Uncovering circuit mechanisms driving traumatic coma

The National Institute of Neurological Disorders and Stroke awarded Rhode Island Hospital $153,560 on December 16, 2026, under the Extramural Research Programs in the Neurosciences and Neurological Disorders program (CFDA 93.853) to support research uncovering circuit mechanisms driving traumatic coma.

The research systematically tests the contribution of the parabrachial nucleus–diagonal band nucleus (PB-NDB) circuit to the maintenance of consciousness using a novel mouse model of reversible traumatic midbrain compression-induced loss of consciousness. Aim 1 employs dual-color 2-photon calcium imaging to test whether parabrachial nucleus to diagonal band nucleus neuron communication is decreased under compression, examining both all synaptically connected diagonal band nucleus neurons and parvalbumin-expressing diagonal band nucleus neuron targets in comatose animals during progressive midbrain compression. Aim 2 tests whether midbrain compression impairs cortical network activity. The work builds on preliminary data from the Malik Laboratory's "coma clamp" model demonstrating marked disengagement of the basal forebrain diagonal band nucleus under compression, a region harboring parabrachial nucleus afferents and GABAergic corticopetal efferents capable of modulating arousal and perceptual processes central to consciousness.

Performance occurs in Providence, Rhode Island, with a period of performance ending July 5, 2028. The assistance type is a Project Grant.

Abstract

Disorders of consciousness, chiefly coma, are the most debilitating consequences of traumatic brain injury (TBI) and provide a unique window into the distributed neural computations underlying the core components of consciousness: arousal and awareness. Clinical data shows that midbrain compression following severe TBI can progressively impair consciousness, ultimately resulting in coma. Historically, this compression has been thought to cause loss of consciousness through impairment of the ascending arousal system, critically involving the mesopontine parabrachial nucleus (PB), its midbrain-traversing projections, and postsynaptic targets in the basal forebrain (BF). Our preliminary data collected from whole brain activity mapping following the malik laboratory's novel mouse model of reversible traumatic midbrain compression-induced loss of consciousness (the "coma clamp") supports this view, highlighting a marked disengagement of the BF diagonal band nucleus (NDB), a region harboring PB afferents and gabaergic corticopetal efferents capable of modulating arousal and distributed perceptual processes central to consciousness. The studies proposed here will systematically test the contribution of the PB-NDB circuit to the maintenance of consciousness using tools and techniques for monitoring and manipulating activity of this circuit under midbrain compression-induced loss of consciousness using the coma clamp model. Aim 1 will systematically test the hypothesis that PB-NDB neuron communication is decreased under compression. To test this prediction, we will employ dual-color 2-photon calcium imaging of PB afferents and (aim 1.1) all synaptically connected NDB or (aim 1.2) parvalbumin-expressing NDB neuron (ndbpv) targets in comatose animals during progressive midbrain compression. Aim 2 will systematically test the hypothesis that midbrain compression impairs cortical network activity underlying sensory perception. We will pair in vivo calcium imaging of ndbpv neurons and single-unit electrophysiological recordings of primary somatosensory (SI) fast-spiking neurons central to vibrissa sensory perception (described in shin & moore, 2019) during a vibrissa threshold detection task in semiconscious animals through progressive midbrain compression. Aim 3 will systematically test the hypothesis that PB-NDB activation can restore consciousness. To test this, we will employ an interluminescence strategy to selectively activate synaptically connected (aim 3.1) PB-NDB or (aim 3.2) PB-ndbpv neurons during midbrain compression while measuring arousal and performance in a vibrissa threshold detection task. These studies may uncover circuit-specific pathogenesis in coma, and offer mechanistic insight into the crucial, complex problem of consciousness.