The hippocampal circuit of the brain is considered to be responsible for storage and recall of episodic memory. Within this circuit, activity propagates through at least two distinct pathways. Comprising the input to CA1 neurons, neural activity arrives either directly from layer III of the entorhinal cortex, or through a multi-synaptic chain involving the recurrently connected CA3 region. A number of important experimental and theoretical studies have targeted the role and effect of each of these pathways on neural activity observable at CA1 but, due to various limitations, have resulted in incomplete and often contradictory viewpoints. In this project, we aim to untangle the postsynaptic effect of these two input pathways to region CA1 by performing optogenetic inactivation of region CA3 pyramidal neurons in the rat hippocampus during a specific set of in vivo network states while recording large-scale neuronal activity in CA3 and CA1. Our working hypothesis is that the multi-synaptic pathway through CA3 represents a major source of input to CA1 and as such should have a significant postsynaptic effect during key phases of oscillatory activity. We will test this hypothesis in a number of specific aims to determine and characterize the effect of region CA3 on CA1 activity separately during theta, gamma, and sharp-wave ripple oscillations, in urethane-anesthetized rats (Aims 1a and 1b), during behavior in a delayed alternation task (Aim 2), and to correlate these with behavioral effects on performance in a spatial alternation task (Aim 3). The neuronal firing patterns of CA1 neurons during theta, gamma and ripple oscillations are widely considered to play critical roles in serving the mnemonic function of the hippocampus. Thus, we expect that this work will provide a major advance forward on two fronts: in our understanding of the role of the hippocampal multi-synaptic pathway and in our understanding of how the convergence of input at different phases of theta and gamma oscillations subserves the functions of the hippocampus.
By clarifying the role of region CA3 on the signature features of CA1 spiking activity, this work will advance our understanding of multi-stage processing features in carrying out the memory functions of the hippocampus. A better understanding will ultimately help in the study and targeted therapy of memory deficits caused by neurodegenerative diseases, such as Alzheimer's Disease and dementia, that affect the hippocampus even before clinical symptoms appear. Additionally, the recurrent CA3 circuit under focused investigation here is considered to play an important role in a number of crippling neuropathologies, including schizophrenia (1) and epilepsy (2) and may further be causally linked to dysfunction in these diseases (3-9).
| Miyawaki, Hiroyuki; Diba, Kamran (2016) Regulation of Hippocampal Firing by Network Oscillations during Sleep. Curr Biol 26:893-902 |
