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Avoiding potentially dangerous situations is key for the survival of any organism. Throughout life, animals learn to avoid environments, stimuli or actions that can lead to bodily harm. While the neural bases for appetitive learning, evaluation and value-based decision-making have received much attention, recent studies have revealed more complex computations for aversive signals during learning and decision-making than previously thought. Furthermore, previous experience, internal state and systems level appetitive-aversive interactions seem crucial for learning specific aversive value signals and making appropriate choices. The emergence of novel methodologies (computation analysis coupled with large-scale neuronal recordings, neuronal manipulations at unprecedented resolution offered by genetics, viral strategies and connectomics) has helped to provide novel circuit-based models for aversive (and appetitive) valuation. In this review, we focus on recent vertebrate and invertebrate studies yielding strong evidence that aversive value information can be computed by a multitude of interacting brain regions, and that past experience can modulate future aversive learning and therefore influence value-based decisions., Competing Interests: Conflict of interest statement Nothing declared., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Although most neurons are generated embryonically, neurogenesis is maintained at low rates in specific brain areas throughout adulthood, including the dentate gyrus of the mammalian hippocampus. Episodic-like memories encoded in the hippocampus require the dentate gyrus to decorrelate similar experiences by generating distinct neuronal representations from overlapping inputs (pattern separation). Adult-born neurons integrating into the dentate gyrus circuit compete with resident mature cells for neuronal inputs and outputs, and recruit inhibitory circuits to limit hippocampal activity. They display transient hyperexcitability and hyperplasticity during maturation, making them more likely to be recruited by any given experience. Behavioral evidence suggests that adult-born neurons support pattern separation in the rodent dentate gyrus during encoding, and they have been proposed to provide a temporal stamp to memories encoded in close succession. The constant addition of neurons gradually degrades old connections, promoting generalization and ultimately forgetting of remote memories in the hippocampus. This makes space for new memories, preventing saturation and interference. Overall, a small population of adult-born neurons appears to make a unique contribution to hippocampal information encoding and removal. Although several inconsistencies regarding the functional relevance of neurogenesis remain, in this review we argue that immature neurons confer a unique form of transience on the dentate gyrus that complements synaptic plasticity to help animals flexibly adapt to changing environments., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Fölsz, Trouche and Croset.)

By investigating the topology of neuronal co-activity, we found that mnemonic information spans multiple operational axes in the mouse hippocampus network. High-activity principal cells form the core of each memory along a first axis, segregating spatial contexts and novelty. Low-activity cells join co-activity motifs across behavioral events and enable their crosstalk along two other axes. This reveals an organizational principle for continuous integration and interaction of hippocampal memories.

Both the basal amygdala (BA) and the bed nucleus of the stria terminalis (BNST) can participate in contextual fear, but it is unclear whether contextual fear engrams involve a direct interaction between these two brain regions. To determine whether dorsal BNST (dBNST)-projecting neurons in the BA participate in contextual fear engrams, we combined the TetTag mouse with a retrograde tracer to label dBNST-projecting cells in the BA. We identified a population of neurons located in the anterior subdivision of the BA (aBA) that was activated during fear conditioning and reactivated during retrieval but that did not project to the dBNST. In contrast, dBNST-projecting neurons located in the posterior BA (pBA) were activated during contextual fear conditioning but were not reactivated during retrieval. Similarly, we found neurons in the oval BNST subdivision (ovBNST) that were activated during contextual fear conditioning without being reactivated during retrieval. However, the anterodorsal BNST (adBNST) subdivision was not activated during either contextual fear conditioning or retrieval, underscoring the divergent functionality of these two dBNST subdivisions. Finally, we found that the ovBNST receives a monosynaptic projection from neurons located in the BA. Our results indicate that aBA neurons that do not project to the dBNST participate in contextual fear engrams. In contrast, dBNST-projecting neurons in the BA do not appear to participate in contextual fear engrams, but might instead contain a BA → ovBNST pathway that is active during the initial encoding of contextual fear memories., (Copyright © 2020 Sasaki Russell et al.)

