroimaging of a spatial memory task, stress-induction, and administration of an MR-antagonist in a full-factorial, randomized, placebo-controlled between-subjects design in 101 healthy males. We demonstrate that stress-induced increases in cortisol lead to enhanced stimulus-response learning, accompanied by increased amygdala activity and connectivity to the striatum. Importantly, this shift was prevented by an acute administration of the MR-antagonist spironolactone. Our findings support a model in which the MR and the amygdala play an important role in the stress-induced shift towards habit memory systems, revealing a fundamental mechanism of adaptively allocating neural resources that may have implications for stress-related mental disorders.

In the absence of effective therapies for dementia and its precursors, enhancing neuroplasticity by means of non-invasive brain stimulation such as anodal transcranial direct current stimulation (atDCS) might be a promising approach to counteract or delay the onset of cognitive decline, but effect sizes have been moderate so far. Previous reports indicate that increasing serotonin levels may enhance atDCS-induced neuroplasticity. However, evidence for serotonergic modulation of atDCS effects on memory is still lacking. Here, we conducted a double-blind, randomized, sham-/placebo-controlled trial to investigate the impact of a selective serotonin reuptake inhibitor (SSRI; single dose of 20 mg citalopram) and atDCS over the right temporoparietal cortex (1 mA, 20 min) on memory formation. Twenty young and 20 older subjects completed an object-location learning task in each of the four conditions: sham+placebo, sham+SSRI, atDCS+placebo, and atDCS+SSRI. Outcome measures were performance in immediate (primary outcome) and delayed cued recall. While we found an SSRI effect, but no statistically significant effect of atDCS on immediate recall scores, young and older adults benefited most from the combined application (comparisons: atDCS+SSRI>atDCS+placebo and atDCS+SSRI>sham+placebo). Thus, our data provide evidence that atDCS improves memory formation if serotonergic neurotransmission is enhanced simultaneously. Further studies are needed to assess whether these findings extend to clinical populations with memory impairment and translate into clinically relevant improvements after long-term serotonergic enhancement and repeated stimulation.

Obesity is one of the most serious public health challenges in the world. Obesity during early life has been associated with an increased risk of neurodevelopmental disorders, including deficits in learning and memory, yet the underlying mechanisms remain unclear. Here, we show that early life high-fat diet (HFD) feeding impairs hippocampus–dependent contextual/spatial learning and memory, and alters the gut microbiota, particularly by depleting Akkermansia muciniphila (A. muciniphila), in mice. Transplantation of the HFD microbiota confers hippocampus-dependent learning and memory deficits to mice fed a chow diet. Oral treatment of HFD-fed mice with the gut commensal A. muciniphila corrects gut permeability, reduces hippocampal microgliosis and proinflammatory cytokines (tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and IL-6) expression, and restores neuronal development and synapse plasticity, thus ameliorates defects in learning and memory. Interestingly, treatment of mice with lipopolysaccharide (LPS) mimics HFD-induced hippocampus-dependent cognitive impairment in chow-fed mice. In line with these findings, pharmacologic blockade of Toll-like receptor 4 (TLR4) signalling or antibiotics treatment both effectively prevent hippocampus-dependent learning and memory deficits in HFD-fed mice. Collectively, our findings demonstrate an unexpected pivotal role of gut microbiota in HFD-induced cognitive deficits and identify a potential probiotic therapy for obesity associated with cognitive dysfunction during early life.

