Our team is interested in understanding the micro-circuits and synaptic plasticity underlying the formation of new memories. The hippocampus is a brain region that has long been considered to be central in memory storage and retrieval. Our research is focused on area CA2, a region that receives direct synaptic input from intra- and extra- hippocampal structures such as the cortex and hypothalamus, and has been shown to be central in social memory and encoding spatial information during immobility. Long overlooked, this small hippocampal region is emerging as a distinct region of the hippocampus with unique properties and cellular composition. Furthermore, neurons in area CA2 are uniquely vulnerable during psychiatric disease onset such as schizophrenia and dementia.
We use a combination of techniques including electrophysiology, optogenetics, imaging and behavior to investigate how environmental factors and experience alter the physiology and plasticity of cells in area CA2, and then determine the consequences of these changes on overall hippocampal function under both normal conditions and during disease.
1 / Robert V, Ludivine T, Davatolhagh MF, Bernardo-Garcia FJ, Clements KN, Chevaleyre V, Piskorowski RA. “The Mechanisms Shaping CA2 Pyramidal Neuron Action Potential Bursting Induced by Muscarinic Acetylcholine Receptor Activation.” (2020) Journal of General Physiology. 152(4). Apr 6. doi: 10.1085/jgp.201912462.
2 / Chen S, He L, Huang AJ, Boehringer R, Robert V, Wintzer M, Polygalov D, Weitemier AZ, Tao Y, Gu M1, Middleton SJ, Namiki K, Hama H, Therreau L, Chevaleyre V, Hioki H, Miyawaki A, Piskorowski RA, McHugh TJ. “A Hypthalamic Novelty Signal Modulates Hippocampal Memory.” (2020) Nature. https://doi.org/10.1038/s41586-020-2771-1
3 / Domínguez S, Rey CC, Therreau T, Fanton A, Massotte D, Verret L, Piskorowski RA and V Chevaleyre. “Maturation of PNN and ErbB4 signaling in area CA2 during adolescence underlies the emergence of PV interneuron plasticity and social memory.” (2019) Cell Reports. 2019 Oct 29;29(5):1099-1112.e4. doi: 10.1016/j.celrep.2019.09.044.
4 / Nasrallah K, Therreau L, Robert V, Huang A, McHugh T, Piskorowski* RA and V Chevaleyre*. “Routing hippocampal information flow throught Parvalbumin interneuron plasticity in area CA2.” (2019) Cell Reports. 27, 86-98. *Corresponding author.
5 / Piskorowski RA, Nasrallah K, Diamantopoulou A, Mukai J, Hassan SI, Siegelbaum SA, Gogos JA and Chevaleyre V. (2016). “Age-dependent specific changes in area CA2 of the hippocampus and social memory deficit in a mouse model of the 22q11.2 deletion syndrome.” Neuron. 2016. Jan 6;89(1)163-176.
Why study hippocampal area CA2? This relatively small yet under-studied region in the hippocampus receives powerful excitatory sensory information from the cortex and dentate gyrus. Unlike areas CA1 and CA3, CA2 receives input from hypothalamic regions that are very active during emotional and social context, resulting in the release of neuromodulators such as vasopressin and oxytocin that are known to effect learning and social interaction. Furthermore, the pyramidal neurons and interneurons of area CA2 have unique circuitry, physiology and molecular make-up that sets this region apart from other hippocampal areas. The receptors for numerous neuromodulators including enkephalin, vasopressin, estrogen, somatostatin, corticoids, substance P and oxytocin are either highly enriched or uniquely expressed in this hippocampal region. CA2 pyramidal neurons strongly project to areas CA3, CA1, and to external hippocampal structures including the hypothalamus and septum. Thus, the neurons in area CA2 are poised to modulate memory formation and act on long-range brain network connections during emotionally laden tasks. Supporting this hypothesis are the recent findings that area CA2 is critical for social memory (Hitti et al, Nature 2014) and the re-expression of vasopressin 1b receptors only in CA2 pyramidal neurons in a vasopressin 1b receptor KO mouse can rescue aggressive behavior (Pagani, Mol Psychiatry 2014).
Our goal is to better understand how area CA2 is incorporated into the hippocampal circuit and under which circumstances this region is most active. Our team currently has a cutting-edge set of tools that allows us to examine the circuitry and physiology of the interneurons and pyramidal cells in area CA2 and the hypothalamus in adult mice. We routinely use electrophysiology, optogenetics and pharmacogenetics (i.e. DREADDs) to selectively excite or silence CA2 pyramidal neurons. With these methods, our team has discovered a unique plasticity of inhibitory transmission that occurs in area CA2 (Piskorowski and Chevaleyre, 2013; Nasrallah et al 2015) that requires the activation of delta-opioid receptors.
Area CA2 shows marked vulnerability in multiple psychiatric disorders (Knable, Mol Psychiatry 2004). Reports from human post-mortem studies as well as research performed by our team have discovered that both interneurons and pyramidal cells undergo profound age-dependent changes in area CA2 (Piskorowski et al, Neuron, 2016). TThus, a better understanding of area CA2 can have profound consequences not only for understanding learning and memory, but also for the understanding of psychiatric disease. Because of the unique molecular identity of neurons in area CA2, this region holds particular promise for the development of potential pharmacological treatments for the symptoms in numerous psychological disorders.
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