Social cognition enables individuals to understand others' intentions. Social memory is a necessary component of this process, for without it, subsequent encounters are devoid of any historical information. The CA2 area of the hippocampus, particularly the vasopressin 1b receptor (Avpr1b) expressed there, is necessary for memory formation. We used optogenetics to excite vasopressin terminals, originating from the hypothalamic paraventricular nucleus, in the CA2 of mice. This markedly enhanced their social memory if the stimulation occurred during memory acquisition, but not retrieval. This effect was blocked by an Avpr1b antagonist. Finally, this enhanced memory is resistant to the social distraction of an introduced second mouse, important for socially navigating populations of individuals. Our results indicate the CA2 can increase the salience of social signals. Targeted pharmacotherapy with Avpr1b agonists or deep brain stimulation of the CA2 are potential avenues of treatment for those with declining social memory as in various dementias.
Complex social behavior requires integration of social, spatial and interoceptive information and often depends on individual recognition. From discriminating among two individuals to the loving bond that is imprinted on a mother and her child, social memories are forged, in part, as a result of encoding information by the hippocampus. These memories are a type of episodic memory whose formation depends on a complex interplay of various inputs to and circuits within the hippocampus. The signaling by these circuits, of course, relies on a rich variety of neurotransmitters and neuromodulators, including peptides.1
In particular, the neurohypophysial peptide vasopressin (Avp) affects social recognition (SR) across many mammalian species.2, 3 For example, pharmacological excitation or inhibition of Avpr1a in the rat brain affects recognition of a juvenile conspecific.4, 5 This work has focused on Avpr1a in the septum as a regulator of social memory.6 However, burgeoning evidence is connecting a potentially distinct hippocampal Avpr1b circuit to social memory. Specifically, we have shown genetic silencing of Avpr1b expression limits normal expression of SR while not affecting spatial or non-social contextual memories.7, 8 Furthermore, Avpr1b is rather restricted in its expression in the brain, prominently expressed in the CA2 region of the hippocampus,9 a region first described over 80 years ago10 and distinctive from the CA3 and CA1 in terms of cytoarchitecture, connectivity, physiology, and gene expression patterns.10, 11, 12, 13 These data and recent behavioral studies14, 15, 16 have generated curiosity from neuroscientists about the CA2, as the mapping of social memories within the hippocampus has remained undetermined. This type of hippocampal mapping would benefit a large swath of the population, from the elderly to individuals with varying forms of dementia, hippocampal amnesia and select cognitive impairment, as these people can experience symptoms that strain their relationships.17, 18, 19
Thus, we explored the involvement of Avp signaling to the CA2, specifically to Avpr1b-expressing neurons, on the regulation of social memory. We genetically targeted excitation of the CA2 by projecting vasopressin neurons from the paraventricular nucleus of the hypothalamus (PVN) and dramatically prolonged social memory in mice from 30 min after a single encounter to at least 7 days. Memory enhancement occurs with optical stimulation during memory acquisition, but not during retrieval; an effect prevented by pharmacological antagonism of Avpr1b. Finally, the enhanced memory is resistant to interference by an introduced second female mouse. Our work provides new knowledge about how the CA2 is integrated into a circuit regulating social memories and suggests an avenue of exploration to treat social cognition deficits in dementia.
Materials and methods
All experiments were conducted according to US National Institutes of Health guidelines for animal research and were approved by the National Institute of Mental Health Animal Care and Use Committee. Adult Avp promoter-driven Cre (Avp-Cre) males (GENSAT line QZ27 (ref. 20) were used for experiments conducted 5–6 weeks after viral injections. All mice were single housed during experiments and maintained on a 12-h light cycle (lights off at 1500 h) with ad libitum access to food and water.
Retrograde tracing experiments used a total of four Avp-Cre male mice taken from two litters and injected with Cre-dependent herpes simplex virus (ST HSV-LS1L-WGA-CMV-GFP). Our previous research assessing the effects of genetically silencing Avpr1b on SR8 produced an effect size of r=0.64. With a desired power of 0.80, an n=8 for each treatment was the estimated sample size required for this study. SR experiments used a total of 73 male mice taken from 32 litters run in six separate squads: 25 wild-type (WT) mice (Supplementary data) and 25 WT and 22 Avp-Cre mice injected with an adeno-associated virus (AAV) that expresses a Cre recombinase-activatable channel rhodopsin (ChR2) fused to mCherry (AAV2-DIO-EF1α-ChR2-mCherry). WT mice without injections were used to evaluate the time course for SR test. The AAV injected WT and Avp-Cre were randomly assigned to experimental conditions. All mice were between 92 and 139 days old at testing. A total of 41 ovariectomized BalbC female mice obtained from Jackson Laboratories (Bar Harbor, ME, USA) at 8 weeks of age were used as social stimuli.
