Large neuroimaging datasets, including information about structural connectivity (SC) and functional connectivity (FC), play an increasingly important role in clinical research, where they guide the design of algorithms for automated stratification, diagnosis or prediction. A major obstacle is, however, the problem of missing features [e.g., lack of concurrent DTI SC and resting-state functional magnetic resonance imaging (rsfMRI) FC measurements for many of the subjects]. We propose here to address the missing connectivity features problem by introducing strategies based on computational whole-brain network modeling. Using two datasets, the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset and a healthy aging dataset, for proof-of-concept, we demonstrate the feasibility of virtual data completion (i.e., inferring “virtual FC” from empirical SC or “virtual SC” from empirical FC), by using self-consistent simulations of linear and nonlinear brain network models. Furthermore, by performing machine l...

The capacity of human brain to sustain complex cortical dynamics appears to be strongly associated with conscious experience and consistently drops when consciousness fades. For example, several recent studies in humans found a remarkable reduction of the spatiotemporal complexity of cortical responses to local stimulation during dreamless sleep, general anesthesia, and coma. However, this perturbational complexity has never been directly estimated in non-human animals in vivo previously, and the mechanisms that prevent neocortical neurons to engage in complex interactions are still unclear. Here, we quantify the complexity of electroencephalographic (EEG) responses to intracranial electrical stimulation in rats, comparing wakefulness to propofol, sevoflurane, and ketamine anesthesia. The evoked activity changed from highly complex in wakefulness to far simpler with propofol and sevoflurane. The reduced complexity was associated with a suppression of high frequencies that preceded a reduced phase-locking, ...

Neuronal population activity in the hippocampal CA3 subfield is implicated in cognitive brain functions such as memory processing and spatial navigation. However, because of its deep location in the brain, the CA3 area has been difficult to target with modern calcium imaging approaches. Here, we achieved chronic two-photon calcium imaging of CA3 pyramidal neurons with the red fluorescent calcium indicator R-CaMP1.07 in anesthetized and awake mice. We characterize CA3 neuronal activity at both the single-cell and population level and assess its stability across multiple imaging days. During both anesthesia and wakefulness, nearly all CA3 pyramidal neurons displayed calcium transients. Most of the calcium transients were consistent with a high incidence of bursts of action potentials (APs), based on calibration measurements using simultaneous juxtacellular recordings and calcium imaging. In awake mice, we found state-dependent differences with striking large and prolonged calcium transients during locomotion...

The ability of neurons to produce behaviorally relevant activity in the absence of pathology relies on the fine balance of synaptic inhibition to excitation. In the hippocampal CA1 microcircuit, this balance is maintained by a diverse population of inhibitory interneurons that receive largely similar glutamatergic afferents as their target pyramidal cells, with EPSCs generated by both AMPA receptors (AMPARs) and NMDA receptors (NMDARs). In this study, we take advantage of a recently generated GluN2A-null rat model to assess the contribution of GluN2A subunits to glutamatergic synaptic currents in three subclasses of interneuron found in the CA1 region of the hippocampus. For both parvalbumin-positive and somatostatin-positive interneurons, the GluN2A subunit is expressed at glutamatergic synapses and contributes to the EPSC. In contrast, in cholecystokinin (CCK)-positive interneurons, the contribution of GluN2A to the EPSC is negligible. Furthermore, synaptic potentiation at glutamatergic synapses on CCK-p...

Mitochondrial composition varies by organ and their constituent cell types. This mitochondrial diversity likely determines variations in mitochondrial function. However, the heterogeneity of mitochondria in the brain remains underexplored despite the large diversity of cell types in neuronal tissue. Here, we used molecular systems biology tools to address whether mitochondrial composition varies by brain region and neuronal cell type in mice. We reasoned that proteomics and transcriptomics of microdissected brain regions combined with analysis of single-cell mRNA sequencing (scRNAseq) could reveal the extent of mitochondrial compositional diversity. We selected nuclear encoded gene products forming complexes of fixed stoichiometry, such as the respiratory chain complexes and the mitochondrial ribosome, as well as molecules likely to perform their function as monomers, such as the family of SLC25 transporters. We found that the proteome encompassing these nuclear-encoded mitochondrial genes and obtained fro...

