This project examines the neural circuitry of the CA2 region of the hippocampus and its role in hippocampal-dependent learning and behavior. Although the hippocampus has been one of the most intensively studied brain areas, based on its importance for declarative memory, relatively little is known about the CA2 region since its initial description by Lorente de N? in 1934. In contrast there is a wealth of information about th functional properties and synaptic connections of the other major regions of hippocampus including dentate gyrus, CA3 and CA1. The lack of attention paid to CA2 has been largely due to experimental and technical difficulties in studying this relatively small region that occupies a transitional zone between CA3 and CA1. This situation has impeded our understanding of how hippocampus encodes memories and how alterations in hippocampal function contribute to psychiatric and neurological disorders as CA2 has been implicated schizophrenia and bipolar disorder, as well as in epilepsy. Moreover, CA2 pyramidal neurons exhibit some of the highest levels of expression in the brain of the vasopressin 1b receptor, which has been implicated in both normal social behavior and autism. Over the past several years it has become increasingly clear that CA2 does indeed form a separate region with its own molecular identity and distinct electrophysiological properties (as shown, in part, by recent data from our laboratory). These molecular studies have enabled us to generate a mouse line that expresses Cre recombinase in CA2 pyramidal neurons, thereby allowing us to selectively label and manipulate CA2 excitatory output. Our initial experiments have used this mouse to identify some of the major inputs and outputs of the CA2 pyramidal neurons. Moreover by expressing tetanus toxin selectively in CA2 we have been able to inactivate its synaptic output and explore the behavioral consequences of CA2 silencing. Surprisingly, we find that inactivation of CA2 has little effect on a number of mouse behaviors, with no significant change in hippocampal-dependent spatial memory (Morris water maze), contextual fear conditioning, or novel object recognition. In stark contrast, silencing of CA2 results in a profound loss of social memory, the ability of a mouse to recognize a previously encountered mouse. Here we propose to employ this mouse line to examine in more detail both the anatomical and functional synaptic connectivity of CA2 pyramidal neurons and to explore more deeply the role of CA2 in various social and non-social forms of hippocampal-dependent learning and memory. Given the changes in social behavior associated with various neurological and psychiatric disorders, some of which have been linked to CA2, our experiments offer potential insights into both basic mechanisms of memory storage and the neural bases of altered cognitive processing important for social interactions.
A key challenge in neuroscience is to define the role of specific brain regions in mental processes, in both health and disease. In this proposal we aim to explore for the first time the role of the CA2 region of the hippocampus in various forms of learning and memory. We are particularly interested in the importance of CA2 for social memory, the ability of an individual to recognize and remember another, which is thought to be perturbed in various neuropsychiatric disorders, including schizophrenia and autism.
|Leroy, Felix; Brann, David H; Meira, Torcato et al. (2017) Input-Timing-Dependent Plasticity in the Hippocampal CA2 Region and Its Potential Role in Social Memory. Neuron 95:1089-1102.e5|
|Srinivas, Kalyan V; Buss, Eric W; Sun, Qian et al. (2017) The Dendrites of CA2 and CA1 Pyramidal Neurons Differentially Regulate Information Flow in the Cortico-Hippocampal Circuit. J Neurosci 37:3276-3293|
|Sun, Qian; Sotayo, Alaba; Cazzulino, Alejandro S et al. (2017) Proximodistal Heterogeneity of Hippocampal CA3 Pyramidal Neuron Intrinsic Properties, Connectivity, and Reactivation during Memory Recall. Neuron 95:656-672.e3|