Viruses and chemicals
The recombinant AAV vectors were serotyped with AAV2 coat proteins and packaged by the University of North Carolina Vector Core (Chapel Hill, NC, USA). The herpes simplex virus vectors were packaged by the Massachusetts Institute of Technology Viral Gene Transfer Core (Cambridge, MA, USA). SSR149415 was obtained from Axon Medchem (Groningen, Netherlands).
Male mice (10–12 weeks old) were anesthetized with tribromoethanol (Avertin) and placed into a stereotaxic apparatus. After exposing the skull via a small incision and leveling the head position using bregma and lambda as reference points, two small holes were drilled for injections and implants. A 5 -μl microliter syringe (26 g, Hamilton, Reno, NV) with a 33- g small gauge RN needle attachment was inserted in the brain, and the virus was injected using a Micro4 microsyringe pump (World Precision Instruments, Sarasota, FL). For retrograde tracing (n=4), ST HSV-LS1L-WGA-CMV-GFP (5 × 108 transducing units per ml) was injected unilaterally in two sites of the CA2 (300 nl, site 1: bregma: anterior-posterior (AP): −1.46, dorsal-ventral (DV): −1.56, medial-lateral (ML): −1.46; site 2: AP: −1.82, DV: −1.73, ML: −2.06). For behavior and Arc studies, AAV-DIO-EF1α-hChR2(H134R)-mCherry (1.5 × 1012 transducing units per ml) serotype 2 was injected bilaterally in the PVN (250 nl, bregma: AP: −0.82, DV: −4.73, ML: ±0.15), and optical fibers were implanted bilaterally in the CA2 (AP: −2.18, DV: −1.67, ML: ±2.56). Pharmaco-optogenetic surgeries (WT, n=8; Avp-Cre, n=8) included the same targeting of AAV to the PVN plus with a 26-gauge guide cannulae (Plastics One, Roanoke, VA) implanted at 10° above the CA2 (AP: −2.18, DV: −1.19, ML: ±2.76). All stereotaxic injections sites were histologically verified. All ‘misses’ or ‘partial hits’ were excluded from the data analyses.
To photostimulate the ChR2-positive fibers, we used low-intensity illumination from a LED light source (465 nm; PlexBright; Plexon, Dallas, TX) coupled with an LED driver (LD-1; Plexon). The light power at the specimen was 1–2 mW mm−2, measured by an optical power meter (PM100D; Thorlabs, Newton, NJ). The light output was modulated to 20-ms pulses at 20 Hz by a programmable pulse stimulator (NI USB-6229; National Instruments, Austin, TX) and Labview software (version 12.0.1f4; National Instruments). Tests were conduced during the dark cycle. Using Ethovision XT (version 10.0.826; Noldus Information Technology, Leesburg, VA), SR was measured in a direct interaction test with or without an interference trial. For the two-trial SR test (WT, n=8; Avp-Cre, n=7), mice were exposed to an unfamiliar OVX female for 5 min and re-exposed to the original or a novel female after a 30-min, 2-h, 1-day, or 7-day retention interval. This protocol was adapted to study the effect of activating afferent Avp inputs to the CA2 on memory acquisition vs retrieval (WT, n=8; Avp-Cre, n=7) and extended retention intervals (WT, n=9; Avp-Cre, n=7). For the three-trial retroactive interference test (WT, n=9; Avp-Cre, n=7), mice were exposed twice to the same OVX female similar to the two-trial SR test. However, 5 min into the 30-minute retention interval, subject mice were exposed to a different female for 5 min as an interference trial. The SR tests were scored by the experimenter blind to the group identities.
Statistical analyses were performed using IBM SPSS Statistics 19 (SPSS, an IBM Company, Chicago, IL) and were expressed as mean±s.e.m.
