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The consolidation of spatial memory depends on the reactivation (‘replay’) of hippocampal place cells that were active during recent behaviour. Such reactivation is observed during sharp-wave ripples (SWRs)—synchronous oscillatory electrical events that occur during non-rapid-eye-movement (non-REM) sleep 1 – 8 and whose disruption impairs spatial memory 3 , 5 , 6 , 8 . Although the hippocampus also encodes a wide range of non-spatial forms of declarative memory, it is not yet known whether SWRs are necessary for such memories. Moreover, although SWRs can arise from either the CA3 or the CA2 region of the hippocampus 7 , 9 , the relative importance of SWRs from these regions for memory consolidation is unknown. Here we examine the role of SWRs during the consolidation of social memory—the ability of an animal to recognize and remember a member of the same species—focusing on CA2 because of its essential role in social memory 10 – 12 . We find that ensembles of CA2 pyramidal neurons that are active during social exploration of previously unknown conspecifics are reactivated during SWRs. Notably, disruption or enhancement of CA2 SWRs suppresses or prolongs social memory, respectively. Thus, SWR-mediated reactivation of hippocampal firing related to recent experience appears to be a general mechanism for binding spatial, temporal and sensory information into high-order memory representations, including social memory. Social memory is consolidated in the brain through the reactivation of neuronal firing by sharp-wave ripples in the CA2 region of the hippocampus, in a similar way to the consolidation of spatial memory.

Abstract Primary age-related tauopathy (PART) is a neurodegenerative entity defined as Alzheimer-type neurofibrillary degeneration primarily affecting the medial temporal lobe with minimal to absent amyloid-β (Aβ) plaque deposition. The extent to which PART can be differentiated pathoanatomically from Alzheimer disease (AD) is unclear. Here, we examined the regional distribution of tau pathology in a large cohort of postmortem brains (n = 914). We found an early vulnerability of the CA2 subregion of the hippocampus to neurofibrillary degeneration in PART, and semiquantitative assessment of neurofibrillary degeneration in CA2 was significantly greater than in CA1 in PART. In contrast, subjects harboring intermediate-to-high AD neuropathologic change (ADNC) displayed relative sparing of CA2 until later stages of their disease course. In addition, the CA2/CA1 ratio of neurofibrillary degeneration in PART was significantly higher than in subjects with intermediate-to-high ADNC burden. Furthermore, the distribution of tau pathology in PART diverges from the Braak NFT staging system and Braak stage does not correlate with cognitive function in PART as it does in individuals with intermediate-to-high ADNC. These findings highlight the need for a better understanding of the contribution of PART to cognitive impairment and how neurofibrillary degeneration interacts with Aβ pathology in AD and PART.

The ability to recognize information that is incongruous with previous experience is critical for survival. Novelty signals have therefore evolved in the mammalian brain to enhance attention, perception and memory 1 , 2 . Although the importance of regions such as the ventral tegmental area 3 , 4 and locus coeruleus 5 in broadly signalling novelty is well-established, these diffuse monoaminergic transmitters have yet to be shown to convey specific information on the type of stimuli that drive them. Whether distinct types of novelty, such as contextual and social novelty, are differently processed and routed in the brain is unknown. Here we identify the supramammillary nucleus (SuM) as a novelty hub in the hypothalamus 6 . The SuM region is unique in that it not only responds broadly to novel stimuli, but also segregates and selectively routes different types of information to discrete cortical targets—the dentate gyrus and CA2 fields of the hippocampus—for the modulation of mnemonic processing. Using a new transgenic mouse line, SuM-Cre, we found that SuM neurons that project to the dentate gyrus are activated by contextual novelty, whereas the SuM–CA2 circuit is preferentially activated by novel social encounters. Circuit-based manipulation showed that divergent novelty channelling in these projections modifies hippocampal contextual or social memory. This content-specific routing of novelty signals represents a previously unknown mechanism that enables the hypothalamus to flexibly modulate select components of cognition. The supramammillary nucleus in the hypothalamus acts as a novelty hub that selectively directs different types of novelty signals to different subregions of the hippocampus and flexibly modulates the encoding of memory.