The authors report that genetic disruption of the connectivity of CCK + basket cells during development reveals a critical role for these interneurons in the regulation of theta oscillatory activity and in the coding of spatial information in the adult mouse hippocampus. The function of cortical GABAergic interneurons is largely determined by their integration into specific neural circuits, but the mechanisms controlling the wiring of these cells remain largely unknown. This is particularly true for a major population of basket cells that express the neuropeptide cholecystokinin (CCK). Here we found that the tyrosine kinase receptor ErbB4 was required for the normal integration into cortical circuits of basket cells expressing CCK and vesicular glutamate transporter 3 (VGlut3). The number of inhibitory synapses made by CCK + VGlut3 + basket cells and the inhibitory drive they exerted on pyramidal cells were reduced in conditional mice lacking ErbB4. Developmental disruption of the connectivity of these cells diminished the power of theta oscillations during exploratory behavior, disrupted spatial coding by place cells, and caused selective alterations in spatial learning and memory in adult mice. These results suggest that normal integration of CCK + basket cells in cortical networks is key to support spatial coding in the hippocampus.

Adult neurogenesis is a unique form of neuronal plasticity in which newly generated neurons are integrated into the adult dentate gyrus in a process that is modulated by environmental stimuli. Adult-born neurons can contribute to spatial memory, but it is unknown whether they alter neural representations of space in the hippocampus. Using in vivo two-photon calcium imaging, we find that male and female mice previously housed in an enriched environment, which triggers an increase in neurogenesis, have increased spatial information encoding in the dentate gyrus. Ablating adult neurogenesis blocks the effect of enrichment and lowers spatial information, as does the chemogenetic silencing of adult-born neurons. Both ablating neurogenesis and silencing adult-born neurons decreases the calcium activity of dentate gyrus neurons, resulting in a decreased amplitude of place-specific responses. These findings are in contrast with previous studies that suggested a predominantly inhibitory action for adult-born neurons. We propose that adult neurogenesis improves representations of space by increasing the gain of dentate gyrus neurons and thereby improving their ability to tune to spatial features. This mechanism may mediate the beneficial effects of environmental enrichment on spatial learning and memory. Adult neurogenesis is a unique form of neuronal plasticity, involving the genesis and integration of newborn neurons into the mouse dentate gyrus. Here the authors demonstrate that adult neurogenesis improves representations of space in the dentate gyrus by increasing the place-specific responses of mature neurons.

The behavioral strategies that mammals use to learn multi-step routes are unknown. In this study, we investigated how mice navigate to shelter in response to threats when the direct path is blocked. Initially, they fled toward the shelter and negotiated obstacles using sensory cues. Within 20 min, they spontaneously adopted a subgoal strategy, initiating escapes by running directly to the obstacle’s edge. Mice continued to escape in this manner even after the obstacle had been removed, indicating use of spatial memory. However, standard models of spatial learning—habitual movement repetition and internal map building—did not explain how subgoal memories formed. Instead, mice used a hybrid approach: memorizing salient locations encountered during spontaneous ‘practice runs’ to the shelter. This strategy was also used during a geometrically identical food-seeking task. These results suggest that subgoal memorization is a fundamental strategy by which rodents learn efficient multi-step routes in new environments. Shamash et al. examine how mice learn to get past an obstacle blocking their path to a goal. They found that mice instinctively adopt a subgoal memory strategy, which combines elements from both habitual learning and the cognitive map theory.

Sleep is beneficial for learning. However, it remains unclear whether learning is facilitated by non-rapid eye movement (NREM) sleep or by REM sleep, whether it results from plasticity increases or stabilization, and whether facilitation results from learning-specific processing. Here, we trained volunteers on a visual task and measured the excitatory and inhibitory (E/I) balance in early visual areas during subsequent sleep as an index of plasticity. The E/I balance increased during NREM sleep irrespective of whether pre-sleep learning occurred, but it was associated with post-sleep performance gains relative to pre-sleep performance. In contrast, the E/I balance decreased during REM sleep but only after pre-sleep training, and the decrease was associated with stabilization of pre-sleep learning. These findings indicate that NREM sleep promotes plasticity, leading to performance gains independent of learning, while REM sleep decreases plasticity to stabilize learning in a learning-specific manner.Tamaki et al. measured MRS changes in sleeping humans trained on a visual task. During NREM sleep, learning gains were associated with enhanced visual cortical plasticity that was also seen independent of learning. REM sleep stabilized plasticity only after pre-sleep learning.