Afferent Avp inputs to the hippocampal CA2 originate selectively from the PVN
We and others recently described21, 22 Avp innervation of the CA2 arriving from the PVN (AvpPVN→CA2) (Figures 1a–g). To understand more fully the specificity of this pathway, we studied whether AvpPVN→CA2 neurons collateralize and project to other brain regions as well as whether other populations of Avp neurons, outside of the PVN, project to the CA2. We bilaterally injected into the CA2 of Avp-Cre mice a retrogradely propagating Cre-dependent herpes simplex virus (ST HSV-LS1L-WGA-CMV-GFP) to express green fluorescent protein (GFP). Mice were perfused 1 week later, and brain sections were probed with antibodies to Avp and GFP (see Supplementary Experimental Procedures for more details). As expected, GFP+ neurons were detected in the PVN (Figures 1b–d) but not in other brain regions with Avp-ir (immunoreactivity) neurons, such as the supraoptic nucleus, suprachiasmatic nucleus, anterior hypothalamus or bed nucleus of the stria terminalis. In addition to the PVN, GFP+ axonal fibers densely innervate the CA2 and immediately adjacent CA3, with sparse innervation in the surrounding structures, such as the CA1, dentate gyrus or somatosensory and parietal cortices (Figures 1e and f). Thus, the AvpPVN→CA2 is an anatomically distinct Avp pathway that only projects to the CA2 and has no collaterals to other structures, including regions where AvpPVN neurons have been known to send afferent projections (e.g., lateral septum, ventral pallidum, medial preoptic area; Supplementary Figure 1).23
Targeted activation of the AvpPVN→CA2 pathway enhances social memory
We next studied directly the relevance of the AvpPVN→CA2 pathway to SR. We stimulated fibers in the CA2 after injection of an AAV that expresses a Cre recombinase-activatable channelrhodopsin (ChR2) fused to mCherry (AAV2-DIO-EF1α-ChR2-mCherry) into the PVN of Avp-Cre mice (Figures 1h–j). Optical fibers were also implanted bilaterally in the CA2. We then waited 5 to 6 weeks for the ChR2 to be transported to the CA2. When we examined the brains after the behavioral testing, we observed robust ChR2-mCherry expression in the PVN, CA2 and immediately adjacent CA3. Both WT and Avp-Cre mice were tested in a two-trial SR test, in which the subject mouse is exposed to an unfamiliar ovariectomized (OVX) female. After a specific retention interval, the subject mouse is either exposed to the same female or a novel female. SR is defined by the normal decline or habituation of olfactory investigation (e.g., close nasal contact with the stimulus mouse, as in this study) in response to repeated exposure to the same OVX female. WT mice recognize familiar females within a limited retention interval, from 30 min to 1 h, and display little to no recognition response after 2 h24 (Supplementary Figure 2). Like WT mice, Avp-Cre mice are unable to recognize familiar females after a 2-h retention period (Figures 2a–c). However, low-intensity illumination (using 20-ms pulses at 20 Hz of 465-nm light at 1.5 mW mm−2; Figure 1h) focused on the CA2 during both social exposures enhances SR (Figures 2a–c) and neuronal activity in the PVN and CA2 (Supplementary Figure 3). In contrast, mice sociability is unaffected by this optical stimulation as the durations of investigation are similar in both trials if the subject mice encounter two different unfamiliar females in the two trials (Figure 2b). In addition, no change in investigation of an inanimate object is observed during a recognition test.
Previous pharmacological studies demonstrated Avp signaling in specific brain regions could affect either the acquisition and formation of new memories5 or retention and retrieval of stored memories.2 Therefore, to learn when the Avp terminal stimulation strengthened social memory, we restricted the period of stimulation to either the initial encounter (acquisition trial) or subsequent encounter (retrieval trial). We found that optical stimulation to release Avp within the CA2 during the acquisition trial is sufficient to enhance SR. Stimulation only during the retrieval trial has no affect on SR (Figures 2d–f). Interestingly, SR is lengthened for at least 7 days after acquisition trial stimulation (Figures 2g–i). This represents at least an 80-fold increase in the duration of this social memory.
As Avpr1b KO mice have impairments in temporal order memory,7 we also examined whether the effect of optical stimulation could survive a social distraction through the use of a retroactive interference paradigm. Briefly, mice were exposed to an SR test with a 30-minute retention interval; however, during the retention period, mice were presented a second unfamiliar OVX female, known as an ‘interference trial.’ We found that WT mice are able to recognize OVX females after a 30-minute interval, but recognition for the original female is impaired after an interference trial (Figures 2j–l). This retroactive interference is eliminated when the AvpPVN→CA2 pathway is stimulated during the acquisition trial with the original female, thus preserving temporal order memory.