Retrieving and acting on memories of food-predicting environments are fundamental processes for animal survival. Hippocampal pyramidal cells (PYRs) of the mammalian brain provide mnemonic representations of space. Yet the substrates by which these hippocampal representations support memory-guided behavior remain unknown. Here, we uncover a direct connection from dorsal CA1 (dCA1) hippocampus to nucleus accumbens (NAc) that enables the behavioral manifestation of place-reward memories. By monitoring neuronal ensembles in mouse dCA1→NAc pathway, combined with cell-type selective optogenetic manipulations of input-defined postsynaptic neurons, we show that dCA1 PYRs drive NAc medium spiny neurons and orchestrate their spiking activity using feedforward inhibition mediated by dCA1-connected parvalbumin-expressing fast-spiking interneurons. This tripartite cross-circuit motif supports spatial appetitive memory and associated NAc assemblies, being independent of dorsal subiculum and dispensable for both spatial novelty detection and reward seeking. Our findings demonstrate that the dCA1→NAc pathway instantiates a limbic-motor interface for neuronal representations of space to promote effective appetitive behavior., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Theta oscillations reflect rhythmic inputs that continuously converge to the hippocampus during exploratory and memory-guided behavior. The theta-nested operations that organize hippocampal spiking could either occur regularly from one cycle to the next or be tuned on a cycle-by-cycle basis. To resolve this, we identified spectral components nested in individual theta cycles recorded from the mouse CA1 hippocampus. Our single-cycle profiling revealed theta spectral components associated with different firing modulations and distinguishable ensembles of principal cells. Moreover, novel co-firing patterns of principal cells in theta cycles nesting mid-gamma oscillations were the most strongly reactivated in subsequent offline sharp-wave/ripple events. Finally, theta-nested spectral components were differentially altered by behavioral stages of a memory task; the 80-Hz mid-gamma component was strengthened during learning, whereas the 22-Hz beta, 35-Hz slow gamma, and 54-Hz mid-gamma components increased during retrieval. We conclude that cycle-to-cycle variability of theta-nested spectral components allows parsing of theta oscillations into transient operating modes with complementary mnemonic roles., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

The hippocampus provides the brain's memory system with a subset of neurons holding a map-like representation of each environment experienced. We found in mice that optogenetic silencing those neurons active in an environment unmasked a subset of quiet neurons, enabling the emergence of an alternative map. When applied in a cocaine-paired environment, this intervention neutralized an otherwise long-lasting drug-place preference, showing that recoding a spatial memory engram can alleviate associated maladaptive behavior.

The neural cell adhesion molecule NCAM and its association with the polysialic acid (PSA) are believed to contribute to brain structural plasticity that underlies memory formation. Indeed, the attachment of long chains of PSA to the glycoprotein NCAM down-regulates its adhesive properties by altering cell-cell interactions. In the brain, the biosynthesis of PSA is catalyzed by two polysialyltransferases, which are differentially regulated during lifespan. One of them, ST8SiaIV (PST), is predominantly expressed during adulthood whereas the other one, ST8SiaII (STX), dominates during embryonic and post-natal development. To understand the role played by ST8SiaIV during learning and memory and its underlying hippocampal plasticity, we used knockout mice deleted for the enzyme ST8SiaIV (PST-ko mice). At adult age, PST-ko mice show a drastic reduction of PSA-NCAM expression in the hippocampus and intact hippocampal adult neurogenesis. We found that these mice display impaired long-term but not short-term memory in both, spatial and non-spatial behavioral tasks. Remarkably, memory deficits of PST-ko mice were abolished by exposure to environmental enrichment that was also associated with an increased number of PSA-NCAM expressing new neurons in the dentate gyrus of these mice. Whether the presence of a larger pool of immature, likely plastic, new neurons favored the rescue of long-term memory in PST-ko mice remains to be determined. Our findings add new evidence to the role played by PSA in memory consolidation. They also suggest that PSA synthesized by PST critically controls the tempo of new neurons maturation in the adult hippocampus.

