Circuit Tweak Boosts Social Memory in Mice

Staying power soars at least 80-fold

January 7, 2016 • Science Update

NIMH researchers have boosted the staying power of a social memory at least 80-fold by stimulating a circuit they discovered in mouse brain. A male mouse that would normally forget a female mouse it had just met within an hour instead remembered it at least a week later! Researchers precisely tweaked the circuit by genetically priming it to respond to pulses of light –a cutting edge technique called optogenetics. The study is the first to enhance social memory by stimulating a specific circuit.

The enhancement worked only if the male’s circuit had been stimulated while the memory was being formed, not recalled – and only during its first encounter with the female animal. The memory remained strong even after the male was distracted by the introduction of a second female mouse, which would normally degrade it.

“Someday, brain stimulation treatments might similarly target this pathway to help patients with declining social memories,” explained NIMH’s Scott Young, M.D., Ph.D. “The circuit allows the organism to remember and respond appropriately to social encounters, be they aversive or pleasant. If the same system is at work in humans, one can imagine how it would strengthen one’s memory for a bully to avoid in the future – or how it could be activated in ‘love at first sight’ to produce a lifelong memory.”

Young, Adam Smith, Ph.D., and colleagues in the NIMH intramural Section on Neural Gene Expression, Laboratory of Cellular and Molecular Regulation, report on their discovery January 5, 2016 in the journal Molecular Psychiatry.

Prior to the new study, Young’s team had shown that genetically silencing activity of a receptor for the social behavior-related hormone vasopressin blocks social memory. They also knew that brain expression of this vasopressin 1b receptor is confined mostly to a little studied part of the memory hub, or hippocampus, called CA2 – and that blocking CA2 reduces social memory. So the researchers set out to discover the upstream circuitry that triggers release of vasopressin in CA2.

A prime candidate was a set of neurons that project to CA2 from a part of the hypothalamus called the PVN (paraventricular nucleus). The PVN integrates information from external and internal environments to orchestrate stress responses.

As suspected, pathway tracing revealed a single, anatomically distinct circuit from the PVN that releases vasopressin in CA2. The researchers used implanted LED fiber optics to stimulate the circuit – genetically engineered to be light-activated – while male mice sniffed out novel females. When exposed to the same female later, less sniffing signaled that the male remembered it. As noted, such memories persisted at least 80 times longer-than-normal in optogenetically-stimulated males and resisted weakening effects of distractions. Chemically blocking vasopressin activity in CA2 blocked the stimulated social memory enhancement.

This confirmed that vasopressin activity in CA2, triggered by the circuit from PVN, is a key player in social memory – although other vasopressin pathways are also likely involved.

“If circuitry similar to what we’re seeing in mice turns out to be also at work in the human brain, treatments based on similar targeted brain pathway stimulation might someday help to improve the relationships of people experiencing social memory impairment due to dementias and mental illnesses,” said Young.

The researchers first genetically primed a social memory circuit (red) in male mice to be activated by light. Then they simulated it with a blue LED while a male mouse first encountered a female mouse. This drastically increased the staying power of the male’s memory for the female. The circuit runs from an area in area of the hypothalamus (PVN) to an area in the hippocampus (CA2). Source: Adam Smith Ph.D., NIMH

vasopressin nerve fibers from male mouse

Nerve fibers (red) genetically primed to be activated by light in the CA2 region of the hippocampus increased the activity of the chemical messenger vasopressin when stimulated by an LED. Adjacent hippocampus areas are involved in other types of memory, such as spatial location (CA1). Source: Adam Smith Ph.D., NIMH

REFERENCE:

Targeted activation of the hippocampal CA2 area strongly enhances social memory. Smith AS, Williams Avram SK, Cymerblit-Sabba A, Song J, Young WS. Mol Psychiatry. 2016 Jan 5. doi: 10.1038/mp.2015.189. [Epub ahead of print] PMID:26728562