Cholecystokinin Administration Rescues Thalamocortical Neuroplasticity in Old Rodents

Description

The thalamocortical network has been shown to be strongly involved in neuronal plasticity and memory consolidation. The thalamocortical network displays tonic, slow wave, spindle, and high-frequency-burst firing modes. Our earlier studies have demonstrated that the auditory thalamus, medial geniculate body (MGB), displays slow-wave, spindle oscillations, and burst firing. Most interestingly, retrograde labeling showed that nearly all the thalamocortical neurons express CCK. In our recent experiments, we found that the medial temporal lobe modulates the neuroplasticity in the auditory cortex through cholecystokinin (CCK) and high-frequency firing of the thalamocortical CCK positive neurons triggers CCK release in the cortex and leads to neuroplasticity in the auditory cortex. This led us to consider whether CCK is involved in thalamocortical neuroplasticity.In the proposed study, our first objective is to confirm whether high-frequency stimulation (HFS) of CCK neurons could induce thalamocortical long-term potentiation (LTP) by activating CCK neurons in the MGB with laser stimulation in Cre-dependent virus injected CCK-Cre mice. CCK-CreER (CCK-/-) mice and low-frequency stimulation (LFS) will be used as control. Specific CCK knockdown in the MGB will be done to further consolidate our hypothesis. Secondly, to investigate whether HFS-induced thalamocortical LTP is age-dependent and to figure out the correlation between thalamocortical LTP and CCK expression levels in the MGB, rats of different ages (from P10 to 2 years old) will be used to induce LTP during the electrophysiological recording. Immunohistochemical staining (IHC) and mRNA quantification will be performed to detect the changes of CCK expression with age. Finally, assuming the loss of thalamocortical neuroplasticity is related to decreased CCK expression in the MGB, we will then test whether local infusion of CCK-8S in the auditory cortex (or intravenous injection of CCK-4) can rescue the thalamocortical LTP formation. An anatomical confirmation of CCKBR expression in the auditory cortex will be carried out with antibodies for CCKBR in the brain slice of the old rats.Based on our preliminary results, thalamocortical LTP is likely CCK-dependent since minimal thalamocortical LTP was induced in the old rats. We hypothesize that the thalamocortical neurons have minimal CCK expression and their CCK receptors in the cortical neurons that receive thalamic projections are still functional in the old rats. To examine these hypotheses, we will confirm whether the minimal thalamocortical LTP we observed in old rats was related to reduced CCK levels and examine whether administration of CCK in the auditory cortex can rescue the HFS-induced thalamocortical LTP in old rats.