Classically, pyramidal cells of the hippocampus are viewed as flexibly representing spatial and non-spatial information. Recent work has illustrated distinct types of hippocampal excitatory neurons, suggesting that hippocampal representations and functions may be constrained and interpreted by these underlying cell-type identities. In mice, here we reveal a non-pyramidal excitatory neuron type — the “ovoid” neuron — that is spatially adjacent to subiculum pyramidal cells but differs in gene expression, electrophysiology, morphology, and connectivity. Functionally, novel object encounters drive sustained ovoid neuron activity, whereas familiar objects fail to drive activity even months after single-trial learning. Silencing ovoid neurons prevents non-spatial object learning but leaves spatial learning intact, and activating ovoid neurons toggles novel-object seeking to familiar-object seeking. Such function is doubly dissociable from pyramidal neurons, wherein manipulation of pyramidal cells affects spatial assays but not non-spatial learning. Ovoid neurons of the subiculum thus illustrate selective cell-type-specific control of non-spatial memory and behavioral preference. Pyramidal cells are classically thought to comprise the excitatory output of the subiculum. Here, the authors show the existence of “ovoid cells”, excitatory subiculum neurons with specialized gene expression, morphology, projections, and function.

Traumatic brain injury (TBI) is a leading cause of long-term neurological disability, yet the mechanisms underlying the chronic cognitive deficits associated with TBI remain unknown. Consequently, there are no effective treatments for patients suffering from the long-lasting symptoms of TBI. Here, we show that TBI persistently activates the integrated stress response (ISR), a universal intracellular signaling pathway that responds to a variety of cellular conditions and regulates protein translation via phosphorylation of the translation initiation factor eIF2α. Treatment with ISRIB, a potent drug-like small-molecule inhibitor of the ISR, reversed the hippocampaldependent cognitive deficits induced by TBI in two different injury mouse models—focal contusion and diffuse concussive injury. Surprisingly, ISRIB corrected TBI-induced memory deficits when administered weeks after the initial injury and maintained cognitive improvement after treatment was terminated. At the physiological level, TBI suppressed long-term potentiation in the hippocampus, which was fully restored with ISRIB treatment. Our results indicate that ISR inhibition at time points late after injury can reverse memory deficits associated with TBI. As such, pharmacological inhibition of the ISR emerges as a promising avenue to combat head traumainduced chronic cognitive deficits.

The hippocampus and the medial entorhinal cortex are part of a brain system that maps self-location during navigation in the proximal environment 1 , 2 . In this system, correlations between neural firing and an animal’s position or orientation are so evident that cell types have been given simple descriptive names, such as place cells 3 , grid cells 4 , border cells 5 , 6 and head-direction cells 7 . While the number of identified functional cell types is growing at a steady rate, insights remain limited by an almost-exclusive reliance on recordings from rodents foraging in empty enclosures that are different from the richly populated, geometrically irregular environments of the natural world. In environments that contain discrete objects, animals are known to store information about distance and direction to those objects and to use this vector information to guide navigation 8 – 10 . Theoretical studies have proposed that such vector operations are supported by neurons that use distance and direction from discrete objects 11 , 12 or boundaries 13 , 14 to determine the animal’s location, but—although some cells with vector-coding properties may be present in the hippocampus 15 and subiculum 16 , 17 —it remains to be determined whether and how vectorial operations are implemented in the wider neural representation of space. Here we show that a large fraction of medial entorhinal cortex neurons fire specifically when mice are at given distances and directions from spatially confined objects. These ‘object-vector cells’ are tuned equally to a spectrum of discrete objects, irrespective of their location in the test arena, as well as to a broad range of dimensions and shapes, from point-like objects to extended surfaces. Our findings point to vector coding as a predominant form of position coding in the medial entorhinal cortex. Cells in the mouse medial entorhinal cortex that fire when mice are at a specific distance and direction from a stationary object suggest that vector coding is important for rodent navigation.