Walter Scott Young

The dorsal cornu ammonis 2 (dCA2) region of the hippocampus enables the discrimination of novel from familiar conspecifics. However, the neural bases for more complex social–spatial episodic memories are unknown. Here we report that the spatial and social contents of an aversive social experience require distinct hippocampal regions. While dorsal CA1 (dCA1) pyramidal neurons mediate the memory of an aversive location, dCA2 pyramidal neurons enable the discrimination of threat-associated (CS⁺) from safety-associated (CS⁻) conspecifics in both female and male mice. Silencing dCA2 during encoding or recall trials disrupted social fear discrimination memory, resulting in fear responses toward both the CS⁺ and CS⁻ mice. Calcium imaging revealed that the aversive experience strengthened and stabilized dCA2 representations of both the CS⁺ and CS⁻ mice, with the incorporation of an abstract representation of social valence into representations of social identity. Thus, dCA2 contributes to both social novelty detection and the adaptive discrimination of threat-associated from safety-associated individuals during an aversive social episodic experience.

Although it is well-known that the hippocampus mediates declarative memory (the repository of information of people, places, things and events) and influences behavior, the differential contributions of the dorsal and ventral hippocampus to specific forms of memory and behavior remain largely unknown. Studies to date show that the dorsal hippocampal CA1 region is important for cognitive and spatial tasks whereas the ventral CA1 region is associated with affective or emotional processing. Whether other regions and forms of hippocampal-dependent memory and behavior show a similar distinction remains unclear. Here we examine how social memory and related social behaviors are encoded across the dorso-ventral axis of the hippocampus. Although recent studies show that the dorsal hippocampal CA2 region is required for social memory and acts to promote social aggression, the behavioral role of ventral CA2 remains unknown. Indeed, whether a defined CA2 region extends throughout ventral hippocampus is controversial. Here, we report that a molecularly, anatomically and electrophysiologically defined CA2 region extends to the extreme ventral pole of hippocampus, with both similarities and important differences in its projection patterns and synaptic impact compared to dorsal CA2. Of particular importance, we find that ventral CA2 is not required for social memory but is critical for promoting social aggression. These results support the view that the ventral region of hippocampus is more generally tuned for emotionally-related behaviors compared to the cognitively-tuned dorsal hippocampus.

The arginine vasopressin 1b receptor (Avpr1b) plays an important role in social behaviors including social learning, memory, and aggression, and is known to be a specific marker for the cornu ammonis area 2 (CA2) regions of the hippocampus. The fasciola cinereum (FC) is an anatomical region in which Avpr1b expressing neurons are prominent, but the functional roles of the FC have yet to be investigated. Surprisingly, the FC is absent in the inbred BTBR T+tf/J (BTBR) mouse strain used to study core behavioral deficits of autism. Here, we characterized and compared transcriptomic expression profiles using single nucleus RNA sequencing and identified 7 different subpopulations and heterogeneity within the dorsal CA2 (dCA2) and FC. Mef2c, involved in autism spectrum disorder, is more highly expressed in the FC. Using Hiplex in situ hybridization, we examined the neuroanatomical locations of these subpopulations in the proximal and distal regions of the hippocampus. Anterograde tracing of Avpr1b neurons specific for the FC showed projections to the IG, dCA2, lacunosum molecular layer of CA1, dorsal fornix, septofibrial nuclei, and intermediate lateral septum (iLS). In contrast to the dCA2, inhibition of Avpr1b neurons in the FC by the inhibitory DREADD system during behavioral testing did not impair social memory. We performed single nucleus RNA sequencing in the dCA2 region and compared between wildtype (WT) and BTBR mice. We found that transcriptomic profiles of dCA2 neurons between BTBR and WT mice are very similar as they did not form any unique clusters; yet, we found there were differentially expressed genes between the dCA2s of BTBR and WT mice. Overall, this is a comprehensive study of the comparison of Avpr1b neuronal subpopulations between the FC and dCA2. The fact that FC is absent in BTBR mice, a mouse model for autism spectrum disorder, suggests that the FC may play a role in understanding neuropsychiatric disease.

