Hyperactivation of distinct thalamic nuclei differentially impairs sleep physiology in rats

Abstract Sleep disturbances and altered sensory processing are key features of neurodevelopmental and neuropsychiatric disorders (NDDs/NPDs). Clinical assessments of brain function in these conditions reveal increased connectivity between the thalamus and cortical areas, alongside changes in restorative sleep patterns that rely on thalamic function, like decreased sleep spindle density and slow-wave oscillations. To assess the role of individual thalamic nuclei in such impairments, we activated thalamic nuclei within three different thalamocortical circuits in rats using the chemogenetic receptor hM3Dq. Activation of the mediodorsal thalamic (MDT) nuclei impaired restorative sleep by reducing spindle density and slow-wave oscillations, recapitulating phenotypes associated with NDDs/NPDs. Conversely, activating ventral posterior thalamic (VPT) and ventromedial thalamic (VMT) nuclei increased wakefulness, reducing sleep spindle density and alpha/beta band power during sleep. To examine downstream network effects, we used perfusion-based pharmacological MRI; MDT activation significantly modulated neural activity in MDT and interconnected regions, including prelimbic cortex and thalamic nuclei. Finally, we tested whether pharmacologically increasing inhibition in the thalamus using the GABAAδ agonist gaboxadol and positive allosteric modulator DS-2, could counter phenotypes driven by thalamic hyperactivity. Gaboxadol normalized the balance between light and deep NREM sleep in the MDT-hM3Dq group, and in VPT- and VMT-hM3Dq animals, partially normalized resting-state oscillations but failed to rescue sleep physiology. DS-2 had minimal effects across groups. Collectively, our findings reveal that thalamic nuclei-specific activation impacts restorative sleep, and that this thalamocortical circuit model may provide valuable insights into the neural mechanisms underlying dysfunctions associated with NDDs/NPDs and neuropsychiatric conditions.