CA2 neuron inactivation leads to a severe deficit in social memory, while having little effect on other well-known hippocampal functions such as contextual or spatial memory. Social memory in the hippocampus While years of research have assigned a variety of functions to the CA1 and CA3 areas of the hippocampus, the role of the smaller CA2 region has remained obscure. Here, using a transgenic mouse that allows for specific manipulations of CA2 hippocampal neurons, Frederick Hitti and Steven Siegelbaum map the specific cortical inputs to the CA2 region and determine that CA2 neuron inactivation can lead to a severe deficit in social memory, while having no effects on other well-known hippocampal functions such as contextual or spatial memory. The authors speculate that deficits in CA2 function may contribute to the social problems of individuals with autism or schizophrenia. The hippocampus is critical for encoding declarative memory, our repository of knowledge of who, what, where and when 1 . Mnemonic information is processed in the hippocampus through several parallel routes involving distinct subregions. In the classic trisynaptic pathway, information proceeds from entorhinal cortex (EC) to dentate gyrus to CA3 and then to CA1, the main hippocampal output 2 . Genetic lesions of EC (ref. 3 ) and hippocampal dentate gyrus (ref. 4 ), CA3 (ref. 5 ) and CA1 (ref. 6 ) regions have revealed their distinct functions in learning and memory. In contrast, little is known about the role of CA2, a relatively small area interposed between CA3 and CA1 that forms the nexus of a powerful disynaptic circuit linking EC input with CA1 output 7 . Here we report a novel transgenic mouse line that enabled us to selectively examine the synaptic connections and behavioural role of the CA2 region in adult mice. Genetically targeted inactivation of CA2 pyramidal neurons caused a pronounced loss of social memory—the ability of an animal to remember a conspecific—with no change in sociability or several other hippocampus-dependent behaviours, including spatial and contextual memory. These behavioural and anatomical results thus reveal CA2 as a critical hub of sociocognitive memory processing.

Recent results suggest that social memory requires the dorsal hippocampal CA2 region as well as a subset of ventral CA1 neurons. However, it is unclear whether dorsal CA2 and ventral CA1 represent parallel or sequential circuits. Moreover, because evidence implicating CA2 in social memory comes largely from long-term inactivation experiments, the dynamic role of CA2 in social memory remains unclear. Here, we use pharmacogenetics and optogenetics in mice to acutely and reversibly silence dorsal CA2 and its projections to ventral hippocampus. We show that dorsal CA2 activity is critical for encoding, consolidation, and recall phases of social memory. Moreover, dorsal CA2 contributes to social memory by providing strong excitatory input to the same subregion of ventral CA1 that contains the subset of neurons implicated in social memory. Thus, our studies provide new insights into a dorsal CA2 to ventral CA1 circuit whose dynamic activity is necessary for social memory. Although the CA2 region of the hippocampus has been implicated in social memory, its precise role has been unclear. Here, the authors show that the dorsal subregion of CA2 is required for the encoding, consolidation and recall of social memory through a circuit linking it to ventral CA1.

Key Points Hippocampal area CA2, contrary to popular perception, has a distinct molecular profile and connectivity compared with its neighbouring areas CA1 and CA3. The 'molecular' definition of area CA2 differs substantially from the 'classic' definition in rodents. Plasticity at some synapses in CA2 is severely limited by robust calcium handling processes and some gene expression in CA2 pyramidal neurons. Nevertheless, CA2 synapses can be modulated by caffeine and by the neuropeptides oxytocin and vasopressin, which mediate social behaviours. Knockout of a vasopressin receptor, which is highly expressed in area CA2, causes impairments in several forms of social recognition memory in mice. Silencing or destroying CA2 neurons leads to similar deficits. CA2 neurons have place fields, but carry less spatial information than those in area CA1 or CA3. CA2 place fields are highly unstable over time and remap upon exposure to social and novel contexts, suggesting a potential mechanism for encoding time and modified contexts. CA2 neurons are resistant to cell death in response to many forms of insults in humans and animal models. Moreover, CA2 neurons may contribute to epileptic activity found in temporal lobe epilepsy. CA2 has several characteristics that distinguishes it from CA1 and CA3. In this Review, Dudek and colleagues discuss an updated definition of the CA2 boundaries, and provide an overview of the unique synaptic properties and behavioural functions of this region. Hippocampal area CA2 has several features that distinguish it from CA1 and CA3, including a unique gene expression profile, failure to display long-term potentiation and relative resistance to cell death. A recent increase in interest in the CA2 region, combined with the development of new methods to define and manipulate its neurons, has led to some exciting new discoveries on the properties of CA2 neurons and their role in behaviour. Here, we review these findings and call attention to the idea that the definition of area CA2 ought to be revised in light of gene expression data.