Animal models are necessary tools for solving the most serious challenges facing medical research. In aging and neurodegenerative disease studies, rodents occupy a place of choice. However, the most challenging questions about longevity, the complexity and functioning of brain networks or social intelligence can almost only be investigated in nonhuman primates. Beside the fact that their brain structure is much closer to that of humans, they develop highly complex cognitive strategies and they are visually-oriented like humans. For these reasons, they deserve consideration, although their management and care are more complicated and the related costs much higher. Despite these caveats, considerable scientific advances have been possible using nonhuman primates. This review concisely summarizes their role in the study of aging and of the mechanisms involved in neurodegenerative disorders associated mainly with cognitive dysfunctions (Alzheimer's and prion diseases) or motor deficits (Parkinson's and related diseases).

We found that optogenetic burst stimulation of hippocampal dopaminergic fibers from midbrain neurons in mice exploring novel environments enhanced the reactivation of pyramidal cell assemblies during subsequent sleep/rest. When applied during spatial learning of new goal locations, dopaminergic photostimulation improved the later recall of neural representations of space and stabilized memory performance. These findings reveal that midbrain dopaminergic neurons promote hippocampal network dynamics associated with memory persistence.

Hippocampal adult neurogenesis contributes to key functions of the dentate gyrus (DG), including contextual discrimination. This is due, at least in part, to the unique form of plasticity that new neurons display at a specific stage of their development when compared with the surrounding principal neurons. In addition, the contribution that newborn neurons make to dentate function can be enhanced by an increase in their numbers induced by a stimulating environment. However, signaling mechanisms that regulate these properties of newborn neurons are poorly understood. Here, we show that Ras-GRF2 (GRF2), a calcium-regulated exchange factor that can activate Ras and Rac GTPases, contributes to both of these properties of newborn neurons. Using Ras-GRF2 knockout mice and wild-type mice stereotactically injected with retrovirus containing shRNA against the exchange factor, we demonstrate that GRF2 promotes the survival of newborn neurons of the DG at approximately 1-2 weeks after their birth. GRF2 also controls the distinct form of long-term potentiation that is characteristic of new neurons of the hippocampus through its effector Erk MAP kinase. Moreover, the enhancement of neuron survival that occurs after mice are exposed to an enriched environment also involves GRF2 function. Consistent with these observations, GRF2 knockout mice display defective contextual discrimination. Overall, these findings indicate that GRF2 regulates both the basal level and environmentally induced increase of newborn neuron survival, as well as in the induction of a distinct form of synaptic plasticity of newborn neurons that contributes to distinct features of hippocampus-derived learning and memory., (Copyright © 2014 Wiley Periodicals, Inc.)

The dentate gyrus of the hippocampus plays a pivotal role in pattern separation, a process required for the behavioral task of contextual discrimination. One unique feature of the dentate gyrus that contributes to pattern separation is adult neurogenesis, where newly born neurons play a distinct role in neuronal circuitry. Moreover,the function of neurogenesis in this brain region differs in adolescent and adult mice. The signaling mechanisms that differentially regulate the distinct steps of adult neurogenesis in adolescence and adulthood remain poorly understood. We used mice lacking RASGRF1(GRF1), a calcium-dependent exchange factor that regulates synaptic plasticity and participates in contextual discrimination performed by mice, to test whether GRF1 plays a role in adult neurogenesis.We show Grf1 knockout mice begin to display a defect in neurogenesis at the onset of adulthood (~2 months of age), when wild-type mice first acquire the ability to distinguish between closely related contexts. At this age, young hippocampal neurons in Grf1 knockout mice display severely reduced dendritic arborization. By 3 months of age, new neuron survival is also impaired. BrdU labeling of new neurons in 2-month-old Grf1 knockout mice shows they begin to display reduced survival between 2 and 3 weeks after birth, just as new neurons begin to develop complex dendritic morphology and transition into using glutamatergic excitatory input. Interestingly, GRF1 expression appears in new neurons at the developmental stage when GRF1 loss begins to effect neuronal function. In addition, we induced a similar loss of new hippocampal neurons by knocking down expression of GRF1 solely in new neurons by injecting retrovirus that express shRNA against GRF1 into the dentate gyrus. Together, these findings show that GRF1 expressed in new neurons promotes late stages of adult neurogenesis. Overall our findings show GRF1 to be an age-dependent regulator of adult hippocampal neurogenesis, which contributes to ability of mice to distinguish closely related contexts.

