Specific activity patterns in the central nervous system have been correlated with various behavioral states associated with wakefulness, attention and memory formation. However, the neurons, synapses, and networks that contribute to generating these activity patterns are not completely understood. It is important to comprehend the various mechanisms that contribute to behaviorally relevant activity as this information may help identify sites of CNS dysfunction associated with memory impairment and attention deficit - a priority of the NIMH. This proposal seeks to help identify mechanisms contributing to the synchronous oscillation of principal cells in the hippocampus called the theta rhythm (4 to 12 Hz), which plays a role in attention and memory formation. Network components essential for theta rhythm generation in the hippocampus include projections from the medial septum/diagonal band of Broca complex (MS/DBB) and the entorhinal cortex (EC). MS/DBB GABAergic projection neurons play a role in hippocampal theta rhythm generation by synchronously inhibiting hippocampal principal neuron somata indirectly through the rhythmic inhibition of local hippocampal inhibitory interneurons. However, how the MS/DBB GABAergic projection neurons selectively affect hippocampal pyramidal neuronal somata and not their dendrites is not fully understood. This proposal hypothesizes that one type of theta rhythm generation (type 2) requires the concerted actions of acetylcholine release and inhibition by MS/DBB GABAergic projection neurons to rhythmically activate interneurons that preferentially target pyramidal cell somata. We further propose that EC inputs rhythmically engage subsets of hippocampal interneurons that are involve in generating type 1 acetylcholine-independent theta rhythm. We will test these hypotheses using optogenetics and electrophysiology in brain slices.
Aim 1 will characterize the MS/DBB GABAergic input onto hippocampal CA1 interneurons.
Aim 2 will determine which interneurons can be rhythmically activated by acetylcholine and MS/DBB GABAergic inputs.
Aim 3 will characterize the mechanisms that prevent rhythmicity in other interneurons.
Aim 4 will investigate the impact that EC input have on generating rhythmicity in specific subsets of hippocampal CA1 interneurons in the absence and presence of cholinergic receptor activation.

Public Health Relevance

Normal brain function depends on ongoing periodic brain activity. Understanding the processes that contribute to activity and rhythmicity in the brain are essential to understanding mental disorders. This proposal seeks to identify mechanisms that control global brain states and activity that is essential for normal brain function.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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Neurobiology of Learning and Memory Study Section (LAM)
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Nadler, Laurie S
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Virginia Commonwealth University
Anatomy/Cell Biology
Schools of Medicine
United States
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Schier, Christina J; Marks, William D; Paris, Jason J et al. (2017) Selective Vulnerability of Striatal D2 versus D1 Dopamine Receptor-Expressing Medium Spiny Neurons in HIV-1 Tat Transgenic Male Mice. J Neurosci 37:5758-5769