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How do we recognize others?
How do we recognize others? How do we know friend from foe, threat from reward? How does the brain compute the multitude of cues telling us that Susan is not Erica even though they look alike? The complexity of social interaction, in humans as well as in other mammals, has mystified brain research for decades.
Now a new study conducted in mice by regenerative neuroscientists at Harvard Medical School, the Harvard Stem Cell Institute, and Massachusetts General Hospital brings critical insights into neural circuitry and the cascade of signals that lie behind social recognition.
The experiments, described Dec. 8 in Nature Communications, reveal social recognition is regulated by a lattice of oxytocin-sensitive neurons in a part of our hippocampus, the seahorse shaped structure in our brain responsible for forming memories. These results add to scarce but growing research casting the hippocampus in a new light. Commonly described as the brain's librarian — where short-term memories are consolidated into long-term ones, labeling and storing them for later retrieval — the hippocampus spatial navigation role is well established. However, its involvement in social behavior, and social recognition in particular, is poorly understood.
Enter oxytocin, known for its role in bonding, empathy and sexual pleasure. New findings indicate the hippocampus is enabled by oxytocin to differentiate social memories. Specifically, experiments reveal that computation of social stimuli takes place in the dentate gyrus-CA3 (DG-CA3) circuit, a subunit of the hippocampus and believed to be its master cataloguer, responsible for filing similar memories in distinct areas ensuring that the correct data is retrieved when needed. The research indicates oxytocin is critical as a catalyst that switches the dentate gyrus-CA3 (DG-CA3) circuit into functional mode. In the absence of oxytocin, the circuit otherwise regulates object recognition.
"Our results indicate that oxytocin usurps this preexisting neural circuit within the hippocampus that normally regulates the differentiation of similar memories. In the presence of oxytocin, the circuit assumes an additional role as a regulator of social cognition."
Such "co-opting" illustrates evolution's efficiency. Senior investigator Amar Sahay, associate professor, Harvard Medical School Center for Regenerative Medicine, and Department of Psychiatry, Massachusetts General Hospital, explains: "Nature is thrifty, it's parsimonious. It doesn't like to invent different components for different processes. It repurposes existing ones." The findings help explain why disruptions in hippocampal activity can lead to social behavior anomalies in a variety of neurodevelopmental, psychiatric and neurologic conditions, notably autism-spectrum disorders.
Basic neural computations separate similar but different stimuli from one another and are critical in all daily activities. Such neural sifting underlies the ability to distinguish between benign and threatening stimuli within our surroundings. When our neural arithmetic goes awry - as in PTSD - it can perceive a threat where there is none. A soldier returned home from combat can imagine something benign resembles an improvised explosive device. Sahay: "A healthy soldier would dismiss the object, but someone with PTSD would retrieve the full initial memory because of impaired discrimination between similar stimuli. That person will perceive the benign object as a threat. It becomes an overgeneralization of fear."
The hippocampus and DG-CA3 circuit, are centers of memory formation and differentiation, an intricate neuronal circuit. In these areas neurons are studded with receptors for oxytocin, an observation that had, until now, baffled scientists.
The team next wondered: Why are the brain's chief cataloguers endowed with so many receptors for such an affective neurochemical? As far as they were concerned it was a sign that oxytocin performed a critical function worth exploration. And in a series of experiments, they revealed that the presence of oxytocin sparks signaling to guide social interaction.
In one set of experiments, they used viruses to delete oxytocin receptors in DG-CA3 circuits in mice. Despite losing their oxytocin receptors, the animals retained their ability to differentiate between old and new objects, such as cups and bowls. They could also distinguish between inanimate and animate objects - appropriately opting to spend time with another mouse instead of an empty bowl. The story changed when oxytocin-insensitive mice were put in social situations. Presented with known and unknown mice, normal mice spend more time with unknown mice. However, animals lacking oxytocin receptors could no longer tell old acquaintances from new, spending as much time with old buddies as with strangers. In mouse social etiquette, animals lacking oxytocin receptors are socially inept.
Oxytocin-insensitive mice in social situations mixed equally with strangers and friends.
While the hippocampus indexes new memories, social behavior is guided by other brain regions. The next question became: Once social computations are made in the DG-CA3 circuit, how are they relayed out of the hippocampus to guide behavior? To observe this interplay of neuronal connections, researchers used optogenetics, modifing neuronal genes making them sensitive to light. They then illuminated all neural routes emanating from DG-CA3 to map the precise route traveled by signals to other parts of the brain. Switching off and on various neural pathways, researchers pinpointed the exact route conducted by social memories, while observing animal behavior.
Results revealed a neural highway that
• Begins in the DG-CA3 circuit
• Sends a signal to the posterior of the hippocampus
• Transmits out of the hippocampus to the forebrain nucleus accumbens
The nucleus accumbens is known to govern a range of social behaviors and play a role in reward seeking, aversion, addiction as well as pleasure.
The findings reveal oxytocin receptors act as critical catalysts igniting neural computation of social stimuli within the hippocampus and relaying those signals to other brain regions for further analysis and decision making.
Oxytocin receptor (Oxtr) signaling in neural circuits mediating discrimination of social stimuli and affiliation or avoidance behavior is thought to guide social recognition. Remarkably, the physiological functions of Oxtrs in the hippocampus are not known. Here we demonstrate using genetic and pharmacological approaches that Oxtrs in the anterior dentate gyrus (aDG) and anterior CA2/CA3 (aCA2/CA3) of mice are necessary for discrimination of social, but not non-social, stimuli. Further, Oxtrs in aCA2/CA3 neurons recruit a population-based coding mechanism to mediate social stimuli discrimination. Optogenetic terminal-specific attenuation revealed a critical role for aCA2/CA3 outputs to posterior CA1 for discrimination of social stimuli. In contrast, aCA2/CA3 projections to aCA1 mediate discrimination of non-social stimuli. These studies identify a role for an aDG-CA2/CA3 axis of Oxtr expressing cells in discrimination of social stimuli and delineate a pathway relaying social memory computations in the anterior hippocampus to the posterior hippocampus to guide social recognition.
Authors: Tara Raam, Kathleen M. McAvoy, Antoine Besnard, Alexa Veenema & Amar Sahay
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RED: The human hypothalamus Image credit: Wikimedia