Dissociable encoding of motivated behavior by parallel thalamo-striatal projections.

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)1,2,3,4,5,6,7,8 and monitors internal state via interoceptive inputs from the hypothalamus and brainstem.3,9,10,11,12,13,14 Recent studies indicate that the PVT can be subdivided into two major neuronal subpopulations, namely PVTD2(+) and PVTD2(-), which differ in genetic identity, functionality, and anatomical connectivity to other brain regions, including the NAc.4,15,16 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 PVTD2(+) and PVTD2(-) neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVTD2(+) neuronal population mirrored motivation parameters such as vigor and satiety. Similarly, PVTD2(-) 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.

Neuroscience of eating: Pace and portion control.

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.

Dissociable encoding of motivated behavior by parallel thalamo-striatal projections.

The successful pursuit of goals requires the coordinated execution and termination of actions that lead to positive outcomes. This process is thought to rely 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)1-8 and monitors internal state via interoceptive inputs from the hypothalamus and brainstem3,9-14. Recent studies indicate that the PVT can be subdivided into two major neuronal subpopulations, namely PVTD2(+) and PVTD2(-), which differ in genetic identity, functionality, and anatomical connectivity to other brain regions, including the NAc4,15,16. In this study, we used fiber photometry to investigate the in vivo dynamics of these two distinct PVT neuronal types in mice performing a reward foraging-like behavioral task. We discovered that PVTD2(+) and PVTD2(-) neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVTD2(+) neuronal population mirrored motivation parameters such as vigor and satiety. Similarly, PVTD2(-) 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.

Molecular and spatial profiling of the paraventricular nucleus of the thalamus.

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.

The paraventricular nucleus of the thalamus: an integrative node underlying homeostatic behavior.

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.

Two genetically, anatomically and functionally distinct cell types segregate across anteroposterior axis of paraventricular thalamus.

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.

Expanded access with intravenous hydroxypropyl-ß-cyclodextrin to treat children and young adults with Niemann-Pick disease type C1: a case report analysis.

BACKGROUND: 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 (HPßPD) 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. HPßCD has been administered to NPC patients with approved INDs globally since 2009. RESULTS: Here we present safety, tolerability and efficacy data from 12 patients treated intravenously (IV) for over 7 years with HPßCD in the US and Brazil. Some patients subsequently received intrathecal (IT) treatment with HPßCD following on average 13 months of IV HPßCD. Several patients transitioned to an alternate HPßCD. Moderately affected NPC patients treated with HPßCD 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. CONCLUSIONS: These expanded access data support the safety and potential benefit of systemic IV administration of HPßCD and provide a platform for two clinical trials to study the effect of intravenous administration of HPßCD in NPC patients.