Early anatomical evidence suggested that the paraventricular nucleus of the thalamus (PVT) regulates arousal, as well as emotional and motivated behaviors. We discuss recent studies using modern ...techniques which now confirm and expand the involvement of the rodent PVT in these functions. Despite the emerging notion that the PVT is implicated in various behavioral processes, a recurrent theme is that activity in this brain region depends on internal state information arriving from the hypothalamus and brainstem, and is influenced by prior experience. We propose that the primary function of the PVT is to detect homeostatic challenges by integrating information about prior experiences, competing needs, and internal state to guide adaptive behavioral responses aimed at restoring homeostasis.
Emerging evidence indicates that the PVT plays a previously overlooked but fundamental role in the control of emotional and motivated behaviors. Heterogeneity within the PVT is thought to underlie diverse functions in behavioral control.We propose that the PVT is an integrative node in which information about prior experiences converges with interoceptive and exteroceptive signals to guide the selection of adaptive behavioral responses that promote homeostasis.We argue that the role of the PVT in homeostatic control is largely influenced by hypothalamic and hindbrain inputs that convey information about internal state.We further argue that, although PVT projections to the nucleus accumbens and the central nucleus of the amygdala may appear to reflect a de facto valenced organization (e.g., reward and fear, respectively), these segregated circuits likely provide a means by which the PVT can influence both goal-directed and Pavlovian-related behavioral responses to homeostatic challenges.The role of the PVT in driving goal-directed behavior may be particularly motivated by negative reinforcement.
Unlike the sensory thalamus, studies on the functional organization of the midline and intralaminar nuclei are scarce, and this has hindered the establishment of conceptual models of the function of ...this brain region. We investigated the functional organization of the paraventricular nucleus of the thalamus (PVT), a midline thalamic structure that is 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 convey 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.
Niemann-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.
Here 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.
These 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.
The paraventricular nucleus of the thalamus (PVT) is known to regulate various cognitive and behavioral processes. However, while functional diversity among PVT circuits has often been linked to ...cellular differences, the molecular identity and spatial distribution of PVT cell types remain unclear. To address this gap, here we used single nucleus RNA sequencing (snRNA-seq) and identified five molecularly distinct PVT neuronal subtypes in the mouse brain. Additionally, multiplex fluorescent in situ hybridization of top marker genes revealed that PVT subtypes are organized by a combination of previously unidentified molecular gradients. Lastly, comparing our dataset with a recently published single-cell sequencing atlas of the thalamus yielded novel insight into the PVT's connectivity with the cortex, including unexpected innervation of auditory and visual areas. This comparison also revealed that our data contains a largely non-overlapping transcriptomic map of multiple midline thalamic nuclei. Collectively, our findings uncover previously unknown features of the molecular diversity and anatomical organization of the PVT and provide a valuable resource for future investigations.
Satiety-promoting neurons of the hindbrain have long been known for their role in meal termination. An innovative new study now reveals how different hindbrain cell types mediate appetite on distinct ...timescales.
Satiety-promoting neurons of the hindbrain have long been known for their role in meal termination. An innovative new study now reveals how different hindbrain cell types mediate appetite on distinct timescales.
The successful pursuit of goals requires the coordinated execution and termination of actions that lead to positive outcomes. This process relies on motivational states that are guided by internal ...drivers, such as hunger or fear. However, the mechanisms by which the brain tracks motivational states to shape instrumental actions are not fully understood. The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus that shapes motivated behaviors via its projections to the nucleus accumbens (NAc)
and monitors internal state via interoceptive inputs from the hypothalamus and brainstem.
Recent studies indicate that the PVT can be subdivided into two major neuronal subpopulations, namely PVT
and PVT
, which differ in genetic identity, functionality, and anatomical connectivity to other brain regions, including the NAc.
In this study, we used fiber photometry to investigate the in vivo dynamics of these two distinct PVT neuronal types in mice performing a foraging-like behavioral task. We discovered that PVT
and PVT
neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVT
neuronal population mirrored motivation parameters such as vigor and satiety. Similarly, PVT
neurons also mirrored some of these parameters, but to a much lesser extent. Importantly, these features were largely preserved when activity in PVT projections to the NAc was selectively assessed. Collectively, our results highlight the existence of two parallel thalamo-striatal projections that participate in the dynamic regulation of goal pursuits and provide insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.
The mediodorsal thalamus (MDT) is critical for many executive functions, such as attention and working memory. Reduced structural and functional connectivity between the MDT and the prefrontal cortex ...is consistently found in people living with schizophrenia and their first-degree relatives, potentially explaining their executive deficits. To understand the biological basis of these connectivity changes, characterizing the cellular and genetic elements within MDT is critical. Prior studies in mice have revealed unappreciated heterogeneity of cell types in MDT. Here we created a cell type atlas of the human MDT, compared the cell type composition of the mouse and human MDT, and integrated gene expression signatures of thalamic cell types with common genetic risk for major psychiatric disorders.
We dissected human MDT in a small group of neurotypical controls from two brain banks (n=10), followed by nuclei isolation and single-nucleus RNA-seq on the 10X Genomics platform. Data were processed via CellRanger, filtered, clustered in Seurat and cell types annotated. For cross-species analyses, mouse MDT was dissected and pooled from four male and four female mice, followed by nuclei isolation, single-nucleus RNA-seq and data analysis via CellRanger and Seurat. The mouse data was then integrated with human MDT data using canonical correlation analysis in Seurat. We tested if gene-level risk for psychiatric traits was associated with specificity scores for different thalamic cell types using MAGMA and GWAS summary statistics.
Excitatory neurons in human MDT are dominated by a major transcriptional gradient. Genes expressed along this gradient were enriched for neurotransmitter receptors and ion channels, aligning with a thalamus-wide gradient in mice, where cells on one end had narrow projections (primary) and those on the other end had broad projections (secondary/tertiary). Inhibitory neurons in human MDT displayed greater homogeneity and expressed reelin. Non-neuronal populations included astrocytes, oligodendrocytes, oligodendrocyte precursors, microglia, ventricle-lining cells, and vascular cells. Integration of mouse and human MDT revealed corresponding cell types across species. Inhibitory neurons were absent in mouse MDT. Distribution of excitatory neurons showed a larger fraction of primary neurons in human MDT compared to mouse MDT. Gene-level analyses using MAGMA for schizophrenia (SCZ) and bipolar disorder (BD) showed the highest association with excitatory neurons (SCZ p=1.1e-15; BD p= 5.8e-09), followed by inhibitory neurons (SCZ p=1.4e-11; BD p= 1.9e-06). At subcluster level, neurons on the primary end of the gradient had stronger associations with SCZ and BD than those on the tertiary end.
The human MDT consists of diverse cell populations. Excitatory neurons span a major gradient that maps onto a previously described trans-thalamic gradient with distinct functional properties. Cross-species analyses show a relative expansion of primary neurons in human MDT relative to mice. Genetic risk for SCZ and BD is associated with excitatory neurons, with the strongest associations on the primary end of the spectrum. While mapping of SNPs to genes is inherently limited, our findings implicate excitatory neurons in human MDT in serious mental illness. Future work will aim to explore gene expression in psychiatric cases and controls, and investigate cell type-specific chromatin accessibility to uncover potential gene regulatory mechanisms.
These expanded access data support the safety and potential benefit of systemic IV administration of HPbetaCD and provide a platform for two clinical trials to study the effect of intravenous ...administration of HPbetaCD in NPC patients.
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