Memory enhancement in the hippocampal CA2 depends on local Avpr1b action
Finally, we wanted to verify the pharmacological specificity of the optical stimulation of the Avp terminals in CA2. Previous studies have implicated the dorsal and ventral hippocampus, dorsal and lateral septum, olfactory bulb and medial amygdala as sites at which the related Avpr1a can influence SR.25 We do not find this receptor expressed in the mouse dorsal hippocampus (Supplementary Figure 4). However, as mentioned above, the Avpr1b is prominently expressed in the CA2 region of the hippocampus.9 Therefore, we examined whether pharmacological antagonism of Avpr1b in the CA2 hindered Avp-enhancement of social memory. Intra-CA2 microinjections of the Avpr1b antagonist (SSR149415), through guide cannulas designed to accommodate micro-injector needles for drug infusion as well as optical fibers, blocked SR enhancement (Figure 3). Thus, the PVN, through an anatomically distinct AvpPVN→CA2 pathway that is dependent on Avpr1b signaling, potentiates acquisition of new memories, enhancing and extending social memory.
Memories for people, places and events are a fundamental facet of the concept of self. The hippocampus is a critical region for declarative memory.26 O’Keefe and Nadel27 suggested that the hippocampus provides a neural basis of cognitive mapping. This original proposal has served as the starting point of many studies that demonstrated CA1 place cells encode a map of an individual’s spatial location.28 Although these findings are highly important, they present a narrow approach to the original proposal, limiting the hippocampus to spatial organization. However, recently, an effort has been made to re-evaluate the literature gap as it pertains to other potential functions of the hippocampus,29, 30 and even more recent data suggest its crucial role in social cognition.31 Still, the social computing paths remain unclear—more specifically, the mapping of social memories within the hippocampus.
If the CA1 region encodes spatial memory, where is social memory processed in the hippocampus? And why might some memories be stronger than others? We have previously shown that adult mouse brain Avpr1b is confined to the CA2, immediately adjacent CA3, and fasciola cinerium9 (and unpublished observations) and is essential for normal social memory.8, 32 Recently, others have shown that inhibition of the CA2 selectively impairs SR.14, 16 It is possible that the CA2 processes the declarative social information from the environment and reforms or strengthens hippocampal representations while leaving the hippocampal mapping system fundamentally intact. Indeed, the CA2 forms strong excitatory synapses with the CA1 allowing for cortical inputs to influence CA1 neuronal output via a disynaptic circuit,33 and a conspecific in the environment decreases the intensity and precision of, but does not eliminate, spatial firing of CA1 place cells.34 Our data expand upon these findings and demonstrate that direct excitation of PVN Avp neuron terminals that innervate the CA2 enhances memory formation and extends social memories. Mice sociability is unaffected by this optical stimulation as the durations of investigation are similar in both trials if the subject mice encounter two different unfamiliar females in the two trials. As Avp signaling induces significant potentiation of excitatory synaptic responses in the CA2,15 this could prime, or raise the probability, that these neurons will be recruited or allocated into a memory trace.35 This action also fits nicely with the roles of the PVN as a key integrator of, and responder to, signals from external and internal milieus. Many current theories of hippocampal-dependent learning and memory processes may be challenged by the potential impact of the CA2 region, including the influence of Avp signaling.
WT mice living in single housing retain the memory of briefly encountered social stimuli for about 30 min to 1 h, as demonstrated in this study and previous research.24, 36 Social memory can be extended by retroactive facilitation (i.e., repeated exposures to the original social stimulus) or pharmacologically by systemic Avp treatments.37 Our results demonstrate a circuit through which Avp can act to generate extended social memories. The fact that this new memory endures for at least 7 days suggests that Avp signaling in the CA2 during memory acquisition strengthens the salience of social information and allows this information to be consolidated into a long-term memory, dissociating decay of the memory trace from the passage of time. Further, the memory trace of a conspecific is sensitive to disruption after acquisition by newly learned information or subsequent interactions with other social stimuli. This is called retroactive interference and can occur up to 15 h after the original memory trace in rodents.38 Avp signaling appears to modulate the impact that new information has on a lingering memory trace. For example, Avpr1b knockout mice have deficits in SR and struggle to create temporal associations or to remember the temporal order in which objects are presented to them.7 In addition, peripheral administration of a non-specific Avpr1 antagonist during memory consolidation can interfere with SR.37 Our data demonstrate that Avp signaling in the CA2 during acquisition can block retroactive interference and facilitate temporal order memory. The fact that these effects occur in a matter of minutes provides insight into how mice, and potentially other social species, are able to navigate a dynamic social environment while still being able to retain pertinent information about conspecifics to generate familiarity and build relationships.