A more complete understanding of how fear extinction alters neuronal activity and connectivity within fear circuits may aid in the development of strategies to treat human fear disorders. Using a c-fos-based transgenic mouse, we found that contextual fear extinction silenced basal amygdala (BA) excitatory neurons that had been previously activated during fear conditioning. We hypothesized that the silencing of BA fear neurons was caused by an action of extinction on BA inhibitory synapses. In support of this hypothesis, we found extinction-induced target-specific remodeling of BA perisomatic inhibitory synapses originating from parvalbumin and cholecystokinin-positive interneurons. Interestingly, the predicted changes in the balance of perisomatic inhibition matched the silent and active states of the target BA fear neurons. These observations suggest that target-specific changes in perisomatic inhibitory synapses represent a mechanism through which experience can sculpt the activation patterns within a neural circuit., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Levels of educational and occupational attainment, as components of cognitive reserve, may modify the relationship between the pathological hallmarks and cognition in Alzheimer's disease (AD). We examined whether exposure of a Tg2576 transgenic mouse model of AD to environmental enrichment (EE) at a specific period during the amyloidogenic process favored the establishment of a cognitive reserve. We found that exposure to EE during early adulthood of Tg2576 mice--before amyloidogenesis has started--reduced the severity of AD-related cognitive deficits more efficiently than exposure later in life, when the pathology is already present. Interestingly, early-life exposure to EE, while slightly reducing forebrain surface covered by amyloid plaques, did not significantly impact aberrant inhibitory remodeling in the hippocampus of Tg2576 mice. Thus, transient early-life exposure to EE exerts long-lasting protection against cognitive impairment during AD pathology. In addition, these data define the existence of a specific life time frame during which stimulatory activity most efficiently builds a cognitive reserve, limiting AD progression and favoring successful aging., (Copyright © 2013 Elsevier Inc. All rights reserved.)

The dentate gyrus (DG), a hippocampal subregion, continuously produces new neurons in the adult mammalian brain that become functionally integrated into existing neural circuits. To what extent this form of plasticity contributes to memory functions remains to be elucidated. Using mapping of activity-dependent gene expression, we visualized in mice injected with the birthdating marker 5-bromo-2'-deoxyuridine the recruitment of new neurons in a set of controlled water maze procedures that engage specific spatial memory processes and require hippocampal-cortical networks. Here, we provide new evidence that adult-generated hippocampal neurons make a specific but differential contribution to the processing of remote spatial memories. First, we show that new neurons in the DG are recruited into neuronal networks that support retrieval of remote spatial memory and that their activation is situation-specific. We further reveal that once selected, new hippocampal neurons are durably incorporated into memory circuits, and also that their recruitment into hippocampal networks contributes predominantly to the updating and strengthening of a previously encoded memory. We find that initial spatial training during a critical period, when new neurons are more receptive to surrounding neuronal activity, favors their subsequent recruitment upon remote memory retrieval. We therefore hypothesize that new neurons activated during this critical period become tagged so that once mature, they are preferentially recruited into hippocampal networks underlying remote spatial memory representation when encountering a similar experience.

It is now widely accepted that new neurons continue to be added to the brain throughout life including during normal aging. The finding of adult neurogenesis in the hippocampus, a structure involved in the processing of memories, has favored the idea that newborn neurons might subserve cognitive functions. Recent work on human post-mortem tissues and mice models of Alzheimer's disease (AD) has reported persistent hippocampal proliferative capacity during pathological aging. Although it is not yet clear whether neurogenesis leads to the production of fully functional mature neurons in AD brains, these findings open prospects for cell-replacement therapies. Strategies aimed at promoting neurogenesis may also contribute to improve cognitive deficits caused by normal or pathological aging.