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Recovery of consciousness after traumatic brain injury (TBI) is heterogeneous and difficult to predict. Structures such as the thalamus and prefrontal cortex are thought to be important in facilitating consciousness. We sought to investigate whether the integrity of thalamo-prefrontal circuits, assessed via diffusion tensor imaging (DTI), was associated with the return of goal-directed behavior after severe TBI. We classified a cohort of severe TBI patients ( N = 25, 20 males) into Early and Late/Never outcome groups based on their ability to follow commands within 30 days post-injury. We assessed connectivity between whole thalamus, and mediodorsal thalamus (MD), to prefrontal cortex (PFC) subregions including dorsolateral PFC (dlPFC), medial PFC (mPFC), anterior cingulate (ACC), and orbitofrontal (OFC) cortices. We found that the integrity of thalamic projections to PFC subregions (L OFC, L and R ACC, and R mPFC) was significantly associated with Early command-following. This association persisted when the analysis was restricted to prefrontal-mediodorsal (MD) thalamus connectivity. In contrast, dlPFC connectivity to thalamus was not significantly associated with command-following. Using the integrity of thalamo-prefrontal connections, we created a linear regression model that demonstrated 72% accuracy in predicting command-following after a leave-one-out analysis. Together, these data support a role for thalamo-prefrontal connectivity in the return of goal-directed behavior following TBI.
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Cerebellar contributions to a brainwide network for flexible behavior in mice
Abstract The cerebellum regulates nonmotor behavior, but the routes of influence are not well characterized. Here we report a necessary role for the posterior cerebellum in guiding a reversal learning task through a network of diencephalic and neocortical structures, and in flexibility of free behavior. After chemogenetic inhibition of lobule VI vermis or hemispheric crus I Purkinje cells, mice could learn a water Y-maze but were impaired in ability to reverse their initial choice. To map targets of perturbation, we imaged c-Fos activation in cleared whole brains using light-sheet microscopy. Reversal learning activated diencephalic and associative neocortical regions. Distinctive subsets of structures were altered by perturbation of lobule VI (including thalamus and habenula) and crus I (including hypothalamus and prelimbic/orbital cortex), and both perturbations influenced anterior cingulate and infralimbic cortex. To identify functional networks, we used correlated variation in c-Fos activation within each group. Lobule VI inactivation weakened within-thalamus correlations, while crus I inactivation divided neocortical activity into sensorimotor and associative subnetworks. In both groups, high-throughput automated analysis of whole-body movement revealed deficiencies in across-day behavioral habituation to an open-field environment. Taken together, these experiments reveal brainwide systems for cerebellar influence that affect multiple flexible responses.
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- Award ID(s):
- 1734030
- PAR ID:
- 10429921
- Date Published:
- Journal Name:
- Communications Biology
- Volume:
- 6
- Issue:
- 1
- ISSN:
- 2399-3642
- Format(s):
- Medium: X
- Sponsoring Org:
- National Science Foundation
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The human brain is sexually dimorphic and these sex differences have shown to affect brain response to trauma. We investigated the sex differences in the tract structures by studying diffusion weighted (DW) images of 594 females and 506 males from the Human-Connectome-Project dataset. All the female and male DW images were reconstructed in the ICBM152 space using Q-Space diffeomorphic reconstruction technique and their mapped orientation distribution function images were averaged to generate the female- and male-DW-templates. The tract streamlines were generated through tractography for female and male templates and normalized to the total brain volume . The distributions of normalized tract lengths were significantly different between female- and male-templates and the female-template showed to have more longer normalized tracts compared to the male template. For the regional analysis, the templates were parcellated into sixteen regions of interests (ROI) including brain-stem, five subregions of corpus-callosum, and right and left hippocampus, thalamus, cerebellum white-matter (WM), cerebral WM, and cerebellum cortex using a FreeSurfer-based segmentation atlas. For all the ROIs, the average fractional anisotropy (0.5-5.7%) and normalized tract lengths (1.1-2.7%) were larger in female template while the average mean diffusion was larger (1.3-5.6%) in male-template. Quantifying brain connectivity by counting number of tracts passing through pairs of ROIs, showed more pairs with a higher connectivity in female-template, and one of the highest percentages of sex differences in right/left cerebellum WM/cortex connections. Our results reinforce the need to continue investigating the sex variations in axonal structure and their effects to brain trauma.more » « less
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Hilgetag, Claus C (Ed.)The mouse brain’s activity changes drastically over a day despite being generated from the same neurons and physical connectivity. To better understand this, we develop an experimental-computational pipeline to determine which neurons and networks are most active at different times of the day. We genetically mark active neurons of freely behaving mice at four times of the day with a c-Fos activity-dependent TRAP2 system. Neurons are imaged and digitized in 3D, and their molecular properties are inferred from the latest brain spatial transcriptomic dataset. We then develop a new computational method to analyze the network formed by the identified active neurons. Applying this pipeline, we observe region and layer-specific activation of neurons in the cortex, especially activation of layer five neurons at the end of the dark (wake) period. We also observe a shift in the balance of excitatory (glutamatergic) neurons versus inhibitory (GABAergic) neurons across the whole brain, especially in the thalamus. Moreover, as the dark (wake) period progresses, the network formed by the active neurons becomes less modular, and the hubs switch from subcortical regions, such as the posterior hypothalamic nucleus, to cortical regions in the default mode network. Taken together, we present a pipeline to understand which neurons and networks may be most activated in the mouse brain during an experimental protocol, and use this pipeline to understand how brain activity changes over the course of a day.more » « less
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- Free Publicly Accessible Full Text
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Accepted Manuscript1.0
- Journal Article:
- https://doi.org/10.1038/s42003-023-04920-0