The cornu ammonis area 2 (CA2) region is essential for social behaviors, especially in social aggression and social memory. Recently, we showed that targeted CA2 stimulation of vasopressin presynaptic fibers from the paraventricular nuclei of hypothalamus strongly enhances social memory in mice. In addition, the CA2 area of the mouse hippocampus receives neuronal inputs from other regions including the septal nuclei, the diagonal bands of Broca, supramammillary nuclei, and median raphe nucleus. However, the functions of these projections have been scarcely investigated. A functional role of median raphe (MR) – CA2 projection is supported by the MR to CA2 projections and 82% reduction of hippocampal serotonin (5-HT) levels following MR lesions. Thus, we investigated the behavioral role of presynaptic fibers from the median raphe nucleus projecting to the dorsal CA2 (dCA2). Here, we demonstrate the optogenetic stimulation of 5-HT projections to dCA2 from the MR do not alter social memory, but instead reduce social interaction. We show that optical stimulation of MR fibers excites interneurons in the stratum radiatum (SR) and stratum lacunosum moleculare (SLM) of CA2 region. Consistent with these observations, we show that bath application of 5-HT increases spontaneous GABA release onto CA2 pyramidal neurons and excites presumed interneurons located in the SR/SLM. This is the first study, to our knowledge, which investigates the direct effect of 5-HT release from terminals onto dCA2 neurons on social behaviors. This highlights the different roles for these inputs (i.e., vasopressin inputs regulating social memory versus serotonin inputs regulating social interaction).

Oxytocin (OT) orchestrates social and emotional behaviors through modulation of neural circuits. In the central amygdala, the release of OT modulates inhibitory circuits and, thereby, suppresses fear responses and decreases anxiety levels. Using astrocyte-specific gain and loss of function and pharmacological approaches, we demonstrate that a morphologically distinct subpopulation of astrocytes expresses OT receptors and mediates anxiolytic and positive reinforcement effects of OT in the central amygdala of mice and rats. The involvement of astrocytes in OT signaling challenges the long-held dogma that OT acts exclusively on neurons and highlights astrocytes as essential components for modulation of emotional states under normal and chronic pain conditions.

Recognition memory, often compromised in psychiatric disorders, is a major component of declarative memory, which permits the realization that an event, object or social subject has been previously encountered. The CA2 region of the dorsal hippocampus (dCA2) is involved in social memory and responds to novel objects, in time and space. However, it remains unclear how these neurons encode either social or inanimate object recognition. Here, we show that in dCA2, encoding of social recognition memory entails suppression of pyramidal neurons’ activity leading to a sparse representation of the familiar conspecific. We discuss the neural coding scheme by which dCA2 pyramidal neurons contribute to social memory.

Oxytocin, acting through the oxytocin receptor (Oxtr) in the periphery, is best known for its roles in regulating parturition and lactation. However, it is also now known to possess a number of important social functions within the central nervous system, including social preference, memory and aggression, that vary to different degrees in different species. The Oxtr is found in both excitatory and inhibitory neurons within the brain and research is focusing on how, for example, activation of the receptor in interneurons can enhance the signal-to-noise of neuronal transmission. It is important to understand which neurons in the mouse dorsal hippocampus might be activated during memory formation. Therefore, we examined the colocalization of transcripts in over 5,000 neurons for Oxtr with those for nine different markers often found in interneurons using hairpin chain reaction in situ hybridization on hippocampal sections. Most pyramidal cell neurons of CA2 and many in the CA3 express Oxtr. Outside of those excitatory neurons, over 90% of Oxtr-expressing neurons co-express glutamic acid decarboxylase-1 (Gad-1) with progressively decreasing numbers of co-expressing cholecystokinin, somatostatin, parvalbumin, neuronal nitric oxide synthase, the serotonin 3a receptor, the vesicular glutamate transporter 3, calbindin 2 (calretinin), and vasoactive intestinal polypeptide neurons. Distributions were analyzed within hippocampal layers and regions as well. These findings indicate that Oxtr activation will modulate the activity of ~30% of the Gad-1 interneurons and the majority of the diverse population of those, mostly, interneuron types specifically examined in the mouse hippocampus.

SUMMARY: Oxytocin orchestrates social and emotional behaviors through modulation of neural circuits in brain structures such as the central amygdala (CeA). The long-standing dogma is that oxytocin signaling in the central nervous system occurs exclusively via direct actions on neurons. However, several findings over the last decades showed that astrocytes actively participate in the modulation of neuronal circuits. Here, we investigate the degree of astrocytes’ involvement in oxytocin functions. Using astrocyte’ specific gain and loss of function approaches, we demonstrate that CeA astrocytes not only directly respond to oxytocin, but are actually necessary for its effects on neuronal circuits and ultimately behavior. Our work identifies astrocytes as a crucial cellular substrate underlying the promotion of a positive emotional state by oxytocin. These results further corroborate that astrocytes are key regulators of neuronal circuits activity by responding to specific neuropeptidergic inputs, and opens up new perspectives to understand how neuromodulators gate brain functions.