Neurocognitive impairment is present in cirrhosis and may be more severe in cirrhosis with overt hepatic encephalopathy (OHE). Liver transplantation (LT) can restore liver function, but how it reverses the impaired brain function is still unclear. MRI of resting-state functional connectivity can help reveal the underlying mechanisms that lead to these cognitive deficits and cognitive recovery. In this study, 64 patients with cirrhosis (28 with OHE; 36 without OHE) and 32 healthy control subjects were recruited for resting-state fMRI. The patients were scanned before and after LT. We evaluated presurgical and postsurgical neurocognitive performance in cirrhosis patients using psychomotor tests. Network-based statistics found significant disrupted connectivity in both groups of cirrhotic patients, with OHE and without OHE, compared with control subjects. However, the presurgical connectivity disruption in patients with OHE affected a greater number of connections than those without OHE. The decrease in funct...

Increased mTOR activity has been shown to enhance regeneration of injured axons by increasing neuronal protein synthesis, while PTEN signaling can block mTOR activity to attenuate protein synthesis. MicroRNAs (miRs) have been implicated in regulation of PTEN and mTOR expression, and previous work in spinal cord showed an increase in miR-199a-3p after spinal cord injury (SCI) and increase in miR-21 in SCI animals that had undergone exercise. Pten mRNA is a target for miR-21 and miR-199a-3p is predicted to target mTor mRNA. Here, we show that miR-21 and miR-199a-3p are expressed in adult dorsal root ganglion (DRG) neurons, and we used culture preparations to test functions of the rat miRs in adult DRG and embryonic cortical neurons. miR-21 increases and miR-199a-3p decreases in DRG neurons after in vivo axotomy. In both the adult DRG and embryonic cortical neurons, miR-21 promotes and miR-199a-3p attenuates neurite growth. miR-21 directly bound to Pten mRNA and miR-21 overexpression decreased Pten mRNA level...

Bombesin receptor subtype-3 (BRS3) is an orphan receptor that regulates energy homeostasis. We compared Brs3 driver mice with constitutive or inducible Cre recombinase activity. The constitutive BRS3-Cre mice show a reporter signal (Cre-dependent tdTomato) in the adult brain because of lineage tracing in the dentate gyrus, striatal patches, and indusium griseum, in addition to sites previously identified in the inducible BRS3-Cre mice (including hypothalamic and amygdala subregions, and parabrachial nucleus). We detected Brs3 reporter expression in the dentate gyrus at day 23 but not at postnatal day 1 or 5 months of age. Hypothalamic sites expressed reporter at all three time points, and striatal patches expressed Brs3 reporter at 1 day but not 5 months. Parabrachial nucleus Brs3 neurons project to the preoptic area, hypothalamus, amygdala, and thalamus. Both Cre recombinase insertions reduced Brs3 mRNA levels and BRS3 function, causing obesity phenotypes of different severity. These results demonstrate t...

Patch clamp electrophysiology is a common technique used in neuroscience to understand individual neuron behavior, allowing one to record current and voltage changes with superior spatiotemporal resolution compared with most electrophysiology methods. While patch clamp experiments produce high fidelity electrophysiology data, the technique is onerous and labor intensive. Despite the emergence of patch clamp systems that automate key stages in the typical patch clamp procedure, full automation remains elusive. Patch clamp pipettes can miss the target cell during automated experiments because of positioning errors in the robotic manipulators, which can easily exceed the diameter of a neuron. Further, when patching in acute brain slices, the inherent light scattering from non-uniform brain tissue can complicate pipette tip identification. We present a convolutional neural network (CNN), based on ResNet101, to identify and correct pipette positioning errors before each patch clamp attempt, thereby preventing t...

In macaque monkeys, dorsal intraparietal areas are involved in several daily visuomotor actions. However, their border and sources of cortical afferents remain loosely defined. Combining retrograde histologic tracing and MRI diffusion-based tractography, we found a complex hodology of the dorsal bank of the intraparietal sulcus (db-IPS), which can be subdivided into a rostral intraparietal area PEip, projecting to the spinal cord, and a caudal medial intraparietal area MIP lacking such projections. Both include an anterior and a posterior sector, emerging from their ipsilateral, gradient-like connectivity profiles. As tractography estimations, we used the cross-sectional area of the white matter bundles connecting each area with other parietal and frontal regions, after selecting regions of interest (ROIs) corresponding to the injection sites of neural tracers. For most connections, we found a significant correlation between the proportions of cells projecting to all sectors of PEip and MIP along the conti...