Social memory—the ability to recognize and remember familiar conspecifics—is critical for the survival of an animal in its social group 1 , 2 . The dorsal CA2 (dCA2) 3 – 5 and ventral CA1 (vCA1) 6 subregions of the hippocampus, and their projection targets 6 , 7 , have important roles in social memory. However, the relevant extrahippocampal input regions remain poorly defined. Here we identify the medial septum (MS) as a dCA2 input region that is critical for social memory and reveal that modulation of the MS by serotonin (5-HT) bidirectionally controls social memory formation, thereby affecting memory stability. Novel social interactions increase activity in dCA2-projecting MS neurons and induce plasticity at glutamatergic synapses from MS neurons onto dCA2 pyramidal neurons. The activity of dCA2-projecting MS cells is enhanced by the neuromodulator 5-HT acting on 5-HT 1B receptors. Moreover, optogenetic manipulation of median raphe 5-HT terminals in the MS bidirectionally regulates social memory stability. This work expands our understanding of the neural mechanisms by which social interactions lead to social memory and provides evidence that 5-HT has a critical role in promoting not only prosocial behaviours 8 , 9 , but also social memory, by influencing distinct target structures. Experiments in mice identify the medial septum as an extrahippocampal input region that is critical for social memory formation, and show that modulation of the medial septum by serotonin regulates the stability of social memories.

Although the hippocampus is known to be important for declarative memory, it is less clear how hippocampal output regulates motivated behaviours, such as social aggression. Here we report that pyramidal neurons in the CA2 region of the hippocampus, which are important for social memory, promote social aggression in mice. This action depends on output from CA2 to the lateral septum, which is selectively enhanced immediately before an attack. Activation of the lateral septum by CA2 recruits a circuit that disinhibits a subnucleus of the ventromedial hypothalamus that is known to trigger attack. The social hormone arginine vasopressin enhances social aggression by acting on arginine vasopressin 1b receptors on CA2 presynaptic terminals in the lateral septum to facilitate excitatory synaptic transmission. In this manner, release of arginine vasopressin in the lateral septum, driven by an animal’s internal state, may serve as a modulatory control that determines whether CA2 activity leads to declarative memory of a social encounter and/or promotes motivated social aggression. Pyramidal neurons in the hippocampal CA2 region in mice promote social aggression via a disinhibitory circuit involving the lateral septum and ventromedial hypothalamus.

DNA methylation in the promoter region of the glucocorticoid receptor gene (NR3C1) is closely associated with childhood adversity and suicide. However, few studies have examined NR3C1 methylation in relation to major depressive disorder (MDD) and hippocampal subfield volumes. We investigated the possible association between NR3C1 methylation and structural brain alterations in MDD in comparison with healthy controls. We compared the degree of NR3C1 promoter methylation in the peripheral blood of non-psychotic outpatients with MDD and that of healthy controls. Correlations among NR3C1 promoter methylation, structural abnormalities in hippocampal subfield volumes and whole-brain cortical thickness, and clinical variables were also analyzed. In total, 117 participants (45 with MDD and 72 healthy controls) were recruited. Patients with MDD had significantly lower methylation than healthy controls at 2 CpG sites. In MDD, methylations had positive correlations with the bilateral cornu ammonis (CA) 2-3 and CA4-dentate gyrus (DG) subfields. However, in healthy controls, methylations had positive correlation with the subiculum and presubiculum. There were no differences in total and subfield volumes of the hippocampus between patients with MDD and healthy controls. Compared with healthy controls, patients with MDD had a significantly thinner cortex in the left rostromiddle frontal, right lateral orbitofrontal, and right pars triangularis areas. Lower methylation in the NR3C1 promoter, which might have compensatory effects relating to CA2-3 and CA4-DG, is a distinct epigenetic characteristic in non-psychotic outpatients with MDD. Future studies with a longitudinal design and a comprehensive neurobiological approach are warranted in order to elucidate the effects of NR3C1 methylation.

The authors use cell type–specific transgenic mouse lines, optogenetics and patch-clamp recordings to provide new insights into hippocampal anatomy and function. They find that dentate granule cells of the hippocampus, which were believed to not project to CA2, do indeed send functional monosynaptic inputs to CA2 pyramidal cells. CA2 innervates CA1, but, unlike CA3, projects preferentially to the deep rather than superficial sublayer of CA1. Moreover, the authors find that layer 3 of the entorhinal cortex does not project to CA2. The formation and recall of episodic memory requires precise information processing by the entorhinal-hippocampal network. For several decades, the trisynaptic circuit entorhinal cortex layer II (ECII)→dentate gyrus→CA3→CA1 and the monosynaptic circuit ECIII→CA1 have been considered the primary substrates of the network responsible for learning and memory. Circuits linked to another hippocampal region, CA2, have only recently come to light. Using highly cell type–specific transgenic mouse lines, optogenetics and patch-clamp recordings, we found that dentate gyrus cells, long believed to not project to CA2, send functional monosynaptic inputs to CA2 pyramidal cells through abundant longitudinal projections. CA2 innervated CA1 to complete an alternate trisynaptic circuit, but, unlike CA3, projected preferentially to the deep, rather than to the superficial, sublayer of CA1. Furthermore, contrary to existing knowledge, ECIII did not project to CA2. Our results allow a deeper understanding of the biology of learning and memory.