2012 — 2016 |
Beierlein, Michael |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Synaptic Integration in Neurons of the Thalamic Reticular Nucleus @ University of Texas Hlth Sci Ctr Houston
DESCRIPTION (provided by applicant): GABAergic neurons of the thalamic reticular nucleus (TRN) have critical roles in controlling sensory processing, in generating synchronous oscillations in thalamocortical networks, and in modulating attention. TRN neurons are rapidly activated by glutamatergic inputs that originate in both cortex and thalamus. In turn, they form powerful inhibitory connections with relay cells in several dorsal thalamic nuclei. TRN neuronal output is regulated by networks of local GABAergic synapses as well as by a system of cholinergic afferents that originate in the brainstem and basal forebrain. The long-term goal of this proposal is to better understand the complex roles TRN plays in regulating thalamic activity. The primary objective is to determine how distinct types of GABAergic and cholinergic synaptic inputs control the output of TRN neurons. The central hypothesis states that both GABAergic and cholinergic inputs can powerfully excite TRN neurons and that specific types of dendritically expressed voltage- and calcium gated conductances are involved in the integration of these inputs. The rationale for the proposed research is that understanding the mechanisms that underlie GABAergic and cholinergic signaling in the TRN will aid in revealing the principles underlying network activity in the TRN, ultimately translating into a better understanding of the specific processes leading to TRN dysfunction associated with a number of neurological diseases. Guided by strong preliminary data, the central hypothesis will be tested by three specific aims: 1) Determine the functional properties of GABAergic synaptic transmission in the TRN. Under this aim, both the mechanisms underlying GABA-evoked activation of TRN neurons as well as its functional consequences on relay cell activity will be examined. 2) Determine the functional role of dendritic voltage- and calcium activated conductances. Under this aim, the contribution of T-type calcium and SK potassium conductances for the processing of GABAergic synaptic inputs will be tested. 3) Determine the properties of cholinergic inputs to TRN. Under this aim, the dynamics underlying activation of postsynaptic nicotinic and muscarinic receptors by the release of endogenous acetylcholine in the TRN will be examined. This approach will lead to novel insights concerning synaptic transmission in the thalamus. The proposed research is significant, because it is expected to advance and expand understanding of how distinct synaptic inputs shape network activity in TRN. PUBLIC HEALTH RELEVANCE: The thalamic reticular nucleus is a brain area critical for the processing of sensory inputs and for the regulation of attention. This proposal will determine how local GABAergic synapses and afferent cholinergic synaptic inputs regulate activity in TRN neurons. Results from these studies will help to identify novel therapeutic targets to treat neurological diseases associated with TRN dysfunction, such as absence seizures or schizophrenia.
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0.981 |
2020 — 2021 |
Beierlein, Michael (co-PI) Chin, Jeannie [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Thalamic Reticular Nucleus Dysfunction in Alzheimer's Disease @ Baylor College of Medicine
PROJECT SUMMARY Sleep disturbances predict risk of Alzheimer?s disease (AD). Sleep-wake cycles critically regulate brain interstitial fluid (ISF) levels of A? and tau, two critical proteins that accumulate in AD. Both A? and tau are released by neuronal activity, which is higher during wakefulness than in sleep. Moreover, sleep is a critical phase during which factors in the ISF are cleared from the brain. Therefore, sleep disturbances affect daily function and also contribute to disease progression. However, little is known about which brain regions are affected in AD to give rise to sleep disturbances, making it difficult to identify the circuit level mechanisms that drive dysfunction, or to design targeted therapeutic strategies. This project tests the hypothesis that the thalamic reticular nucleus (TRN) is a critical brain region in AD, and that impairments in its activity drive sleep disturbances and exacerbate disease progression. The TRN is a major component of the thalamocortical- corticothalamic network that regulates sleep, attention, and memory, which are all affected in AD. However, little is known about the state of TRN in AD patients or in animal models. We found that in transgenic mice expressing mutant human amyloid precursor protein (APP mice), TRN activity is strikingly reduced, in the absence of cell loss. Such reductions in TRN activity led to sleep fragmentation and reductions in slow wave sleep (SWS), and predicted the magnitude of A? deposition in both hippocampus and cortex, which may relate to the fact that SWS is the phase of sleep during which activity-dependent production of A? is reduced, and A? is cleared from the brain. Moreover, deficits in SWS and sleep maintenance manifest early in disease in APP mice, prior to hippocampal deficits, suggesting that TRN impairment may both predict and contribute to disease progression. The goals of this proposal are to identify cellular mechanisms that impair TRN activity, and test if selectively manipulating neuronal activity in the TRN can normalize sleep, reduce A? accumulation, and improve memory. To achieve these goals, in Aim 1 we will use electrophysiology and pharmacology in thalamic slices to identify the intrinsic, synaptic, and network properties of TRN that result in its hypoactivity in APP mice. In Aim 2, we will use DREADDs to acutely activate TRN cells in APP mice to test if TRN activation affects dynamics of interstitial A?, and/or memory consolidation. In Aim 3, we will use DREADD-mediated activation of TRN in APP mice to test if chronic activation of TRN can normalize sleep parameters, reduce A? accumulation, and improve memory. Results from this project will have major impact because they: 1) highlight a vulnerable network early in disease that may predict and contribute to disease progression, and 2) identify a novel therapeutic strategy with potential to normalize sleep, improve memory, and delay disease progression in Alzheimer?s disease. Insights gained will also be used to derive general principles about the dynamics of AD-related proteins like A? and tau in the brain, which will impact our ability to treat this complex disease.
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0.904 |