In the mammalian brain, cortical disengagement from sensory processing is observed at multiple spatial and temporal scales. During active behavior, this process may alter routing of information relevant to selective attention, while during quiescence, it may be relevant for sleep stability and memory consolidation. Several lines of evidence suggest that cortical disengagement is mediated by thalamo-cortical dynamics, including spindle oscillations. Spindles are discrete 7- 15Hz cortical oscillations linked to activty of the thalamic reticular nucleus (TRN), a group of GABAergic cells surround the dorsal thalamus. Attenuated spindles are observed in schizophrenia, and may contribute to the sensory gating deficits observed in this disorder, while hypersynchronous spindles are thought to represent spike and wave discharges (SWDs) of absence epilepsy;the inappropriate expression of sensory disengagement during active waking. Despite their discovery seven decades ago, the basic phenomenology of spindles is undergoing major revision. While surface electroencephalographic (EEG) recordings in humans and local field potential (LFP) recordings in anesthetized animals have shown spindles to be coherent across cortical areas, recent human magnetoencephalographic (MEG) and implanted electrode recordings have revealed local expression of these events, suggesting that spindles have a local computational value linked to their roles in sensory filtering and memory. Using newly developed light-weight multi-electrode microdrives, I will record and manipulate electrophysiological activity across multiple sectors of the TRN in freely behaving mice. I will first refine an optogenetic approach that I have been using to determine the parameters under which local, modality-specific, control of TRN and related neocortex can be controlled (Aim I).
In Aim II, I will use these parameters to causally control spindle generation and explore whether spindle type is dependent on the locus of TRN induction.
In Aim III, I will test whether spindle expression attenuates sensory input in a modality-specific manner using somatosensory stimulation.
These aims will directly test an important hypothesis about spindle expression and function, leading to greater insight into the pathogenesis of schizophrenia and absence seizures. In addition, insight into the principles by which thalamic firing modes contribute to routing of sensory information will be relevant to designing neural prosthetics for augmenting sensory function and cognition. Importantly, this proposal will allow me to learn optogenetic, electrophysiological, and behavioral techniques in mice, under the mentorship of Drs. Christopher Moore and Matthew Wilson. I will learn statistical and analytic techniques under the mentorship of Dr. Emery Brown. My future career goal is to combine my clinical experience with rodent studies to lead a translational research program that transcends species boundaries. I will use the human model to look for electrophysiological endophenotypes of neuropsychiatric disorders, and the rodent model to perform circuit-level dissection of these processes under physiological conditions and in models of disease.
This project will investigate how a certain type of cortical oscillation, spindles, are generated by thalamic mechanisms, and what functional significance their expression has on sleep and sensory function. Spindles are thought to be important for sleep stability, sensory filtering during sleep and sleep-dependent memory consolidation. Attenuated spindles are thought to contribute to the pathophysiology of schizophrenia, while excess spindles underlie the generation of spike and wave discharges of absence seizures. The proposed research, therefore, will have broad implications in understanding disease mechanisms and approach to rational correction.
| Schmitt, L I; Halassa, M M (2017) Interrogating the mouse thalamus to correct human neurodevelopmental disorders. Mol Psychiatry 22:183-191 |
| Liang, Li; Oline, Stefan N; Kirk, Justin C et al. (2017) Scalable, Lightweight, Integrated and Quick-to-Assemble (SLIQ) Hyperdrives for Functional Circuit Dissection. Front Neural Circuits 11:8 |
| Halassa, Michael M; Acsády, László (2016) Thalamic Inhibition: Diverse Sources, Diverse Scales. Trends Neurosci 39:680-693 |
| Wells, Michael F; Wimmer, Ralf D; Schmitt, L Ian et al. (2016) Thalamic reticular impairment underlies attention deficit in Ptchd1(Y/-) mice. Nature 532:58-63 |
| Wimmer, Ralf D; Schmitt, L Ian; Davidson, Thomas J et al. (2015) Thalamic control of sensory selection in divided attention. Nature 526:705-9 |
| Cohen, Samuel M; Tsien, Richard W; Goff, Donald C et al. (2015) The impact of NMDA receptor hypofunction on GABAergic neurons in the pathophysiology of schizophrenia. Schizophr Res 167:98-107 |
| Chen, Zhe; Wimmer, Ralf D; Wilson, Matthew A et al. (2015) Thalamic Circuit Mechanisms Link Sensory Processing in Sleep and Attention. Front Neural Circuits 9:83 |
| Halassa, Michael M; Chen, Zhe; Wimmer, Ralf D et al. (2014) State-dependent architecture of thalamic reticular subnetworks. Cell 158:808-821 |