Our demonstration that excitation of the AvpPVN→CA2 pathway during acquisition, but not retrieval, enhances social memory suggests that the mechanisms regulating social memory acquisition and retrieval in the hippocampus are distinct. At a cellular level, a selective Avpr1b agonist induces significant potentiation of excitatory synaptic responses in CA2, but not in CA1 or in slices from Avpr1b knockout mice.15 Furthermore, this synaptic potentiation relies on N-methyl-d-aspartic acid receptor activation, calcium and calcium/calmodulin-dependent protein kinase II activity; but not on cAMP-dependent protein kinase activity or presynaptic mechanisms. Interestingly, N-methyl-d-aspartic acidreceptors and protein kinase II activity in the hippocampus are critical for acquisition of spatial and fear memories, but retrieval of these memories appears independent of such activity.39 Thus, it is possible that social memory acquisition occurs through similar cellular mechanisms as spatial and fear memories in the hippocampus, with the distinction that N-methyl-d-aspartic acid receptor-dependent function in the CA2 is sensitive to Avp signaling.
It has become apparent that more than one Avp circuit is involved in social memory. Avp release occurs in the dorsal hippocampus,40 and local administration of anti-Avp serum impairs SR in rats.41 Recently, the PVN has been identified as the source of Avp innervation to the CA2 in mice22 and rats.21 Here, we document that the AvpPVN→CA2 pathway enhances SR and is anatomically distinct as a subset of Avp neurons in the PVN that project to the CA2. Further, we observed that these neurons have no collaterals to other structures. Still, the impact of Avp on social memory is not limited to the hippocampus.25 The lateral septum, among other regions in the mouse and rat brain, has been associated with Avp regulation of SR. Pharmacological activation or antagonism of Avpr1a in the rat lateral septum enhances or impairs SR, respectively.5 The Avp fibers in the lateral septum originate from the bed nucleus of the stria terminalis and medial amygdala,42, 43 not the PVN as those in the CA2. This would suggest that multiple discrete Avp circuits are involved in regulating social memory.
In the first decade of the twentieth century, Richard Semon,44 first described engrams as the ensemble of neurons serving as the physical representation of memory in the brain. While many have attempted to identify the biological locus for memory, most notably in a series of lesion studies by Karl Lashley,45 technology has only now advanced to a state to allow neuroscientists to identify specific populations of cells activated during learning and evoked in recall of the original memory. It is now possible to label neuronal populations active during learning to either inhibit or reactivate memory-related neuronal populations.46 Using a method that permits optogenetic labeling and manipulation of specific neuronal populations, fear memory recall can be impaired by limiting the activity of neuronal populations in the hippocampal CA3, CA1 and dentate gyrus that were active during the acquisition of the fear memory.47, 48 This same method has been applied to reactivate populations of neurons in the hippocampus to mimic cue-induced behavioral recall. This has allowed the reactivation of genuine memories,49 creation of false memories50 and switching memory valence.51 The results of these studies promote the understanding of the biological basis of memory, or engrams, in the hippocampus. Nevertheless, the exploration of the network-level processes specific for the acquisition of engrams is fundamental for a comprehensive understanding of memory. The first study to enhance memory by stimulating a hippocampal-dependent circuit was published last year. In that work, excitation of a midbrain to CA1 dopaminergic circuit during spatial exploration and learning improved spatial memory performance.52 Our work presents the first evidence of a specific neural circuit that directly regulates hippocampal-dependent social memory, and that its stimulation is sufficient to enhance long-term SR and overcome interference. As technology advances, we expect to expand our understanding of the ‘social memory engrams’ and gain more insights into the pathologies involving social memory deficits.
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We thank Emily Shepard for assistance with mouse colony maintenance and genotyping. We are grateful for the gifts of the vasopressin antibody from Harold Gainer and HSV from Ted Usdin. Alex Avram kindly wrote the software we used to control the optogenetic stimulations. We also thank Stafford Lightman and Michael Brownstein for their comments on a previous version of this manuscript. This research was supported by the intramural research program of the NIMH (ZIA-MH-002498-24).
The authors declare no conflict of interest.
Supplementary Information accompanies the paper on the Molecular Psychiatry website
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Smith, A., Williams Avram, S., Cymerblit-Sabba, A. et al. Targeted activation of the hippocampal CA2 area strongly enhances social memory. Mol Psychiatry 21, 1137–1144 (2016). https://doi.org/10.1038/mp.2015.189
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