Ann E. Fink, Ph.D. - US grants

[unreadable] DESCRIPTION (provided by applicant): Changes in neuronal intrinsic excitability (IE) might be crucial mechanisms for memory formation in the hippocampus. Many studies have demonstrated that long-term potentiation of IE (LTP-IE) is associated with behavioral learning and that changes in neuronal excitability accompany memory disorders associated with aging and chronic stress. Thus, understanding LTP-IE might be vital to clarifying how changes in hippocampal circuit function underly some cognitive disorders. Despite these findings, the cellular and molecular mechanisms of this type of plasticity are not well understood. Additionally, little is known about how LTP-IE might interact with and regulate synaptic forms of plasticity such as LTP and LTD. We have recently discovered a novel stimulation protocol that selectively induces LTP-IE in the absence of synaptic potentiation in the CA1 region of the mouse hippocampus. Using this stimulation protocol, we plan to use extracellular and whole-cell electrophysiological recordings combined with pharmacological manipulations to investigate: 1. The cellular basis of LTP-IE: We will use dendritic patch-clamp recordings to test the hypothesis that LTP-IE is due to a localized increase in dendritic excitability, resulting in enhanced propagation of depolarizing currents along CA1 pyramidal neuron dendrites. 2. The molecular mechanisms of LTP-IE: We will use pharmacological blockers of protein kinases paired with electrophysiological recordings to test the prediction that LTP-IE results from PKA, PKC, or CaMKII activation. 3. The functional importance of LTP-IE: We will use electrophysiological recordings to test the hypothesis that LTP-IE facilitates synaptic LTP and LTD. Relevance of Research to Public Health: The experiments proposed here are directly relevant to the mission of the NIMH, because they will provide novel information about how the hippocampus, a part of the brain vital to learning and memory processes, functions at a molecular, cell and circuit level. This information can then be used to directly test how the cell and network physiology of the hippocampus is affected in cognitive disorders. Discovering how hippocampal functioning is disrupted in neurological, mood, and cognitive disorders can allow the development of more effective targeted therapies. [unreadable] [unreadable] [unreadable]

DESCRIPTION (provided by applicant): While synaptic plasticity in the lateral amygdala (LA) has been extensively studied as a mechanism for aversive learning, little is known about generalized changes in neuronal spiking activity. Moreover, we do not understand the mechanisms of metaplasticity, or neuronal changes that modulate synaptic plasticity. Generalized plasticity and metaplasticity are important, however, because they could play a crucial role in aversive learning as well as contributing to the development of anxiety disorders and other mood disturbances. We have discovered a novel form of spike firing plasticity in principal neurons of the LA that is induced by high- frequency stimulation protocols. This form of plasticity could be induced during learning events, and could also have an important impact on subsequent synaptic plasticity. This project is directly relevant to the mission of the NIMH, because we have identified a novel and potentially critical form of neuronal plasticity underlying emotional learning. A long-lasting change in excitability in the amygdala could explain persistent aspects of anxiety disorders like PTSD that are notoriously refractory to treatment. Identifying the functional role of this change could lead directly to improved pharmacological and psychotherapeutic interventions for anxiety disorders. Using behavioral, viral and electrophysiological methods, we propose to test directly whether LA cells activated during fear conditioning exhibit this form of spike firing plasticity. We will then be able to confirm whether the spike firing plasticity, as predicted, alters the induction of synaptic plasticity. We propose he following Specific Aims to carry out this work: 1. Test the hypothesis that fear conditioning induces changes in spiking characteristics of LA principal cells. We will use a viral vector to express green fluorescent protein (GFP) under a component of the promoter for Arc, an immediate-early gene expressed during neuronal plasticity. We will then use GFP as a marker for cells activated by fear conditioning to visually target and record from activated neurons in acute brain slices. We will test whether the activated cells have altered firing properties compared to their non- activated neighbors. 2. Test the hypothesis that fear conditioning induces metaplastic changes at thalamo-LA synapses. Using similar techniques, we will determine whether fear conditioning and spike firing plasticity biases thalamo- LA synapses toward synaptic depression rather than potentiation.