Unlike sensory thalamus, studies on the functional organization of midline and intralaminar nuclei are scarce, and this has hampered the establishment of conceptual models on the function of this brain region. We have investigated the functional organization of the paraventricular nucleus of the thalamus (PVT), a midline thalamic structure increasingly being recognized as a critical node in the control of diverse processes such as arousal, stress, emotional memory and motivation, in mice. We identify two major classes of PVT neurons – termed Type I and Type II – that differ in terms of gene expression, anatomy and function. In addition, we demonstrate that Type II neurons belong to a previously neglected class of PVT neurons that conveys arousal-related information to corticothalamic neurons of the infralimbic cortex. Our results uncover the existence of an arousal-modulated thalamo-corticothalamic loop that links the PVT and the ventromedial prefrontal cortex.

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BackgroundNiemann-Pick Disease Type C (NPC) is an inherited, often fatal neurovisceral lysosomal storage disease characterized by cholesterol accumulation in every cell with few known treatments. Defects in cholesterol transport cause sequestration of unesterified cholesterol within the endolysosomal system. The discovery that systemic administration of hydroxypropyl-beta cyclodextrin (HPβPD) to NPC mice could release trapped cholesterol from lysosomes, normalize cholesterol levels in the liver, and prolong life, led to expanded access use in NPC patients. HPβCD has been administered to NPC patients with approved INDs globally since 2009.ResultsHere we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPβCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPβCD following on average 13 months of IV HPβCD. Several patients transitioned to an alternate HPβCD. Moderately affected NPC patients treated with HPβCD showed slowing of disease progression. Severely affected patients demonstrated periods of stability but eventually showed progression of disease. Neurologic and neurocognitive benefits were seen in most patients with IV alone, independent of the addition of IT administration. Physicians and caregivers reported improvements in quality of life for the patients on IV therapy. There were no safety issues, and the drug was well tolerated and easy to administer.ConclusionsThese expanded access data support the safety and potential benefit of systemic IV administration of HPβCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPβCD in NPC patients.